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Ginsburg, Geoffrey Steven

Overview:

Dr. Geoffrey S. Ginsburg's research interests are in the development of novel paradigms for developing and translating genomic information into medical practice and the integration of personalized medicine into health care.

Positions:

Professor of Medicine

Medicine, Cardiology
School of Medicine

Director of Duke Center for Applied Genomics and Precision Medicine

Duke Center for Applied Genomics and Precision Medicine
School of Medicine

Professor in Pathology

Pathology
School of Medicine

Professor in the School of Nursing

School of Nursing
School of Nursing

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

M.D. 1984

M.D. — Boston University

Ph.D. 1984

Ph.D. — Boston University

Medical Resident, Medicine

Children's Hospital, Boston

Fellow in Cardiology, Medicine

Children's Hospital, Boston

News:

Grants:

Duke University Program in Environmental Health

Administered By
Environmental Sciences and Policy
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
July 01, 2013
End Date
June 30, 2024

Transplant Infectious Diseases Interdisciplinary Research Training Grant

Administered By
Medicine, Infectious Diseases
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
September 01, 2018
End Date
August 31, 2023

Building and Deploying a Genomic-Medicine Risk Assessment Model for Diverse Primary Care Populations.

Administered By
Duke Center for Applied Genomics and Precision Medicine
AwardedBy
National Institutes of Health
Role
Investigator
Start Date
September 24, 2018
End Date
June 30, 2023

The IGNITE II CC: Engagement, Coordination, Demonstration, and Dissemination

Administered By
Duke Center for Applied Genomics and Precision Medicine
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
September 22, 2018
End Date
June 30, 2023

The IGNITE II CC: Engagement, Coordination, Demonstration, and Dissemination

Administered By
Duke Center for Applied Genomics and Precision Medicine
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
September 22, 2018
End Date
June 30, 2023

Summer Scholars Program in Genome Sciences and Medicine

Administered By
Duke Center for Applied Genomics and Precision Medicine
AwardedBy
National Institutes of Health
Role
Significant Contributor
Start Date
September 22, 2017
End Date
June 30, 2022

Medical Scientist Training Program

Administered By
School of Medicine
AwardedBy
National Institutes of Health
Role
Steering Committee Member
Start Date
July 01, 1997
End Date
June 30, 2022

The Role of Junctophilin Type 2 in Cardiac Node Automaticity

Administered By
Pediatrics, Cardiology
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
August 01, 2018
End Date
May 31, 2022

Postdoctoral Training in Genomic Medicine Research

Administered By
Duke Center for Applied Genomics and Precision Medicine
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
June 14, 2017
End Date
May 31, 2022

Predicting prebiotic effects on human microbiota, behavior, and cognition.

Administered By
Molecular Genetics and Microbiology
AwardedBy
Office of Naval Research
Role
Collaborator
Start Date
August 01, 2018
End Date
July 31, 2021

Transfusion Medicine and Hematology

Administered By
Medicine, Hematology
AwardedBy
National Institutes of Health
Role
Preceptor
Start Date
July 01, 1975
End Date
June 30, 2021

Transfusion Medicine and Hematology

Administered By
Medicine, Hematology
AwardedBy
National Institutes of Health
Role
Preceptor
Start Date
July 01, 1975
End Date
June 30, 2021

Mapping Epigenetic Memory of Exposure New To Observe (MEMENTO)

Administered By
Biomedical Engineering
Role
Co Investigator
Start Date
June 07, 2019
End Date
June 06, 2021

Multidisciplinary Heart and Vascular Diseases

Administered By
Medicine, Cardiology
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
July 01, 1975
End Date
March 31, 2021

MicroRNA Profiling to Characterize and Predict Posttraumatic Epilepsy following Traumatic Brain Injury

Administered By
Duke Center for Applied Genomics and Precision Medicine
AwardedBy
Department of Defense
Role
Co Investigator
Start Date
September 15, 2018
End Date
September 14, 2020

PREdicting contagion using Systems And GEnomic analysis (PRESAGE)

Administered By
Duke Center for Applied Genomics and Precision Medicine
Role
Co-Principal Investigator
Start Date
May 31, 2017
End Date
June 14, 2020

Interdisciplinary Training Program in Lung Disease

Administered By
Medicine, Pulmonary, Allergy, and Critical Care Medicine
AwardedBy
National Institutes of Health
Role
Preceptor
Start Date
July 01, 2009
End Date
March 31, 2020

Human-Based Sensor System for Presymptomatic Biological Exposure Detection

Administered By
Duke Center for Applied Genomics and Precision Medicine
Role
Investigator
Start Date
February 11, 2019
End Date
February 10, 2020

Resilience Prediction to RSV Infection

Administered By
Duke Center for Applied Genomics and Precision Medicine
Role
Co-Principal Investigator
Start Date
November 29, 2018
End Date
December 30, 2019

Abbott Diagnostics Collaborative Sponsored Research Agreement

Administered By
Duke Center for Applied Genomics and Precision Medicine
Role
Principal Investigator
Start Date
December 22, 2016
End Date
December 21, 2019

Study of Prognostic Biomarkers of Severe Systemic Bacterial Infection

Administered By
Medicine, Infectious Diseases
Role
Co Investigator
Start Date
December 09, 2016
End Date
December 08, 2019

Implementation, Adoption, and Utility of Family History in Diverse Care Settings

Administered By
Duke Center for Applied Genomics and Precision Medicine
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
June 16, 2013
End Date
September 30, 2019

Novel host-based diagnostics of febrile illness in the warfighter

Administered By
Duke Center for Applied Genomics and Precision Medicine
AwardedBy
Department of Defense
Role
Co-Principal Investigator
Start Date
September 26, 2016
End Date
September 25, 2019

Duke University Program in Environmental Health

Administered By
Environmental Sciences and Policy
AwardedBy
National Institute of Environmental Health Sciences
Role
Mentor
Start Date
July 01, 2013
End Date
June 30, 2019

Duke-UNC Clinical Hematology and Transfusion Research Career Development Program

Administered By
Medicine, Hematology
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
September 28, 2006
End Date
June 30, 2019

Development Of Prognostic Platelet RNA Biomarkers To Tailor Antiplatelet Therapy

Administered By
Duke Center for Applied Genomics and Precision Medicine
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
July 05, 2013
End Date
May 31, 2019

Development and Application of Mathematical Methods for Tracking Biochronicity and Baseline Variation

Administered By
Duke Center for Applied Genomics and Precision Medicine
Role
Principal Investigator
Start Date
December 29, 2016
End Date
March 28, 2019

Impact of Personal Genomic Testing on Primary Care Physician Knowledge and Attitudes

Administered By
Duke Center for Applied Genomics and Precision Medicine
Role
Investigator
Start Date
January 09, 2017
End Date
July 31, 2018

Novel Dialysis-Like Therapeutics in Sepsis-induced Shock and Organ Failure

Administered By
Medicine, Pulmonary, Allergy, and Critical Care Medicine
Role
Co Investigator
Start Date
September 28, 2015
End Date
May 31, 2018

Genetics of Normal Human Variation: Implications for Disease

Administered By
Duke Center for Applied Genomics and Precision Medicine
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
April 15, 2013
End Date
March 31, 2017

Genetic Risk Testing & Health Coaching for T2D and CHD

Administered By
School of Nursing
AwardedBy
Air Force Office of Scientific Research
Role
Co Investigator
Start Date
January 30, 2013
End Date
January 29, 2017

Feasibility for Predicting Warfighter Health Using Transcriptional Markers on the MAP Platform

Administered By
Duke Center for Applied Genomics and Precision Medicine
Role
Co Investigator
Start Date
January 29, 2016
End Date
December 30, 2016

Baseline Bio-molecular Models to Predict Infectious Disease Susceptibility

Administered By
Duke Center for Applied Genomics and Precision Medicine
Role
Principal Investigator
Start Date
June 01, 2015
End Date
November 30, 2016

The Duke Multidisciplinary Training Program in Pediatric Lung Disease

Administered By
Pediatrics, Pulmonary and Sleep Medicine
AwardedBy
National Institutes of Health
Role
Faculty Member
Start Date
September 01, 2010
End Date
August 31, 2016

Plasmonics-Active SERS Nanoplatforms for In Vivo Diagnostics

Administered By
Biomedical Engineering
Role
Collaborator
Start Date
December 13, 2012
End Date
June 30, 2016

Validation of the host transcription diagnostic for prediction of incipient respiratory viral infection

Administered By
Duke Center for Applied Genomics and Precision Medicine
Role
Principal Investigator
Start Date
February 15, 2014
End Date
February 14, 2016

Pharmacogenetic Testing: Challenges of Clinical Integration

Administered By
Institutes and Centers
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
July 01, 2007
End Date
August 31, 2015

Multidisciplinary Neonatal Training Grant

Administered By
Pediatrics, Neonatology
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
April 01, 2010
End Date
June 30, 2015

Implications of Health and Genetic Literacy for Genomic Medicine

Administered By
Institutes and Centers
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
June 15, 2010
End Date
September 30, 2012

CTSA UL

Administered By
Institutes and Centers
AwardedBy
National Institutes of Health
Role
Core Lab Dir
Start Date
September 30, 2006
End Date
September 01, 2012

Phase I Clinical Trial Describing the Pharmacogenomics of Aspirin

Administered By
Duke Center for Applied Genomics and Precision Medicine
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
September 30, 2009
End Date
August 31, 2012

Programs in Clinical Effectiveness of Cancer Pharmacogenomics

Administered By
Duke Center for Applied Genomics and Precision Medicine
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
September 30, 2009
End Date
August 31, 2012

Enabling Personalized Medicine through Clinical Decision Support

Administered By
Family Medicine and Community Health
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
September 01, 2008
End Date
July 31, 2011

Duke Clinical and Translational Science Institute

Administered By
Institutes and Centers
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
September 30, 2006
End Date
June 30, 2011
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Publications:

Correction: Opportunities to implement a sustainable genomic medicine program: lessons learned from the IGNITE Network.

The original version of this Article contained an error in the spelling of the author Geoffrey S. Ginsburg, which was incorrectly given as Geoffrey Ginsburg. This has now been corrected in both the PDF and HTML versions of the Article.

Authors
Levy, KD; Blake, K; Fletcher-Hoppe, C; Franciosi, J; Goto, D; Hicks, JK; Holmes, AM; Kanuri, SH; Madden, EB; Musty, MD; Orlando, L; Pratt, VM; Ramos, M; Wu, R; Ginsburg, GS
MLA Citation
Levy, Kenneth D., et al. “Correction: Opportunities to implement a sustainable genomic medicine program: lessons learned from the IGNITE Network..” Genet Med, vol. 21, no. 7, July 2019. Pubmed, doi:10.1038/s41436-018-0280-5.
PMID
30158693
Source
pubmed
Published In
Genet Med
Volume
21
Issue
7
Publish Date
2019
Start Page
1670
DOI
10.1038/s41436-018-0280-5

Qualitative study of system-level factors related to genomic implementation.

PURPOSE: Research on genomic medicine integration has focused on applications at the individual level, with less attention paid to implementation within clinical settings. Therefore, we conducted a qualitative study using the Consolidated Framework for Implementation Research (CFIR) to identify system-level factors that played a role in implementation of genomic medicine within Implementing GeNomics In PracTicE (IGNITE) Network projects. METHODS: Up to four study personnel, including principal investigators and study coordinators from each of six IGNITE projects, were interviewed using a semistructured interview guide that asked interviewees to describe study site(s), progress at each site, and factors facilitating or impeding project implementation. Interviews were coded following CFIR inner-setting constructs. RESULTS: Key barriers included (1) limitations in integrating genomic data and clinical decision support tools into electronic health records, (2) physician reluctance toward genomic research participation and clinical implementation due to a limited evidence base, (3) inadequate reimbursement for genomic medicine, (4) communication among and between investigators and clinicians, and (5) lack of clinical and leadership engagement. CONCLUSION: Implementation of genomic medicine is hindered by several system-level barriers to both research and practice. Addressing these barriers may serve as important facilitators for studying and implementing genomics in practice.

Authors
Zebrowski, AM; Ellis, DE; Barg, FK; Sperber, NR; Bernhardt, BA; Denny, JC; Dexter, PR; Ginsburg, GS; Horowitz, CR; Johnson, JA; Levy, MA; Orlando, LA; Pollin, TI; Skaar, TC; Kimmel, SE
MLA Citation
Zebrowski, Alexis M., et al. “Qualitative study of system-level factors related to genomic implementation..” Genet Med, vol. 21, no. 7, July 2019, pp. 1534–40. Pubmed, doi:10.1038/s41436-018-0378-9.
PMID
30467402
Source
pubmed
Published In
Genet Med
Volume
21
Issue
7
Publish Date
2019
Start Page
1534
End Page
1540
DOI
10.1038/s41436-018-0378-9

High-Sensitivity Troponin I and Coronary Computed Tomography in Symptomatic Outpatients With Suspected CAD: Insights From the PROMISE Trial.

OBJECTIVES: The goal of this study was to examine associations between concentrations of high-sensitivity troponin I (hsTnI) (measured by using a single-molecule counting method) and obstructive coronary artery disease (CAD) in 1,844 stable, symptomatic outpatients with suspected CAD randomized to undergo coronary computed tomography angiography (CTA) in the PROMISE (Prospective Multicenter Imaging Study for Evaluation of Chest Pain) trial. BACKGROUND: Elevated concentrations of hsTnI are associated with CAD in patients with myocardial infarction. The meaning of hsTnI concentrations in stable symptomatic outpatients is not well understood. METHODS: Clinical characteristics and CTA results (including coronary artery calcium [CAC] scores) were expressed across hsTnI quartiles. Determinants of hsTnI concentration were identified. Multivariable logistic regression identified independent predictors of obstructive CAD50 (≥50% stenosis in any vessel) and CAD70 (≥70% stenosis or ≥50% left main). RESULTS: The median hsTnI concentration was 1.5 ng/l; nearly all (98.5%) subjects had measurable hsTnI, and 6.1% had concentrations ≥99th percentile concentration for this assay (6 ng/l). Higher CAC scores, as well as more prevalent and diffuse CAD, was seen in upper hsTnI quartiles (all p < 0.001). Independent predictors of hsTnI concentrations included age, sex, and CAC score (all p < 0.05). After adjusting for demographic and clinical characteristics, log-transformed hsTnI concentrations were associated with obstructive CAD50 (odds ratio: 1.15 per interquartile range; p = 0.02) and CAD70 (odds ratio: 1.25 per interquartile range; p = 0.001). CONCLUSIONS: In stable symptomatic outpatients undergoing nonemergent coronary CTA for the diagnosis of suspected CAD, higher concentrations of hsTnI were associated with increasing presence and severity of coronary atherosclerosis. (Prospective Multicenter Imaging Study for Evaluation of Chest Pain [PROMISE]; NCT01174550).

Authors
Januzzi, JL; Suchindran, S; Coles, A; Ferencik, M; Patel, MR; Hoffmann, U; Ginsburg, GS; Douglas, PS; PROMISE Investigators,
MLA Citation
Januzzi, James L., et al. “High-Sensitivity Troponin I and Coronary Computed Tomography in Symptomatic Outpatients With Suspected CAD: Insights From the PROMISE Trial..” Jacc Cardiovasc Imaging, vol. 12, no. 6, June 2019, pp. 1047–55. Pubmed, doi:10.1016/j.jcmg.2018.01.021.
PMID
29550314
Source
pubmed
Published In
Jacc Cardiovasc Imaging
Volume
12
Issue
6
Publish Date
2019
Start Page
1047
End Page
1055
DOI
10.1016/j.jcmg.2018.01.021

Primary Care Physicians' Knowledge, Attitudes, and Experience with Personal Genetic Testing.

Primary care providers (PCPs) will play an important role in precision medicine. However, their lack of training and knowledge about genetics and genomics may limit their ability to advise patients or interpret or utilize test results. We evaluated PCPs' awareness of the role of genetics/genomics in health, knowledge about key concepts in genomic medicine, perception/attitudes towards direct-to-consumer (DTC) genetic testing, and their level of confidence/comfort in discussing testing with patients prior to and after undergoing DTC testing through the 23andMe Health + Ancestry Service. A total of 130 PCPs completed the study. Sixty-three percent were board-certified in family practice, 32% graduated between 1991 and 2000, and 88% had heard of 23andMe prior to the study. Seventy-two percent decided to participate in the study to gain a better understanding about testing. At baseline, 23% of respondents indicated comfort discussing genetics as a risk factor for common diseases, increasing to 59% after undergoing personal genetic testing (PGT) (p < 0.01). In summary, we find that undergoing PGT augments physicians' confidence, comfort, and interest in DTC testing.

Authors
Haga, SB; Kim, E; Myers, RA; Ginsburg, GS
MLA Citation
Haga, Susanne B., et al. “Primary Care Physicians' Knowledge, Attitudes, and Experience with Personal Genetic Testing..” J Pers Med, vol. 9, no. 2, May 2019. Pubmed, doi:10.3390/jpm9020029.
PMID
31137623
Source
pubmed
Published In
Journal of Personalized Medicine
Volume
9
Issue
2
Publish Date
2019
DOI
10.3390/jpm9020029

Reply: hs-cTnI in Stable Chest Pain.

Authors
Januzzi, JL; Ginsburg, GS; Douglas, PS
MLA Citation
Januzzi, James L., et al. “Reply: hs-cTnI in Stable Chest Pain..” J Am Coll Cardiol, vol. 73, no. 16, Apr. 2019, pp. 2121–22. Pubmed, doi:10.1016/j.jacc.2019.02.050.
PMID
31023439
Source
pubmed
Published In
J Am Coll Cardiol
Volume
73
Issue
16
Publish Date
2019
Start Page
2121
End Page
2122
DOI
10.1016/j.jacc.2019.02.050

A Global Collaborative to Advance Genomic Medicine.

Authors
Ginsburg, GS
MLA Citation
Ginsburg, Geoffrey S. “A Global Collaborative to Advance Genomic Medicine..” Am J Hum Genet, vol. 104, no. 3, Mar. 2019, pp. 407–09. Pubmed, doi:10.1016/j.ajhg.2019.02.010.
PMID
30849327
Source
pubmed
Published In
Am J Hum Genet
Volume
104
Issue
3
Publish Date
2019
Start Page
407
End Page
409
DOI
10.1016/j.ajhg.2019.02.010

Opportunities to implement a sustainable genomic medicine program: lessons learned from the IGNITE Network.

PURPOSE: While there is growing scientific evidence for and significant advances in the use of genomic technologies in medicine, there is a significant lag in the clinical adoption and sustainability of genomic medicine. Here we describe the findings from the National Human Genome Research Institute's (NHGRI) Implementing GeNomics In pracTicE (IGNITE) Network in identifying key constructs, opportunities, and challenges associated with driving sustainability of genomic medicine in clinical practice. METHODS: Network members and affiliates were surveyed to identify key drivers associated with implementing and sustaining a genomic medicine program. Tallied results were used to develop and weigh key constructs/drivers required to support sustainability of genomic medicine programs. RESULTS: The top three driver-stakeholder dyads were (1) genomic training for providers, (2) genomic clinical decision support (CDS) tools embedded in the electronic health record (EHR), and (3) third party reimbursement for genomic testing. CONCLUSION: Priorities may differ depending on healthcare systems when comparing the current state of key drivers versus projected needs for supporting genomic medicine sustainability. Thus we provide gap-filling guidance based on IGNITE members' experiences. Although results are limited to findings from the IGNITE network, their implementation, scientific, and clinical experience may be used as a road map by others considering implementing genomic medicine programs.

Authors
Levy, KD; Blake, K; Fletcher-Hoppe, C; Franciosi, J; Goto, D; Hicks, JK; Holmes, AM; Kanuri, SH; Madden, EB; Musty, MD; Orlando, L; Pratt, VM; Ramos, M; Wu, R; Ginsburg, GS
MLA Citation
Levy, Kenneth D., et al. “Opportunities to implement a sustainable genomic medicine program: lessons learned from the IGNITE Network..” Genet Med, vol. 21, no. 3, Mar. 2019, pp. 743–47. Pubmed, doi:10.1038/s41436-018-0080-y.
PMID
29997387
Source
pubmed
Published In
Genet Med
Volume
21
Issue
3
Publish Date
2019
Start Page
743
End Page
747
DOI
10.1038/s41436-018-0080-y

Effect of Sociodemographic Factors on Uptake of a Patient-Facing Information Technology Family Health History Risk Assessment Platform.

OBJECTIVE:  Investigate sociodemographic differences in the use of a patient-facing family health history (FHH)-based risk assessment platform. METHODS:  In this large multisite trial with a diverse patient population, we evaluated the relationship between sociodemographic factors and FHH health risk assessment uptake using an information technology (IT) platform. The entire study was administered online, including consent, baseline survey, and risk assessment completion. We used multivariate logistic regression to model effect of sociodemographic factors on study progression. Quality of FHH data entered as defined as relatives: (1) with age of onset reported on relevant conditions; (2) if deceased, with cause of death and (3) age of death reported; and (4) percentage of relatives with medical history marked as unknown was analyzed using grouped logistic fixed effect regression. RESULTS:  A total of 2,514 participants consented with a mean age of 57 and 10.4% minority. Multivariate modeling showed that progression through study stages was more likely for younger (p-value = 0.005), more educated (p-value = 0.004), non-Asian (p-value = 0.009), and female (p-value = 0.005) participants. Those with lower health literacy or information-seeking confidence were also less likely to complete the study. Most significant drop-out occurred during the risk assessment completion phase. Overall, quality of FHH data entered was high with condition's age of onset reported 87.85%, relative's cause of death 85.55% and age of death 93.76%, and relative's medical history marked as unknown 19.75% of the time. CONCLUSION:  A demographically diverse population was able to complete an IT-based risk assessment but there were differences in attrition by sociodemographic factors. More attention should be given to ensure end-user functionality of health IT and leverage electronic medical records to lessen patient burden.

Authors
Wu, RR; Myers, RA; Buchanan, AH; Dimmock, D; Fulda, KG; Haller, IV; Haga, SB; Harry, ML; McCarty, C; Neuner, J; Rakhra-Burris, T; Sperber, N; Voils, CI; Ginsburg, GS; Orlando, LA
MLA Citation
Wu, R. Ryanne, et al. “Effect of Sociodemographic Factors on Uptake of a Patient-Facing Information Technology Family Health History Risk Assessment Platform..” Appl Clin Inform, vol. 10, no. 2, Mar. 2019, pp. 180–88. Pubmed, doi:10.1055/s-0039-1679926.
PMID
30866001
Source
pubmed
Published In
Applied Clinical Informatics
Volume
10
Issue
2
Publish Date
2019
Start Page
180
End Page
188
DOI
10.1055/s-0039-1679926

Implementation, adoption, and utility of family health history risk assessment in diverse care settings: evaluating implementation processes and impact with an implementation framework.

PURPOSE: This paper describes the implementation outcomes associated with integrating a family health history-based risk assessment and clinical decision support platform within primary care clinics at four diverse healthcare systems. METHODS: A type III hybrid implementation-effectiveness trial. Uptake and implementation processes were evaluated using the Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) framework. RESULTS: One hundred (58%) primary care providers and 2514 (7.8%) adult patients enrolled. Enrolled patients were 69% female, 22% minority, and 32% Medicare/Medicaid. Compared with their respective clinic's population, patient-participants were more likely to be female (69 vs. 59%), older (mean age 57 vs. 49), and Caucasian (88 vs. 69%) (all p values <0.001). Female (81.3% of females vs. 78.5% of males, p value = 0.018) and Caucasian (Caucasians 90.4% vs. minority 84.1%, p value = 0.02) patient-participants were more likely to complete the study once enrolled. Patient-participant survey responses indicated MeTree was easy to use (95%), and patient-participants would recommend it to family/friends (91%). Minorities and those with less education reported greatest benefit. Enrolled providers reflected demographics of underlying provider population. CONCLUSION: Family health history-based risk assessment can be effectively implemented in diverse primary care settings and can effectively engage patients and providers. Future research should focus on finding better ways to engage young adults, males, and minorities in preventive healthcare.

Authors
Wu, RR; Myers, RA; Sperber, N; Voils, CI; Neuner, J; McCarty, CA; Haller, IV; Harry, M; Fulda, KG; Cross, D; Dimmock, D; Rakhra-Burris, T; Buchanan, AH; Ginsburg, GS; Orlando, LA
MLA Citation
Wu, R. Ryanne, et al. “Implementation, adoption, and utility of family health history risk assessment in diverse care settings: evaluating implementation processes and impact with an implementation framework..” Genet Med, vol. 21, no. 2, Feb. 2019, pp. 331–38. Pubmed, doi:10.1038/s41436-018-0049-x.
PMID
29875427
Source
pubmed
Published In
Genet Med
Volume
21
Issue
2
Publish Date
2019
Start Page
331
End Page
338
DOI
10.1038/s41436-018-0049-x

Single-Molecule hsTnI and Short-Term Risk in Stable Patients With Chest Pain.

BACKGROUND: Evaluation of stable symptomatic outpatients with suspected coronary artery disease (CAD) may be challenging because they have a wide range of cardiovascular risk. The role of troponin testing to assist clinical decision making in this setting is unexplored. OBJECTIVES: This study sought to evaluate the prognostic meaning of single-molecule counting high-sensitivity troponin I (hsTnI) (normal range <6 ng/l) among outpatients with stable chest symptoms and suspected CAD. METHODS: Participants with available blood samples in PROMISE (Prospective Multicenter Imaging Study for Evaluation of Chest Pain) were studied, and hsTnI results were analyzed relative to the primary outcome of death, acute myocardial infarction (MI), or hospitalization for unstable angina by 1 year. The secondary outcome was the composite of cardiovascular death or acute MI. RESULTS: The study sample consisted of 4,021 participants; 98.6% had measurable hsTnI concentrations. The median hsTnI value was 1.6 ng/l. In upper hsTnI quartiles, patients had higher-risk clinical profiles. Higher hsTnI concentrations were associated with greater event probabilities for death, acute MI, or hospitalization for unstable angina. In multivariable models, hsTnI concentrations independently predicted death, acute MI, or hospitalization for unstable angina (hazard ratio: 1.54 per increase in log-hsTnI interquartile range; p < 0.001) and cardiovascular death or acute MI (hazard ratio: 1.52 per increase in log-hsTnI interquartile range; p < 0.001) and were particularly associated with near-term events, compared with longer follow-up. CONCLUSIONS: In symptomatic outpatients with suspected CAD, higher concentrations of hsTnI within the normal range were associated with heightened near-term risk for death, acute MI, or hospitalization. (Prospective Multicenter Imaging Study for Evaluation of Chest Pain [PROMISE]; NCT01174550).

Authors
Januzzi, JL; Suchindran, S; Hoffmann, U; Patel, MR; Ferencik, M; Coles, A; Tardif, J-C; Ginsburg, GS; Douglas, PS; PROMISE Investigators,
MLA Citation
Januzzi, James L., et al. “Single-Molecule hsTnI and Short-Term Risk in Stable Patients With Chest Pain..” J Am Coll Cardiol, vol. 73, no. 3, Jan. 2019, pp. 251–60. Pubmed, doi:10.1016/j.jacc.2018.10.065.
PMID
30678753
Source
pubmed
Published In
J Am Coll Cardiol
Volume
73
Issue
3
Publish Date
2019
Start Page
251
End Page
260
DOI
10.1016/j.jacc.2018.10.065

Pilot study of myocardial ischemia-induced metabolomic changes in emergency department patients undergoing stress testing.

BACKGROUND: The heart is a metabolically active organ, and plasma acylcarnitines are associated with long-term risk for myocardial infarction. We hypothesized that myocardial ischemia from cardiac stress testing will produce dynamic changes in acylcarnitine and amino acid levels compared to levels seen in matched control patients with normal stress tests. METHODS: We analyzed targeted metabolomic profiles in a pilot study of 20 case patients with inducible ischemia on stress testing from an existing prospectively collected repository of 357 consecutive patients presenting with symptoms of Acute Coronary Syndrome (ACS) in an Emergency Department (ED) observation unit between November 2012 and September 2014. We selected 20 controls matched on age, sex, and body-mass index (BMI). A peripheral blood sample was drawn <1 hour before stress testing and 2 hours after stress testing on each patient. We assayed 60 select acylcarnitines and amino acids by tandem mass spectrometry (MS/MS) using a Quattro Micro instrument (Waters Corporation, Milford, MA). Metabolite values were log transformed for skew. We then performed bivariable analysis for stress test outcome and both individual timepoint metabolite concentrations and stress-delta metabolite ratios (T2/T0). False discovery rates (FDR) were calculated for 60 metabolites while controlling for age, sex, and BMI. We built multivariable regularized linear models to predict stress test outcome from metabolomics data at times 0, 2 hours, and log ratio between these two. We used leave-one-out cross-validation to estimate the performance characteristics of the model. RESULTS: Nine of our 20 case subjects were male. Cases' average age was 55.8, with an average BMI 29.5. Bivariable analysis identified 5 metabolites associated with positive stress tests (FDR < 0.2): alanine, C14:1-OH, C16:1, C18:2, C20:4. The multivariable regularized linear models built on T0 and T2 had Area Under the ROC Curve (AUC-ROC) between 0.5 and 0.55, however, the log(T2/T0) model yielded 0.625 AUC, with 65% sensitivity and 60% specificity. The top metabolites selected by the model were: Ala, Arg, C12-OH/C10-DC, C14:1-OH, C16:1, C18:2, C18:1, C20:4 and C18:1-DC. CONCLUSIONS: Stress-delta metabolite analysis of patients undergoing stress testing is feasible. Future studies with a larger sample size are warranted.

Authors
Limkakeng, AT; Henao, R; Voora, D; O'Connell, T; Griffin, M; Tsalik, EL; Shah, S; Woods, CW; Ginsburg, GS
MLA Citation
Limkakeng, Alexander T., et al. “Pilot study of myocardial ischemia-induced metabolomic changes in emergency department patients undergoing stress testing..” Plos One, vol. 14, no. 2, 2019. Pubmed, doi:10.1371/journal.pone.0211762.
PMID
30707740
Source
pubmed
Published In
Plos One
Volume
14
Issue
2
Publish Date
2019
Start Page
e0211762
DOI
10.1371/journal.pone.0211762

A host gene expression approach for identifying triggers of asthma exacerbations.

RATIONALE: Asthma exacerbations often occur due to infectious triggers, but determining whether infection is present and whether it is bacterial or viral remains clinically challenging. A diagnostic strategy that clarifies these uncertainties could enable personalized asthma treatment and mitigate antibiotic overuse. OBJECTIVES: To explore the performance of validated peripheral blood gene expression signatures in discriminating bacterial, viral, and noninfectious triggers in subjects with asthma exacerbations. METHODS: Subjects with suspected asthma exacerbations of various etiologies were retrospectively selected for peripheral blood gene expression analysis from a pool of subjects previously enrolled in emergency departments with acute respiratory illness. RT-PCR quantified 87 gene targets, selected from microarray-based studies, followed by logistic regression modeling to define bacterial, viral, or noninfectious class. The model-predicted class was compared to clinical adjudication and procalcitonin. RESULTS: Of 46 subjects enrolled, 7 were clinically adjudicated as bacterial, 18 as viral, and 21 as noninfectious. Model prediction was congruent with clinical adjudication in 15/18 viral and 13/21 noninfectious cases, but only 1/7 bacterial cases. None of the adjudicated bacterial cases had confirmatory microbiology; the precise etiology in this group was uncertain. Procalcitonin classified only one subject in the cohort as bacterial. 47.8% of subjects received antibiotics. CONCLUSIONS: Our model classified asthma exacerbations by the underlying bacterial, viral, and noninfectious host response. Compared to clinical adjudication, the majority of discordances occurred in the bacterial group, due to either imperfect adjudication or model misclassification. Bacterial infection was identified infrequently by all classification schemes, but nearly half of subjects were prescribed antibiotics. A gene expression-based approach may offer useful diagnostic information in this population and guide appropriate antibiotic use.

Authors
Lydon, EC; Bullard, C; Aydin, M; Better, OM; Mazur, A; Nicholson, BP; Ko, ER; McClain, MT; Ginsburg, GS; Woods, CW; Burke, TW; Henao, R; Tsalik, EL
MLA Citation
Lydon, Emily C., et al. “A host gene expression approach for identifying triggers of asthma exacerbations..” Plos One, vol. 14, no. 4, 2019. Pubmed, doi:10.1371/journal.pone.0214871.
PMID
30958855
Source
pubmed
Published In
Plos One
Volume
14
Issue
4
Publish Date
2019
Start Page
e0214871
DOI
10.1371/journal.pone.0214871

A crowdsourced analysis to identify ab initio molecular signatures predictive of susceptibility to viral infection.

The response to respiratory viruses varies substantially between individuals, and there are currently no known molecular predictors from the early stages of infection. Here we conduct a community-based analysis to determine whether pre- or early post-exposure molecular factors could predict physiologic responses to viral exposure. Using peripheral blood gene expression profiles collected from healthy subjects prior to exposure to one of four respiratory viruses (H1N1, H3N2, Rhinovirus, and RSV), as well as up to 24 h following exposure, we find that it is possible to construct models predictive of symptomatic response using profiles even prior to viral exposure. Analysis of predictive gene features reveal little overlap among models; however, in aggregate, these genes are enriched for common pathways. Heme metabolism, the most significantly enriched pathway, is associated with a higher risk of developing symptoms following viral exposure. This study demonstrates that pre-exposure molecular predictors can be identified and improves our understanding of the mechanisms of response to respiratory viruses.

Authors
Fourati, S; Talla, A; Mahmoudian, M; Burkhart, JG; Klén, R; Henao, R; Yu, T; Aydın, Z; Yeung, KY; Ahsen, ME; Almugbel, R; Jahandideh, S; Liang, X; Nordling, TEM; Shiga, M; Stanescu, A; Vogel, R; Respiratory Viral DREAM Challenge Consortium, ; Pandey, G; Chiu, C; McClain, MT; Woods, CW; Ginsburg, GS; Elo, LL; Tsalik, EL; Mangravite, LM; Sieberts, SK
MLA Citation
Fourati, Slim, et al. “A crowdsourced analysis to identify ab initio molecular signatures predictive of susceptibility to viral infection..” Nat Commun, vol. 9, no. 1, Oct. 2018. Pubmed, doi:10.1038/s41467-018-06735-8.
PMID
30356117
Source
pubmed
Published In
Nature Communications
Volume
9
Issue
1
Publish Date
2018
Start Page
4418
DOI
10.1038/s41467-018-06735-8

RAB11FIP5 Expression and Altered Natural Killer Cell Function Are Associated with Induction of HIV Broadly Neutralizing Antibody Responses.

HIV-1 broadly neutralizing antibodies (bnAbs) are difficult to induce with vaccines but are generated in ∼50% of HIV-1-infected individuals. Understanding the molecular mechanisms of host control of bnAb induction is critical to vaccine design. Here, we performed a transcriptome analysis of blood mononuclear cells from 47 HIV-1-infected individuals who made bnAbs and 46 HIV-1-infected individuals who did not and identified in bnAb individuals upregulation of RAB11FIP5, encoding a Rab effector protein associated with recycling endosomes. Natural killer (NK) cells had the highest differential expression of RAB11FIP5, which was associated with greater dysregulation of NK cell subsets in bnAb subjects. NK cells from bnAb individuals had a more adaptive/dysfunctional phenotype and exhibited impaired degranulation and cytokine production that correlated with RAB11FIP5 transcript levels. Moreover, RAB11FIP5 overexpression modulated the function of NK cells. These data suggest that NK cells and Rab11 recycling endosomal transport are involved in regulation of HIV-1 bnAb development.

Authors
Bradley, T; Peppa, D; Pedroza-Pacheco, I; Li, D; Cain, DW; Henao, R; Venkat, V; Hora, B; Chen, Y; Vandergrift, NA; Overman, RG; Edwards, RW; Woods, CW; Tomaras, GD; Ferrari, G; Ginsburg, GS; Connors, M; Cohen, MS; Moody, MA; Borrow, P; Haynes, BF
MLA Citation
Bradley, Todd, et al. “RAB11FIP5 Expression and Altered Natural Killer Cell Function Are Associated with Induction of HIV Broadly Neutralizing Antibody Responses..” Cell, vol. 175, no. 2, Oct. 2018, pp. 387-399.e17. Pubmed, doi:10.1016/j.cell.2018.08.064.
PMID
30270043
Source
pubmed
Published In
Cell
Volume
175
Issue
2
Publish Date
2018
Start Page
387
End Page
399.e17
DOI
10.1016/j.cell.2018.08.064

Association of hepatic steatosis with adverse cardiovascular events: insights from the PROspective Multicenter Imaging Study for Evaluation of chest pain (PROMISE) trial

Authors
Meyersohn, NM; Mayrhofer, T; Ivanov, A; Bittner, DO; Staziaki, PV; Szilveszter, B; Hallett, T; Lu, ML; Puchner, SB; Simon, TG; Corey, KE; Ginsburg, GS; Douglas, PS; Hoffmann, U; Ferencik, M
MLA Citation
Meyersohn, N. M., et al. “Association of hepatic steatosis with adverse cardiovascular events: insights from the PROspective Multicenter Imaging Study for Evaluation of chest pain (PROMISE) trial.” European Heart Journal, vol. 39, OXFORD UNIV PRESS, 2018, pp. 1286–1286.
Source
wos
Published In
European Heart Journal
Volume
39
Publish Date
2018
Start Page
1286
End Page
1286

A note from the editors.

Authors
Ginsburg, GS; McCarthy, JJ; Patrinos, GP
MLA Citation
Ginsburg, Geoffrey S., et al. “A note from the editors..” Per Med, vol. 15, no. 4, July 2018, pp. 237–38. Pubmed, doi:10.2217/pme-2018-0040.
PMID
29927353
Source
pubmed
Published In
Personalized Medicine
Volume
15
Issue
4
Publish Date
2018
Start Page
237
End Page
238
DOI
10.2217/pme-2018-0040

Unsupervised Analysis of Transcriptomics in Bacterial Sepsis Across Multiple Datasets Reveals Three Robust Clusters.

OBJECTIVES: To find and validate generalizable sepsis subtypes using data-driven clustering. DESIGN: We used advanced informatics techniques to pool data from 14 bacterial sepsis transcriptomic datasets from eight different countries (n = 700). SETTING: Retrospective analysis. SUBJECTS: Persons admitted to the hospital with bacterial sepsis. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A unified clustering analysis across 14 discovery datasets revealed three subtypes, which, based on functional analysis, we termed "Inflammopathic, Adaptive, and Coagulopathic." We then validated these subtypes in nine independent datasets from five different countries (n = 600). In both discovery and validation data, the Adaptive subtype is associated with a lower clinical severity and lower mortality rate, and the Coagulopathic subtype is associated with higher mortality and clinical coagulopathy. Further, these clusters are statistically associated with clusters derived by others in independent single sepsis cohorts. CONCLUSIONS: The three sepsis subtypes may represent a unifying framework for understanding the molecular heterogeneity of the sepsis syndrome. Further study could potentially enable a precision medicine approach of matching novel immunomodulatory therapies with septic patients most likely to benefit.

Authors
Sweeney, TE; Azad, TD; Donato, M; Haynes, WA; Perumal, TM; Henao, R; Bermejo-Martin, JF; Almansa, R; Tamayo, E; Howrylak, JA; Choi, A; Parnell, GP; Tang, B; Nichols, M; Woods, CW; Ginsburg, GS; Kingsmore, SF; Omberg, L; Mangravite, LM; Wong, HR; Tsalik, EL; Langley, RJ; Khatri, P
MLA Citation
Sweeney, Timothy E., et al. “Unsupervised Analysis of Transcriptomics in Bacterial Sepsis Across Multiple Datasets Reveals Three Robust Clusters..” Crit Care Med, vol. 46, no. 6, June 2018, pp. 915–25. Pubmed, doi:10.1097/CCM.0000000000003084.
PMID
29537985
Source
pubmed
Published In
Crit Care Med
Volume
46
Issue
6
Publish Date
2018
Start Page
915
End Page
925
DOI
10.1097/CCM.0000000000003084

Insurance Coverage Policies for Pharmacogenomic and Multi-Gene Testing for Cancer.

Insurance coverage policies are a major determinant of patient access to genomic tests. The objective of this study was to examine differences in coverage policies for guideline-recommended pharmacogenomic tests that inform cancer treatment. We analyzed coverage policies from eight Medicare contractors and 10 private payers for 23 biomarkers (e.g., HER2 and EGFR) and multi-gene tests. We extracted policy coverage and criteria, prior authorization requirements, and an evidence basis for coverage. We reviewed professional society guidelines and their recommendations for use of pharmacogenomic tests. Coverage for KRAS, EGFR, and BRAF tests were common across Medicare contractors and private payers, but few policies covered PML/RARA, CD25, or G6PD. Thirteen payers cover multi-gene tests for nonsmall lung cancer, citing emerging clinical recommendations. Coverage policies for single and multi-gene tests for cancer treatments are consistent among Medicare contractors despite the lack of national coverage determinations. In contrast, coverage for these tests varied across private payers. Patient access to tests is governed by prior authorization among eight private payers. Substantial variations in how payers address guideline-recommended pharmacogenomic tests and the common use of prior authorization underscore the need for additional studies of the effects of coverage variation on cancer care and patient outcomes.

Authors
Lu, CY; Loomer, S; Ceccarelli, R; Mazor, KM; Sabin, J; Clayton, EW; Ginsburg, GS; Wu, AC
MLA Citation
Lu, Christine Y., et al. “Insurance Coverage Policies for Pharmacogenomic and Multi-Gene Testing for Cancer..” J Pers Med, vol. 8, no. 2, May 2018. Pubmed, doi:10.3390/jpm8020019.
PMID
29772692
Source
pubmed
Published In
Journal of Personalized Medicine
Volume
8
Issue
2
Publish Date
2018
DOI
10.3390/jpm8020019

Research Directions in the Clinical Implementation of Pharmacogenomics: An Overview of US Programs and Projects.

Response to a drug often differs widely among individual patients. This variability is frequently observed not only with respect to effective responses but also with adverse drug reactions. Matching patients to the drugs that are most likely to be effective and least likely to cause harm is the goal of effective therapeutics. Pharmacogenomics (PGx) holds the promise of precision medicine through elucidating the genetic determinants responsible for pharmacological outcomes and using them to guide drug selection and dosing. Here we survey the US landscape of research programs in PGx implementation, review current advances and clinical applications of PGx, summarize the obstacles that have hindered PGx implementation, and identify the critical knowledge gaps and possible studies needed to help to address them.

Authors
Volpi, S; Bult, CJ; Chisholm, RL; Deverka, PA; Ginsburg, GS; Jacob, HJ; Kasapi, M; McLeod, HL; Roden, DM; Williams, MS; Green, ED; Rodriguez, LL; Aronson, S; Cavallari, LH; Denny, JC; Dressler, LG; Johnson, JA; Klein, TE; Leeder, JS; Piquette-Miller, M; Perera, M; Rasmussen-Torvik, LJ; Rehm, HL; Ritchie, MD; Skaar, TC; Wagle, N; Weinshilboum, R; Weitzel, KW; Wildin, R; Wilson, J; Manolio, TA; Relling, MV
MLA Citation
Volpi, Simona, et al. “Research Directions in the Clinical Implementation of Pharmacogenomics: An Overview of US Programs and Projects..” Clin Pharmacol Ther, vol. 103, no. 5, May 2018, pp. 778–86. Pubmed, doi:10.1002/cpt.1048.
PMID
29460415
Source
pubmed
Published In
Clinical Pharmacology and Therapeutics
Volume
103
Issue
5
Publish Date
2018
Start Page
778
End Page
786
DOI
10.1002/cpt.1048

Precision Medicine: From Science To Value.

Precision medicine is making an impact on patients, health care delivery systems, and research participants in ways that were only imagined fifteen years ago when the human genome was first sequenced. Discovery of disease-causing and drug-response genetic variants has accelerated, while adoption into clinical medicine has lagged. We define precision medicine and the stakeholder community required to enable its integration into research and health care. We explore the intersection of data science, analytics, and precision medicine in the formation of health systems that carry out research in the context of clinical care and that optimize the tools and information used to deliver improved patient outcomes. We provide examples of real-world impact and conclude with a policy and economic agenda necessary for the adoption of this new paradigm of health care both in the United States and globally.

Authors
Ginsburg, GS; Phillips, KA
MLA Citation
Ginsburg, Geoffrey S., and Kathryn A. Phillips. “Precision Medicine: From Science To Value..” Health Aff (Millwood), vol. 37, no. 5, May 2018, pp. 694–701. Pubmed, doi:10.1377/hlthaff.2017.1624.
PMID
29733705
Source
pubmed
Published In
Health Aff (Millwood)
Volume
37
Issue
5
Publish Date
2018
Start Page
694
End Page
701
DOI
10.1377/hlthaff.2017.1624

THE INTERSECTION OF POPULATION HEALTH AND PRECISION MEDICINE: EMPLOYING TECHNOLOGY TO OPTIMIZE RISK ASSESSMENT IN PRIMARY CARE

Authors
Orlando, LA; Wu, RR; Buchanan, A; Myers, RA; Ginsburg, GS
MLA Citation
Orlando, Lori A., et al. “THE INTERSECTION OF POPULATION HEALTH AND PRECISION MEDICINE: EMPLOYING TECHNOLOGY TO OPTIMIZE RISK ASSESSMENT IN PRIMARY CARE.” Journal of General Internal Medicine, vol. 33, SPRINGER, 2018, pp. S362–S362.
Source
wos
Published In
Journal of General Internal Medicine
Volume
33
Publish Date
2018
Start Page
S362
End Page
S362

A proposed approach to accelerate evidence generation for genomic-based technologies in the context of a learning health system.

Genomic technologies should demonstrate analytical and clinical validity and clinical utility prior to wider adoption in clinical practice. However, the question of clinical utility remains unanswered for many genomic technologies. In this paper, we propose three building blocks for rapid generation of evidence on clinical utility of promising genomic technologies that underpin clinical and policy decisions. We define promising genomic tests as those that have proven analytical and clinical validity. First, risk-sharing agreements could be implemented between payers and manufacturers to enable temporary coverage that would help incorporate promising technologies into routine clinical care. Second, existing data networks, such as the Sentinel Initiative and the National Patient-Centered Clinical Research Network (PCORnet) could be leveraged, augmented with genomic information to track the use of genomic technologies and monitor clinical outcomes in millions of people. Third, endorsement and engagement from key stakeholders will be needed to establish this collaborative model for rapid evidence generation; all stakeholders will benefit from better information regarding the clinical utility of these technologies. This collaborative model can create a multipurpose and reusable national resource that generates knowledge from data gathered as part of routine care to drive evidence-based clinical practice and health system changes.

Authors
Lu, CY; Williams, MS; Ginsburg, GS; Toh, S; Brown, JS; Khoury, MJ
MLA Citation
Lu, Christine Y., et al. “A proposed approach to accelerate evidence generation for genomic-based technologies in the context of a learning health system..” Genet Med, vol. 20, no. 4, Apr. 2018, pp. 390–96. Pubmed, doi:10.1038/gim.2017.122.
PMID
28796238
Source
pubmed
Published In
Genet Med
Volume
20
Issue
4
Publish Date
2018
Start Page
390
End Page
396
DOI
10.1038/gim.2017.122

A community approach to mortality prediction in sepsis via gene expression analysis.

Improved risk stratification and prognosis prediction in sepsis is a critical unmet need. Clinical severity scores and available assays such as blood lactate reflect global illness severity with suboptimal performance, and do not specifically reveal the underlying dysregulation of sepsis. Here, we present prognostic models for 30-day mortality generated independently by three scientific groups by using 12 discovery cohorts containing transcriptomic data collected from primarily community-onset sepsis patients. Predictive performance is validated in five cohorts of community-onset sepsis patients in which the models show summary AUROCs ranging from 0.765-0.89. Similar performance is observed in four cohorts of hospital-acquired sepsis. Combining the new gene-expression-based prognostic models with prior clinical severity scores leads to significant improvement in prediction of 30-day mortality as measured via AUROC and net reclassification improvement index These models provide an opportunity to develop molecular bedside tests that may improve risk stratification and mortality prediction in patients with sepsis.

Authors
Sweeney, TE; Perumal, TM; Henao, R; Nichols, M; Howrylak, JA; Choi, AM; Bermejo-Martin, JF; Almansa, R; Tamayo, E; Davenport, EE; Burnham, KL; Hinds, CJ; Knight, JC; Woods, CW; Kingsmore, SF; Ginsburg, GS; Wong, HR; Parnell, GP; Tang, B; Moldawer, LL; Moore, FE; Omberg, L; Khatri, P; Tsalik, EL; Mangravite, LM; Langley, RJ
MLA Citation
Sweeney, Timothy E., et al. “A community approach to mortality prediction in sepsis via gene expression analysis..” Nat Commun, vol. 9, no. 1, Feb. 2018. Pubmed, doi:10.1038/s41467-018-03078-2.
PMID
29449546
Source
pubmed
Published In
Nature Communications
Volume
9
Issue
1
Publish Date
2018
Start Page
694
DOI
10.1038/s41467-018-03078-2

Evaluation of the WHO 2009 classification for diagnosis of acute dengue in a large cohort of adults and children in Sri Lanka during a dengue-1 epidemic.

BACKGROUND: Dengue is a leading cause of fever and mimics other acute febrile illnesses (AFI). In 2009, the World Health Organization (WHO) revised criteria for clinical diagnosis of dengue. METHODOLOGY/PRINCIPAL FINDINGS: The new WHO 2009 classification of dengue divides suspected cases into three categories: dengue without warning signs, dengue with warning signs and severe dengue. We evaluated the WHO 2009 classification vs physicians' subjective clinical diagnosis (gestalt clinical impression) in a large cohort of patients presenting to a tertiary care center in southern Sri Lanka hospitalized with acute febrile illness. We confirmed acute dengue in 388 patients (305 adults ≥ 18 years and 83 children), including 103 primary and 245 secondary cases, of 976 patients prospectively enrolled with AFI. At presentation, both adults and children with acute dengue were more likely than those with other AFI to have leukopenia and thrombocytopenia. Additionally, adults were more likely than those with other AFI to have joint pain, higher temperatures, and absence of crackles on examination whereas children with dengue were more likely than others to have sore throat, fatigue, oliguria, and elevated hematocrit and transaminases. Similarly, presence of joint pain, thrombocytopenia, and absence of cough were independently associated with secondary vs primary dengue in adults whereas no variables were different in children. The 2009 WHO dengue classification was more sensitive than physicians' clinical diagnosis for identification of acute dengue (71.5% vs 67.1%), but was less specific. However, despite the absence of on-site diagnostic confirmation of dengue, clinical diagnosis was more sensitive on discharge (75.2%). The 2009 WHO criteria classified almost 75% as having warning signs, even though only 9 (2.3%) patients had evidence of plasma leakage and 16 (4.1%) had evidence of bleeding. CONCLUSIONS/SIGNIFICANCE: In a large cohort with AFI, we identified features predictive of dengue vs other AFI and secondary vs primary dengue in adults versus children. The 2009 WHO dengue classification criteria had high sensitivity but low specificity compared to physicians' gestaldt diagnosis. Large cohort studies will be needed to validate the diagnostic yield of clinical impression and specific features for dengue relative to the 2009 WHO classification criteria.

Authors
Bodinayake, CK; Tillekeratne, LG; Nagahawatte, A; Devasiri, V; Kodikara Arachchi, W; Strouse, JJ; Sessions, OM; Kurukulasooriya, R; Uehara, A; Howe, S; Ong, XM; Tan, S; Chow, A; Tummalapalli, P; De Silva, AD; Østbye, T; Woods, CW; Gubler, DJ; Reller, ME
MLA Citation
Bodinayake, Champica K., et al. “Evaluation of the WHO 2009 classification for diagnosis of acute dengue in a large cohort of adults and children in Sri Lanka during a dengue-1 epidemic..” Plos Negl Trop Dis, vol. 12, no. 2, Feb. 2018. Pubmed, doi:10.1371/journal.pntd.0006258.
PMID
29425194
Source
pubmed
Published In
Plos Neglected Tropical Diseases
Volume
12
Issue
2
Publish Date
2018
Start Page
e0006258
DOI
10.1371/journal.pntd.0006258

A GENE EXPRESSION SIGNATURE ACCURATELY IDENTIFIES VIRAL ACUTE RESPIRATORY INFECTIONS IN A SRI LANKAN POPULATION

Authors
Tillekeratne, L; Suchindran, S; Ko, E; Petzold, E; Bodinayake, C; Nagahawatte, A; Devasiri, V; Kurukulasooriya, R; Reller, M; Nicholson, B; McClain, M; Burke, T; Tsalik, E; Henao, R; Ginsburg, G; Woods, C
MLA Citation
Tillekeratne, L., et al. “A GENE EXPRESSION SIGNATURE ACCURATELY IDENTIFIES VIRAL ACUTE RESPIRATORY INFECTIONS IN A SRI LANKAN POPULATION.” American Journal of Tropical Medicine and Hygiene, vol. 99, no. 4, AMER SOC TROP MED & HYGIENE, 2018, pp. 641–42.
Source
wos
Published In
The American Journal of Tropical Medicine and Hygiene
Volume
99
Issue
4
Publish Date
2018
Start Page
641
End Page
642

Immune System Dysregulation During Spaceflight: Potential Countermeasures for Deep Space Exploration Missions.

Recent studies have established that dysregulation of the human immune system and the reactivation of latent herpesviruses persists for the duration of a 6-month orbital spaceflight. It appears certain aspects of adaptive immunity are dysregulated during flight, yet some aspects of innate immunity are heightened. Interaction between adaptive and innate immunity also seems to be altered. Some crews experience persistent hypersensitivity reactions during flight. This phenomenon may, in synergy with extended duration and galactic radiation exposure, increase specific crew clinical risks during deep space exploration missions. The clinical challenge is based upon both the frequency of these phenomena in multiple crewmembers during low earth orbit missions and the inability to predict which specific individual crewmembers will experience these changes. Thus, a general countermeasure approach that offers the broadest possible coverage is needed. The vehicles, architecture, and mission profiles to enable such voyages are now under development. These include deployment and use of a cis-Lunar station (mid 2020s) with possible Moon surface operations, to be followed by multiple Mars flyby missions, and eventual human Mars surface exploration. Current ISS studies will continue to characterize physiological dysregulation associated with prolonged orbital spaceflight. However, sufficient information exists to begin consideration of both the need for, and nature of, specific immune countermeasures to ensure astronaut health. This article will review relevant in-place operational countermeasures onboard ISS and discuss a myriad of potential immune countermeasures for exploration missions. Discussion points include nutritional supplementation and functional foods, exercise and immunity, pharmacological options, the relationship between bone and immune countermeasures, and vaccination to mitigate herpes (and possibly other) virus risks. As the immune system has sentinel connectivity within every other physiological system, translational effects must be considered for all potential immune countermeasures. Finally, we shall discuss immune countermeasures in the context of their individualized implementation or precision medicine, based on crewmember specific immunological biases.

Authors
Crucian, BE; Choukèr, A; Simpson, RJ; Mehta, S; Marshall, G; Smith, SM; Zwart, SR; Heer, M; Ponomarev, S; Whitmire, A; Frippiat, JP; Douglas, GL; Lorenzi, H; Buchheim, J-I; Makedonas, G; Ginsburg, GS; Ott, CM; Pierson, DL; Krieger, SS; Baecker, N; Sams, C
MLA Citation
Crucian, Brian E., et al. “Immune System Dysregulation During Spaceflight: Potential Countermeasures for Deep Space Exploration Missions..” Front Immunol, vol. 9, 2018. Pubmed, doi:10.3389/fimmu.2018.01437.
PMID
30018614
Source
pubmed
Published In
Frontiers in Immunology
Volume
9
Publish Date
2018
Start Page
1437
DOI
10.3389/fimmu.2018.01437

A miRNA Host Response Signature Accurately Discriminates Acute Respiratory Infection Etiologies.

Background: Acute respiratory infections (ARIs) are the leading indication for antibacterial prescriptions despite a viral etiology in the majority of cases. The lack of available diagnostics to discriminate viral and bacterial etiologies contributes to this discordance. Recent efforts have focused on the host response as a source for novel diagnostic targets although none have explored the ability of host-derived microRNAs (miRNA) to discriminate between these etiologies. Methods: In this study, we compared host-derived miRNAs and mRNAs from human H3N2 influenza challenge subjects to those from patients with Streptococcus pneumoniae pneumonia. Sparse logistic regression models were used to generate miRNA signatures diagnostic of ARI etiologies. Generalized linear modeling of mRNAs to identify differentially expressed (DE) genes allowed analysis of potential miRNA:mRNA relationships. High likelihood miRNA:mRNA interactions were examined using binding target prediction and negative correlation to further explore potential changes in pathway regulation in response to infection. Results: The resultant miRNA signatures were highly accurate in discriminating ARI etiologies. Mean accuracy was 100% [88.8-100; 95% Confidence Interval (CI)] in discriminating the healthy state from S. pneumoniae pneumonia and 91.3% (72.0-98.9; 95% CI) in discriminating S. pneumoniae pneumonia from influenza infection. Subsequent differential mRNA gene expression analysis revealed alterations in regulatory networks consistent with known biology including immune cell activation and host response to viral infection. Negative correlation network analysis of miRNA:mRNA interactions revealed connections to pathways with known immunobiology such as interferon regulation and MAP kinase signaling. Conclusion: We have developed novel human host-response miRNA signatures for bacterial and viral ARI etiologies. miRNA host response signatures reveal accurate discrimination between S. pneumoniae pneumonia and influenza etiologies for ARI and integrated analyses of the host-pathogen interface are consistent with expected biology. These results highlight the differential miRNA host response to bacterial and viral etiologies of ARI, offering new opportunities to distinguish these entities.

Authors
Poore, GD; Ko, ER; Valente, A; Henao, R; Sumner, K; Hong, C; Burke, TW; Nichols, M; McClain, MT; Huang, ES; Ginsburg, GS; Woods, CW; Tsalik, EL
MLA Citation
Poore, Gregory D., et al. “A miRNA Host Response Signature Accurately Discriminates Acute Respiratory Infection Etiologies..” Front Microbiol, vol. 9, 2018. Pubmed, doi:10.3389/fmicb.2018.02957.
PMID
30619110
Source
pubmed
Published In
Frontiers in Microbiology
Volume
9
Publish Date
2018
Start Page
2957
DOI
10.3389/fmicb.2018.02957

NMR Lipoprotein Profiling Identifies HDL Subclasses Associated With Obstructive CAD: Insights From the PROMISE Clinical Trial

Authors
McGarrah, RW; Navar, AM; Giamberardino, S; Coles, A; Kwee, LC; Hoffmann, U; Ginsburg, GS; Kraus, WE; Douglas, PS; Shah, SH
MLA Citation
McGarrah, Robert W., et al. “NMR Lipoprotein Profiling Identifies HDL Subclasses Associated With Obstructive CAD: Insights From the PROMISE Clinical Trial.” Circulation, vol. 136, LIPPINCOTT WILLIAMS & WILKINS, 2017.
Source
wos
Published In
Circulation
Volume
136
Publish Date
2017

Genomic and precision medicine: Cardiovascular disease: Third edition

© 2018 Elsevier Inc. All rights reserved. Genomic and Precision Medicine: Cardiovascular Disease, Third Edition, focuses on the applications of genome discovery on the broad spectrum of cardiovascular disorders. Each chapter is organized for the application of genomics and personalized medicine tools and technologies to a) Risk Assessment and Susceptibility, b) Diagnosis and Prognosis, c) Pharmacogenomics and Precision Therapeutics, and d) Emerging and Future Opportunities in the field. Presents a comprehensive volume written and edited by cardiovascular genomic specialists. Covers succinct commentary and key learning points that will assist providers with their local needs for the implementation of genomic and personalized medicine into practice. Provides an overview on major opportunities for genomic and personalized medicine in practice. Includes case studies that highlight the practical use of genomics in the management of patients.

Authors
Ginsburg, GS; Willard, HF
MLA Citation
Ginsburg, G. S., and H. F. Willard. Genomic and precision medicine: Cardiovascular disease: Third edition. 2017, pp. 1–321.
Source
scopus
Publish Date
2017
Start Page
1
End Page
321

Making genomic medicine evidence-based and patient-centered: a structured review and landscape analysis of comparative effectiveness research.

Comparative effectiveness research (CER) in genomic medicine (GM) measures the clinical utility of using genomic information to guide clinical care in comparison to appropriate alternatives. We summarized findings of high-quality systematic reviews that compared the analytic and clinical validity and clinical utility of GM tests. We focused on clinical utility findings to summarize CER-derived evidence about GM and identify evidence gaps and future research needs. We abstracted key elements of study design, GM interventions, results, and study quality ratings from 21 systematic reviews published in 2010 through 2015. More than half (N = 13) of the reviews were of cancer-related tests. All reviews identified potentially important clinical applications of the GM interventions, but most had significant methodological weaknesses that largely precluded any conclusions about clinical utility. Twelve reviews discussed the importance of patient-centered outcomes, although few described evidence about the impact of genomic medicine on these outcomes. In summary, we found a very limited body of evidence about the effect of using genomic tests on health outcomes and many evidence gaps for CER to address.Genet Med advance online publication 13 April 2017.

Authors
Phillips, KA; Deverka, PA; Sox, HC; Khoury, MJ; Sandy, LG; Ginsburg, GS; Tunis, SR; Orlando, LA; Douglas, MP
MLA Citation
Phillips, Kathryn A., et al. “Making genomic medicine evidence-based and patient-centered: a structured review and landscape analysis of comparative effectiveness research..” Genet Med, vol. 19, no. 10, Oct. 2017, pp. 1081–91. Pubmed, doi:10.1038/gim.2017.21.
Website
http://hdl.handle.net/10161/14222
PMID
28406488
Source
pubmed
Published In
Genet Med
Volume
19
Issue
10
Publish Date
2017
Start Page
1081
End Page
1091
DOI
10.1038/gim.2017.21

RESPONSE: Training in Precision Cardiology The Time Is Now

Authors
Ginsburg, GS
MLA Citation
Ginsburg, Geoffrey S. “RESPONSE: Training in Precision Cardiology The Time Is Now.” Journal of the American College of Cardiology, vol. 70, no. 13, ELSEVIER SCIENCE INC, Sept. 2017, pp. 1678–79.
Source
wos
Published In
Journal of the American College of Cardiology
Volume
70
Issue
13
Publish Date
2017
Start Page
1678
End Page
1679

Studying genetic resilience to improve human health.

Authors
Cirulli, ET; Ginsburg, GS
MLA Citation
Cirulli, E. T., and G. S. Ginsburg. “Studying genetic resilience to improve human health..” Oral Dis, vol. 23, no. 6, Sept. 2017, pp. 685–88. Pubmed, doi:10.1111/odi.12567.
PMID
27510747
Source
pubmed
Published In
Oral Dis
Volume
23
Issue
6
Publish Date
2017
Start Page
685
End Page
688
DOI
10.1111/odi.12567

Influence of vancomycin minimum inhibitory concentration on the outcome of methicillin-susceptible Staphylococcus aureus left-sided infective endocarditis treated with antistaphylococcal β-lactam antibiotics: a prospective cohort study by the International Collaboration on Endocarditis.

OBJECTIVES: Left-sided methicillin-susceptible Staphylococcus aureus (MSSA) endocarditis treated with cloxacillin has a poorer prognosis when the vancomycin minimum inhibitory concentration (MIC) is ≥1.5 mg/L. We aimed to validate this using the International Collaboration on Endocarditis cohort and to analyse whether specific genetic characteristics were associated with a high vancomycin MIC (≥1.5 mg/L) phenotype. METHODS: All patients with left-sided MSSA infective endocarditis treated with antistaphylococcal β-lactam antibiotics between 2000 and 2006 with available isolates were included. Vancomycin MIC was determined by Etest as either high (≥1.5 mg/L) or low (<1.5 mg/L). Isolates underwent spa typing to infer clonal complexes and multiplex PCR for identifying virulence genes. Univariate analysis was performed to evaluate the association between in-hospital and 1-year mortality, and vancomycin MIC phenotype. RESULTS: Sixty-two cases met the inclusion criteria. Vancomycin MIC was low in 28 cases (45%) and high in 34 cases (55%). No significant differences in patient demographic data or characteristics of infection were observed between patients with infective endocarditis due to high and low vancomycin MIC isolates. Isolates with high and low vancomycin MIC had similar distributions of virulence genes and clonal lineages. In-hospital and 1-year mortality did not differ significantly between the two groups (32% (9/28) vs. 27% (9/34), p 0.780; and 43% (12/28) vs. 29% (10/34), p 0.298, for low and high vancomycin MIC respectively). CONCLUSIONS: In this international cohort of patients with left-sided MSSA endocarditis treated with antistaphylococcal β-lactams, vancomycin MIC phenotype was not associated with patient demographics, clinical outcome or virulence gene repertoire.

Authors
Pericàs, JM; Messina, JA; Garcia-de-la-Mària, C; Park, L; Sharma-Kuinkel, BK; Marco, F; Wray, D; Kanafani, ZA; Carugati, M; Durante-Mangoni, E; Tattevin, P; Chu, VH; Moreno, A; Fowler, VG; Miró, JM; International Collaboration on Endocarditis Microbiology Investigators,
MLA Citation
Pericàs, J. M., et al. “Influence of vancomycin minimum inhibitory concentration on the outcome of methicillin-susceptible Staphylococcus aureus left-sided infective endocarditis treated with antistaphylococcal β-lactam antibiotics: a prospective cohort study by the International Collaboration on Endocarditis..” Clin Microbiol Infect, vol. 23, no. 8, Aug. 2017, pp. 544–49. Pubmed, doi:10.1016/j.cmi.2017.01.017.
PMID
28159672
Source
pubmed
Published In
Clin Microbiol Infect
Volume
23
Issue
8
Publish Date
2017
Start Page
544
End Page
549
DOI
10.1016/j.cmi.2017.01.017

Performance of the cobas MRSA/SA Test for Simultaneous Detection of Methicillin-Susceptible and Methicillin-Resistant Staphylococcus aureus From Nasal Swabs.

Health care-associated methicillin-resistant Staphylococcus aureus (MRSA) and Staphylococcus aureus (SA) infections are continuing problems. Rapidly determining the MRSA colonization status of a patient facilitates practice to reduce spread of MRSA clinical disease. Sensitive detection of all SA prior to surgery, followed by decolonization, can significantly reduce postoperative infection from this pathogen. Our goal was to validate a new automated assay for this testing.We compared performance of the cobas MRSA/SA Test on the cobas 4800 System to direct and enriched chromogenic culture using nasal swabs collected from patients at six United States sites.Compared to direct and enriched culture, the sensitivity for MRSA and SA was 93.1% and 93.9%, and the specificity was 97.5% and 94.2%, respectively. After discrepancy analysis, the sensitivity for MRSA and SA was 97.1% and 98.6%, and the specificity was 98.3% and 95.5%, respectively. Compared to direct culture, sensitivity for detecting any SA was 99.6%.The cobas MRSA/SA Test is an effective tool to simultaneously perform surveillance testing for nasal colonization of both MRSA and MSSA.

Authors
Peterson, LR; Woods, CW; Davis, TE; Wang, Z-X; Young, SA; Osiecki, JC; Lewinski, MA; Liesenfeld, O
MLA Citation
Peterson, Lance R., et al. “Performance of the cobas MRSA/SA Test for Simultaneous Detection of Methicillin-Susceptible and Methicillin-Resistant Staphylococcus aureus From Nasal Swabs..” American Journal of Clinical Pathology, vol. 148, no. 2, Aug. 2017, pp. 119–27. Epmc, doi:10.1093/ajcp/aqx040.
PMID
28898981
Source
epmc
Published In
American Journal of Clinical Pathology
Volume
148
Issue
2
Publish Date
2017
Start Page
119
End Page
127
DOI
10.1093/ajcp/aqx040

Culture, PCR, DNA sequencing, and second harmonic generation (SHG) visualization of Bartonella henselae from a surgically excised human femoral head.

Authors
Ericson, M; Balakrishnan, N; Mozayeni, BR; Woods, CW; Dencklau, J; Kelly, S; Breitschwerdt, EB
MLA Citation
Ericson, M., et al. “Culture, PCR, DNA sequencing, and second harmonic generation (SHG) visualization of Bartonella henselae from a surgically excised human femoral head..” Clin Rheumatol, vol. 36, no. 7, July 2017, pp. 1669–75. Pubmed, doi:10.1007/s10067-016-3524-2.
PMID
28028681
Source
pubmed
Published In
Clin Rheumatol
Volume
36
Issue
7
Publish Date
2017
Start Page
1669
End Page
1675
DOI
10.1007/s10067-016-3524-2

Burden and Seasonality of Viral Acute Respiratory Tract Infections among Outpatients in Southern Sri Lanka.

In tropical and subtropical settings, the epidemiology of viral acute respiratory tract infections varies widely between countries. We determined the etiology, seasonality, and clinical presentation of viral acute respiratory tract infections among outpatients in southern Sri Lanka. From March 2013 to January 2015, we enrolled outpatients presenting with influenza-like illness (ILI). Nasal/nasopharyngeal samples were tested in duplicate using antigen-based rapid influenza testing and multiplex polymerase chain reaction (PCR) for respiratory viruses. Monthly proportion positive was calculated for each virus. Bivariable and multivariable logistic regression were used to identify associations between sociodemographic/clinical information and viral detection. Of 571 subjects, most (470, 82.3%) were ≥ 5 years of age and 53.1% were male. A respiratory virus was detected by PCR in 63.6% (N = 363). Common viral etiologies included influenza (223, 39%), human enterovirus/rhinovirus (HEV/HRV, 14.5%), respiratory syncytial virus (RSV, 4.2%), and human metapneumovirus (hMPV, 3.9%). Both ILI and influenza showed clear seasonal variation, with peaks from March to June each year. RSV and hMPV activity peaked from May to July, whereas HEV/HRV was seen year-round. Patients with respiratory viruses detected were more likely to report pain with breathing (odds ratio [OR] = 2.60, P = 0.003), anorexia (OR = 2.29, P < 0.001), and fatigue (OR = 2.00, P = 0.002) compared with patients with no respiratory viruses detected. ILI showed clear seasonal variation in southern Sri Lanka, with most activity during March to June; peak activity was largely due to influenza. Targeted infection prevention activities such as influenza vaccination in January-February may have a large public health impact in this region.

Authors
Shapiro, D; Bodinayake, CK; Nagahawatte, A; Devasiri, V; Kurukulasooriya, R; Hsiang, J; Nicholson, B; De Silva, AD; Østbye, T; Reller, ME; Woods, CW; Tillekeratne, LG
MLA Citation
Shapiro, David, et al. “Burden and Seasonality of Viral Acute Respiratory Tract Infections among Outpatients in Southern Sri Lanka..” Am J Trop Med Hyg, vol. 97, no. 1, July 2017, pp. 88–96. Pubmed, doi:10.4269/ajtmh.17-0032.
PMID
28719323
Source
pubmed
Published In
Am J Trop Med Hyg
Volume
97
Issue
1
Publish Date
2017
Start Page
88
End Page
96
DOI
10.4269/ajtmh.17-0032

Analysis of Dengue Serotype 4 in Sri Lanka during the 2012-2013 Dengue Epidemic.

The four serotypes of dengue virus (DENV-1, -2, -3, and -4) have had a rapidly expanding geographic range and are now endemic in over 100 tropical and subtropical countries. Sri Lanka has experienced periodic dengue outbreaks since the 1960s, but since 1989 epidemics have become progressively larger and associated with more severe disease. The dominant virus in the 2012 epidemic was DENV-1, but DENV-4 infections were also commonly observed. DENV-4 transmission was first documented in Sri Lanka when it was isolated from a traveler in 1978, but has been comparatively uncommon since dengue surveillance began in the early 1980s. To better understand the molecular epidemiology of DENV-4 infections in Sri Lanka, we conducted whole-genome sequencing on dengue patient samples from two different geographic locations. Phylogenetic analysis indicates that all sequenced DENV-4 strains belong to genotype 1 and are most closely related to DENV-4 viruses previously found in Sri Lanka and those recently found to be circulating in India and Pakistan.

Authors
Uehara, A; Tissera, HA; Bodinayake, CK; Amarasinghe, A; Nagahawatte, A; Tillekeratne, LG; Cui, J; Reller, ME; Palihawadana, P; Gunasena, S; Desilva, AD; Wilder-Smith, A; Gubler, DJ; Woods, CW; Sessions, OM
MLA Citation
Uehara, Anna, et al. “Analysis of Dengue Serotype 4 in Sri Lanka during the 2012-2013 Dengue Epidemic..” Am J Trop Med Hyg, vol. 97, no. 1, July 2017, pp. 130–36. Pubmed, doi:10.4269/ajtmh.16-0540.
PMID
28719296
Source
pubmed
Published In
Am J Trop Med Hyg
Volume
97
Issue
1
Publish Date
2017
Start Page
130
End Page
136
DOI
10.4269/ajtmh.16-0540

Challenges and strategies for implementing genomic services in diverse settings: experiences from the Implementing GeNomics In pracTicE (IGNITE) network.

BACKGROUND: To realize potential public health benefits from genetic and genomic innovations, understanding how best to implement the innovations into clinical care is important. The objective of this study was to synthesize data on challenges identified by six diverse projects that are part of a National Human Genome Research Institute (NHGRI)-funded network focused on implementing genomics into practice and strategies to overcome these challenges. METHODS: We used a multiple-case study approach with each project considered as a case and qualitative methods to elicit and describe themes related to implementation challenges and strategies. We describe challenges and strategies in an implementation framework and typology to enable consistent definitions and cross-case comparisons. Strategies were linked to challenges based on expert review and shared themes. RESULTS: Three challenges were identified by all six projects, and strategies to address these challenges varied across the projects. One common challenge was to increase the relative priority of integrating genomics within the health system electronic health record (EHR). Four projects used data warehousing techniques to accomplish the integration. The second common challenge was to strengthen clinicians' knowledge and beliefs about genomic medicine. To overcome this challenge, all projects developed educational materials and conducted meetings and outreach focused on genomic education for clinicians. The third challenge was engaging patients in the genomic medicine projects. Strategies to overcome this challenge included use of mass media to spread the word, actively involving patients in implementation (e.g., a patient advisory board), and preparing patients to be active participants in their healthcare decisions. CONCLUSIONS: This is the first collaborative evaluation focusing on the description of genomic medicine innovations implemented in multiple real-world clinical settings. Findings suggest that strategies to facilitate integration of genomic data within existing EHRs and educate stakeholders about the value of genomic services are considered important for effective implementation. Future work could build on these findings to evaluate which strategies are optimal under what conditions. This information will be useful for guiding translation of discoveries to clinical care, which, in turn, can provide data to inform continual improvement of genomic innovations and their applications.

Authors
Sperber, NR; Carpenter, JS; Cavallari, LH; J Damschroder, L; Cooper-DeHoff, RM; Denny, JC; Ginsburg, GS; Guan, Y; Horowitz, CR; Levy, KD; Levy, MA; Madden, EB; Matheny, ME; Pollin, TI; Pratt, VM; Rosenman, M; Voils, CI; W Weitzel, K; Wilke, RA; Ryanne Wu, R; Orlando, LA
MLA Citation
Sperber, Nina R., et al. “Challenges and strategies for implementing genomic services in diverse settings: experiences from the Implementing GeNomics In pracTicE (IGNITE) network..” Bmc Med Genomics, vol. 10, no. 1, May 2017. Pubmed, doi:10.1186/s12920-017-0273-2.
Website
http://hdl.handle.net/10161/15443
PMID
28532511
Source
pubmed
Published In
Bmc Medical Genomics
Volume
10
Issue
1
Publish Date
2017
Start Page
35
DOI
10.1186/s12920-017-0273-2

Integrative health care services utilization as a function of body mass index: A BraveNet practice-based research network study

© 2017 Elsevier Ltd Background Obesity is a significant public health issue with no consensus regarding optimal medical management. Integrative medicine (IM) may help to fill this gap. Objectives (1) To characterize the sociodemographics, psychosocial functioning, health behaviors, and current medical conditions across BMI classifications in patients seeking IM; and (2) to examine how patients’ reasons for seeking IM care, treatment goals, services sought, and services provided differ based on BMI. Methods Survey data were collected from patients seeking care at nine BraveNet IM centers. Sociodemographics, psychosocial health, lifestyle behaviors, and reasons for seeking specific IM services were compared across BMI categories using Chi-square test, Fisher's exact test, or one-way analysis of variance. Logistical regression was used to compare reasons for seeking IM care, treatment goals, and services sought and provided across BMI categories. Results 2015 patients were included in this study; 300 (14.9%) were obese and 580 (28.8%) were overweight. Obese patients were more likely to be non-White, unmarried, and uninsured, and have lower education, lower income, and at least one chronic disease (p < 0.05). They also had the lowest rates of aerobic activity (67.4% exercise < 3×/week, p < 0.01), and greater depression (CESD-10 score 10.1 ± 6.6, p < 0.01), stress (PSS score 6.3 ± 3.5, p < 0.01), fatigue (avg 5.5 ± 2.4 on scale 1–10, p < 0.01), and pain (avg 3.6 ± 2.5 on scale 1–10, p < 0.01). Obese patients were more likely to seek manipulative/body-based services (OR = 1.46, 95% CI = 1.10–1.93, p < 0.05) and to seek and receive energy therapies (seek: OR = 1.49, 95% CI = 1.07–2.07; receive: OR = 2.56, 95% CI = 1.28–5.10), but less likely to seek IM care for greater compatibility with their beliefs and culture (OR = 0.72, 95% CI = 0.53–0.97). There were no significant differences between BMI categories for IM treatment goals. Conclusion Obese adults seeking IM care may represent a unique patient population with potential unmet health needs. IM may provide approaches to more effectively address the multifaceted complexities of obesity.

Authors
Yang, NY; Wolever, RQ; Roberts, R; Perlman, A; Dolor, RJ; Abrams, DI; Ginsburg, GS; Simmons, LA
MLA Citation
Yang, N. Y., et al. “Integrative health care services utilization as a function of body mass index: A BraveNet practice-based research network study.” Advances in Integrative Medicine, vol. 4, no. 1, Apr. 2017, pp. 14–21. Scopus, doi:10.1016/j.aimed.2017.02.003.
Source
scopus
Published In
Advances in Integrative Medicine
Volume
4
Issue
1
Publish Date
2017
Start Page
14
End Page
21
DOI
10.1016/j.aimed.2017.02.003

Preface

Authors
David, SP; Willard, HF; Ginsburg, GS
MLA Citation
David, S. P., et al. Preface. 2017, pp. xv–xvxvi. Scopus, doi:10.1016/B978-0-12-800685-6.00021-7.
Source
scopus
Publish Date
2017
Start Page
xv
End Page
xvxvi
DOI
10.1016/B978-0-12-800685-6.00021-7

Antibiotic overuse for acute respiratory tract infections in Sri Lanka: a qualitative study of outpatients and their physicians.

BACKGROUND: Acute respiratory tract infections (ARTIs) are a common reason for antibiotic overuse worldwide. We previously showed that over 80% of outpatients presenting to a tertiary care hospital in Sri Lanka with influenza-like illness received antibiotic prescriptions, although almost half were later confirmed to have influenza. The purpose of this qualitative study was to assess Sri Lankan patients' and physicians' attitudes towards ARTI diagnosis and treatment. METHODS: Semi-structured interviews were conducted with 50 outpatients with ARTIs and five physicians in the Outpatient Department (OPD) at a large, public tertiary care hospital in southern Sri Lanka. Interviews were audio-recorded, transcribed, and analyzed for themes related to ARTI diagnosis and treatment. RESULTS: Patients frequently sought ARTI care in the public sector due to the receipt of free care and the perception that government hospitals carried a sense of responsibility for patients' health. Patients reported multiple medical visits for their illnesses of short duration and many indicated that they were seeking care in the OPD while at the hospital for another reason. While patients generally expected to receive medication prescriptions at their visit, most patients were not specifically seeking an antibiotic prescription. However, more than 70% of patients received antibiotic prescriptions at their OPD visit. Physicians incorrectly perceived that patients desired antibiotics or "capsules," a common formulation of antibiotics dispensed in this outpatient setting, and cited patient demand as an important cause of antibiotic overuse. Physicians also indicated that high patient volume and fear of bacterial superinfection drove antibiotic overuse. CONCLUSIONS: Patients in this study were seeking medication prescriptions for their ARTIs, but physicians incorrectly perceived that antibiotic prescriptions were desired. High patient volume and fear of bacterial superinfection were also important factors in antibiotic overuse. Training of physicians regarding guideline-concordant management and dealing with diagnostic uncertainty, education of patients regarding ARTI etiology and management, and systematic changes in the public outpatient care structure may help decrease unnecessary antibiotic prescriptions for ARTIs in this setting.

Authors
Tillekeratne, LG; Bodinayake, CK; Dabrera, T; Nagahawatte, A; Arachchi, WK; Sooriyaarachchi, A; Stewart, K; Watt, M; Østbye, T; Woods, CW
MLA Citation
Tillekeratne, L. Gayani, et al. “Antibiotic overuse for acute respiratory tract infections in Sri Lanka: a qualitative study of outpatients and their physicians..” Bmc Fam Pract, vol. 18, no. 1, Mar. 2017. Pubmed, doi:10.1186/s12875-017-0619-z.
Website
http://hdl.handle.net/10161/16127
PMID
28302056
Source
pubmed
Published In
Bmc Family Practice
Volume
18
Issue
1
Publish Date
2017
Start Page
37
DOI
10.1186/s12875-017-0619-z

Nasopharyngeal Protein Biomarkers of Acute Respiratory Virus Infection.

Infection of respiratory mucosa with viral pathogens triggers complex immunologic events in the affected host. We sought to characterize this response through proteomic analysis of nasopharyngeal lavage in human subjects experimentally challenged with influenza A/H3N2 or human rhinovirus, and to develop targeted assays measuring peptides involved in this host response allowing classification of acute respiratory virus infection. Unbiased proteomic discovery analysis identified 3285 peptides corresponding to 438 unique proteins, and revealed that infection with H3N2 induces significant alterations in protein expression. These include proteins involved in acute inflammatory response, innate immune response, and the complement cascade. These data provide insights into the nature of the biological response to viral infection of the upper respiratory tract, and the proteins that are dysregulated by viral infection form the basis of signature that accurately classifies the infected state. Verification of this signature using targeted mass spectrometry in independent cohorts of subjects challenged with influenza or rhinovirus demonstrates that it performs with high accuracy (0.8623 AUROC, 75% TPR, 97.46% TNR). With further development as a clinical diagnostic, this signature may have utility in rapid screening for emerging infections, avoidance of inappropriate antibacterial therapy, and more rapid implementation of appropriate therapeutic and public health strategies.

Authors
Burke, TW; Henao, R; Soderblom, E; Tsalik, EL; Thompson, JW; McClain, MT; Nichols, M; Nicholson, BP; Veldman, T; Lucas, JE; Moseley, MA; Turner, RB; Lambkin-Williams, R; Hero, AO; Woods, CW; Ginsburg, GS
MLA Citation
Burke, Thomas W., et al. “Nasopharyngeal Protein Biomarkers of Acute Respiratory Virus Infection..” Ebiomedicine, vol. 17, Mar. 2017, pp. 172–81. Pubmed, doi:10.1016/j.ebiom.2017.02.015.
PMID
28238698
Source
pubmed
Published In
Ebiomedicine
Volume
17
Publish Date
2017
Start Page
172
End Page
181
DOI
10.1016/j.ebiom.2017.02.015

Primary care providers' use of pharmacist support for delivery of pharmacogenetic testing.

AIM: To investigate provider utilization of pharmacist support in the delivery of pharmacogenetic testing in a primary care setting. METHODS: Two primary care clinics within Duke University Health System participated in the study between December 2012 and July 2013. One clinic was provided with an in-house pharmacist and the second clinic had an on-call pharmacist. RESULTS: Providers in the in-house pharmacist arm consulted with the pharmacist for 13 of 15 cases, or about one of every four patients tested compared with one of every 7.5 patients in the on-call pharmacist arm. A total of 63 tests were ordered, 48 by providers in the pharmacist-in-house arm. CONCLUSION: These findings suggest that the availability of an in-house pharmacist increases the likelihood of pharmacogenetic test utilization.

Authors
Haga, SB; Mills, R; Moaddeb, J; Allen LaPointe, N; Cho, A; Ginsburg, GS
MLA Citation
Haga, Susanne B., et al. “Primary care providers' use of pharmacist support for delivery of pharmacogenetic testing..” Pharmacogenomics, vol. 18, no. 4, Mar. 2017, pp. 359–67. Pubmed, doi:10.2217/pgs-2016-0177.
PMID
28244812
Source
pubmed
Published In
Pharmacogenomics
Volume
18
Issue
4
Publish Date
2017
Start Page
359
End Page
367
DOI
10.2217/pgs-2016-0177

Human genetic and metabolite variation reveals that methylthioadenosine is a prognostic biomarker and an inflammatory regulator in sepsis.

Sepsis is a deleterious inflammatory response to infection with high mortality. Reliable sepsis biomarkers could improve diagnosis, prognosis, and treatment. Integration of human genetics, patient metabolite and cytokine measurements, and testing in a mouse model demonstrate that the methionine salvage pathway is a regulator of sepsis that can accurately predict prognosis in patients. Pathway-based genome-wide association analysis of nontyphoidal Salmonella bacteremia showed a strong enrichment for single-nucleotide polymorphisms near the components of the methionine salvage pathway. Measurement of the pathway's substrate, methylthioadenosine (MTA), in two cohorts of sepsis patients demonstrated increased plasma MTA in nonsurvivors. Plasma MTA was correlated with levels of inflammatory cytokines, indicating that elevated MTA marks a subset of patients with excessive inflammation. A machine-learning model combining MTA and other variables yielded approximately 80% accuracy (area under the curve) in predicting death. Furthermore, mice infected with Salmonella had prolonged survival when MTA was administered before infection, suggesting that manipulating MTA levels could regulate the severity of the inflammatory response. Our results demonstrate how combining genetic data, biomolecule measurements, and animal models can shape our understanding of disease and lead to new biomarkers for patient stratification and potential therapeutic targeting.

Authors
Wang, L; Ko, ER; Gilchrist, JJ; Pittman, KJ; Rautanen, A; Pirinen, M; Thompson, JW; Dubois, LG; Langley, RJ; Jaslow, SL; Salinas, RE; Rouse, DC; Moseley, MA; Mwarumba, S; Njuguna, P; Mturi, N; Wellcome Trust Case Control Consortium 2, ; Kenyan Bacteraemia Study Group, ; Williams, TN; Scott, JAG; Hill, AVS; Woods, CW; Ginsburg, GS; Tsalik, EL; Ko, DC
MLA Citation
Wang, Liuyang, et al. “Human genetic and metabolite variation reveals that methylthioadenosine is a prognostic biomarker and an inflammatory regulator in sepsis..” Sci Adv, vol. 3, no. 3, Mar. 2017. Pubmed, doi:10.1126/sciadv.1602096.
Website
http://hdl.handle.net/10161/13814
PMID
28345042
Source
pubmed
Published In
Science Advances
Volume
3
Issue
3
Publish Date
2017
Start Page
e1602096
DOI
10.1126/sciadv.1602096

Impact of Genetic Testing and Family Health History Based Risk Counseling on Behavior Change and Cognitive Precursors for Type 2 Diabetes.

Family health history (FHH) in the context of risk assessment has been shown to positively impact risk perception and behavior change. The added value of genetic risk testing is less certain. The aim of this study was to determine the impact of Type 2 Diabetes (T2D) FHH and genetic risk counseling on behavior and its cognitive precursors. Subjects were non-diabetic patients randomized to counseling that included FHH +/- T2D genetic testing. Measurements included weight, BMI, fasting glucose at baseline and 12 months and behavioral and cognitive precursor (T2D risk perception and control over disease development) surveys at baseline, 3, and 12 months. 391 subjects enrolled of which 312 completed the study. Behavioral and clinical outcomes did not differ across FHH or genetic risk but cognitive precursors did. Higher FHH risk was associated with a stronger perceived T2D risk (pKendall < 0.001) and with a perception of "serious" risk (pKendall < 0.001). Genetic risk did not influence risk perception, but was correlated with an increase in perception of "serious" risk for moderate (pKendall = 0.04) and average FHH risk subjects (pKendall = 0.01), though not for the high FHH risk group. Perceived control over T2D risk was high and not affected by FHH or genetic risk. FHH appears to have a strong impact on cognitive precursors of behavior change, suggesting it could be leveraged to enhance risk counseling, particularly when lifestyle change is desirable. Genetic risk was able to alter perceptions about the seriousness of T2D risk in those with moderate and average FHH risk, suggesting that FHH could be used to selectively identify individuals who may benefit from genetic risk testing.

Authors
Wu, RR; Myers, RA; Hauser, ER; Vorderstrasse, A; Cho, A; Ginsburg, GS; Orlando, LA
MLA Citation
Wu, R. Ryanne, et al. “Impact of Genetic Testing and Family Health History Based Risk Counseling on Behavior Change and Cognitive Precursors for Type 2 Diabetes..” J Genet Couns, vol. 26, no. 1, Feb. 2017, pp. 133–40. Pubmed, doi:10.1007/s10897-016-9988-z.
Website
http://hdl.handle.net/10161/12509
PMID
27296809
Source
pubmed
Published In
J Genet Couns
Volume
26
Issue
1
Publish Date
2017
Start Page
133
End Page
140
DOI
10.1007/s10897-016-9988-z

Host-Based Peripheral Blood Gene Expression Analysis for Diagnosis of Infectious Diseases.

Emerging pandemic infectious threats, inappropriate antibacterial use contributing to multidrug resistance, and increased morbidity and mortality from diagnostic delays all contribute to a need for improved diagnostics in the field of infectious diseases. Historically, diagnosis of infectious diseases has relied on pathogen detection; however, a novel concept to improve diagnostics in infectious diseases relies instead on the detection of changes in patterns of gene expression in circulating white blood cells in response to infection. Alterations in peripheral blood gene expression in the infected state are robust and reproducible, yielding diagnostic and prognostic information to help facilitate patient treatment decisions.

Authors
Holcomb, ZE; Tsalik, EL; Woods, CW; McClain, MT
MLA Citation
Holcomb, Zachary E., et al. “Host-Based Peripheral Blood Gene Expression Analysis for Diagnosis of Infectious Diseases..” J Clin Microbiol, vol. 55, no. 2, Feb. 2017, pp. 360–68. Pubmed, doi:10.1128/JCM.01057-16.
PMID
27795332
Source
pubmed
Published In
J Clin Microbiol
Volume
55
Issue
2
Publish Date
2017
Start Page
360
End Page
368
DOI
10.1128/JCM.01057-16

An age- and sex-specific gene expression score is associated with revascularization and coronary artery disease: Insights from the Prospective Multicenter Imaging Study for Evaluation of Chest Pain (PROMISE) trial.

BACKGROUND: Identifying predictors of coronary artery disease (CAD)-related procedures and events remains a priority. METHODS: We measured an age- and sex-specific gene expression score (ASGES) previously validated to detect obstructive CAD (oCAD) in symptomatic nondiabetic patients in the PROMISE trial. The outcomes were oCAD (≥70% stenosis in ≥1 vessel or ≥50% left main stenosis on CT angiography [CTA]) and a composite endpoint of death, myocardial infarction, revascularization, or unstable angina. RESULTS: The ASGES was determined in 2370 nondiabetic participants (47.5% male, median age 59.5 years, median follow-up 25 months), including 1137 with CTA data. An ASGES >15 was associated with oCAD (odds ratio 2.5 [95% CI 1.6-3.8], P<.001) and the composite endpoint (hazard ratio [HR] 2.6 [95% CI 1.8-3.9], P<.001) in unadjusted analyses. After adjustment for Framingham risk, an ASGES >15 remained associated with the composite endpoint (P=.02); the only component that was associated was revascularization (adjusted HR 2.69 [95% CI 1.52-4.79], P<.001). Compared to noninvasive testing, the ASGES improved prediction for the composite (increase in c-statistic=0.036; continuous net reclassification index=43.2%). Patients with an ASGES ≤15 had a composite endpoint rate no different from those with negative noninvasive test results (3.2% vs. 2.6%, P=.29). CONCLUSIONS: A blood-based genomic test for detecting oCAD significantly predicts near-term revascularization procedures, but not non-revascularization events. Larger studies will be needed to clarify the risk with non-revascularization events.

Authors
Voora, D; Coles, A; Lee, KL; Hoffmann, U; Wingrove, JA; Rhees, B; Huang, L; Daniels, SE; Monane, M; Rosenberg, S; Shah, SH; Kraus, WE; Ginsburg, GS; Douglas, PS
MLA Citation
Voora, Deepak, et al. “An age- and sex-specific gene expression score is associated with revascularization and coronary artery disease: Insights from the Prospective Multicenter Imaging Study for Evaluation of Chest Pain (PROMISE) trial..” Am Heart J, vol. 184, Feb. 2017, pp. 133–40. Pubmed, doi:10.1016/j.ahj.2016.11.004.
PMID
28224927
Source
pubmed
Published In
American Heart Journal
Volume
184
Publish Date
2017
Start Page
133
End Page
140
DOI
10.1016/j.ahj.2016.11.004

The effective rate of influenza reassortment is limited during human infection.

We characterise the evolutionary dynamics of influenza infection described by viral sequence data collected from two challenge studies conducted in human hosts. Viral sequence data were collected at regular intervals from infected hosts. Changes in the sequence data observed across time show that the within-host evolution of the virus was driven by the reversion of variants acquired during previous passaging of the virus. Treatment of some patients with oseltamivir on the first day of infection did not lead to the emergence of drug resistance variants in patients. Using an evolutionary model, we inferred the effective rate of reassortment between viral segments, measuring the extent to which randomly chosen viruses within the host exchange genetic material. We find strong evidence that the rate of effective reassortment is low, such that genetic associations between polymorphic loci in different segments are preserved during the course of an infection in a manner not compatible with epistasis. Combining our evidence with that of previous studies we suggest that spatial heterogeneity in the viral population may reduce the extent to which reassortment is observed. Our results do not contradict previous findings of high rates of viral reassortment in vitro and in small animal studies, but indicate that in human hosts the effective rate of reassortment may be substantially more limited.

Authors
Sobel Leonard, A; McClain, MT; Smith, GJD; Wentworth, DE; Halpin, RA; Lin, X; Ransier, A; Stockwell, TB; Das, SR; Gilbert, AS; Lambkin-Williams, R; Ginsburg, GS; Woods, CW; Koelle, K; Illingworth, CJR
MLA Citation
Sobel Leonard, Ashley, et al. “The effective rate of influenza reassortment is limited during human infection..” Plos Pathog, vol. 13, no. 2, Feb. 2017. Pubmed, doi:10.1371/journal.ppat.1006203.
PMID
28170438
Source
pubmed
Published In
Plos Pathog
Volume
13
Issue
2
Publish Date
2017
Start Page
e1006203
DOI
10.1371/journal.ppat.1006203

Thrombocytopenia in hospitalized patients with severe clostridium difficile infection.

Clostridium difficile infection (CDI) is a common cause of nosocomial diarrhea and colitis. The incidence and prognostic significance of thrombocytopenia as related to mode of acquisition (hospital vs. community), NAP1/027 strain, and disease severity has not been examined. We performed a single-institution retrospective analysis of all adult inpatients from 2013 to 2014 diagnosed with CDI during their hospitalization to document the incidence/prevalence of thrombocytopenia and associated outcomes. Severe disease was defined by a composite endpoint of inpatient death, death within 30 days of discharge, presence of septic shock, or need for colectomy during hospitalization. Of the 533 patients diagnosed with CDI, moderate thrombocytopenia (platelet count <100 × 109/L at time of CDI diagnosis) was present in 15 % of the total cohort and incident thrombocytopenia developed in 3 % of patients after admission. Thrombocytopenia was more common in hospital-acquired disease and associated with increased length of stay, but was not associated with treatment failure. Those with moderate thrombocytopenia were more likely to have severe disease, after controlling for white blood cell count, albumin, and creatinine. Moderate thrombocytopenia is associated with poor prognosis and is a potential risk stratification tool for severe CDI.

Authors
Fountain, EM; Moses, MC; Park, LP; Woods, CW; Arepally, GM
MLA Citation
Fountain, Eric M., et al. “Thrombocytopenia in hospitalized patients with severe clostridium difficile infection..” J Thromb Thrombolysis, vol. 43, no. 1, Jan. 2017, pp. 38–42. Pubmed, doi:10.1007/s11239-016-1423-7.
PMID
27614757
Source
pubmed
Published In
Journal of Thrombosis and Thrombolysis
Volume
43
Issue
1
Publish Date
2017
Start Page
38
End Page
42
DOI
10.1007/s11239-016-1423-7

Cardiovascular Disease: Impact of Biomarkers, Proteomics, and Genomics.

Authors
Apple, FS; Cullen, L; Felker, GM; Ginsburg, G; Morrow, D
MLA Citation
Apple, Fred S., et al. “Cardiovascular Disease: Impact of Biomarkers, Proteomics, and Genomics..” Clin Chem, vol. 63, no. 1, Jan. 2017, pp. 1–4. Pubmed, doi:10.1373/clinchem.2016.263350.
PMID
28062604
Source
pubmed
Published In
Clin Chem
Volume
63
Issue
1
Publish Date
2017
Start Page
1
End Page
4
DOI
10.1373/clinchem.2016.263350

Genomics-Inspired Biomarkers and Diagnostics-Where Are They?

Authors
Ginsburg, GS
MLA Citation
Ginsburg, Geoffrey S. “Genomics-Inspired Biomarkers and Diagnostics-Where Are They?.” Clin Chem, vol. 63, no. 1, Jan. 2017, pp. 255–57. Pubmed, doi:10.1373/clinchem.2016.266114.
PMID
28062622
Source
pubmed
Published In
Clin Chem
Volume
63
Issue
1
Publish Date
2017
Start Page
255
End Page
257
DOI
10.1373/clinchem.2016.266114

Candidate genes on murine chromosome 8 are associated with susceptibility to Staphylococcus aureus infection in mice and are involved with Staphylococcus aureus septicemia in humans.

We previously showed that chromosome 8 of A/J mice was associated with susceptibility to S. aureus infection. However, the specific genes responsible for this susceptibility are unknown. Chromosome substitution strain 8 (CSS8) mice, which have chromosome 8 from A/J but an otherwise C57BL/6J genome, were used to identify the genetic determinants of susceptibility to S. aureus on chromosome 8. Quantitative trait loci (QTL) mapping of S. aureus-infected N2 backcross mice (F1 [C8A] × C57BL/6J) identified a locus 83180780-88103009 (GRCm38/mm10) on A/J chromosome 8 that was linked to S. aureus susceptibility. All genes on the QTL (n~ 102) were further analyzed by three different strategies: 1) different expression in susceptible (A/J) and resistant (C57BL/6J) mice only in response to S. aureus, 2) consistently different expression in both uninfected and infected states between the two strains, and 3) damaging non-synonymous SNPs in either strain. Eleven candidate genes from the QTL region were significantly differently expressed in patients with S. aureus infection vs healthy human subjects. Four of these 11 genes also exhibited significantly different expression in S. aureus-challenged human neutrophils: Ier2, Crif1, Cd97 and Lyl1. CD97 ligand binding was evaluated within peritoneal neutrophils from A/J and C57BL/6J. CD97 from A/J had stronger CD55 but weaker integrin α5β1 ligand binding as compared with C57BL/6J. Because CD55/CD97 binding regulates immune cell activation and cytokine production, and integrin α5β1 is a membrane receptor for fibronectin, which is also bound by S. aureus, strain-specific differences could contribute to susceptibility to S. aureus. Down-regulation of Crif1 with siRNA was associated with increased host cell apoptosis among both naïve and S. aureus-infected bone marrow-derived macrophages. Specific genes in A/J chromosome 8, including Cd97 and Crif1, may play important roles in host defense against S. aureus.

Authors
Yan, Q; Ahn, SH; Medie, FM; Sharma-Kuinkel, BK; Park, LP; Scott, WK; Deshmukh, H; Tsalik, EL; Cyr, DD; Woods, CW; Yu, C-HA; Adams, C; Qi, R; Hansen, B; Fowler, VG
MLA Citation
Yan, Qin, et al. “Candidate genes on murine chromosome 8 are associated with susceptibility to Staphylococcus aureus infection in mice and are involved with Staphylococcus aureus septicemia in humans..” Plos One, vol. 12, no. 6, 2017. Pubmed, doi:10.1371/journal.pone.0179033.
PMID
28594911
Source
pubmed
Published In
Plos One
Volume
12
Issue
6
Publish Date
2017
Start Page
e0179033
DOI
10.1371/journal.pone.0179033

Deep Sequencing of Influenza A Virus from a Human Challenge Study Reveals a Selective Bottleneck and Only Limited Intrahost Genetic Diversification.

Knowledge of influenza virus evolution at the point of transmission and at the intrahost level remains limited, particularly for human hosts. Here, we analyze a unique viral data set of next-generation sequencing (NGS) samples generated from a human influenza challenge study wherein 17 healthy subjects were inoculated with cell- and egg-passaged virus. Nasal wash samples collected from 7 of these subjects were successfully deep sequenced. From these, we characterized changes in the subjects' viral populations during infection and identified differences between the virus in these samples and the viral stock used to inoculate the subjects. We first calculated pairwise genetic distances between the subjects' nasal wash samples, the viral stock, and the influenza virus A/Wisconsin/67/2005 (H3N2) reference strain used to generate the stock virus. These distances revealed that considerable viral evolution occurred at various points in the human challenge study. Further quantitative analyses indicated that (i) the viral stock contained genetic variants that originated and likely were selected for during the passaging process, (ii) direct intranasal inoculation with the viral stock resulted in a selective bottleneck that reduced nonsynonymous genetic diversity in the viral hemagglutinin and nucleoprotein, and (iii) intrahost viral evolution continued over the course of infection. These intrahost evolutionary dynamics were dominated by purifying selection. Our findings indicate that rapid viral evolution can occur during acute influenza infection in otherwise healthy human hosts when the founding population size of the virus is large, as is the case with direct intranasal inoculation. IMPORTANCE: Influenza viruses circulating among humans are known to rapidly evolve over time. However, little is known about how influenza virus evolves across single transmission events and over the course of a single infection. To address these issues, we analyze influenza virus sequences from a human challenge experiment that initiated infection with a cell- and egg-passaged viral stock, which appeared to have adapted during its preparation. We find that the subjects' viral populations differ genetically from the viral stock, with subjects' viral populations having lower representation of the amino-acid-changing variants that arose during viral preparation. We also find that most of the viral evolution occurring over single infections is characterized by further decreases in the frequencies of these amino-acid-changing variants and that only limited intrahost genetic diversification through new mutations is apparent. Our findings indicate that influenza virus populations can undergo rapid genetic changes during acute human infections.

Authors
Sobel Leonard, A; McClain, MT; Smith, GJD; Wentworth, DE; Halpin, RA; Lin, X; Ransier, A; Stockwell, TB; Das, SR; Gilbert, AS; Lambkin-Williams, R; Ginsburg, GS; Woods, CW; Koelle, K
MLA Citation
Sobel Leonard, Ashley, et al. “Deep Sequencing of Influenza A Virus from a Human Challenge Study Reveals a Selective Bottleneck and Only Limited Intrahost Genetic Diversification..” J Virol, vol. 90, no. 24, Dec. 2016, pp. 11247–58. Pubmed, doi:10.1128/JVI.01657-16.
PMID
27707932
Source
pubmed
Published In
J Virol
Volume
90
Issue
24
Publish Date
2016
Start Page
11247
End Page
11258
DOI
10.1128/JVI.01657-16

Local and Global Challenges in the Clinical Implementation of Precision Medicine

© 2017 Elsevier Inc. All rights reserved. Advances in high-throughput genomic technologies and the growing number of clinically useful results have driven novel implementation programs in many nations around the globe. These efforts capitalize on unique local capabilities arising from the structure of their health care systems, their cultural or political milieu, as well as from their unusual burdens of disease or risk alleles. Four significant challenges stand in the way of widespread use of genomic and precision medicine (GPM): evidence generation, implementation into clinical care, data ownership, sharing, and infrastructure, and participant engagement and trust. Opportunities for collaboration in GPM abound in these areas as well as in health information technology, workforce development, pharmacogenomics, variant interpretation, and policy and regulation. Efforts to coalesce the global community to generate and assess evidence of the impact of genomic medicine, and to disseminate best practices for effective implementation, will enhance the use of genomics to improve clinical care worldwide.

Authors
Ward, R; Ginsburg, GS
MLA Citation
Ward, R., and G. S. Ginsburg. “Local and Global Challenges in the Clinical Implementation of Precision Medicine.” Genomic and Precision Medicine: Foundations, Translation, and Implementation: Third Edition, 2016, pp. 105–17. Scopus, doi:10.1016/B978-0-12-800681-8.00007-4.
Source
scopus
Publish Date
2016
Start Page
105
End Page
117
DOI
10.1016/B978-0-12-800681-8.00007-4

Genomic and Precision Medicine: Foundations, Translation, and Implementation: Third Edition

© 2017 Elsevier Inc. All rights reserved. Genomic and Precision Medicine: Translation and Implementation highlights the various points along the continuum from health to disease where genomic information is impacting clinical decision-making and leading to more personalization of health care. The book pinpoints the challenges, barriers, and solutions that have been, or are being, brought forward to enable translation of genome based technologies into health care. A variety of infrastructure (data systems and EMRs), policy (regulatory, reimbursement, privacy), and research (comparative effectiveness research, learning health system approaches) strategies are also discussed. Readers will find this volume to be an invaluable resource for the translational genomics and implementation science that is required to fully realize personalized health care. Provides a comprehensive volume on the translation and implementation of biology into health care provision Presents succinct commentary and key learning points that will assist readers with their local needs for translation and implementation Includes an up-to-date overview on major 'translational events' in genomic and personalized medicine, along with lessons learned.

Authors
Ginsburg, GS; Willard, HF
MLA Citation
Ginsburg, G. S., and H. F. Willard. Genomic and Precision Medicine: Foundations, Translation, and Implementation: Third Edition. 2016, pp. 1–381.
Source
scopus
Publish Date
2016
Start Page
1
End Page
381

First Identification and Description of Rickettsioses and Q Fever as Causes of Acute Febrile Illness in Nicaragua.

BACKGROUND: Rickettsial infections and Q fever present similarly to other acute febrile illnesses, but are infrequently diagnosed because of limited diagnostic tools. Despite sporadic reports, rickettsial infections and Q fever have not been prospectively studied in Central America. METHODOLOGY/PRINCIPAL FINDINGS: We enrolled consecutive patients presenting with undifferentiated fever in western Nicaragua and collected epidemiologic and clinical data and acute and convalescent sera. We used ELISA for screening and paired sera to confirm acute (≥4-fold rise in titer) spotted fever and typhus group rickettsial infections and Q fever as well as past (stable titer) infections. Characteristics associated with both acute and past infection were assessed. CONCLUSIONS/SIGNIFICANCE: We enrolled 825 patients and identified acute rickettsial infections and acute Q fever in 0.9% and 1.3%, respectively. Clinical features were non-specific and neither rickettsial infections nor Q fever were considered or treated. Further study is warranted to define the burden of these infections in Central America.

Authors
Reller, ME; Chikeka, I; Miles, JJ; Dumler, JS; Woods, CW; Mayorga, O; Matute, AJ
MLA Citation
Reller, Megan E., et al. “First Identification and Description of Rickettsioses and Q Fever as Causes of Acute Febrile Illness in Nicaragua..” Plos Negl Trop Dis, vol. 10, no. 12, Dec. 2016. Pubmed, doi:10.1371/journal.pntd.0005185.
PMID
28036394
Source
pubmed
Published In
Plos Neglected Tropical Diseases
Volume
10
Issue
12
Publish Date
2016
Start Page
e0005185
DOI
10.1371/journal.pntd.0005185

Philanthropy for Science: Is It a Viable Option?

Authors
Ohman, EM; Douglas, PS; Dean, LB; Ginsburg, GS
MLA Citation
Ohman, E. Magnus, et al. “Philanthropy for Science: Is It a Viable Option?.” Circ Res, vol. 119, no. 10, Oct. 2016, pp. 1057–59. Pubmed, doi:10.1161/CIRCRESAHA.116.309657.
PMID
27789583
Source
pubmed
Published In
Circulation Research
Volume
119
Issue
10
Publish Date
2016
Start Page
1057
End Page
1059
DOI
10.1161/CIRCRESAHA.116.309657

Realizing the Full Potential of Precision Medicine in Health and Health Care.

Authors
Dzau, VJ; Ginsburg, GS
MLA Citation
Dzau, Victor J., and Geoffrey S. Ginsburg. “Realizing the Full Potential of Precision Medicine in Health and Health Care..” Jama, vol. 316, no. 16, Oct. 2016, pp. 1659–60. Pubmed, doi:10.1001/jama.2016.14117.
PMID
27669484
Source
pubmed
Published In
Jama
Volume
316
Issue
16
Publish Date
2016
Start Page
1659
End Page
1660
DOI
10.1001/jama.2016.14117

Clinical utility of a Web-enabled risk-assessment and clinical decision support program.

PURPOSE: Risk-stratified guidelines can improve quality of care and cost-effectiveness, but their uptake in primary care has been limited. MeTree, a Web-based, patient-facing risk-assessment and clinical decision support tool, is designed to facilitate uptake of risk-stratified guidelines. METHODS: A hybrid implementation-effectiveness trial of three clinics (two intervention, one control). PARTICIPANTS: consentable nonadopted adults with upcoming appointments. PRIMARY OUTCOME: agreement between patient risk level and risk management for those meeting evidence-based criteria for increased-risk risk-management strategies (increased risk) and those who do not (average risk) before MeTree and after. MEASURES: chart abstraction was used to identify risk management related to colon, breast, and ovarian cancer, hereditary cancer, and thrombosis. RESULTS: Participants = 488, female = 284 (58.2%), white = 411 (85.7%), mean age = 58.7 (SD = 12.3). Agreement between risk management and risk level for all conditions for each participant, except for colon cancer, which was limited to those <50 years of age, was (i) 1.1% (N = 2/174) for the increased-risk group before MeTree and 16.1% (N = 28/174) after and (ii) 99.2% (N = 2,125/2,142) for the average-risk group before MeTree and 99.5% (N = 2,131/2,142) after. Of those receiving increased-risk risk-management strategies at baseline, 10.5% (N = 2/19) met criteria for increased risk. After MeTree, 80.7% (N = 46/57) met criteria. CONCLUSION: MeTree integration into primary care can improve uptake of risk-stratified guidelines and potentially reduce "overuse" and "underuse" of increased-risk services.Genet Med 18 10, 1020-1028.

Authors
Orlando, LA; Wu, RR; Myers, RA; Buchanan, AH; Henrich, VC; Hauser, ER; Ginsburg, GS
MLA Citation
Orlando, Lori A., et al. “Clinical utility of a Web-enabled risk-assessment and clinical decision support program..” Genet Med, vol. 18, no. 10, Oct. 2016, pp. 1020–28. Pubmed, doi:10.1038/gim.2015.210.
Website
http://hdl.handle.net/10161/11787
PMID
26938783
Source
pubmed
Published In
Genet Med
Volume
18
Issue
10
Publish Date
2016
Start Page
1020
End Page
1028
DOI
10.1038/gim.2015.210

Patient experiences with pharmacogenetic testing in a primary care setting.

AIM: To investigate patient experiences with pharmacogenetic (PGx) testing. METHODS: Patients were offered PGx testing through a study on pharmacist-assisted delivery of PGx testing and invited to complete pre- and post-testing surveys about their experience. RESULTS: Of 63 patients tested, 17 completed the baseline survey (27%). Interest in testing was mostly impacted by desire to inform selection of best treatment (n = 13). Seven of 12 patients that completed the follow-up survey indicated that their provider discussed the test result with them. Five patients understood their test result very or somewhat well. All would be likely to have PGx testing again. CONCLUSION: Patients perceived PGx testing to be useful, though more effort may be needed to improve patient-provider communication of test results.

Authors
Haga, SB; Mills, R; Moaddeb, J; Allen Lapointe, N; Cho, A; Ginsburg, GS
MLA Citation
Haga, Susanne B., et al. “Patient experiences with pharmacogenetic testing in a primary care setting..” Pharmacogenomics, vol. 17, no. 15, Oct. 2016, pp. 1629–36. Pubmed, doi:10.2217/pgs-2016-0077.
PMID
27648637
Source
pubmed
Published In
Pharmacogenomics
Volume
17
Issue
15
Publish Date
2016
Start Page
1629
End Page
1636
DOI
10.2217/pgs-2016-0077

Emergence of Epidemic Dengue-1 Virus in the Southern Province of Sri Lanka.

BACKGROUND: Dengue is a frequent cause of acute febrile illness with an expanding global distribution. Since the 1960s, dengue in Sri Lanka has been documented primarily along the heavily urbanized western coast with periodic shifting of serotypes. Outbreaks from 2005-2008 were attributed to a new clade of DENV-3 and more recently to a newly introduced genotype of DENV-1. In 2007, we conducted etiologic surveillance of acute febrile illness in the Southern Province and confirmed dengue in only 6.3% of febrile patients, with no cases of DENV-1 identified. To re-evaluate the importance of dengue as an etiology of acute febrile illness in this region, we renewed fever surveillance in the Southern Province to newly identify and characterize dengue. METHODOLOGY/PRINCIPAL FINDINGS: A cross-sectional surveillance study was conducted at the largest tertiary care hospital in the Southern Province from 2012-2013. A total of 976 patients hospitalized with acute undifferentiated fever were enrolled, with 64.3% male and 31.4% children. Convalescent blood samples were collected from 877 (89.6%). Dengue virus isolation, dengue RT-PCR, and paired IgG ELISA were performed. Acute dengue was confirmed as the etiology for 388 (39.8%) of 976 hospitalizations, with most cases (291, 75.0%) confirmed virologically and by multiple methods. Among 351 cases of virologically confirmed dengue, 320 (91.2%) were due to DENV-1. Acute dengue was associated with self-reported rural residence, travel, and months having greatest rainfall. Sequencing of selected dengue viruses revealed that sequences were most closely related to those described from China and Southeast Asia, not nearby India. CONCLUSIONS/SIGNIFICANCE: We describe the first epidemic of DENV-1 in the Southern Province of Sri Lanka in a population known to be susceptible to this serotype because of prior study. Dengue accounted for 40% of acute febrile illnesses in the current study. The emergence of DENV-1 as the foremost serotype in this densely populated but agrarian population highlights the changing epidemiology of dengue and the need for continued surveillance and prevention.

Authors
Bodinayake, CK; Tillekeratne, LG; Nagahawatte, A; Devasiri, V; Kodikara Arachichi, W; Strouse, JJ; Sessions, OM; Kurukulasooriya, R; Uehara, A; Howe, S; Ong, XM; Tan, S; Chow, A; Tummalapalli, P; De Silva, AD; Østbye, T; Woods, CW; Gubler, DJ; Reller, ME
MLA Citation
Bodinayake, Champica K., et al. “Emergence of Epidemic Dengue-1 Virus in the Southern Province of Sri Lanka..” Plos Negl Trop Dis, vol. 10, no. 10, Oct. 2016. Pubmed, doi:10.1371/journal.pntd.0004995.
Website
http://hdl.handle.net/10161/13031
PMID
27711206
Source
pubmed
Published In
Plos Neglected Tropical Diseases
Volume
10
Issue
10
Publish Date
2016
Start Page
e0004995
DOI
10.1371/journal.pntd.0004995

Unsuspected Dengue as a Cause of Acute Febrile Illness in Children and Adults in Western Nicaragua.

BACKGROUND: Dengue is an emerging infectious disease of global significance. Suspected dengue, especially in children in Nicaragua's heavily-urbanized capital of Managua, has been well documented, but unsuspected dengue among children and adults with undifferentitated fever has not. METHODOLOGY/PRINCIPAL FINDINGS: To prospectively study dengue in semi-urban and rural western Nicaragua, we obtained epidemiologic and clinical data as well as acute and convalescent sera (2 to 4 weeks after onset of illness) from a convenience sample (enrollment Monday to Saturday daytime to early evening) of consecutively enrolled patients (n = 740) aged ≥ 1 years presenting with acute febrile illness. We tested paired sera for dengue IgG and IgM and serotyped dengue virus using reverse transcriptase-PCR. Among 740 febrile patients enrolled, 90% had paired sera. We found 470 (63.5%) were seropositive for dengue at enrollment. The dengue seroprevalance increased with age and reached >90% in people over the age of 20 years. We identified acute dengue (serotypes 1 and 2) in 38 (5.1%) patients. Only 8.1% (3/37) of confirmed cases were suspected clinically. CONCLUSIONS/SIGNIFICANCE: Dengue is an important and largely unrecognized cause of fever in rural western Nicaragua. Since Zika virus is transmitted by the same vector and has been associated with severe congenital infections, the population we studied is at particular risk for being devastated by the Zika epidemic that has now reached Central America.

Authors
Reller, ME; de Silva, AM; Miles, JJ; Jadi, RS; Broadwater, A; Walker, K; Woods, C; Mayorga, O; Matute, A
MLA Citation
Reller, Megan E., et al. “Unsuspected Dengue as a Cause of Acute Febrile Illness in Children and Adults in Western Nicaragua..” Plos Negl Trop Dis, vol. 10, no. 10, Oct. 2016. Pubmed, doi:10.1371/journal.pntd.0005026.
PMID
27792777
Source
pubmed
Published In
Plos Neglected Tropical Diseases
Volume
10
Issue
10
Publish Date
2016
Start Page
e0005026
DOI
10.1371/journal.pntd.0005026

Response.

Authors
Berry, SM; Petzold, EA; Dull, P; Thielman, NM; Cunningham, CK; McClain, MT; Hoover, DL; Russell, J; Griffiss, JM; Woods, CW
MLA Citation
Berry, Scott M., et al. “Response..” Clin Trials, vol. 13, no. 5, Oct. 2016, pp. 568–69. Pubmed, doi:10.1177/1740774516654446.
Website
http://hdl.handle.net/10161/6331
PMID
27365016
Source
pubmed
Published In
Clin Trials
Volume
13
Issue
5
Publish Date
2016
Start Page
568
End Page
569
DOI
10.1177/1740774516654446

Systems Pharmacogenomics Finds RUNX1 Is an Aspirin-Responsive Transcription Factor Linked to Cardiovascular Disease and Colon Cancer.

Aspirin prevents cardiovascular disease and colon cancer; however aspirin's inhibition of platelet COX-1 only partially explains its diverse effects. We previously identified an aspirin response signature (ARS) in blood consisting of 62 co-expressed transcripts that correlated with aspirin's effects on platelets and myocardial infarction (MI). Here we report that 60% of ARS transcripts are regulated by RUNX1 - a hematopoietic transcription factor - and 48% of ARS gene promoters contain a RUNX1 binding site. Megakaryocytic cells exposed to aspirin and its metabolite (salicylic acid, a weak COX-1 inhibitor) showed up regulation in the RUNX1 P1 isoform and MYL9, which is transcriptionally regulated by RUNX1. In human subjects, RUNX1 P1 expression in blood and RUNX1-regulated platelet proteins, including MYL9, were aspirin-responsive and associated with platelet function. In cardiovascular disease patients RUNX1 P1 expression was associated with death or MI. RUNX1 acts as a tumor suppressor gene in gastrointestinal malignancies. We show that RUNX1 P1 expression is associated with colon cancer free survival suggesting a role for RUNX1 in aspirin's protective effect in colon cancer. Our studies reveal an effect of aspirin on RUNX1 and gene expression that may additionally explain aspirin's effects in cardiovascular disease and cancer.

Authors
Voora, D; Rao, AK; Jalagadugula, GS; Myers, R; Harris, E; Ortel, TL; Ginsburg, GS
MLA Citation
Voora, Deepak, et al. “Systems Pharmacogenomics Finds RUNX1 Is an Aspirin-Responsive Transcription Factor Linked to Cardiovascular Disease and Colon Cancer..” Ebiomedicine, vol. 11, Sept. 2016, pp. 157–64. Pubmed, doi:10.1016/j.ebiom.2016.08.021.
PMID
27566955
Source
pubmed
Published In
Ebiomedicine
Volume
11
Publish Date
2016
Start Page
157
End Page
164
DOI
10.1016/j.ebiom.2016.08.021

Extended-spectrum ß-Lactamase-producing Enterobacteriaceae as a Common Cause of Urinary Tract Infections in Sri Lanka.

BACKGROUND: Extended-spectrum ß-lactamase-producing Enterobacteriaceae (ESBL-PE) are increasingly reported as pathogens in urinary tract infections (UTIs). However, in Sri Lanka, the clinical and molecular epidemiology of ESBL-PE implicated in UTIs has not been well described. MATERIALS AND METHODS: We conducted prospective, laboratory-based surveillance from October to December 2013 at a tertiary care hospital in southern Sri Lanka and enrolled patients ≥1 year of age with clinically relevant UTIs due to ESBL-PE. Isolate identity, antimicrobial drug susceptibility, and ESBL production were determined. Presence of ß-lactamase genes, bla(SHV), bla(TEM), and bla(CTX-M), was identified by polymerase chain reaction. RESULTS: During the study period, Enterobacteriaceae were detected in 184 urine samples, with 74 (40.2%) being ESBL producers. Among 47 patients with ESBL-PE who had medical records available, 38 (80.9%) had clinically significant UTIs. Most UTIs (63.2%) were community acquired and 34.2% were in patients with diabetes. Among 36 cultured ESBL-PE isolates, significant susceptibility (>80%) was only retained to amikacin and the carbapenems. The group 1 bla(CTX-M) gene was present in 90.0% of Escherichia coli isolates and all Klebsiella pneumoniae and Enterobacter cloacae isolates. The bla(SHV) and bla(TEM) genes were more common in K. pneumoniae (75% and 50%) and E. cloacae (50% and 50%) isolates than in E. coli (10% and 20%) isolates, respectively. CONCLUSION: The majority of UTIs caused by ESBL-PE were acquired in the community and due to organisms carrying the group 1 CTX-M ß-lactamase. Further epidemiologic studies of infections due to ESBL-PE are urgently needed to better prevent and treat these infections in South Asia.

Authors
Tillekeratne, LG; Vidanagama, D; Tippalagama, R; Lewkebandara, R; Joyce, M; Nicholson, BP; Nagahawatte, A; Bodinayake, CK; De Silva, AD; Woods, CW
MLA Citation
Tillekeratne, L. Gayani, et al. “Extended-spectrum ß-Lactamase-producing Enterobacteriaceae as a Common Cause of Urinary Tract Infections in Sri Lanka..” Infect Chemother, vol. 48, no. 3, Sept. 2016, pp. 160–65. Pubmed, doi:10.3947/ic.2016.48.3.160.
PMID
27704730
Source
pubmed
Published In
Infection & Chemotherapy
Volume
48
Issue
3
Publish Date
2016
Start Page
160
End Page
165
DOI
10.3947/ic.2016.48.3.160

Patterns of Healthcare Utilization Among Veterans Infected With Hepatitis C Virus (HCV) and Human Immunodeficiency Virus (HIV) and Coinfected With HIV/HCV: Unique Burdens of Disease.

Background.  Hepatitis C virus (HCV) infection is a leading cause of cirrhosis and the primary cause of liver transplantation in the United States, and coinfection with human immunodeficiency virus (HIV) increases the risk of comorbidities. However, healthcare utilization (HCU) patterns among HIV/HCV-coinfected patients are poorly understood. This study compared the rates of HCU and reasons for hospital admission among HCV-infected, HIV-infected, and HIV/HCV-coinfected veterans. Methods.  Hepatitis C virus- and HIV-infected and HIV/HCV-coinfected veterans in care with the Department of Veterans Affairs (VA) from 1998 to 2009 (n = 335 371, n = 28 179, n = 13 471, respectively) were identified by HIV- and HCV-associated International Classification of Diseases, Ninth Revision codes from the clinical case registry. We assessed rates of HCU using emergency department (ED) visits, outpatient visits, and hospitalization and primary diagnoses associated with hospitalization. Independent risk factors associated with hospitalization were also examined. Results.  Rates of outpatient and ED visits increased over the 11-year study period for all groups, with inpatient admission rates remaining stable. The HCU rates were consistently higher for the coinfected than other cohorts. The primary reason for hospital admission for all groups was psychiatric disease/substance use, accounting for 44% of all admissions. Nadir CD4 <350 cells/mm3 was associated with higher rates of hospitalization versus nadir CD4 >500 cells/mm3. Conclusions.  As the current population of HCV-infected, HIV-infected, and HIV/HCV-coinfected veterans age, they will continue to place a substantial and increasing demand on the US healthcare system, particularly in their utilization of ED and outpatient services. These data suggest the need for an ongoing investment in mental health and primary care within the VA healthcare system.

Authors
Katrak, S; Park, LP; Woods, C; Muir, A; Hicks, C; Naggie, S
MLA Citation
Katrak, Shereen, et al. “Patterns of Healthcare Utilization Among Veterans Infected With Hepatitis C Virus (HCV) and Human Immunodeficiency Virus (HIV) and Coinfected With HIV/HCV: Unique Burdens of Disease..” Open Forum Infect Dis, vol. 3, no. 3, Sept. 2016. Pubmed, doi:10.1093/ofid/ofw173.
PMID
27704025
Source
pubmed
Published In
Open Forum Infectious Diseases
Volume
3
Issue
3
Publish Date
2016
Start Page
ofw173
DOI
10.1093/ofid/ofw173

Clinical implementation of genomic medicine: the importance of global collaboration

Authors
Manolio, TA; Ward, R; Ginsburg, GS
MLA Citation
Manolio, T. A., et al. “Clinical implementation of genomic medicine: the importance of global collaboration.” Expert Review of Precision Medicine and Drug Development, vol. 1, no. 4, July 2016, pp. 349–51. Scopus, doi:10.1080/23808993.2016.1192460.
Source
scopus
Published In
Expert Review of Precision Medicine and Drug Development
Volume
1
Issue
4
Publish Date
2016
Start Page
349
End Page
351
DOI
10.1080/23808993.2016.1192460

Use of Peptide-Based Enzyme-Linked Immunosorbent Assay followed by Immunofluorescence Assay To Document Ehrlichia chaffeensis as a Cause of Febrile Illness in Nicaragua.

Ehrlichia chaffeensis, the etiologic agent of human monocytic ehrlichiosis (HME), has been extensively studied as a cause of acute febrile illness and an emerging tick-borne zoonosis in the United States. Limited data suggest its presence in other regions, including Central and South America but not Nicaragua to date. Diagnosis of E. chaffeensis infection by indirect immunofluorescence assay (IFA) is the reference standard due to its presumed high sensitivity and specificity, but IFA is impractical, variably reproducible, and cumbersome for large epidemiologic studies and for clinical diagnosis in resource-poor regions. We evaluated a high-throughput, objective peptide-based enzyme-linked immunosorbent assay (ELISA) for use alone or in combination with IFA. We found that it performed best as a screening test (sensitivity, 100%; specificity, 84%) to reduce the proportion of serum samples that were required by the more cumbersome and subjective IFA testing to <20%. Using a two-step diagnostic approach (IFA is performed if the ELISA is positive), we identified E. chaffeensis or a serologically and antigenically similar organism as a heretofore unrecognized cause of acute febrile illness in humans in Nicaragua and demonstrated the utility of the peptide ELISA as a screening tool for large-scale clinical studies.

Authors
Chikeka, I; Matute, AJ; Dumler, JS; Woods, CW; Mayorga, O; Reller, ME
MLA Citation
Chikeka, Ijeuru, et al. “Use of Peptide-Based Enzyme-Linked Immunosorbent Assay followed by Immunofluorescence Assay To Document Ehrlichia chaffeensis as a Cause of Febrile Illness in Nicaragua..” J Clin Microbiol, vol. 54, no. 6, June 2016, pp. 1581–85. Pubmed, doi:10.1128/JCM.03331-15.
PMID
27053675
Source
pubmed
Published In
J Clin Microbiol
Volume
54
Issue
6
Publish Date
2016
Start Page
1581
End Page
1585
DOI
10.1128/JCM.03331-15

Transcriptomic Analysis of the Host Response and Innate Resilience to Enterotoxigenic Escherichia coli Infection in Humans.

BACKGROUND: Enterotoxigenic Escherichia coli (ETEC) is a globally prevalent cause of diarrhea. Though usually self-limited, it can be severe and debilitating. Little is known about the host transcriptional response to infection. We report the first gene expression analysis of the human host response to experimental challenge with ETEC. METHODS: We challenged 30 healthy adults with an unattenuated ETEC strain, and collected serial blood samples shortly after inoculation and daily for 8 days. We performed gene expression analysis on whole peripheral blood RNA samples from subjects in whom severe symptoms developed (n = 6) and a subset of those who remained asymptomatic (n = 6) despite shedding. RESULTS: Compared with baseline, symptomatic subjects demonstrated significantly different expression of 406 genes highlighting increased immune response and decreased protein synthesis. Compared with asymptomatic subjects, symptomatic subjects differentially expressed 254 genes primarily associated with immune response. This comparison also revealed 29 genes differentially expressed between groups at baseline, suggesting innate resilience to infection. Drug repositioning analysis identified several drug classes with potential utility in augmenting immune response or mitigating symptoms. CONCLUSIONS: There are statistically significant and biologically plausible differences in host gene expression induced by ETEC infection. Differential baseline expression of some genes may indicate resilience to infection.

Authors
Yang, WE; Suchindran, S; Nicholson, BP; McClain, MT; Burke, T; Ginsburg, GS; Harro, CD; Chakraborty, S; Sack, DA; Woods, CW; Tsalik, EL
MLA Citation
Yang, William E., et al. “Transcriptomic Analysis of the Host Response and Innate Resilience to Enterotoxigenic Escherichia coli Infection in Humans..” J Infect Dis, vol. 213, no. 9, May 2016, pp. 1495–504. Pubmed, doi:10.1093/infdis/jiv593.
Website
http://hdl.handle.net/10161/12537
PMID
26787651
Source
pubmed
Published In
J Infect Dis
Volume
213
Issue
9
Publish Date
2016
Start Page
1495
End Page
1504
DOI
10.1093/infdis/jiv593

Genomics, clinical research, and learning health care systems: Strategies to improve patient care.

Authors
Williams, JK; Cashion, AK; Shekar, S; Ginsburg, GS
MLA Citation
Williams, Janet K., et al. “Genomics, clinical research, and learning health care systems: Strategies to improve patient care..” Nurs Outlook, vol. 64, no. 3, May 2016, pp. 225–28. Pubmed, doi:10.1016/j.outlook.2015.12.006.
PMID
26821732
Source
pubmed
Published In
Nurs Outlook
Volume
64
Issue
3
Publish Date
2016
Start Page
225
End Page
228
DOI
10.1016/j.outlook.2015.12.006

Developing Biomarker Arrays Predicting Sleep and Circadian-Coupled Risks to Health.

Authors
Mullington, JM; Abbott, SM; Carroll, JE; Davis, CJ; Dijk, D-J; Dinges, DF; Gehrman, PR; Ginsburg, GS; Gozal, D; Haack, M; Lim, DC; Macrea, M; Pack, AI; Plante, DT; Teske, JA; Zee, PC
MLA Citation
Mullington, Janet M., et al. “Developing Biomarker Arrays Predicting Sleep and Circadian-Coupled Risks to Health..” Sleep, vol. 39, no. 4, Apr. 2016, pp. 727–36. Pubmed, doi:10.5665/sleep.5616.
PMID
26951388
Source
pubmed
Published In
Sleep
Volume
39
Issue
4
Publish Date
2016
Start Page
727
End Page
736
DOI
10.5665/sleep.5616

Differential evolution of peripheral cytokine levels in symptomatic and asymptomatic responses to experimental influenza virus challenge.

Exposure to influenza virus triggers a complex cascade of events in the human host. In order to understand more clearly the evolution of this intricate response over time, human volunteers were inoculated with influenza A/Wisconsin/67/2005 (H3N2), and then had serial peripheral blood samples drawn and tested for the presence of 25 major human cytokines. Nine of 17 (53%) inoculated subjects developed symptomatic influenza infection. Individuals who will go on to become symptomatic demonstrate increased circulating levels of interleukin (IL)-6, IL-8, IL-15, monocyte chemotactic protein (MCP)-1 and interferon (IFN) gamma-induced protein (IP)-10 as early as 12-29 h post-inoculation (during the presymptomatic phase), whereas challenged patients who remain asymptomatic do not. Overall, the immunological pathways of leucocyte recruitment, Toll-like receptor (TLR)-signalling, innate anti-viral immunity and fever production are all over-represented in symptomatic individuals very early in disease, but are also dynamic and evolve continuously over time. Comparison with simultaneous peripheral blood genomics demonstrates that some inflammatory mediators (MCP-1, IP-10, IL-15) are being expressed actively in circulating cells, while others (IL-6, IL-8, IFN-α and IFN-γ) are probable effectors produced locally at the site of infection. Interestingly, asymptomatic exposed subjects are not quiescent either immunologically or genomically, but instead exhibit early and persistent down-regulation of important inflammatory mediators in the periphery. The host inflammatory response to influenza infection is variable but robust, and evolves over time. These results offer critical insight into pathways driving influenza-related symptomatology and offer the potential to contribute to early detection and differentiation of infected hosts.

Authors
McClain, MT; Henao, R; Williams, J; Nicholson, B; Veldman, T; Hudson, L; Tsalik, EL; Lambkin-Williams, R; Gilbert, A; Mann, A; Ginsburg, GS; Woods, CW
MLA Citation
McClain, M. T., et al. “Differential evolution of peripheral cytokine levels in symptomatic and asymptomatic responses to experimental influenza virus challenge..” Clin Exp Immunol, vol. 183, no. 3, Mar. 2016, pp. 441–51. Pubmed, doi:10.1111/cei.12736.
PMID
26506932
Source
pubmed
Published In
Clin Exp Immunol
Volume
183
Issue
3
Publish Date
2016
Start Page
441
End Page
451
DOI
10.1111/cei.12736

Potential Cost-effectiveness of Early Identification of Hospital-acquired Infection in Critically Ill Patients.

RATIONALE: Limitations in methods for the rapid diagnosis of hospital-acquired infections often delay initiation of effective antimicrobial therapy. New diagnostic approaches offer potential clinical and cost-related improvements in the management of these infections. OBJECTIVES: We developed a decision modeling framework to assess the potential cost-effectiveness of a rapid biomarker assay to identify hospital-acquired infection in high-risk patients earlier than standard diagnostic testing. METHODS: The framework includes parameters representing rates of infection, rates of delayed appropriate therapy, and impact of delayed therapy on mortality, along with assumptions about diagnostic test characteristics and their impact on delayed therapy and length of stay. Parameter estimates were based on contemporary, published studies and supplemented with data from a four-site, observational, clinical study. Extensive sensitivity analyses were performed. The base-case analysis assumed 17.6% of ventilated patients and 11.2% of nonventilated patients develop hospital-acquired infection and that 28.7% of patients with hospital-acquired infection experience delays in appropriate antibiotic therapy with standard care. We assumed this percentage decreased by 50% (to 14.4%) among patients with true-positive results and increased by 50% (to 43.1%) among patients with false-negative results using a hypothetical biomarker assay. Cost of testing was set at $110/d. MEASUREMENTS AND MAIN RESULTS: In the base-case analysis, among ventilated patients, daily diagnostic testing starting on admission reduced inpatient mortality from 12.3 to 11.9% and increased mean costs by $1,640 per patient, resulting in an incremental cost-effectiveness ratio of $21,389 per life-year saved. Among nonventilated patients, inpatient mortality decreased from 7.3 to 7.1% and costs increased by $1,381 with diagnostic testing. The resulting incremental cost-effectiveness ratio was $42,325 per life-year saved. Threshold analyses revealed the probabilities of developing hospital-acquired infection in ventilated and nonventilated patients could be as low as 8.4 and 9.8%, respectively, to maintain incremental cost-effectiveness ratios less than $50,000 per life-year saved. CONCLUSIONS: Development and use of serial diagnostic testing that reduces the proportion of patients with delays in appropriate antibiotic therapy for hospital-acquired infections could reduce inpatient mortality. The model presented here offers a cost-effectiveness framework for future test development.

Authors
Tsalik, EL; Li, Y; Hudson, LL; Chu, VH; Himmel, T; Limkakeng, AT; Katz, JN; Glickman, SW; McClain, MT; Welty-Wolf, KE; Fowler, VG; Ginsburg, GS; Woods, CW; Reed, SD
MLA Citation
Tsalik, Ephraim L., et al. “Potential Cost-effectiveness of Early Identification of Hospital-acquired Infection in Critically Ill Patients..” Ann Am Thorac Soc, vol. 13, no. 3, Mar. 2016, pp. 401–13. Pubmed, doi:10.1513/AnnalsATS.201504-205OC.
Website
http://hdl.handle.net/10161/12538
PMID
26700878
Source
pubmed
Published In
Annals of the American Thoracic Society
Volume
13
Issue
3
Publish Date
2016
Start Page
401
End Page
413
DOI
10.1513/AnnalsATS.201504-205OC

Ebola clinical trials: Five lessons learned and a way forward.

Authors
Thielman, NM; Cunningham, CK; Woods, C; Petzold, E; Sprenz, M; Russell, J
MLA Citation
Thielman, Nathan M., et al. “Ebola clinical trials: Five lessons learned and a way forward..” Clin Trials, vol. 13, no. 1, Feb. 2016, pp. 83–86. Pubmed, doi:10.1177/1740774515619897.
PMID
26768559
Source
pubmed
Published In
Clin Trials
Volume
13
Issue
1
Publish Date
2016
Start Page
83
End Page
86
DOI
10.1177/1740774515619897

An individualized predictor of health and disease using paired reference and target samples.

BACKGROUND: Consider the problem of designing a panel of complex biomarkers to predict a patient's health or disease state when one can pair his or her current test sample, called a target sample, with the patient's previously acquired healthy sample, called a reference sample. As contrasted to a population averaged reference this reference sample is individualized. Automated predictor algorithms that compare and contrast the paired samples to each other could result in a new generation of test panels that compare to a person's healthy reference to enhance predictive accuracy. This paper develops such an individualized predictor and illustrates the added value of including the healthy reference for design of predictive gene expression panels. RESULTS: The objective is to predict each subject's state of infection, e.g., neither exposed nor infected, exposed but not infected, pre-acute phase of infection, acute phase of infection, post-acute phase of infection. Using gene microarray data collected in a large scale serially sampled respiratory virus challenge study we quantify the diagnostic advantage of pairing a person's baseline reference with his or her target sample. The full study consists of 2886 microarray chips assaying 12,023 genes of 151 human volunteer subjects under 4 different inoculation regimes (HRV, RSV, H1N1, H3N2). We train (with cross-validation) reference-aided sparse multi-class classifier algorithms on this data to show that inclusion of a subject's reference sample can improve prediction accuracy by as much as 14 %, for the H3N2 cohort, and by at least 6 %, for the H1N1 cohort. Remarkably, these gains in accuracy are achieved by using smaller panels of genes, e.g., 39 % fewer for H3N2 and 31 % fewer for H1N1. The biomarkers selected by the predictors fall into two categories: 1) contrasting genes that tend to differentially express between target and reference samples over the population; 2) reinforcement genes that remain constant over the two samples, which function as housekeeping normalization genes. Many of these genes are common to all 4 viruses and their roles in the predictor elucidate the function that they play in differentiating the different states of host immune response. CONCLUSIONS: If one uses a suitable mathematical prediction algorithm, inclusion of a healthy reference in biomarker diagnostic testing can potentially improve accuracy of disease prediction with fewer biomarkers.

Authors
Liu, T-Y; Burke, T; Park, LP; Woods, CW; Zaas, AK; Ginsburg, GS; Hero, AO
MLA Citation
Liu, Tzu-Yu, et al. “An individualized predictor of health and disease using paired reference and target samples..” Bmc Bioinformatics, vol. 17, Jan. 2016. Pubmed, doi:10.1186/s12859-016-0889-9.
PMID
26801061
Source
pubmed
Published In
Bmc Bioinformatics
Volume
17
Publish Date
2016
Start Page
47
DOI
10.1186/s12859-016-0889-9

Host gene expression classifiers diagnose acute respiratory illness etiology.

Acute respiratory infections caused by bacterial or viral pathogens are among the most common reasons for seeking medical care. Despite improvements in pathogen-based diagnostics, most patients receive inappropriate antibiotics. Host response biomarkers offer an alternative diagnostic approach to direct antimicrobial use. This observational cohort study determined whether host gene expression patterns discriminate noninfectious from infectious illness and bacterial from viral causes of acute respiratory infection in the acute care setting. Peripheral whole blood gene expression from 273 subjects with community-onset acute respiratory infection (ARI) or noninfectious illness, as well as 44 healthy controls, was measured using microarrays. Sparse logistic regression was used to develop classifiers for bacterial ARI (71 probes), viral ARI (33 probes), or a noninfectious cause of illness (26 probes). Overall accuracy was 87% (238 of 273 concordant with clinical adjudication), which was more accurate than procalcitonin (78%, P < 0.03) and three published classifiers of bacterial versus viral infection (78 to 83%). The classifiers developed here externally validated in five publicly available data sets (AUC, 0.90 to 0.99). A sixth publicly available data set included 25 patients with co-identification of bacterial and viral pathogens. Applying the ARI classifiers defined four distinct groups: a host response to bacterial ARI, viral ARI, coinfection, and neither a bacterial nor a viral response. These findings create an opportunity to develop and use host gene expression classifiers as diagnostic platforms to combat inappropriate antibiotic use and emerging antibiotic resistance.

Authors
Tsalik, EL; Henao, R; Nichols, M; Burke, T; Ko, ER; McClain, MT; Hudson, LL; Mazur, A; Freeman, DH; Veldman, T; Langley, RJ; Quackenbush, EB; Glickman, SW; Cairns, CB; Jaehne, AK; Rivers, EP; Otero, RM; Zaas, AK; Kingsmore, SF; Lucas, J; Fowler, VG; Carin, L; Ginsburg, GS; Woods, CW
MLA Citation
Tsalik, Ephraim L., et al. “Host gene expression classifiers diagnose acute respiratory illness etiology..” Sci Transl Med, vol. 8, no. 322, Jan. 2016. Pubmed, doi:10.1126/scitranslmed.aad6873.
Website
http://hdl.handle.net/10161/12536
PMID
26791949
Source
pubmed
Published In
Sci Transl Med
Volume
8
Issue
322
Publish Date
2016
Start Page
322ra11
DOI
10.1126/scitranslmed.aad6873

Opportunities for the Cardiovascular Community in the Precision Medicine Initiative.

The Precision Medicine Initiative recently announced by President Barack Obama seeks to move the field of precision medicine more rapidly into clinical care. Precision medicine revolves around the concept of integrating individual-level data including genomics, biomarkers, lifestyle and other environmental factors, wearable device physiological data, and information from electronic health records to ultimately provide better clinical care to individual patients. The Precision Medicine Initiative as currently structured will primarily fund efforts in cancer genomics with longer-term goals of advancing precision medicine to all areas of health, and will be supported through creation of a 1 million person cohort study across the United States. This focused effort on precision medicine provides scientists, clinicians, and patients within the cardiovascular community an opportunity to work together boldly to advance clinical care; the community needs to be aware and engaged in the process as it progresses. This article provides a framework for potential involvement of the cardiovascular community in the Precision Medicine Initiative, while highlighting significant challenges for its successful implementation.

Authors
Shah, SH; Arnett, D; Houser, SR; Ginsburg, GS; MacRae, C; Mital, S; Loscalzo, J; Hall, JL
MLA Citation
Shah, Svati H., et al. “Opportunities for the Cardiovascular Community in the Precision Medicine Initiative..” Circulation, vol. 133, no. 2, Jan. 2016, pp. 226–31. Pubmed, doi:10.1161/CIRCULATIONAHA.115.019475.
PMID
27028435
Source
pubmed
Published In
Circulation
Volume
133
Issue
2
Publish Date
2016
Start Page
226
End Page
231
DOI
10.1161/CIRCULATIONAHA.115.019475

The IGNITE network: a model for genomic medicine implementation and research.

BACKGROUND: Patients, clinicians, researchers and payers are seeking to understand the value of using genomic information (as reflected by genotyping, sequencing, family history or other data) to inform clinical decision-making. However, challenges exist to widespread clinical implementation of genomic medicine, a prerequisite for developing evidence of its real-world utility. METHODS: To address these challenges, the National Institutes of Health-funded IGNITE (Implementing GeNomics In pracTicE; www.ignite-genomics.org ) Network, comprised of six projects and a coordinating center, was established in 2013 to support the development, investigation and dissemination of genomic medicine practice models that seamlessly integrate genomic data into the electronic health record and that deploy tools for point of care decision making. IGNITE site projects are aligned in their purpose of testing these models, but individual projects vary in scope and design, including exploring genetic markers for disease risk prediction and prevention, developing tools for using family history data, incorporating pharmacogenomic data into clinical care, refining disease diagnosis using sequence-based mutation discovery, and creating novel educational approaches. RESULTS: This paper describes the IGNITE Network and member projects, including network structure, collaborative initiatives, clinical decision support strategies, methods for return of genomic test results, and educational initiatives for patients and providers. Clinical and outcomes data from individual sites and network-wide projects are anticipated to begin being published over the next few years. CONCLUSIONS: The IGNITE Network is an innovative series of projects and pilot demonstrations aiming to enhance translation of validated actionable genomic information into clinical settings and develop and use measures of outcome in response to genome-based clinical interventions using a pragmatic framework to provide early data and proofs of concept on the utility of these interventions. Through these efforts and collaboration with other stakeholders, IGNITE is poised to have a significant impact on the acceleration of genomic information into medical practice.

Authors
Weitzel, KW; Alexander, M; Bernhardt, BA; Calman, N; Carey, DJ; Cavallari, LH; Field, JR; Hauser, D; Junkins, HA; Levin, PA; Levy, K; Madden, EB; Manolio, TA; Odgis, J; Orlando, LA; Pyeritz, R; Wu, RR; Shuldiner, AR; Bottinger, EP; Denny, JC; Dexter, PR; Flockhart, DA; Horowitz, CR; Johnson, JA; Kimmel, SE; Levy, MA; Pollin, TI; Ginsburg, GS; IGNITE Network,
MLA Citation
Weitzel, Kristin Wiisanen, et al. “The IGNITE network: a model for genomic medicine implementation and research..” Bmc Med Genomics, vol. 9, Jan. 2016. Pubmed, doi:10.1186/s12920-015-0162-5.
Website
http://hdl.handle.net/10161/11573
PMID
26729011
Source
pubmed
Published In
Bmc Medical Genomics
Volume
9
Publish Date
2016
Start Page
1
DOI
10.1186/s12920-015-0162-5

A Genomic Signature of Influenza Infection Shows Potential for Presymptomatic Detection, Guiding Early Therapy, and Monitoring Clinical Responses.

Early, presymptomatic intervention with oseltamivir (corresponding to the onset of a published host-based genomic signature of influenza infection) resulted in decreased overall influenza symptoms (aggregate symptom scores of 23.5 vs 46.3), more rapid resolution of clinical disease (20 hours earlier), reduced viral shedding (total median tissue culture infectious dose [TCID50] 7.4 vs 9.7), and significantly reduced expression of several inflammatory cytokines (interferon-γ, tumor necrosis factor-α, interleukin-6, and others). The host genomic response to influenza infection is robust and may provide the means for early detection, more timely therapeutic interventions, a meaningful reduction in clinical disease, and an effective molecular means to track response to therapy.

Authors
McClain, MT; Nicholson, BP; Park, LP; Liu, T-Y; Hero, AO; Tsalik, EL; Zaas, AK; Veldman, T; Hudson, LL; Lambkin-Williams, R; Gilbert, A; Burke, T; Nichols, M; Ginsburg, GS; Woods, CW
MLA Citation
McClain, Micah T., et al. “A Genomic Signature of Influenza Infection Shows Potential for Presymptomatic Detection, Guiding Early Therapy, and Monitoring Clinical Responses..” Open Forum Infect Dis, vol. 3, no. 1, Jan. 2016. Pubmed, doi:10.1093/ofid/ofw007.
Website
http://hdl.handle.net/10161/11785
PMID
26933666
Source
pubmed
Published In
Open Forum Infectious Diseases
Volume
3
Issue
1
Publish Date
2016
Start Page
ofw007
DOI
10.1093/ofid/ofw007

Protocol for the "Implementation, adoption, and utility of family history in diverse care settings" study.

BACKGROUND: Risk assessment with a thorough family health history is recommended by numerous organizations and is now a required component of the annual physical for Medicare beneficiaries under the Affordable Care Act. However, there are several barriers to incorporating robust risk assessments into routine care. MeTree, a web-based patient-facing health risk assessment tool, was developed with the aim of overcoming these barriers. In order to better understand what factors will be instrumental for broader adoption of risk assessment programs like MeTree in clinical settings, we obtained funding to perform a type III hybrid implementation-effectiveness study in primary care clinics at five diverse healthcare systems. Here, we describe the study's protocol. METHODS/DESIGN: MeTree collects personal medical information and a three-generation family health history from patients on 98 conditions. Using algorithms built entirely from current clinical guidelines, it provides clinical decision support to providers and patients on 30 conditions. All adult patients with an upcoming well-visit appointment at one of the 20 intervention clinics are eligible to participate. Patient-oriented risk reports are provided in real time. Provider-oriented risk reports are uploaded to the electronic medical record for review at the time of the appointment. Implementation outcomes are enrollment rate of clinics, providers, and patients (enrolled vs approached) and their representativeness compared to the underlying population. Primary effectiveness outcomes are the percent of participants newly identified as being at increased risk for one of the clinical decision support conditions and the percent with appropriate risk-based screening. Secondary outcomes include percent change in those meeting goals for a healthy lifestyle (diet, exercise, and smoking). Outcomes are measured through electronic medical record data abstraction, patient surveys, and surveys/qualitative interviews of clinical staff. DISCUSSION: This study evaluates factors that are critical to successful implementation of a web-based risk assessment tool into routine clinical care in a variety of healthcare settings. The result will identify resource needs and potential barriers and solutions to implementation in each setting as well as an understanding potential effectiveness. TRIAL REGISTRATION: NCT01956773.

Authors
Wu, RR; Myers, RA; McCarty, CA; Dimmock, D; Farrell, M; Cross, D; Chinevere, TD; Ginsburg, GS; Orlando, LA; Family Health History Network,
MLA Citation
Wu, R. Ryanne, et al. “Protocol for the "Implementation, adoption, and utility of family history in diverse care settings" study..” Implement Sci, vol. 10, Nov. 2015. Pubmed, doi:10.1186/s13012-015-0352-8.
Website
http://hdl.handle.net/10161/11500
PMID
26597091
Source
pubmed
Published In
Implementation Science : Is
Volume
10
Publish Date
2015
Start Page
163
DOI
10.1186/s13012-015-0352-8

In Pursuit of Sleep-Circadian Biomarkers.

Authors
Mullington, J; Pack, AI; Ginsburg, GS
MLA Citation
Mullington, Janet, et al. “In Pursuit of Sleep-Circadian Biomarkers..” Sleep, vol. 38, no. 11, Nov. 2015, pp. 1665–66. Pubmed, doi:10.5665/sleep.5132.
PMID
26446123
Source
pubmed
Published In
Sleep
Volume
38
Issue
11
Publish Date
2015
Start Page
1665
End Page
1666
DOI
10.5665/sleep.5132

Does Type 2 Diabetes Genetic Testing and Counseling Reduce Modifiable Risk Factors? A Randomized Controlled Trial of Veterans.

OBJECTIVE: We examined the clinical utility of supplementing type 2 diabetes mellitus (DM) risk counseling with DM genetic test results and counseling. RESEARCH DESIGN AND METHODS: In this randomized controlled trial, non-diabetic overweight/obese veteran outpatients aged 21 to 65 years received DM risk estimates for lifetime risk, family history, and fasting plasma glucose, followed by either genetic test results (CR+G; N = 303) or control eye disease counseling (CR+EYE; N = 298). All participants received brief lifestyle counseling encouraging weight loss to reduce the risk of DM. RESULTS: The mean age was 54 years, 53% of participants were black, and 80% were men. There was no difference between arms in weight (estimated mean difference between CR+G vs. CR+EYE at 3 months = 0.2 kg, 95% CI: -0.3 to 0.7; at 6 months = 0.4 kg, 95 % CI: -0.3 to 1.1), insulin resistance, perceived risk, or physical activity at 3 or 6 months. Calorie and fat intake were lower in the CR+G arm at 3 months (p's ≤ 0.05) but not at 6 months (p's > 0.20). CONCLUSIONS: Providing patients with genetic test results was not more effective in changing patient behavior to reduce the risk of DM compared to conventional risk counseling. TRIAL REGISTRATION: ClinicalTrials.gov NCT01060540 http://clinicaltrials.gov/show/NCT01060540.

Authors
Voils, CI; Coffman, CJ; Grubber, JM; Edelman, D; Sadeghpour, A; Maciejewski, ML; Bolton, J; Cho, A; Ginsburg, GS; Yancy, WS
MLA Citation
Voils, Corrine I., et al. “Does Type 2 Diabetes Genetic Testing and Counseling Reduce Modifiable Risk Factors? A Randomized Controlled Trial of Veterans..” J Gen Intern Med, vol. 30, no. 11, Nov. 2015, pp. 1591–98. Pubmed, doi:10.1007/s11606-015-3315-5.
PMID
25876740
Source
pubmed
Published In
J Gen Intern Med
Volume
30
Issue
11
Publish Date
2015
Start Page
1591
End Page
1598
DOI
10.1007/s11606-015-3315-5

A Guide for a Cardiovascular Genomics Biorepository: the CATHGEN Experience.

The CATHeterization GENetics (CATHGEN) biorepository was assembled in four phases. First, project start-up began in 2000. Second, between 2001 and 2010, we collected clinical data and biological samples from 9334 individuals undergoing cardiac catheterization. Samples were matched at the individual level to clinical data collected at the time of catheterization and stored in the Duke Databank for Cardiovascular Diseases (DDCD). Clinical data included the following: subject demographics (birth date, race, gender, etc.); cardiometabolic history including symptoms; coronary anatomy and cardiac function at catheterization; and fasting chemistry data. Third, as part of the DDCD regular follow-up protocol, yearly evaluations included interim information: vital status (verified via National Death Index search and supplemented by Social Security Death Index search), myocardial infarction (MI), stroke, rehospitalization, coronary revascularization procedures, medication use, and lifestyle habits including smoking. Fourth, samples were used to generate molecular data. CATHGEN offers the opportunity to discover biomarkers and explore mechanisms of cardiovascular disease.

Authors
Kraus, WE; Granger, CB; Sketch, MH; Donahue, MP; Ginsburg, GS; Hauser, ER; Haynes, C; Newby, LK; Hurdle, M; Dowdy, ZE; Shah, SH
MLA Citation
Kraus, William E., et al. “A Guide for a Cardiovascular Genomics Biorepository: the CATHGEN Experience..” J Cardiovasc Transl Res, vol. 8, no. 8, Nov. 2015, pp. 449–57. Pubmed, doi:10.1007/s12265-015-9648-y.
PMID
26271459
Source
pubmed
Published In
J Cardiovasc Transl Res
Volume
8
Issue
8
Publish Date
2015
Start Page
449
End Page
457
DOI
10.1007/s12265-015-9648-y

Use of Rapid Influenza Testing to Reduce Antibiotic Prescriptions Among Outpatients with Influenza-Like Illness in Southern Sri Lanka.

Acute respiratory tract infections (ARTIs) are a common reason for unnecessary antibiotic prescriptions worldwide. Our objective was to determine if providing access to rapid influenza test results could reduce antibiotic prescriptions for ARTIs in a resource-limited setting. We conducted a prospective, pre-post study from March 2013 to October 2014. Outpatients presenting to a hospital in Sri Lanka were surveyed for influenza-like illness-onset of fever ≥ 38.0°C and cough in prior 7 days. Enrolled patients were administered a structured questionnaire, physical examination, and nasal/nasopharyngeal sampling for rapid influenza A/B testing. Influenza test results were released only during phase 2 (January-October 2014). We enrolled 571 patients with ILI-316 in phase 1 and 241 in phase 2. The proportion positive for influenza was 46.5% in phase 1 and 28.6% in phase 2, P < 0.001. Between phases, antibiotic prescriptions decreased from 81.3% to 69.3% (P = 0.001) among all patients and from 83.7% to 62.3% (P = 0.001) among influenza-positive patients. On multivariable analysis, a positive influenza result during phase 2 was associated with lower odds of antibiotic prescriptions (OR = 0.50, 95% CI = 0.26-0.95). This prospective study suggests that providing access to rapid influenza testing may reduce unnecessary antibiotic prescriptions in resource-limited settings.

Authors
Tillekeratne, LG; Bodinayake, CK; Nagahawatte, A; Vidanagama, D; Devasiri, V; Arachchi, WK; Kurukulasooriya, R; De Silva, AD; Østbye, T; Reller, ME; Woods, CW
MLA Citation
Tillekeratne, L. Gayani, et al. “Use of Rapid Influenza Testing to Reduce Antibiotic Prescriptions Among Outpatients with Influenza-Like Illness in Southern Sri Lanka..” Am J Trop Med Hyg, vol. 93, no. 5, Nov. 2015, pp. 1031–37. Pubmed, doi:10.4269/ajtmh.15-0269.
PMID
26283748
Source
pubmed
Published In
Am J Trop Med Hyg
Volume
93
Issue
5
Publish Date
2015
Start Page
1031
End Page
1037
DOI
10.4269/ajtmh.15-0269

Renal systems biology of patients with systemic inflammatory response syndrome.

A systems biology approach was used to comprehensively examine the impact of renal disease and hemodialysis (HD) on patient response during critical illness. To achieve this, we examined the metabolome, proteome, and transcriptome of 150 patients with critical illness, stratified by renal function. Quantification of plasma metabolites indicated greater change as renal function declined, with the greatest derangements in patients receiving chronic HD. Specifically, 6 uremic retention molecules, 17 other protein catabolites, 7 modified nucleosides, and 7 pentose phosphate sugars increased as renal function declined, consistent with decreased excretion or increased catabolism of amino acids and ribonucleotides. Similarly, the proteome showed increased levels of low-molecular-weight proteins and acute-phase reactants. The transcriptome revealed a broad-based decrease in mRNA levels among patients on HD. Systems integration revealed an unrecognized association between plasma RNASE1 and several RNA catabolites and modified nucleosides. Further, allantoin, N1-methyl-4-pyridone-3-carboxamide, and N-acetylaspartate were inversely correlated with the majority of significantly downregulated genes. Thus, renal function broadly affected the plasma metabolome, proteome, and peripheral blood transcriptome during critical illness; changes were not effectively mitigated by hemodialysis. These studies allude to several novel mechanisms whereby renal dysfunction contributes to critical illness.

Authors
Tsalik, EL; Willig, LK; Rice, BJ; van Velkinburgh, JC; Mohney, RP; McDunn, JE; Dinwiddie, DL; Miller, NA; Mayer, ES; Glickman, SW; Jaehne, AK; Glew, RH; Sopori, ML; Otero, RM; Harrod, KS; Cairns, CB; Fowler, VG; Rivers, EP; Woods, CW; Kingsmore, SF; Langley, RJ
MLA Citation
Tsalik, Ephraim L., et al. “Renal systems biology of patients with systemic inflammatory response syndrome..” Kidney Int, vol. 88, no. 4, Oct. 2015, pp. 804–14. Pubmed, doi:10.1038/ki.2015.150.
Website
http://hdl.handle.net/10161/13306
PMID
25993322
Source
pubmed
Published In
Kidney Int
Volume
88
Issue
4
Publish Date
2015
Start Page
804
End Page
814
DOI
10.1038/ki.2015.150

Clinical MRSA isolates from skin and soft tissue infections show increased in vitro production of phenol soluble modulins.

BACKGROUND: Phenol-soluble modulins (PSMs) are amphipathic, pro-inflammatory proteins secreted by most Staphylococcus aureus isolates. This study tested the hypothesis that in vitro PSM production levels are associated with specific clinical phenotypes. METHODS: 177 methicillin-resistant S. aureus (MRSA) isolates from infective endocarditis (IE), skin and soft tissue infection (SSTI), and hospital-acquired/ventilator-associated pneumonia (HAP) were matched by geographic origin, then genotyped using spa-typing. In vitro PSM production was measured by high performance liquid chromatography/mass spectrometry. Statistical analysis was performed using Chi-squared or Kruskal-Wallis tests as appropriate. RESULTS: Spa type 1 was significantly more common in SSTI isolates (62.7% SSTI; 1.7% IE; 16.9% HAP; p < 0.0001) while HAP and IE isolates were more commonly spa type 2 (0% SSTI; 37.3% IE; 40.7% HAP; p < 0.0001). USA300 isolates produced the highest levels of PSMs in vitro. SSTI isolates produced significantly higher quantities of PSMα1-4, PSMβ1, and δ-toxin than other isolates (p < 0.001). These findings persisted when USA300 isolates were excluded from analysis. CONCLUSIONS: Increased in vitro production of PSMs is associated with an SSTI clinical source. This significant association persisted after exclusion of USA300 genotype isolates from analysis, suggesting that PSMs play a particularly important role in the pathogenesis of SSTI as compared to other infection types.

Authors
Berlon, NR; Qi, R; Sharma-Kuinkel, BK; Joo, H-S; Park, LP; George, D; Thaden, JT; Messina, JA; Maskarinec, SA; Mueller-Premru, M; Athan, E; Tattevin, P; Pericas, JM; Woods, CW; Otto, M; Fowler, VG
MLA Citation
Berlon, Nicholas R., et al. “Clinical MRSA isolates from skin and soft tissue infections show increased in vitro production of phenol soluble modulins..” J Infect, vol. 71, no. 4, Oct. 2015, pp. 447–57. Pubmed, doi:10.1016/j.jinf.2015.06.005.
PMID
26079275
Source
pubmed
Published In
J Infect
Volume
71
Issue
4
Publish Date
2015
Start Page
447
End Page
457
DOI
10.1016/j.jinf.2015.06.005

Genome-wide association study of acute kidney injury after coronary bypass graft surgery identifies susceptibility loci.

Acute kidney injury (AKI) is a common, serious complication of cardiac surgery. Since prior studies have supported a genetic basis for postoperative AKI, we conducted a genome-wide association study (GWAS) for AKI following coronary bypass graft (CABG) surgery. The discovery data set consisted of 873 nonemergent CABG surgery patients with cardiopulmonary bypass (PEGASUS), while a replication data set had 380 cardiac surgical patients (CATHGEN). Single-nucleotide polymorphism (SNP) data were based on Illumina Human610-Quad (PEGASUS) and OMNI1-Quad (CATHGEN) BeadChips. We used linear regression with adjustment for a clinical AKI risk score to test SNP associations with the postoperative peak rise relative to preoperative serum creatinine concentration as a quantitative AKI trait. Nine SNPs meeting significance in the discovery set were detected. The rs13317787 in GRM7|LMCD1-AS1 intergenic region (3p21.6) and rs10262995 in BBS9 (7p14.3) were replicated with significance in the CATHGEN data set and exhibited significantly strong overall association following meta-analysis. Additional fine mapping using imputed SNPs across these two regions and meta-analysis found genome-wide significance at the GRM7|LMCD1-AS1 locus and a significantly strong association at BBS9. Thus, through an unbiased GWAS approach, we found two new loci associated with post-CABG AKI providing new insights into the pathogenesis of perioperative AKI.

Authors
Stafford-Smith, M; Li, Y-J; Mathew, JP; Li, Y-W; Ji, Y; Phillips-Bute, BG; Milano, CA; Newman, MF; Kraus, WE; Kertai, MD; Shah, SH; Podgoreanu, MV; Duke Perioperative Genetics and Safety Outcomes (PEGASUS) Investigative Team,
MLA Citation
Stafford-Smith, Mark, et al. “Genome-wide association study of acute kidney injury after coronary bypass graft surgery identifies susceptibility loci..” Kidney Int, vol. 88, no. 4, Oct. 2015, pp. 823–32. Pubmed, doi:10.1038/ki.2015.161.
Website
http://hdl.handle.net/10161/13721
PMID
26083657
Source
pubmed
Published In
Kidney Int
Volume
88
Issue
4
Publish Date
2015
Start Page
823
End Page
832
DOI
10.1038/ki.2015.161

Pneumococcal Carriage and Vaccine Coverage in Retirement Community Residents.

OBJECTIVES: To evaluate pneumococcal immunization in older adults living in retirement communities and to measure nasopharyngeal carriage of Streptococcus pneumoniae to better assess the potential for herd protection from the 13-valent pneumococcal conjugate vaccine (PCV-13) in these settings. DESIGN: Cross-sectional observational study of adults aged 65 and older living in retirement communities to determine coverage with 23-valent pneumococcal vaccine (PPSV-23), coverage with PCV-13 in immuncompromised individuals according to 2012 Advisory Committee on Immunization Practices (ACIP) guidelines, and nasopharyngeal carriage of S. pneumoniae. SETTING: Two retirement communities in North Carolina. PARTICIPANTS: Older adults recruited between December 2013 and April 2014 (N = 21, 64.8% female, mean age 81.4). MEASUREMENTS: A survey was used to assess chronic illnesses, immunization history, and potential risk factors for pneumococcal carriage; a chart review was used to confirm immunization history and abstract chronic conditions; and a nasopharyngeal swab was collected and cultured for S. pneumoniae. RESULTS: Eighty-seven percent of participants reported receiving PPSV-23 since age 65. Of the 16.2% of participants with an immunocompromising condition, only one had received PCV-13. Nasopharyngeal carriage with S. pneumoniae was detected in 1.9% (95% confidence interval = 0.0-3.8%) of participants. CONCLUSION: In this select sample, PPSV-23 coverage was high, but adherence to the ACIP recommendation for PCV-13 in immunocompromised groups was low. Nasopharyngeal carriage of S. pneumoniae was present, although infrequent, suggesting that immunization with PCV-13 could provide an individual benefit and a small degree of herd protection.

Authors
Becker-Dreps, S; Kistler, CE; Ward, K; Killeya-Jones, LA; Better, OM; Weber, DJ; Zimmerman, S; Nicholson, BP; Woods, CW; Sloane, P
MLA Citation
Becker-Dreps, Sylvia, et al. “Pneumococcal Carriage and Vaccine Coverage in Retirement Community Residents..” J Am Geriatr Soc, vol. 63, no. 10, Oct. 2015, pp. 2094–98. Pubmed, doi:10.1111/jgs.13651.
PMID
26456473
Source
pubmed
Published In
Journal of the American Geriatrics Society
Volume
63
Issue
10
Publish Date
2015
Start Page
2094
End Page
2098
DOI
10.1111/jgs.13651

The oral microbiome and its relationship to genomics and oral disease

Authors
Glurich, I; Shukla, S; Acharya, A; Ginsburg, GS; Brilliant, MH
MLA Citation
Glurich, I., et al. “The oral microbiome and its relationship to genomics and oral disease.” Genomics, Personalized Medicine and Oral Disease, 2015, pp. 35–65. Scopus, doi:10.1007/978-3-319-17942-1_3.
Source
scopus
Publish Date
2015
Start Page
35
End Page
65
DOI
10.1007/978-3-319-17942-1_3

Gene Expression Signatures and the Spectrum of Coronary Artery Disease.

Over the past 10-15 years, developments in gene expression profiling have opened new arenas for the discovery of important factors in the pathogenesis of numerous disease processes, including coronary artery disease. Messenger RNA and microRNA are differentially expressed in patients with coronary plaques, acute plaque rupture, and response to well-established treatments for acute coronary syndromes. In this review, we will explore recent developments in messenger RNA and microRNA technology at each stage of a patient's progression through the natural history of cardiovascular disease, including evaluation of risk factors, prediction and detection of coronary artery disease and acute coronary syndromes, and finally, response to treatments for coronary artery disease and its sequelae including congestive heart failure.

Authors
Friede, KA; Ginsburg, GS; Voora, D
MLA Citation
Friede, Kevin A., et al. “Gene Expression Signatures and the Spectrum of Coronary Artery Disease..” J Cardiovasc Transl Res, vol. 8, no. 6, Aug. 2015, pp. 339–52. Pubmed, doi:10.1007/s12265-015-9640-6.
PMID
26089288
Source
pubmed
Published In
J Cardiovasc Transl Res
Volume
8
Issue
6
Publish Date
2015
Start Page
339
End Page
352
DOI
10.1007/s12265-015-9640-6

Making Personalized Health Care Even More Personalized: Insights From Activities of the IOM Genomics Roundtable.

Genomic research has generated much new knowledge into mechanisms of human disease, with the potential to catalyze novel drug discovery and development, prenatal and neonatal screening, clinical pharmacogenomics, more sensitive risk prediction, and enhanced diagnostics. Genomic medicine, however, has been limited by critical evidence gaps, especially those related to clinical utility and applicability to diverse populations. Genomic medicine may have the greatest impact on health care if it is integrated into primary care, where most health care is received and where evidence supports the value of personalized medicine grounded in continuous healing relationships. Redesigned primary care is the most relevant setting for clinically useful genomic medicine research. Taking insights gained from the activities of the Institute of Medicine (IOM) Roundtable on Translating Genomic-Based Research for Health, we apply lessons learned from the patient-centered medical home national experience to implement genomic medicine in a patient-centered, learning health care system.

Authors
David, SP; Johnson, SG; Berger, AC; Feero, WG; Terry, SF; Green, LA; Phillips, RL; Ginsburg, GS
MLA Citation
David, Sean P., et al. “Making Personalized Health Care Even More Personalized: Insights From Activities of the IOM Genomics Roundtable..” Ann Fam Med, vol. 13, no. 4, July 2015, pp. 373–80. Pubmed, doi:10.1370/afm.1772.
PMID
26195686
Source
pubmed
Published In
Ann Fam Med
Volume
13
Issue
4
Publish Date
2015
Start Page
373
End Page
380
DOI
10.1370/afm.1772

Global implementation of genomic medicine: We are not alone.

Around the world, innovative genomic-medicine programs capitalize on singular capabilities arising from local health care systems, cultural or political milieus, and unusual selected risk alleles or disease burdens. Such individual efforts might benefit from the sharing of approaches and lessons learned in other locales. The U.S. National Human Genome Research Institute and the National Academy of Medicine recently brought together 25 of these groups to compare projects, to examine the current state of implementation and desired near-term capabilities, and to identify opportunities for collaboration that promote the responsible practice of genomic medicine. Efforts to coalesce these groups around concrete but compelling signature projects should accelerate the responsible implementation of genomic medicine in efforts to improve clinical care worldwide.

Authors
Manolio, TA; Abramowicz, M; Al-Mulla, F; Anderson, W; Balling, R; Berger, AC; Bleyl, S; Chakravarti, A; Chantratita, W; Chisholm, RL; Dissanayake, VHW; Dunn, M; Dzau, VJ; Han, B-G; Hubbard, T; Kolbe, A; Korf, B; Kubo, M; Lasko, P; Leego, E; Mahasirimongkol, S; Majumdar, PP; Matthijs, G; McLeod, HL; Metspalu, A; Meulien, P; Miyano, S; Naparstek, Y; O'Rourke, PP; Patrinos, GP; Rehm, HL; Relling, MV; Rennert, G; Rodriguez, LL; Roden, DM; Shuldiner, AR; Sinha, S; Tan, P; Ulfendahl, M; Ward, R; Williams, MS; Wong, JEL; Green, ED; Ginsburg, GS
MLA Citation
Manolio, Teri A., et al. “Global implementation of genomic medicine: We are not alone..” Sci Transl Med, vol. 7, no. 290, June 2015. Pubmed, doi:10.1126/scitranslmed.aab0194.
PMID
26041702
Source
pubmed
Published In
Sci Transl Med
Volume
7
Issue
290
Publish Date
2015
Start Page
290ps13
DOI
10.1126/scitranslmed.aab0194

Aligning incentives to fulfil the promise of personalised medicine.

Authors
Dzau, VJ; Ginsburg, GS; Van Nuys, K; Agus, D; Goldman, D
MLA Citation
Dzau, Victor J., et al. “Aligning incentives to fulfil the promise of personalised medicine..” Lancet, vol. 385, no. 9982, May 2015, pp. 2118–19. Pubmed, doi:10.1016/S0140-6736(15)60722-X.
PMID
25957453
Source
pubmed
Published In
Lancet
Volume
385
Issue
9982
Publish Date
2015
Start Page
2118
End Page
2119
DOI
10.1016/S0140-6736(15)60722-X

An under-recognized influenza epidemic identified by rapid influenza testing, southern Sri Lanka, 2013.

Influenza accounts for a large burden of acute respiratory tract infections in high-income countries; data from lower-income settings are limited due to lack of confirmatory testing. Consecutive outpatients presenting to the largest tertiary care hospital in southern Sri Lanka were surveyed for influenza-like illness (ILI), defined as acute onset of fever ≥ 38.0°C and cough. Patients were administered a questionnaire and nasal/nasopharyngeal sampling for rapid influenza A/B testing. We enrolled 311 patients with ILI from March to November 2013: 170 (54.7%) children and 172 (55.3%) males. Approximately half (147, 47.3%) tested positive for influenza, but 253 (81.4%) were prescribed antibiotics. On bivariable analysis, symptoms associated with influenza included pain with breathing (P < 0.001), headache (P = 0.005), fatigue (P = 0.003), arthralgias (P = 0.003), and myalgias (P = 0.006) in children and pain with breathing (P = 0.01), vomiting (P = 0.03), and arthralgias (P = 0.03) in adults. Our final clinical predictive models had low sensitivity and fair specificity-50.0% (95% CI: 38.6-61.4%) and 83.2% (95% CI: 73.4-90.0%), respectively, in children and 52.2% (95% CI: 39.9-64.2%) and 81.4% (95% CI: 70.0-89.4%), respectively, in adults. Our study confirms the ability of rapid influenza testing to identify an influenza epidemic in a setting in which testing is not routinely available.

Authors
Tillekeratne, LG; Bodinayake, CK; Nagahawatte, A; Vidanagama, D; Devasiri, V; Arachchi, WK; Kurukulasooriya, R; De Silva, AD; Østybe, T; Reller, ME; Woods, CW
MLA Citation
Tillekeratne, L. Gayani, et al. “An under-recognized influenza epidemic identified by rapid influenza testing, southern Sri Lanka, 2013..” Am J Trop Med Hyg, vol. 92, no. 5, May 2015, pp. 1023–29. Pubmed, doi:10.4269/ajtmh.14-0708.
PMID
25732679
Source
pubmed
Published In
Am J Trop Med Hyg
Volume
92
Issue
5
Publish Date
2015
Start Page
1023
End Page
1029
DOI
10.4269/ajtmh.14-0708

Etiology of pediatric fever in western Kenya: a case-control study of falciparum malaria, respiratory viruses, and streptococcal pharyngitis.

In Kenya, more than 10 million episodes of acute febrile illness are treated annually among children under 5 years. Most are clinically managed as malaria without parasitological confirmation. There is an unmet need to describe pathogen-specific etiologies of fever. We enrolled 370 febrile children and 184 healthy controls. We report demographic and clinical characteristics of patients with Plasmodium falciparum, group A streptococcal (GAS) pharyngitis, and respiratory viruses (influenza A and B, respiratory syncytial virus [RSV], parainfluenza [PIV] types 1-3, adenovirus, human metapneumovirus [hMPV]), as well as those with undifferentiated fever. Of febrile children, 79.7% were treated for malaria. However, P. falciparum was detected infrequently in both cases and controls (14/268 [5.2%] versus 3/133 [2.3%], P = 0.165), whereas 41% (117/282) of febrile children had a respiratory viral infection, compared with 24.8% (29/117) of controls (P = 0.002). Only 9/515 (1.7%) children had streptococcal infection. Of febrile children, 22/269 (8.2%) were infected with > 1 pathogen, and 102/275 (37.1%) had fevers of unknown etiology. Respiratory viruses were common in both groups, but only influenza or parainfluenza was more likely to be associated with symptomatic disease (attributable fraction [AF] 67.5% and 59%, respectively). Malaria was overdiagnosed and overtreated. Few children presented to the hospital with GAS pharyngitis. An enhanced understanding of carriage of common pathogens, improved diagnostic capacity, and better-informed clinical algorithms for febrile illness are needed.

Authors
O'Meara, WP; Mott, JA; Laktabai, J; Wamburu, K; Fields, B; Armstrong, J; Taylor, SM; MacIntyre, C; Sen, R; Menya, D; Pan, W; Nicholson, BP; Woods, CW; Holland, TL
MLA Citation
O’Meara, Wendy P., et al. “Etiology of pediatric fever in western Kenya: a case-control study of falciparum malaria, respiratory viruses, and streptococcal pharyngitis..” Am J Trop Med Hyg, vol. 92, no. 5, May 2015, pp. 1030–37. Pubmed, doi:10.4269/ajtmh.14-0560.
PMID
25758648
Source
pubmed
Published In
Am J Trop Med Hyg
Volume
92
Issue
5
Publish Date
2015
Start Page
1030
End Page
1037
DOI
10.4269/ajtmh.14-0560

Perspectives on genetic and genomic technologies in an academic medical center: the duke experience.

UNLABELLED: In this age of personalized medicine, genetic and genomic testing is expected to become instrumental in health care delivery, but little is known about its actual implementation in clinical practice. METHODS: We surveyed Duke faculty and healthcare providers to examine the extent of genetic and genomic testing adoption. We assessed providers' use of genetic and genomic testing options and indications in clinical practice, providers' awareness of pharmacogenetic applications, and providers' opinions on returning research-generated genetic test results to participants. Most clinician respondents currently use family history routinely in their clinical practice, but only 18 percent of clinicians use pharmacogenetics. Only two respondents correctly identified the number of drug package inserts with pharmacogenetic indications. We also found strong support for the return of genetic research results to participants. Our results demonstrate that while Duke healthcare providers are enthusiastic about genomic technologies, use of genomic tools outside of research has been limited. Respondents favor return of research-based genetic results to participants, but clinicians lack knowledge about pharmacogenetic applications. We identified challenges faced by this institution when implementing genetic and genomic testing into patient care that should inform a policy and education agenda to improve provider support and clinician-researcher partnerships.

Authors
Katsanis, SH; Minear, MA; Vorderstrasse, A; Yang, N; Reeves, JW; Rakhra-Burris, T; Cook-Deegan, R; Ginsburg, GS; Simmons, LA
MLA Citation
Katsanis, Sara Huston, et al. “Perspectives on genetic and genomic technologies in an academic medical center: the duke experience..” J Pers Med, vol. 5, no. 2, Apr. 2015, pp. 67–82. Pubmed, doi:10.3390/jpm5020067.
Website
https://hdl.handle.net/10161/17567
PMID
25854543
Source
pubmed
Published In
Journal of Personalized Medicine
Volume
5
Issue
2
Publish Date
2015
Start Page
67
End Page
82
DOI
10.3390/jpm5020067

Candida infective endocarditis: an observational cohort study with a focus on therapy.

Candida infective endocarditis is a rare disease with a high mortality rate. Our understanding of this infection is derived from case series, case reports, and small prospective cohorts. The purpose of this study was to evaluate the clinical features and use of different antifungal treatment regimens for Candida infective endocarditis. This prospective cohort study was based on 70 cases of Candida infective endocarditis from the International Collaboration on Endocarditis (ICE)-Prospective Cohort Study and ICE-Plus databases collected between 2000 and 2010. The majority of infections were acquired nosocomially (67%). Congestive heart failure (24%), prosthetic heart valve (46%), and previous infective endocarditis (26%) were common comorbidities. Overall mortality was high, with 36% mortality in the hospital and 59% at 1 year. On univariate analysis, older age, heart failure at baseline, persistent candidemia, nosocomial acquisition, heart failure as a complication, and intracardiac abscess were associated with higher mortality. Mortality was not affected by use of surgical therapy or choice of antifungal agent. A subgroup analysis was performed on 33 patients for whom specific antifungal therapy information was available. In this subgroup, 11 patients received amphotericin B-based therapy and 14 received echinocandin-based therapy. Despite a higher percentage of older patients and nosocomial infection in the echinocandin group, mortality rates were similar between the two groups. In conclusion, Candida infective endocarditis is associated with a high mortality rate that was not impacted by choice of antifungal therapy or by adjunctive surgical intervention. Additionally, echinocandin therapy was as effective as amphotericin B-based therapy in the small subgroup analysis.

Authors
Arnold, CJ; Johnson, M; Bayer, AS; Bradley, S; Giannitsioti, E; Miró, JM; Tornos, P; Tattevin, P; Strahilevitz, J; Spelman, D; Athan, E; Nacinovich, F; Fortes, CQ; Lamas, C; Barsic, B; Fernández-Hidalgo, N; Muñoz, P; Chu, VH
MLA Citation
Arnold, Christopher J., et al. “Candida infective endocarditis: an observational cohort study with a focus on therapy..” Antimicrob Agents Chemother, vol. 59, no. 4, Apr. 2015, pp. 2365–73. Pubmed, doi:10.1128/AAC.04867-14.
PMID
25645855
Source
pubmed
Published In
Antimicrob Agents Chemother
Volume
59
Issue
4
Publish Date
2015
Start Page
2365
End Page
2373
DOI
10.1128/AAC.04867-14

Impact of early valve surgery on outcome of Staphylococcus aureus prosthetic valve infective endocarditis: analysis in the International Collaboration of Endocarditis-Prospective Cohort Study.

BACKGROUND: The impact of early valve surgery (EVS) on the outcome of Staphylococcus aureus (SA) prosthetic valve infective endocarditis (PVIE) is unresolved. The objective of this study was to evaluate the association between EVS, performed within the first 60 days of hospitalization, and outcome of SA PVIE within the International Collaboration on Endocarditis-Prospective Cohort Study. METHODS: Participants were enrolled between June 2000 and December 2006. Cox proportional hazards modeling that included surgery as a time-dependent covariate and propensity adjustment for likelihood to receive cardiac surgery was used to evaluate the impact of EVS and 1-year all-cause mortality on patients with definite left-sided S. aureus PVIE and no history of injection drug use. RESULTS: EVS was performed in 74 of the 168 (44.3%) patients. One-year mortality was significantly higher among patients with S. aureus PVIE than in patients with non-S. aureus PVIE (48.2% vs 32.9%; P = .003). Staphylococcus aureus PVIE patients who underwent EVS had a significantly lower 1-year mortality rate (33.8% vs 59.1%; P = .001). In multivariate, propensity-adjusted models, EVS was not associated with 1-year mortality (risk ratio, 0.67 [95% confidence interval, .39-1.15]; P = .15). CONCLUSIONS: In this prospective, multinational cohort of patients with S. aureus PVIE, EVS was not associated with reduced 1-year mortality. The decision to pursue EVS should be individualized for each patient, based upon infection-specific characteristics rather than solely upon the microbiology of the infection causing PVIE.

Authors
Chirouze, C; Alla, F; Fowler, VG; Sexton, DJ; Corey, GR; Chu, VH; Wang, A; Erpelding, M-L; Durante-Mangoni, E; Fernández-Hidalgo, N; Giannitsioti, E; Hannan, MM; Lejko-Zupanc, T; Miró, JM; Muñoz, P; Murdoch, DR; Tattevin, P; Tribouilloy, C; Hoen, B; ICE Prospective Investigators,
MLA Citation
Chirouze, Catherine, et al. “Impact of early valve surgery on outcome of Staphylococcus aureus prosthetic valve infective endocarditis: analysis in the International Collaboration of Endocarditis-Prospective Cohort Study..” Clin Infect Dis, vol. 60, no. 5, Mar. 2015, pp. 741–49. Pubmed, doi:10.1093/cid/ciu871.
PMID
25389255
Source
pubmed
Published In
Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America
Volume
60
Issue
5
Publish Date
2015
Start Page
741
End Page
749
DOI
10.1093/cid/ciu871

Use of a patient-entered family health history tool with decision support in primary care: impact of identification of increased risk patients on genetic counseling attendance.

Several barriers inhibit collection and use of detailed family health history (FHH) in primary care. MeTree, a computer-based FHH intake and risk assessment tool with clinical decision support, was developed to overcome these barriers. Here, we describe the impact of MeTree on genetic counseling (GC) referrals and attendance. Non-adopted, English speaking adults scheduled for a well-visit in two community-based primary-care clinics were invited to participate in an Implementation-Effectiveness study of MeTree. Participants' demographic characteristics and beliefs were assessed at baseline. Immediately after an appointment with a patient for whom GC was recommended, clinicians indicated whether they referred the patient and, if not, why. The study genetic counselor kept a database of patients with a GC recommendation and contacted those with a referral. Of 542 patients completing MeTree, 156 (29 %) received a GC recommendation. Of these, 46 % (n = 72) were referred and 21 % (n = 33) underwent counseling. Patient preferences, additional clinical information unavailable to MeTree, and an incomplete clinician evaluation of the FHH accounted for the 85 patients clinicians chose not to refer. Although MeTree identified a significant proportion of patients for whom GC was recommended, persistent barriers indicate the need for improved referral processes and patient and physician education about the benefits of GC.

Authors
Buchanan, AH; Christianson, CA; Himmel, T; Powell, KP; Agbaje, A; Ginsburg, GS; Henrich, VC; Orlando, LA
MLA Citation
Buchanan, Adam H., et al. “Use of a patient-entered family health history tool with decision support in primary care: impact of identification of increased risk patients on genetic counseling attendance..” J Genet Couns, vol. 24, no. 1, Feb. 2015, pp. 179–88. Pubmed, doi:10.1007/s10897-014-9753-0.
PMID
25120038
Source
pubmed
Published In
J Genet Couns
Volume
24
Issue
1
Publish Date
2015
Start Page
179
End Page
188
DOI
10.1007/s10897-014-9753-0

Impact of a combined pediatric and adult pneumococcal immunization program on adult pneumonia incidence and mortality in Nicaragua.

BACKGROUND: In 2010, Nicaragua implemented an adult immunization program with the 23-valent pneumococcal polysaccharide vaccine (PPSV-23) and a pediatric immunization program with the 13-valent pneumococcal conjugate vaccine (PCV-13). We assessed incidence rates of ambulatory visits and hospitalizations for pneumonia and pneumonia-related mortality in adults over the age of 50 years before and after the program's implementation in the Department of León, Nicaragua. METHODS: We collected visit diagnoses from all 107 public health facilities between 2008 and 2012 in León. We compared incidence rates of ambulatory visits for pneumonia, pneumonia hospitalizations, and pneumonia-related mortality in the pre-vaccine (2008-2009) and vaccine (2011-2012) periods among older adults using Poisson regression with generalized estimating equations (GEE), controlling for age group, municipality, and proportions of adults who were immunized against influenza. Exposure time was estimated by official municipality population estimates. RESULTS: We did not observe lower incidence rates of ambulatory visits or hospitalizations for pneumonia among adults during the vaccine period versus the pre-vaccine period. However, pneumonia-related mortality was lower in the vaccine period versus the pre-vaccine period, with an adjusted incidence rate ratio (IRRa) of 0.73 (0.56, 0.94) among adults aged 50-64 years, and 0.55 (0.43, 0.70) among adults aged ≥65 years. CONCLUSIONS: These early results following introduction of a combined pediatric and adult pneumococcal immunization program in Nicaragua show a probable impact of the program on the reduction of pneumonia-related deaths in older adults, but a less clear impact on the reduction of health facility visits for pneumonia.

Authors
Becker-Dreps, S; Amaya, E; Liu, L; Rocha, J; Briceño, R; Moreno, G; Alemán, J; Hudgens, MG; Woods, CW; Weber, DJ
MLA Citation
Becker-Dreps, Sylvia, et al. “Impact of a combined pediatric and adult pneumococcal immunization program on adult pneumonia incidence and mortality in Nicaragua..” Vaccine, vol. 33, no. 1, Jan. 2015, pp. 222–27. Pubmed, doi:10.1016/j.vaccine.2014.10.073.
PMID
25444795
Source
pubmed
Published In
Vaccine
Volume
33
Issue
1
Publish Date
2015
Start Page
222
End Page
227
DOI
10.1016/j.vaccine.2014.10.073

Multiplex DNA biosensor for viral infection diagnosis using SERS molecular sentinel-on-chip

© Springer International Publishing Switzerland 2015. The development of sensitive and selective techniques for multiplex detection of DNA biomarkers is paramount for clinical diagnosis. Various multiplex DNA detection techniques have been reported. However, most of these techniques require multiple incubation and/or washing steps or target sequence labeling. In this work, we demonstrated a unique multiplex DNA biosensor for viral infection diagnosis using the surface-enhanced Raman scattering (SERS) “Molecular Sentinelon- Chip” (MSC) technique. The sensing mechanism is based upon the change of SERS intensity when Raman labels tagged at 3′-ends of molecular sentinel nanoprobes are physically displaced from the Nanowave chip’s surface upon target DNA hybridization. SERS measurements were performed immediately following a single hybridization reaction between the target single-stranded DNA (ssDNA) sequences and the complementary molecular sentinel nanoprobes immobilized on the Nanowave chip without requiring target labeling (i.e., label-free assay), secondary hybridization, or post-hybridization washing, thus reducing the assay time and lowering cost. Two nucleic acid transcripts, interferon alpha-inducible protein 27 (IFI27) and interferon-induced protein 44-like (IFI44L), are used as model systems for the multiplex detection concept demonstration. These two genes are well known for their critical role in host immune response to viral infections and can be used as molecular signature for viral infection diagnosis. The results indicate the effectiveness and potential of the MSC technology for multiplex DNA detection for point-ofcare diagnostics and global health applications.

Authors
Ngo, HT; Wang, HN; Burke, T; Woods, C; Ginsburg, GS; Vo-Dinh, T
MLA Citation
Ngo, H. T., et al. “Multiplex DNA biosensor for viral infection diagnosis using SERS molecular sentinel-on-chip.” Ifmbe Proceedings, vol. 46, 2015, pp. 15–20. Scopus, doi:10.1007/978-3-319-11776-8_4.
Source
scopus
Published In
Ifmbe Proceedings
Volume
46
Publish Date
2015
Start Page
15
End Page
20
DOI
10.1007/978-3-319-11776-8_4

Patient beliefs and behaviors about genomic risk for type 2 diabetes: implications for prevention.

Type 2 diabetes is a major health burden in the United States, and population trends suggest this burden will increase. High interest in, and increased availability of, testing for genetic risk of type 2 diabetes presents a new opportunity for reducing type 2 diabetes risk for many patients; however, to date, there is little evidence that genetic testing positively affects type 2 diabetes prevention. Genetic information may not fit patients' illness representations, which may reduce the chances of risk-reducing behavior changes. The present study aimed to examine illness representations in a clinical sample who are at risk for type 2 diabetes and interested in genetic testing. The authors used the Common Sense Model to analyze survey responses of 409 patients with type 2 diabetes risk factors. Patients were interested in genetic testing for type 2 diabetes risk and believed in its importance. Most patients believed that genetic factors are important to developing type 2 diabetes (67%), that diet and exercise are effective in preventing type 2 diabetes (95%), and that lifestyle changes are more effective than drugs (86%). Belief in genetic causality was not related to poorer self-reported health behaviors. These results suggest that patients' interest in genetic testing for type 2 diabetes might produce a teachable moment that clinicians can use to counsel behavior change.

Authors
Gallagher, P; King, HA; Haga, SB; Orlando, LA; Joy, SV; Trujillo, GM; Scott, WM; Bembe, M; Creighton, DL; Cho, AH; Ginsburg, GS; Vorderstrasse, A
MLA Citation
Gallagher, Patrick, et al. “Patient beliefs and behaviors about genomic risk for type 2 diabetes: implications for prevention..” J Health Commun, vol. 20, no. 6, 2015, pp. 728–35. Pubmed, doi:10.1080/10810730.2015.1018563.
Website
http://hdl.handle.net/10161/11501
PMID
25844569
Source
pubmed
Published In
J Health Commun
Volume
20
Issue
6
Publish Date
2015
Start Page
728
End Page
735
DOI
10.1080/10810730.2015.1018563

SLCO1B1 genetic variants, long-term low-density lipoprotein cholesterol levels and clinical events in patients following cardiac catheterization.

AIM: SLCO1B1 variants are associated with intermediate outcomes that may increase risk of death/myocardial infarction (MI) in statin-treated patients. PATIENTS & METHODS: In high-risk Caucasians undergoing cardiac catheterization, we tested the association between rs4149056/625T>C and rs2306283/492A>G with low-density lipoprotein cholesterol (LDL-c) over 3 years (n = 1402) and death/MI over 6 years (n = 2994), accounting for statin use or type during follow-up. RESULTS: Carriers of the rs4149056 C allele had 6.2 ± 1.7 mg/dl higher LDL-c per C allele (p < 0.001) but were not at higher risk for death/MI (p = 0.9). We found no associations between rs2306283 and LDL-c or death/MI (p > 0.6). CONCLUSION: Functional SLCO1B1 variants are not associated with death/MI in patients commonly treated with statins, despite higher LDL-c in carriers of the rs4149056 C allele.

Authors
Li, JH; Suchindran, S; Shah, SH; Kraus, WE; Ginsburg, GS; Voora, D
MLA Citation
Li, Josephine H., et al. “SLCO1B1 genetic variants, long-term low-density lipoprotein cholesterol levels and clinical events in patients following cardiac catheterization..” Pharmacogenomics, vol. 16, no. 5, 2015, pp. 449–58. Pubmed, doi:10.2217/pgs.15.2.
PMID
25916517
Source
pubmed
Published In
Pharmacogenomics
Volume
16
Issue
5
Publish Date
2015
Start Page
449
End Page
458
DOI
10.2217/pgs.15.2

What was old is new again: using the host response to diagnose infectious disease.

A century of advances in infectious disease diagnosis and treatment changed the face of medicine. However, challenges continue to develop including multi-drug resistance, globalization that increases pandemic risks and high mortality from severe infections. These challenges can be mitigated through improved diagnostics, focusing on both pathogen discovery and the host response. Here, we review how 'omics' technologies improve sepsis diagnosis, early pathogen identification and personalize therapy. Such host response diagnostics are possible due to the confluence of advanced laboratory techniques (e.g., transcriptomics, metabolomics, proteomics) along with advanced mathematical modeling such as machine learning techniques. The road ahead is promising, but obstacles remain before the impact of such advanced diagnostic modalities is felt at the bedside.

Authors
Ko, ER; Yang, WE; McClain, MT; Woods, CW; Ginsburg, GS; Tsalik, EL
MLA Citation
Ko, Emily R., et al. “What was old is new again: using the host response to diagnose infectious disease..” Expert Rev Mol Diagn, vol. 15, no. 9, 2015, pp. 1143–58. Pubmed, doi:10.1586/14737159.2015.1059278.
PMID
26145249
Source
pubmed
Published In
Expert Rev Mol Diagn
Volume
15
Issue
9
Publish Date
2015
Start Page
1143
End Page
1158
DOI
10.1586/14737159.2015.1059278

Gene Expression Profiles Link Respiratory Viral Infection, Platelet Response to Aspirin, and Acute Myocardial Infarction.

BACKGROUND: Influenza infection is associated with myocardial infarction (MI), suggesting that respiratory viral infection may induce biologic pathways that contribute to MI. We tested the hypotheses that 1) a validated blood gene expression signature of respiratory viral infection (viral GES) was associated with MI and 2) respiratory viral exposure changes levels of a validated platelet gene expression signature (platelet GES) of platelet function in response to aspirin that is associated with MI. METHODS: A previously defined viral GES was projected into blood RNA data from 594 patients undergoing elective cardiac catheterization and used to classify patients as having evidence of viral infection or not and tested for association with acute MI using logistic regression. A previously defined platelet GES was projected into blood RNA data from 81 healthy subjects before and after exposure to four respiratory viruses: Respiratory Syncytial Virus (RSV) (n=20), Human Rhinovirus (HRV) (n=20), Influenza A virus subtype H1N1 (H1N1) (n=24), Influenza A Virus subtype H3N2 (H3N2) (n=17). We tested for the change in platelet GES with viral exposure using linear mixed-effects regression and by symptom status. RESULTS: In the catheterization cohort, 32 patients had evidence of viral infection based upon the viral GES, of which 25% (8/32) had MI versus 12.2% (69/567) among those without evidence of viral infection (OR 2.3; CI [1.03-5.5], p=0.04). In the infection cohorts, only H1N1 exposure increased platelet GES over time (time course p-value = 1e-04). CONCLUSIONS: A viral GES of non-specific, respiratory viral infection was associated with acute MI; 18% of the top 49 genes in the viral GES are involved with hemostasis and/or platelet aggregation. Separately, H1N1 exposure, but not exposure to other respiratory viruses, increased a platelet GES previously shown to be associated with MI. Together, these results highlight specific genes and pathways that link viral infection, platelet activation, and MI especially in the case of H1N1 influenza infection.

Authors
Rose, JJ; Voora, D; Cyr, DD; Lucas, JE; Zaas, AK; Woods, CW; Newby, LK; Kraus, WE; Ginsburg, GS
MLA Citation
Rose, Jason J., et al. “Gene Expression Profiles Link Respiratory Viral Infection, Platelet Response to Aspirin, and Acute Myocardial Infarction..” Plos One, vol. 10, no. 7, 2015. Pubmed, doi:10.1371/journal.pone.0132259.
Website
http://hdl.handle.net/10161/12503
PMID
26193668
Source
pubmed
Published In
Plos One
Volume
10
Issue
7
Publish Date
2015
Start Page
e0132259
DOI
10.1371/journal.pone.0132259

Perceptions of Personalized Medicine in an Academic Health System: Educational Findings.

OBJECTIVE: Prior reports demonstrate that personalized medicine implementation in clinical care is lacking. Given the program focus at Duke University on personalized medicine, we assessed health care providers' perspectives on their preparation and educational needs to effectively integrate personalized medicine tools and applications into their clinical practices. METHODS: Data from 78 health care providers who participated in a larger study of personalized and precision medicine at Duke University were analyzed using Qualtrics (descriptive statistics). Individuals age 18 years and older were recruited for the larger study through broad email contacts across the university and health system. All participants completed an online 35-question survey that was developed, pilot-tested, and administered by a team of interdisciplinary researchers and clinicians at the Center for Applied Genomics and Precision Medicine. RESULTS: Overall, providers reported being ill-equipped to implement personalized medicine in clinical practice. Many respondents identified educational resources as critical for strengthening personalized medicine implementation in both research and clinical practice. Responses did not differ significantly between specialists and primary providers or by years since completion of the medical degree. CONCLUSIONS: Survey findings support prior calls for provider and patient education in personalized medicine. Respondents identified focus areas in training, education, and research for improving personalized medicine uptake. Given respondents' emphasis on educational needs, now may be an ideal time to address these needs in clinical training and public education programs.

Authors
Vorderstrasse, A; Katsanis, SH; Minear, MA; Yang, N; Rakhra-Burris, T; Reeves, JW; Cook-Deegan, R; Ginsburg, GS; Ann Simmons, L
MLA Citation
Vorderstrasse, Allison, et al. “Perceptions of Personalized Medicine in an Academic Health System: Educational Findings..” J Contemp Med Educ, vol. 3, no. 1, 2015, pp. 14–19. Pubmed, doi:10.5455/jcme.20150408050414.
Website
https://hdl.handle.net/10161/17574
PMID
26236542
Source
pubmed
Published In
Journal of Contemporary Medical Education
Volume
3
Issue
1
Publish Date
2015
Start Page
14
End Page
19
DOI
10.5455/jcme.20150408050414

Aspirin-Responsive Platelet Genes Are Associated With Platelet Function and Cardiovascular Events

Authors
Suchindran, S; Himmel, T; Ortel, TL; Becker, RC; Kraus, WE; Newby, LK; Ginsburg, GS; Voora, D
MLA Citation
Suchindran, Sunil, et al. “Aspirin-Responsive Platelet Genes Are Associated With Platelet Function and Cardiovascular Events.” Circulation, vol. 130, LIPPINCOTT WILLIAMS & WILKINS, Nov. 2014.
Source
wos
Published In
Circulation
Volume
130
Publish Date
2014

Immunogenicity of avian influenza A/Anhui/01/2005(H5N1) vaccine with MF59 adjuvant: a randomized clinical trial.

IMPORTANCE: The need to respond quickly to potential influenza pandemics is important. Immunologic priming (initial presentation of an antigen to allow antibody responses on revaccination) with vaccine directed toward an older avian influenza H5 strain might lead to secondary antibody responses to a single dose of more current H5 avian influenza vaccine. OBJECTIVES: To assess priming with the older avian influenza A/Vietnam/1203/2004(H5N1) (Vietnam) vaccine and to conduct dose-response studies with vaccine directed against the more contemporary H5N1 avian influenza virus, influenza A/Anhui/01/2005 (Anhui). DESIGN, SETTING, AND PARTICIPANTS: Multicenter US randomized clinical trial beginning in June 2010 with follow-up continuing through October 2011 enrolling 72 healthy adults who were vaccinated 1 year previously with the Vietnam vaccine and 565 vaccine-naive adults. INTERVENTIONS: Participants who were previously vaccinated with 90 µg of unadjuvanted Vietnam vaccine were randomly assigned to receive 3.75 µg of avian influenza Anhui vaccine with or without MF59 adjuvant, stratified by 1 vs 2 previous doses (1 dose: n = 18 with MF59 and n = 17 without; 2 doses: n = 19 with MF59 and n = 18 without). Vaccine-naive individuals were randomly assigned to receive Ahnui vaccine with or without MF59 adjuvant in 1 of 5 doses (3.75 µg [n = 55 with MF59 and n = 59 without], 7.5 µg [n = 51 with MF59 and n = 57 without], 15 µg [n = 48 with MF59 and n = 44 without], 45 µg [n = 47 with MF59 and n = 47 without], or 90 µg [n = 57 without adjuvant]) or placebo (n = 100) given at days 0 and 28. MAIN OUTCOMES AND MEASURES: The primary immunogenicity outcome was hemagglutination inhibition assay (HAI) titer against each vaccine antigen 1 month (day 28) and 6 months (day 180) after last vaccination. The primary safety outcomes were local and systemic adverse events on days 0 to 7 after each vaccination and serious adverse events. RESULTS: Previously vaccinated participants manifested secondary antibody responses after receipt of low-dose Anhui vaccine ("boosting"); by day 28, 21% to 50% developed HAI responses of 1:40 or greater. Use of adjuvant was not associated with increased HAI responses. Among vaccine-naive participants (n = 565), the optimum dose was 7.5 µg of antigen with adjuvant (geometric mean titer [GMT], 63.3; 95% CI, 43.0-93.1). The greatest response to unadjuvanted antigen was seen at the highest dose, 90 µg (GMT, 28.5; 95% CI, 19.7-41.2). Local or systemic reactions occurred, respectively, in 40 (78%) and 25 (49%) of 51 participants who received 7.5 µg plus adjuvant vs 50 (88%) and 29 (51%) of 57 who received 90 µg of unadjuvanted vaccine. In general, antibodies were short-lived, and by day 180, HAI titers had decreased to less than 1:20 in all treatment groups. CONCLUSIONS AND RELEVANCE: Previous receipt of a single dose of influenza A(H5N1) Vietnam vaccine was associated with sufficient immunologic priming to facilitate antibody response to a different H5N1 antigen using low-dose Anhui (booster) vaccine. In participants who had not previously received H5 vaccine, low-dose Anhui vaccine plus adjuvant was more immunogenic compared with higher doses of unadjuvanted vaccine. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00680069.

Authors
Belshe, RB; Frey, SE; Graham, IL; Anderson, EL; Jackson, LA; Spearman, P; Edupuganti, S; Mulligan, MJ; Rouphael, N; Winokur, P; Dolor, RJ; Woods, CW; Walter, EB; Chen, WH; Turley, C; Edwards, KM; Creech, CB; Hill, H; Bellamy, AR; National Institute of Allergy and Infectious Diseases–Funded Vaccine and Treatment Evaluation Units,
MLA Citation
Belshe, Robert B., et al. “Immunogenicity of avian influenza A/Anhui/01/2005(H5N1) vaccine with MF59 adjuvant: a randomized clinical trial..” Jama, vol. 312, no. 14, Oct. 2014, pp. 1420–28. Pubmed, doi:10.1001/jama.2014.12609.
PMID
25291578
Source
pubmed
Published In
Jama
Volume
312
Issue
14
Publish Date
2014
Start Page
1420
End Page
1428
DOI
10.1001/jama.2014.12609

G protein-coupled receptor kinase 5 gene polymorphisms are associated with postoperative atrial fibrillation after coronary artery bypass grafting in patients receiving β-blockers.

BACKGROUND: We hypothesized that genetic variations in the adrenergic signaling pathway and cytochrome P450 2D6 enzyme are associated with new-onset atrial fibrillation (AF) in patients who underwent coronary artery bypass grafting and were treated with perioperative β-blockers (BBs). METHODS AND RESULTS: Two cohorts of patients who underwent coronary artery bypass grafting and received perioperative BBs at Duke University Medical Center were studied. In a discovery cohort of 563 individuals from the Perioperative Genetics and Safety Outcomes Study (PEGASUS), using a covariate-adjusted logistic regression analysis, we tested 492 single-nucleotide polymorphisms (SNPs) in 10 candidate genes of the adrenergic signaling pathway and cytochrome P450 2D6 for association with postoperative AF despite perioperative BB therapy. SNPs meeting a false discovery rate ≤0.20 (P<0.002) were then tested in the replication cohort of 245 individuals from the Catheterization Genetics biorepository. Of the 492 SNPs examined, 4 intronic SNPs of the G protein-coupled kinase 5 (GRK5) gene were significantly associated with postoperative AF despite perioperative BB therapy in the discovery cohort with additive odds ratios between 1.72 and 2.75 (P=4.78×10(-5) to 0.0015). Three of these SNPs met nominal significance levels in the replication cohort with odds ratios between 2.07 and 2.60 (P=0.007 to 0.016). However, meta-analysis of the 2 data sets cohorts suggested strong association with postoperative AF despite perioperative BB therapy in all 4 SNPs (meta-P values from 1.66×10(-6) to 3.39×10(-5)). CONCLUSIONS: In patients undergoing coronary artery bypass grafting, genetic variation in GRK5 is associated with postoperative AF despite perioperative BB therapy.

Authors
Kertai, MD; Li, Y-W; Li, Y-J; Shah, SH; Kraus, WE; Fontes, ML; Stafford-Smith, M; Newman, MF; Podgoreanu, MV; Mathew, JP; Duke Perioperative Genetics and Safety Outcomes (PEGASUS) Investigative Team,
MLA Citation
Kertai, Miklos D., et al. “G protein-coupled receptor kinase 5 gene polymorphisms are associated with postoperative atrial fibrillation after coronary artery bypass grafting in patients receiving β-blockers..” Circ Cardiovasc Genet, vol. 7, no. 5, Oct. 2014, pp. 625–33. Pubmed, doi:10.1161/CIRCGENETICS.113.000451.
PMID
25049040
Source
pubmed
Published In
Circ Cardiovasc Genet
Volume
7
Issue
5
Publish Date
2014
Start Page
625
End Page
633
DOI
10.1161/CIRCGENETICS.113.000451

The current epidemiology and clinical decisions surrounding acute respiratory infections.

Acute respiratory infection (ARI) is a common diagnosis in outpatient and emergent care settings. Currently available diagnostics are limited, creating uncertainty in the use of antibacterial, antiviral, or supportive care. Up to 72% of ambulatory care patients with ARI are treated with an antibacterial, despite only a small fraction actually needing one. Antibiotic overuse is not restricted to ambulatory care: ARI accounts for approximately 5 million emergency department (ED) visits annually in the USA, where 52-61% of such patients receive antibiotics. Thus, an accurate test for the presence or absence of viral or bacterial infection is needed. In this review, we focus on recent research showing that the host-response (genomic, proteomic, or miRNA) can accomplish this task.

Authors
Zaas, AK; Garner, BH; Tsalik, EL; Burke, T; Woods, CW; Ginsburg, GS
MLA Citation
Zaas, Aimee K., et al. “The current epidemiology and clinical decisions surrounding acute respiratory infections..” Trends Mol Med, vol. 20, no. 10, Oct. 2014, pp. 579–88. Pubmed, doi:10.1016/j.molmed.2014.08.001.
PMID
25201713
Source
pubmed
Published In
Trends Mol Med
Volume
20
Issue
10
Publish Date
2014
Start Page
579
End Page
588
DOI
10.1016/j.molmed.2014.08.001

Pilot study of pharmacist-assisted delivery of pharmacogenetic testing in a primary care setting.

AIM: To describe the rationale and design of a pilot program to implement and evaluate pharmacogenetic (PGx) testing in a primary care setting. STUDY RATIONALE: Several factors have impeded the uptake of PGx testing, including lack of provider knowledge and challenges with operationalizing PGx testing in a clinical practice setting. STUDY DESIGN: We plan to compare two strategies for the implementation of PGx testing: a pharmacist-initiated testing arm compared with a physician-initiated PGx testing arm. Providers in both groups will be required to attend an introduction to PGx seminar. Anticipated results: We anticipate that providers in the pharmacist-initiated group will be more likely to order PGx testing than providers in the physician-initiated group. CONCLUSION: Overall, we aim to generate data that will inform an effective delivery model for PGx testing and to facilitate a seamless integration of PGx testing in primary care practices.

Authors
Haga, SB; LaPointe, NMA; Cho, A; Reed, SD; Mills, R; Moaddeb, J; Ginsburg, GS
MLA Citation
Haga, Susanne B., et al. “Pilot study of pharmacist-assisted delivery of pharmacogenetic testing in a primary care setting..” Pharmacogenomics, vol. 15, no. 13, Sept. 2014, pp. 1677–86. Pubmed, doi:10.2217/pgs.14.109.
PMID
25410893
Source
pubmed
Published In
Pharmacogenomics
Volume
15
Issue
13
Publish Date
2014
Start Page
1677
End Page
1686
DOI
10.2217/pgs.14.109

Detection of Bartonella species in the blood of veterinarians and veterinary technicians: a newly recognized occupational hazard?

BACKGROUND: Bartonella species are important emerging pathogens in human and veterinary medicine. In the context of their daily activities, veterinary professionals have frequent animal contact and arthropod exposures. Detection of Bartonella spp. using traditional culture methods has been limited by poor sensitivity, making it difficult to determine the prevalence of infection in this population. We have developed a detection method combining enrichment culture and molecular amplification, which increases testing sensitivity. METHODS: We performed a cross-sectional study to determine the prevalence of detectable Bartonella spp. in the blood of veterinary personnel and nonveterinary control subjects. Bartonella was detected by enrichment blood culture with conventional PCR followed by DNA sequencing. RESULTS were correlated with epidemiological variables and symptoms. RESULTS: We detected DNA from at least one Bartonella species in 32 (28%) of the 114 veterinary subjects. After DNA sequencing, the Bartonella species could be determined for 27 of the 32 infected subjects, including B. henselae in 15 (56%), B. vinsonii subsp. berkhoffii in seven (26%), B. koehlerae in six (22%), and a B. volans-like sequence in one (4%). Seventy percent of Bartonella-positive subjects described headache compared with 40% of uninfected veterinarians (p=0.009). Irritability was also reported more commonly by infected subjects (68% vs. 43%, p=0.04). CONCLUSIONS: Our study supports an emerging body of evidence that cryptic Bartonella bloodstream infection may be more frequent in humans than previously recognized and may induce symptoms. Longitudinal studies are needed to determine the natural course and clinical features of Bartonella infection.

Authors
Lantos, PM; Maggi, RG; Ferguson, B; Varkey, J; Park, LP; Breitschwerdt, EB; Woods, CW
MLA Citation
Lantos, Paul M., et al. “Detection of Bartonella species in the blood of veterinarians and veterinary technicians: a newly recognized occupational hazard?.” Vector Borne Zoonotic Dis, vol. 14, no. 8, Aug. 2014, pp. 563–70. Pubmed, doi:10.1089/vbz.2013.1512.
Website
http://hdl.handle.net/10161/13957
PMID
25072986
Source
pubmed
Published In
Vector Borne Zoonotic Dis
Volume
14
Issue
8
Publish Date
2014
Start Page
563
End Page
570
DOI
10.1089/vbz.2013.1512

Comparing reference-based RNA-Seq mapping methods for non-human primate data.

BACKGROUND: The application of next-generation sequencing technology to gene expression quantification analysis, namely, RNA-Sequencing, has transformed the way in which gene expression studies are conducted and analyzed. These advances are of particular interest to researchers studying organisms with missing or incomplete genomes, as the need for knowledge of sequence information is overcome. De novo assembly methods have gained widespread acceptance in the RNA-Seq community for organisms with no true reference genome or transcriptome. While such methods have tremendous utility, computational cost is still a significant challenge for organisms with large and complex genomes. RESULTS: In this manuscript, we present a comparison of four reference-based mapping methods for non-human primate data. We utilize TopHat2 and GSNAP for mapping to the human genome, and Bowtie2 and Stampy for mapping to the human genome and transcriptome for a total of six mapping approaches. For each of these methods, we explore mapping rates and locations, number of detected genes, correlations between computed expression values, and the utility of the resulting data for differential expression analysis. CONCLUSIONS: We show that reference-based mapping methods indeed have utility in RNA-Seq analysis of mammalian data with no true reference, and the details of mapping methods should be carefully considered when doing so. Critical algorithm features include short seed sequences, the allowance of mismatches, and the allowance of gapped alignments in addition to splice junction gaps. Such features facilitate sensitive alignment of non-human primate RNA-Seq data to a human reference.

Authors
Benjamin, AM; Nichols, M; Burke, TW; Ginsburg, GS; Lucas, JE
MLA Citation
Benjamin, Ashlee M., et al. “Comparing reference-based RNA-Seq mapping methods for non-human primate data..” Bmc Genomics, vol. 15, July 2014. Pubmed, doi:10.1186/1471-2164-15-570.
PMID
25001289
Source
pubmed
Published In
Bmc Genomics
Volume
15
Publish Date
2014
Start Page
570
DOI
10.1186/1471-2164-15-570

Tumor acquisition for biomarker research in lung cancer.

The biopsy collection data from two lung cancer trials that required fresh tumor samples be obtained for microarray analysis were reviewed. In the trial for advanced disease, microarray data were obtained on 50 patient samples, giving an overall success rate of 60.2%. The majority of the specimens were obtained through CT-guided lung biopsies (N = 30). In the trial for early-stage patients, 28 tissue specimens were collected from excess tumor after surgical resection with a success rate of 85.7%. This tissue procurement program documents the feasibility in obtaining fresh tumor specimens prospectively that could be used for molecular testing.

Authors
Stevenson, M; Christensen, J; Shoemaker, D; Foster, T; Barry, WT; Tong, BC; Wahidi, M; Shofer, S; Datto, M; Ginsburg, G; Crawford, J; D'Amico, T; Ready, N
MLA Citation
Stevenson, Marvaretta, et al. “Tumor acquisition for biomarker research in lung cancer..” Cancer Invest, vol. 32, no. 6, July 2014, pp. 291–98. Pubmed, doi:10.3109/07357907.2014.911880.
PMID
24810245
Source
pubmed
Published In
Cancer Invest
Volume
32
Issue
6
Publish Date
2014
Start Page
291
End Page
298
DOI
10.3109/07357907.2014.911880

Unsuspected leptospirosis is a cause of acute febrile illness in Nicaragua.

BACKGROUND: Epidemic severe leptospirosis was recognized in Nicaragua in 1995, but unrecognized epidemic and endemic disease remains unstudied. METHODOLOGY/PRINCIPAL FINDINGS: To determine the burden of and risk factors associated with symptomatic leptospirosis in Nicaragua, we prospectively studied patients presenting with fever at a large teaching hospital. Epidemiologic and clinical features were systematically recorded, and paired sera tested by IgM-ELISA to identify patients with probable and possible acute leptospirosis. Microscopic Agglutination Test and PCR were used to confirm acute leptospirosis. Among 704 patients with paired sera tested by MAT, 44 had acute leptospirosis. Patients with acute leptospirosis were more likely to present during rainy months and to report rural residence and fresh water exposure. The sensitivity of clinical impression and acute-phase IgM detected by ELISA were poor. CONCLUSIONS/SIGNIFICANCE: Leptospirosis is a common (6.3%) but unrecognized cause of acute febrile illness in Nicaragua. Rapid point-of-care tests to support early diagnosis and treatment as well as tests to support population-based studies to delineate the epidemiology, incidence, and clinical spectrum of leptospirosis, both ideally pathogen-based, are needed.

Authors
Reller, ME; Wunder, EA; Miles, JJ; Flom, JE; Mayorga, O; Woods, CW; Ko, AI; Dumler, JS; Matute, AJ
MLA Citation
Reller, Megan E., et al. “Unsuspected leptospirosis is a cause of acute febrile illness in Nicaragua..” Plos Negl Trop Dis, vol. 8, no. 7, July 2014. Pubmed, doi:10.1371/journal.pntd.0002941.
PMID
25058149
Source
pubmed
Published In
Plos Neglected Tropical Diseases
Volume
8
Issue
7
Publish Date
2014
Start Page
e2941
DOI
10.1371/journal.pntd.0002941

Changes in childhood pneumonia and infant mortality rates following introduction of the 13-valent pneumococcal conjugate vaccine in Nicaragua.

BACKGROUND: In 2010, Nicaragua became the first developing nation to add 13-valent pneumococcal conjugate vaccine (PCV-13) to its national immunization schedule, using a "3+0" dosing schedule. We assessed changes in incidence rates of health facility visits for childhood pneumonia and infant mortality after PCV-13 introduction in the Department of León, Nicaragua. METHODS: We collected visit diagnoses from all 107 public health facilities in León between 2008 and 2012. We compared rates of pneumonia hospitalizations, ambulatory visits for pneumonia and infant mortality during the prevaccine (2008-2010) and vaccine (2011-2012) periods among different age groups of children using generalized estimating equations, accounting for clustering by municipality. Exposure time was estimated by official municipality population estimates. RESULTS: The adjusted incidence rate ratio for pneumonia hospitalization in the vaccine versus prevaccine period was 0.67 (0.59-0.75) among infants and 0.74 (0.67-0.81) among 1-year olds. The adjusted incidence rate ratio for ambulatory visits for pneumonia was 0.87 (0.75-1.01) among infants, and 0.84 (0.74, 0.95) among 1-year olds. The adjusted incidence rate ratio for infant mortality was 0.67 (0.57-0.80). We also observed lower rates of health facility visits for pneumonia among age groups (2- to 4-year old and 5- to 14-year old) not eligible to receive PCV-13. CONCLUSIONS: Within the first 2 years of a PCV-13 immunization program in Nicaragua, we observed lower rates of hospitalizations and ambulatory visits for pneumonia among children of all ages and a lower infant mortality rate. Lower rates of pneumonia among age groups not eligible to receive PCV-13 suggest an indirect effect of the vaccine.

Authors
Becker-Dreps, S; Amaya, E; Liu, L; Moreno, G; Rocha, J; Briceño, R; Alemán, J; Hudgens, MG; Woods, CW; Weber, DJ
MLA Citation
Becker-Dreps, Sylvia, et al. “Changes in childhood pneumonia and infant mortality rates following introduction of the 13-valent pneumococcal conjugate vaccine in Nicaragua..” Pediatr Infect Dis J, vol. 33, no. 6, June 2014, pp. 637–42. Pubmed, doi:10.1097/INF.0000000000000269.
PMID
24445827
Source
pubmed
Published In
Pediatr Infect Dis J
Volume
33
Issue
6
Publish Date
2014
Start Page
637
End Page
642
DOI
10.1097/INF.0000000000000269

Providing patient education: impact on quantity and quality of family health history collection.

BACKGROUND: Family health history (FHH) is an underutilized tool in primary care to identify and risk-stratify individuals with increased cancer risk. OBJECTIVE: Evaluate the influence of patient education on quantity and quality of FHH entered into a primary care-based software program, and impact on the program's cancer risk management recommendations. DESIGN: Two primary care practices within a larger type II hybrid implementation-effectiveness controlled clinical trial. PARTICIPANTS: English speaking non-adopted patients with a well visit appointment December 2012-March 2013. INTERVENTIONS: One to two weeks prior to their well visit appointment, participants entered their FHH into the program. PARTICIPANTS were then provided educational materials describing key FHH components. They were instructed to use the interval to collect additional FHH information. Patients then returned for their scheduled appointment, and updated their FHH with any new information. MAIN MEASURES: Percentage per pedigree of relatives meeting individual quality criteria. Changes made after patient education and changes to recommendations for surveillance, chemoprevention or genetic counseling referral. KEY RESULTS: Post patient education, pedigrees exhibited a greater percentage (per pedigree) of: deceased relatives with age at death (84 vs. 81 % p = 0.02), deceased relatives with cause of death (91 vs. 87 % p = 0.02), relatives with a named health condition (45 vs. 42 % p = 0.002), and a greater percentage of relatives with high quality records (91 vs. 89 % p = 0.02). Of 43 participants with pedigree changes that could trigger changes in risk stratified prevention recommendations, 12 participants (28 %) received such changes. CONCLUSIONS: Patient education improves FHH collection and subsequent risk stratification utilized in providing actionable evidence-based care recommendations for cancer risk management.

Authors
Beadles, CA; Ryanne Wu, R; Himmel, T; Buchanan, AH; Powell, KP; Hauser, E; Henrich, VC; Ginsburg, GS; Orlando, LA
MLA Citation
Beadles, Chris A., et al. “Providing patient education: impact on quantity and quality of family health history collection..” Fam Cancer, vol. 13, no. 2, June 2014, pp. 325–32. Pubmed, doi:10.1007/s10689-014-9701-z.
PMID
24515581
Source
pubmed
Published In
Fam Cancer
Volume
13
Issue
2
Publish Date
2014
Start Page
325
End Page
332
DOI
10.1007/s10689-014-9701-z

Dusp3 and Psme3 are associated with murine susceptibility to Staphylococcus aureus infection and human sepsis.

Using A/J mice, which are susceptible to Staphylococcus aureus, we sought to identify genetic determinants of susceptibility to S. aureus, and evaluate their function with regard to S. aureus infection. One QTL region on chromosome 11 containing 422 genes was found to be significantly associated with susceptibility to S. aureus infection. Of these 422 genes, whole genome transcription profiling identified five genes (Dcaf7, Dusp3, Fam134c, Psme3, and Slc4a1) that were significantly differentially expressed in a) S. aureus -infected susceptible (A/J) vs. resistant (C57BL/6J) mice and b) humans with S. aureus blood stream infection vs. healthy subjects. Three of these genes (Dcaf7, Dusp3, and Psme3) were down-regulated in susceptible vs. resistant mice at both pre- and post-infection time points by qPCR. siRNA-mediated knockdown of Dusp3 and Psme3 induced significant increases of cytokine production in S. aureus-challenged RAW264.7 macrophages and bone marrow derived macrophages (BMDMs) through enhancing NF-κB signaling activity. Similar increases in cytokine production and NF-κB activity were also seen in BMDMs from CSS11 (C57BL/6J background with chromosome 11 from A/J), but not C57BL/6J. These findings suggest that Dusp3 and Psme3 contribute to S. aureus infection susceptibility in A/J mice and play a role in human S. aureus infection.

Authors
Yan, Q; Sharma-Kuinkel, BK; Deshmukh, H; Tsalik, EL; Cyr, DD; Lucas, J; Woods, CW; Scott, WK; Sempowski, GD; Thaden, JT; Rude, TH; Ahn, SH; Fowler, VG
MLA Citation
Yan, Qin, et al. “Dusp3 and Psme3 are associated with murine susceptibility to Staphylococcus aureus infection and human sepsis..” Plos Pathog, vol. 10, no. 6, June 2014. Pubmed, doi:10.1371/journal.ppat.1004149.
Website
http://hdl.handle.net/10161/9130
PMID
24901344
Source
pubmed
Published In
Plos Pathog
Volume
10
Issue
6
Publish Date
2014
Start Page
e1004149
DOI
10.1371/journal.ppat.1004149

Development of a novel preclinical model of pneumococcal pneumonia in nonhuman primates.

Pneumococcal pneumonia is a leading cause of bacterial infection and death worldwide. Current diagnostic tests for detecting Streptococcus pneumoniae can be unreliable and can mislead clinical decision-making and treatment. To address this concern, we developed a preclinical model of pneumococcal pneumonia in nonhuman primates useful for identifying novel biomarkers, diagnostic tests, and therapies for human S. pneumoniae infection. Adult colony-bred baboons (n = 15) were infected with escalating doses of S. pneumoniae (Serotype 19A-7). We characterized the pathophysiological and serological profiles of healthy and infected animals over 7 days. Pneumonia was prospectively defined by the presence of three criteria: (1) change in white blood cell count, (2) isolation of S. pneumoniae from bronchoalveolar lavage fluid (BALF) or blood, and (3) concurrent signs/symptoms of infection. Animals given 10(9) CFU consistently met our definition and developed a phenotype of tachypnea, tachycardia, fever, hypoxemia, and radiographic lobar infiltrates at 48 hours. BALF and plasma cytokines, including granulocyte colony-stimulating factor, IL-6, IL-10, and IL-1ra, peaked at 24 to 48 hours. At necropsy, there was lobar consolidation with frequent pleural involvement. Lung histopathology showed alveolar edema and macrophage influx in areas of organizing pneumonia. Hierarchical clustering of peripheral blood RNA data at 48 hours correctly identified animals with and without pneumonia. Dose-dependent inoculation of baboons with S. pneumoniae produces a host response ranging from spontaneous clearance (10(6) CFU) to severe pneumonia (10(9) CFU). Selected BALF and plasma cytokine levels and RNA profiles were associated with severe pneumonia and may provide clinically useful parameters after validation.

Authors
Kraft, BD; Piantadosi, CA; Benjamin, AM; Lucas, JE; Zaas, AK; Betancourt-Quiroz, M; Woods, CW; Chang, AL; Roggli, VL; Marshall, CD; Ginsburg, GS; Welty-Wolf, K
MLA Citation
Kraft, Bryan D., et al. “Development of a novel preclinical model of pneumococcal pneumonia in nonhuman primates..” Am J Respir Cell Mol Biol, vol. 50, no. 5, May 2014, pp. 995–1004. Pubmed, doi:10.1165/rcmb.2013-0340OC.
PMID
24328793
Source
pubmed
Published In
Am J Respir Cell Mol Biol
Volume
50
Issue
5
Publish Date
2014
Start Page
995
End Page
1004
DOI
10.1165/rcmb.2013-0340OC

Multiplex detection of disease biomarkers using SERS molecular sentinel-on-chip.

Developing techniques for multiplex detection of disease biomarkers is important for clinical diagnosis. In this work, we have demonstrated for the first time the feasibility of multiplex detection of genetic disease biomarkers using the surface-enhanced Raman scattering (SERS)-based molecular sentinel-on-chip (MSC) diagnostic technology. The molecular sentinel (MS) sensing mechanism is based upon the decrease of SERS intensity when Raman labels tagged at 3'-ends of MS nanoprobes are physically displaced from the nanowave chip's surface upon DNA hybridization. The use of bimetallic layer (silver and gold) for the nanowave fabrication was investigated. SERS measurements were performed immediately following a single hybridization reaction between the target single-stranded DNA sequences and the complementary MS nanoprobes immobilized on the nanowave chip without requiring target labeling (i.e., label-free), secondary hybridization, or post-hybridization washing, thus shortening the assay time and reducing cost. Two nucleic acid transcripts, interferon alpha-inducible protein 27 and interferon-induced protein 44-like, are used as model systems for the multiplex detection concept demonstration. These two genes are well known for their critical role in host immune response to viral infection and can be used as molecular signature for viral infection diagnosis. The results indicate the potential of the MSC technology for nucleic acid biomarker multiplex detection.

Authors
Ngo, HT; Wang, H-N; Burke, T; Ginsburg, GS; Vo-Dinh, T
MLA Citation
Ngo, Hoan T., et al. “Multiplex detection of disease biomarkers using SERS molecular sentinel-on-chip..” Anal Bioanal Chem, vol. 406, no. 14, May 2014, pp. 3335–44. Pubmed, doi:10.1007/s00216-014-7648-4.
PMID
24577572
Source
pubmed
Published In
Anal Bioanal Chem
Volume
406
Issue
14
Publish Date
2014
Start Page
3335
End Page
3344
DOI
10.1007/s00216-014-7648-4

Genomics-enabled drug repositioning and repurposing: insights from an IOM Roundtable activity.

Authors
Power, A; Berger, AC; Ginsburg, GS
MLA Citation
Power, Aidan, et al. “Genomics-enabled drug repositioning and repurposing: insights from an IOM Roundtable activity..” Jama, vol. 311, no. 20, May 2014, pp. 2063–64. Pubmed, doi:10.1001/jama.2014.3002.
PMID
24867009
Source
pubmed
Published In
Jama
Volume
311
Issue
20
Publish Date
2014
Start Page
2063
End Page
2064
DOI
10.1001/jama.2014.3002

Medical genomics: Gather and use genetic data in health care.

Authors
Ginsburg, G
MLA Citation
Ginsburg, Geoffrey. “Medical genomics: Gather and use genetic data in health care..” Nature, vol. 508, no. 7497, Apr. 2014, pp. 451–53. Pubmed, doi:10.1038/508451a.
PMID
24765668
Source
pubmed
Published In
Nature
Volume
508
Issue
7497
Publish Date
2014
Start Page
451
End Page
453
DOI
10.1038/508451a

Preoperative CYP2D6 metabolism-dependent β-blocker use and mortality after coronary artery bypass grafting surgery.

OBJECTIVE: Recently, the role of β-blockers (BBs) in reducing perioperative mortality has been challenged. The conflicting results might have resulted from the extent of BB metabolism by the cytochrome P-450 (CYP2D6) isoenzyme. The purpose of the present study was to assess the association between the preoperative use of BBs dependent on metabolism of the CYP2D6 isoenzyme with operative mortality after coronary artery bypass grafting surgery. METHODS: We performed a retrospective study of 5248 patients who had undergone coronary bypass grafting surgery from January 1, 2001 to November 30, 2009 at Duke University Medical Center. The cohorts were defined by the preoperative use of BBs and BB type (non-CYP2D6_BBs, CYP2D6_BBs, or no BBs). Operative mortality was analyzed using inverse probability-weighted estimators with propensity score adjustment. RESULTS: Of the 5248 patients, 14% received non-CYP2D6_BBs, 43%, CYP2D6_BBs, and 43%, no BBs. The incidence of operative mortality was 0.8%, 2.1%, and 3.7% in the non-CYP2D6_BB, CYP2D6_BB, and no BB groups, respectively. Multivariable inverse probability-weighted-adjusted analyses showed that non-CYP2D6_BBs were associated with a lower incidence of operative mortality (odds ratio, 0.33; 95% confidence interval, 0.13-0.83; P = .02) compared with no BB use and a trend toward lower operative mortality (odds ratio, 0.44; 95% confidence interval, 0.16-1.07; P = .06) compared with CYP2D6_BBs. No significant decrease occurred in the risk of operative mortality between the CYP2D6_BB and no BB groups (odds ratio, 0.85; 95% confidence interval, 0.54-1.34; P = .48). CONCLUSIONS: Among these patients, preoperative non-CYP2D6_BB use, but not CYP2D6_BB use, was associated with a decreased risk of operative mortality.

Authors
Kertai, MD; Esper, SA; Akushevich, I; Voora, D; Ginsburg, GS; Stafford-Smith, M; Grichnik, K; Newman, MF; Fontes, ML; Smith, P; Podgoreanu, MV; Mathew, JP; Cardiothoracic Anesthesia Research Endeavors (CARE) Group,
MLA Citation
Kertai, Miklos D., et al. “Preoperative CYP2D6 metabolism-dependent β-blocker use and mortality after coronary artery bypass grafting surgery..” J Thorac Cardiovasc Surg, vol. 147, no. 4, Apr. 2014, pp. 1368-1375.e3. Pubmed, doi:10.1016/j.jtcvs.2013.09.067.
Website
http://hdl.handle.net/10161/14831
PMID
24269121
Source
pubmed
Published In
The Journal of Thoracic and Cardiovascular Surgery
Volume
147
Issue
4
Publish Date
2014
Start Page
1368
End Page
1375.e3
DOI
10.1016/j.jtcvs.2013.09.067

Genetically guided statin therapy on statin perceptions, adherence, and cholesterol lowering: a pilot implementation study in primary care patients.

Statin adherence is often limited by side effects. The SLCO1B1*5 variant is a risk factor for statin side effects and exhibits statin-specific effects: highest with simvastatin/atorvastatin and lowest with pravastatin/rosuvastatin. The effects of SLCO1B1*5 genotype guided statin therapy (GGST) are unknown. Primary care patients (n = 58) who were nonadherent to statins and their providers received SLCO1B1*5 genotyping and guided recommendations via the electronic medical record (EMR). The primary outcome was the change in Beliefs about Medications Questionnaire, which measured patients' perceived needs for statins and concerns about adverse effects, measured before and after SLCO1B1*5 results. Concurrent controls (n = 59) were identified through the EMR to compare secondary outcomes: new statin prescriptions, statin utilization, and change in LDL-cholesterol (LDL-c). GGST patients had trends (p = 0.2) towards improved statin necessity and concerns. The largest changes were the "need for statin to prevent sickness" (p < 0.001) and "concern for statin to disrupt life" (p = 0.006). GGST patients had more statin prescriptions (p < 0.001), higher statin use (p < 0.001), and greater decrease in LDL-c (p = 0.059) during follow-up. EMR delivery of SLCO1B1*5 results and recommendations is feasible in the primary care setting. This novel intervention may improve patients' perceptions of statins and physician behaviors that promote higher statin adherence and lower LDL-c.

Authors
Li, JH; Joy, SV; Haga, SB; Orlando, LA; Kraus, WE; Ginsburg, GS; Voora, D
MLA Citation
Li, Josephine H., et al. “Genetically guided statin therapy on statin perceptions, adherence, and cholesterol lowering: a pilot implementation study in primary care patients..” J Pers Med, vol. 4, no. 2, Mar. 2014, pp. 147–62. Pubmed, doi:10.3390/jpm4020147.
PMID
25563221
Source
pubmed
Published In
Journal of Personalized Medicine
Volume
4
Issue
2
Publish Date
2014
Start Page
147
End Page
162
DOI
10.3390/jpm4020147

A novel diagnostic approach may reduce inappropriate antibiotic use for acute respiratory infections.

Respiratory infections can be due to a multitude of etiologies and are common throughout the world. Most are viral and self-limited, yet these infections are commonly treated with antibiotics thus contributing to the increase in resistance. Historically, infectious disease diagnostics have focused on identification of the microbial culprit at the site of infection but the specificity of host response as measured by the host transcriptome, now enables us to classify the etiology of infection agnostic to pathogen class. The ability to rapidly determine whether a similar set of symptoms is due to a virus, bacteria, or other agent from a common specimen (blood) will have far-reaching public health benefits, and further research is warranted to transfer this technology into the clinical setting.

Authors
Hudson, LL; Woods, CW; Ginsburg, GS
MLA Citation
Hudson, Lori L., et al. “A novel diagnostic approach may reduce inappropriate antibiotic use for acute respiratory infections..” Expert Rev Anti Infect Ther, vol. 12, no. 3, Mar. 2014, pp. 279–82. Pubmed, doi:10.1586/14787210.2014.881717.
PMID
24502765
Source
pubmed
Published In
Expert Rev Anti Infect Ther
Volume
12
Issue
3
Publish Date
2014
Start Page
279
End Page
282
DOI
10.1586/14787210.2014.881717

Implementing family health history risk stratification in primary care: impact of guideline criteria on populations and resource demand.

UNLABELLED: The Genomic Medicine Model aims to facilitate patient engagement, patient/provider education of genomics/personalized medicine, and uptake of risk-stratified evidence-based prevention guidelines using MeTree, a patient-facing family health history (FHH) collection and clinical decision support (CDS) program. Here we report the number of increased risk (above population-level risk) patients identified for breast/ovarian cancer, colon cancer, hereditary syndrome risk, and thrombosis; the prevalence of FHH elements triggering increased-risk status; and the resources needed to manage their risk. STUDY DESIGN: hybrid implementation-effectiveness study of adults with upcoming well-visits in 2 primary care practices in Greensboro, NC. PARTICIPANTS: 1,184, mean age = 58.8, female = 58% (N = 694), non-white = 20% (N = 215). Increased Risk: 44% (N = 523). RECOMMENDATIONS: genetic counseling = 26% (N = 308), breast MRI = 0.8% (N = 10), breast chemoprophylaxis = 5% (N = 58), early/frequent colonoscopies = 19% (N = 221), ovarian cancer screening referral = 1% (N = 14), thrombosis testing/counseling = 2.4% (N = 71). FHH elements: 8 FHH elements lead to 37.3% of the increased risk categorizations (by frequency): first-degree-relative (FDR) with polyps age ≥60 (7.1%, N = 85), three relatives with Lynch-related cancers (5.4%, N = 65), FDR with polyps age <60 (5.1%, N = 61), three relatives on same side of family with same cancer (4.9%, N = 59), Gail score ≥1.66% (4.9%, N = 58), two relatives with breast cancer (one ≤age 50) (4.1%, N = 49), one relative with breast cancer ≤age 40 (4.1%, N = 48), FDR with colon cancer age ≥60 (1.7%, N = 20). MeTree identifies a high percentage of individuals in the general primary care population needing non-routine risk management/prevention for the selected conditions. Implementing risk-stratification in primary care will likely increase demand for related-resources, particularly colon screening and GC. Understanding the prevalence of FHH elements helps predict resource needs and may aid in guideline development.

Authors
Orlando, LA; Wu, RR; Beadles, C; Himmel, T; Buchanan, AH; Powell, KP; Hauser, ER; Henrich, VC; Ginsburg, GS
MLA Citation
Orlando, Lori A., et al. “Implementing family health history risk stratification in primary care: impact of guideline criteria on populations and resource demand..” Am J Med Genet C Semin Med Genet, vol. 166C, no. 1, Mar. 2014, pp. 24–33. Pubmed, doi:10.1002/ajmg.c.31388.
PMID
24616329
Source
pubmed
Published In
Am J Med Genet C Semin Med Genet
Volume
166C
Issue
1
Publish Date
2014
Start Page
24
End Page
33
DOI
10.1002/ajmg.c.31388

Quality of family history collection with use of a patient facing family history assessment tool.

BACKGROUND: Studies have shown that the quality of family health history (FHH) collection in primary care is inadequate to assess disease risk. To use FHH for risk assessment, collected data must have adequate detail. To address this issue, we developed a patient facing FHH assessment tool, MeTree. In this paper we report the content and quality of the FHH collected using MeTree. METHODS: DESIGN: A hybrid implementation-effectiveness study. Patients were recruited from 2009 to 2012. SETTING: Two community primary care clinics in Greensboro, NC. PARTICIPANTS: All non-adopted adult English speaking patients with upcoming appointments were invited to participate. INTERVENTION: Education about and collection of FHH with entry into MeTree. MEASURES: We report the proportion of pedigrees that were high-quality. High-quality pedigrees are defined as having all the following criteria: (1) three generations of relatives, (2) relatives' lineage, (3) relatives' gender, (4) an up-to-date FHH, (5) pertinent negatives noted, (6) age of disease onset in affected relatives, and for deceased relatives, (7) the age and (8) cause of death (Prim Care31:479-495, 2004.). RESULTS: Enrollment: 1,184. Participant demographics: age range 18-92 (mean 58.8, SD 11.79), 56% male, and 75% white. The median pedigree size was 21 (range 8-71) and the FHH entered into MeTree resulted in a database of 27,406 individuals. FHHs collected by MeTree were found to be high quality in 99.8% (N = 1,182/1,184) as compared to <4% at baseline. An average of 1.9 relatives per pedigree (range 0-50, SD 4.14) had no data reported. For pedigrees where at least one relative has no data (N = 497/1,184), 4.97 relatives per pedigree (range 1-50, SD 5.44) had no data. Talking with family members before using MeTree significantly decreased the proportion of relatives with no data reported (4.98% if you talked to your relative vs. 10.85% if you did not, p-value < 0.001.). CONCLUSION: Using MeTree improves the quantity and quality of the FHH data that is collected and talking with relatives prior to the collection of FHH significantly improves the quantity and quality of the data provided. This allows more patients to be accurately risk stratified and offered appropriate preventive care guided by their risk level. TRIAL NUMBER: NCT01372553.

Authors
Wu, RR; Himmel, TL; Buchanan, AH; Powell, KP; Hauser, ER; Ginsburg, GS; Henrich, VC; Orlando, LA
MLA Citation
Wu, R. Ryanne, et al. “Quality of family history collection with use of a patient facing family history assessment tool..” Bmc Fam Pract, vol. 15, Feb. 2014. Pubmed, doi:10.1186/1471-2296-15-31.
PMID
24520818
Source
pubmed
Published In
Bmc Family Practice
Volume
15
Publish Date
2014
Start Page
31
DOI
10.1186/1471-2296-15-31

Bayesian modeling of temporal properties of infectious disease in a college student population

A Bayesian statistical model is developed for analysis of the time-evolving properties of infectious disease, with a particular focus on viruses. The model employs a latent semi-Markovian state process, and the state-transition statistics are driven by three terms: (i) a general time-evolving trend of the overall population, (ii) a semi-periodic term that accounts for effects caused by the days of the week, and (iii) a regression term that relates the probability of infection to covariates (here, specifically, to the Google Flu Trends data). Computations are performed using Markov Chain Monte Carlo sampling. Results are presented using a novel data set: daily self-reported symptom scores from hundreds of Duke University undergraduate students, collected over three academic years. The illnesses associated with these students are (imperfectly) labeled using real-time (RT) polymerase chain reaction (PCR) testing for several viruses, and gene-expression data were also analyzed. The statistical analysis is performed on the daily, self-reported symptom scores, and the RT PCR and gene-expression data are employed for analysis and interpretation of the model results. © 2013 The Author(s). Published by Taylor & Francis.

Authors
Xing, Z; Nicholson, B; Jimenez, M; Veldman, T; Hudson, L; Lucas, J; Dunson, D; Zaas, AK; Woods, CW; Ginsburg, GS; Carin, L
MLA Citation
Xing, Z., et al. “Bayesian modeling of temporal properties of infectious disease in a college student population.” Journal of Applied Statistics, vol. 41, no. 6, Jan. 2014, pp. 1358–82. Scopus, doi:10.1080/02664763.2013.870138.
Source
scopus
Published In
Journal of Applied Statistics
Volume
41
Issue
6
Publish Date
2014
Start Page
1358
End Page
1382
DOI
10.1080/02664763.2013.870138

Platelet RNA as a novel biomarker for the response to antiplatelet therapy.

Authors
Voora, D; Ginsburg, GS; Akerblom, A
MLA Citation
Voora, Deepak, et al. “Platelet RNA as a novel biomarker for the response to antiplatelet therapy..” Future Cardiol, vol. 10, no. 1, Jan. 2014, pp. 9–12. Pubmed, doi:10.2217/fca.13.90.
PMID
24344654
Source
pubmed
Published In
Future Cardiol
Volume
10
Issue
1
Publish Date
2014
Start Page
9
End Page
12
DOI
10.2217/fca.13.90

Impact of delivery models on understanding genomic risk for type 2 diabetes.

BACKGROUND: Genetic information, typically communicated in-person by genetic counselors, can be challenging to comprehend; delivery of this information online--as is becoming more common--has the potential of increasing these challenges. METHODS: To address the impact of the mode of delivery of genomic risk information, 300 individuals were recruited from the general public and randomized to receive genomic risk information for type 2 diabetes mellitus in-person from a board-certified genetic counselor or online through the testing company's website. RESULTS: Participants were asked to indicate their genomic risk and overall lifetime risk as reported on their test report as well as to interpret their genomic risk (increased, decreased, or same as population). For each question, 59% of participants correctly indicated their risk. Participants who received their results in-person were more likely than those who reviewed their results on-line to correctly interpret their genomic risk (72 vs. 47%, p = 0.0002) and report their actual genomic risk (69 vs. 49%, p = 0.002). CONCLUSIONS: The delivery of personal genomic risk through a trained health professional resulted in significantly higher comprehension. Therefore, if the online delivery of genomic test results is to become more widespread, further evaluation of this method of communication may be needed to ensure the effective presentation of results to promote comprehension.

Authors
Haga, SB; Barry, WT; Mills, R; Svetkey, L; Suchindran, S; Willard, HF; Ginsburg, GS
MLA Citation
Haga, S. B., et al. “Impact of delivery models on understanding genomic risk for type 2 diabetes..” Public Health Genomics, vol. 17, no. 2, 2014, pp. 95–104. Pubmed, doi:10.1159/000358413.
PMID
24577154
Source
pubmed
Published In
Public Health Genomics
Volume
17
Issue
2
Publish Date
2014
Start Page
95
End Page
104
DOI
10.1159/000358413

Quality of family history collection with use of a patient facing family history assessment tool

Background: Studies have shown that the quality of family health history (FHH) collection in primary care is inadequate to assess disease risk. To use FHH for risk assessment, collected data must have adequate detail. To address this issue, we developed a patient facing FHH assessment tool, MeTree. In this paper we report the content and quality of the FHH collected using MeTree. Methods. Design: A hybrid implementation-effectiveness study. Patients were recruited from 2009 to 2012. Setting: Two community primary care clinics in Greensboro, NC. Participants: All non-adopted adult English speaking patients with upcoming appointments were invited to participate. Intervention: Education about and collection of FHH with entry into MeTree. Measures: We report the proportion of pedigrees that were high-quality. High-quality pedigrees are defined as having all the following criteria: (1) three generations of relatives, (2) relatives' lineage, (3) relatives' gender, (4) an up-to-date FHH, (5) pertinent negatives noted, (6) age of disease onset in affected relatives, and for deceased relatives, (7) the age and (8) cause of death (Prim Care 31:479-495, 2004.). Results: Enrollment: 1,184. Participant demographics: age range 18-92 (mean 58.8, SD 11.79), 56% male, and 75% white. The median pedigree size was 21 (range 8-71) and the FHH entered into MeTree resulted in a database of 27,406 individuals. FHHs collected by MeTree were found to be high quality in 99.8% (N = 1,182/1,184) as compared to <4% at baseline. An average of 1.9 relatives per pedigree (range 0-50, SD 4.14) had no data reported. For pedigrees where at least one relative has no data (N = 497/1,184), 4.97 relatives per pedigree (range 1-50, SD 5.44) had no data. Talking with family members before using MeTree significantly decreased the proportion of relatives with no data reported (4.98% if you talked to your relative vs. 10.85% if you did not, p-value < 0.001.). Conclusion: Using MeTree improves the quantity and quality of the FHH data that is collected and talking with relatives prior to the collection of FHH significantly improves the quantity and quality of the data provided. This allows more patients to be accurately risk stratified and offered appropriate preventive care guided by their risk level. Trial number. NCT01372553. © 2014 Wu et al.; licensee BioMed Central Ltd.

Authors
Wu, RR; Himmel, TL; Buchanan, AH; Powell, KP; Hauser, ER; Ginsburg, GS; Henrich, VC; Orlando, LA
MLA Citation
Wu, R. R., et al. “Quality of family history collection with use of a patient facing family history assessment tool.” Bmc Family Practice, vol. 15, no. 1, 2014. Scival, doi:10.1186/1471-2296-15-31.
Source
scival
Published In
Bmc Family Practice
Volume
15
Issue
1
Publish Date
2014
DOI
10.1186/1471-2296-15-31

An integrated transcriptome and expressed variant analysis of sepsis survival and death.

BACKGROUND: Sepsis, a leading cause of morbidity and mortality, is not a homogeneous disease but rather a syndrome encompassing many heterogeneous pathophysiologies. Patient factors including genetics predispose to poor outcomes, though current clinical characterizations fail to identify those at greatest risk of progression and mortality. METHODS: The Community Acquired Pneumonia and Sepsis Outcome Diagnostic study enrolled 1,152 subjects with suspected sepsis. We sequenced peripheral blood RNA of 129 representative subjects with systemic inflammatory response syndrome (SIRS) or sepsis (SIRS due to infection), including 78 sepsis survivors and 28 sepsis non-survivors who had previously undergone plasma proteomic and metabolomic profiling. Gene expression differences were identified between sepsis survivors, sepsis non-survivors, and SIRS followed by gene enrichment pathway analysis. Expressed sequence variants were identified followed by testing for association with sepsis outcomes. RESULTS: The expression of 338 genes differed between subjects with SIRS and those with sepsis, primarily reflecting immune activation in sepsis. Expression of 1,238 genes differed with sepsis outcome: non-survivors had lower expression of many immune function-related genes. Functional genetic variants associated with sepsis mortality were sought based on a common disease-rare variant hypothesis. VPS9D1, whose expression was increased in sepsis survivors, had a higher burden of missense variants in sepsis survivors. The presence of variants was associated with altered expression of 3,799 genes, primarily reflecting Golgi and endosome biology. CONCLUSIONS: The activation of immune response-related genes seen in sepsis survivors was muted in sepsis non-survivors. The association of sepsis survival with a robust immune response and the presence of missense variants in VPS9D1 warrants replication and further functional studies. TRIAL REGISTRATION: ClinicalTrials.gov NCT00258869. Registered on 23 November 2005.

Authors
Tsalik, EL; Langley, RJ; Dinwiddie, DL; Miller, NA; Yoo, B; van Velkinburgh, JC; Smith, LD; Thiffault, I; Jaehne, AK; Valente, AM; Henao, R; Yuan, X; Glickman, SW; Rice, BJ; McClain, MT; Carin, L; Corey, GR; Ginsburg, GS; Cairns, CB; Otero, RM; Fowler, VG; Rivers, EP; Woods, CW; Kingsmore, SF
MLA Citation
Tsalik, Ephraim L., et al. “An integrated transcriptome and expressed variant analysis of sepsis survival and death..” Genome Med, vol. 6, no. 11, 2014. Pubmed, doi:10.1186/s13073-014-0111-5.
Website
http://hdl.handle.net/10161/13120
PMID
25538794
Source
pubmed
Published In
Genome Medicine
Volume
6
Issue
11
Publish Date
2014
Start Page
111
DOI
10.1186/s13073-014-0111-5

Longitudinal analysis of leukocyte differentials in peripheral blood of patients with acute respiratory viral infections.

BACKGROUND: Leukocyte counts and differentials are commonly acquired in patients with suspected respiratory viral infections and may contribute diagnostic information. However, most published work is limited to a single timepoint at initial presentation to a medical provider, which may correspond to widely varying points in the course of disease. OBJECTIVES: To examine the temporal development and time-dependent utility of routine leukocyte differentials in the diagnosis of respiratory viral infections. STUDY DESIGN: We analyzed data from recent experimental human challenges with influenza A/H3N2, human rhinovirus (HRV), and respiratory syncytial virus (RSV). Routine clinical lab cell counts and differentials were measured daily from the time period immediately prior to inoculation through the eventual resolution of symptomatic disease. RESULTS: Approximately 50% of challenged individuals developed symptoms and viral shedding consistent with clinical disease. Subpopulations of WBC showed marked differences between symptomatic and asymptomatic individuals over time, but these changes were much more profound and consistent in influenza infection. Influenza-infected subjects develop both relative lymphopenia and relative monocytosis, both of which closely mirror symptom development in time. A lymphocyte:monocyte ratio of <2 correctly classifies 100% of influenza (but not RSV or HRV) infected subjects at the time of maximal symptoms. CONCLUSIONS: Leukocyte differentials may suggest a viral etiology in patients with upper respiratory infection, but are not sufficient to allow differentiation between common viruses. Timing of data acquisition relative to the disease course is a key component in determining the utility of these tests.

Authors
McClain, MT; Park, LP; Nicholson, B; Veldman, T; Zaas, AK; Turner, R; Lambkin-Williams, R; Gilbert, AS; Ginsburg, GS; Woods, CW
MLA Citation
McClain, Micah T., et al. “Longitudinal analysis of leukocyte differentials in peripheral blood of patients with acute respiratory viral infections..” J Clin Virol, vol. 58, no. 4, Dec. 2013, pp. 689–95. Pubmed, doi:10.1016/j.jcv.2013.09.015.
PMID
24140015
Source
pubmed
Published In
J Clin Virol
Volume
58
Issue
4
Publish Date
2013
Start Page
689
End Page
695
DOI
10.1016/j.jcv.2013.09.015

Effect of SLCO1B1*5 on Low-Density Lipoprotein Cholesterol Levels and Long-Term Clinical Events in Patients During Statin Therapy Following Cardiac Catheterization

Authors
Li, JH; Suchindran, S; Shah, SH; Kraus, WE; Ginsburg, GS; Voora, D
MLA Citation
Li, Josephine H., et al. “Effect of SLCO1B1*5 on Low-Density Lipoprotein Cholesterol Levels and Long-Term Clinical Events in Patients During Statin Therapy Following Cardiac Catheterization.” Circulation, vol. 128, no. 22, LIPPINCOTT WILLIAMS & WILKINS, 2013.
Source
wos
Published In
Circulation
Volume
128
Issue
22
Publish Date
2013

Plasma microRNA signature as a noninvasive biomarker for acute graft-versus-host disease.

Acute graft-versus-host disease (aGVHD) is the leading cause of morbidity and mortality after allogeneic hematopoietic cell transplantation (HCT). Approximately 35% to 50% of HCT recipients develop aGVHD; however, there are no validated diagnostic and predictive blood biomarkers for aGVHD in clinical use. Here, we show that plasma samples from aGVHD patients have a distinct microRNA (miRNA) expression profile. We found that 6 miRNAs (miR-423, miR-199a-3p, miR-93*, miR-377, miR-155, and miR-30a) were significantly upregulated in the plasma of aGVHD patients (n = 116) when compared with non-GVHD patients (n = 52) in training and validation phases. We have developed a model including 4 miRNAs (miR-423, miR-199a-3p, miR-93*, and miR-377) that can predict the probability of aGVHD with an area under the curve of 0.80. Moreover, these elevated miRNAs were detected before the onset of aGVHD (median = 16 days before diagnosis). In addition, the levels of these miRNAs were positively associated with aGVHD severity, and high expression of the miRNA panel was associated with poor overall survival. Furthermore, the miRNA signature for aGVHD was not detected in the plasma of lung transplant or nontransplant sepsis patients. Our results have identified a specific plasma miRNA signature that may serve as an independent biomarker for the prediction, diagnosis, and prognosis of aGVHD.

Authors
Xiao, B; Wang, Y; Li, W; Baker, M; Guo, J; Corbet, K; Tsalik, EL; Li, Q-J; Palmer, SM; Woods, CW; Li, Z; Chao, NJ; He, Y-W
MLA Citation
Xiao, Bin, et al. “Plasma microRNA signature as a noninvasive biomarker for acute graft-versus-host disease..” Blood, vol. 122, no. 19, Nov. 2013, pp. 3365–75. Pubmed, doi:10.1182/blood-2013-06-510586.
PMID
24041574
Source
pubmed
Published In
Blood
Volume
122
Issue
19
Publish Date
2013
Start Page
3365
End Page
3375
DOI
10.1182/blood-2013-06-510586

Educating future providers of personalized medicine.

Authors
Katsanis, SH; Dungan, JR; Gilliss, CL; Ginsburg, GA
MLA Citation
Katsanis, Sara H., et al. “Educating future providers of personalized medicine..” N C Med J, vol. 74, no. 6, Nov. 2013, pp. 491–92.
Website
https://hdl.handle.net/10161/17568
PMID
24316773
Source
pubmed
Published In
North Carolina Medical Journal
Volume
74
Issue
6
Publish Date
2013
Start Page
491
End Page
492

Aspirin exposure reveals novel genes associated with platelet function and cardiovascular events.

OBJECTIVES: The aim of this study was to develop ribonucleic acid (RNA) profiles that could serve as novel biomarkers for the response to aspirin. BACKGROUND: Aspirin reduces death and myocardial infarction (MI), suggesting that aspirin interacts with biological pathways that may underlie these events. METHODS: Aspirin was administered, followed by whole-blood RNA microarray profiling, in a discovery cohort of healthy volunteers (HV1) (n = 50) and 2 validation cohorts of healthy volunteers (HV2) (n = 53) and outpatient cardiology patients (OPC) (n = 25). Platelet function was assessed using the platelet function score (PFS) in HV1 and HV2 and the VerifyNow Aspirin Test (Accumetrics, Inc., San Diego, California) in OPC. Bayesian sparse factor analysis identified sets of coexpressed transcripts, which were examined for associations with PFS in HV1 and validated in HV2 and OPC. Proteomic analysis confirmed the association of validated transcripts in platelet proteins. Validated gene sets were tested for association with death or MI in 2 patient cohorts (n = 587 total) from RNA samples collected at cardiac catheterization. RESULTS: A set of 60 coexpressed genes named the "aspirin response signature" (ARS) was associated with PFS in HV1 (r = -0.31, p = 0.03), HV2 (r = -0.34, Bonferroni p = 0.03), and OPC (p = 0.046). Corresponding proteins for the 17 ARS genes were identified in the platelet proteome, of which 6 were associated with PFS. The ARS was associated with death or MI in both patient cohorts (odds ratio: 1.2 [p = 0.01]; hazard ratio: 1.5 [p = 0.001]), independent of cardiovascular risk factors. Compared with traditional risk factors, reclassification (net reclassification index = 31% to 37%, p ≤ 0.0002) was improved by including the ARS or 1 of its genes, ITGA2B. CONCLUSIONS: RNA profiles of platelet-specific genes are novel biomarkers for identifying patients who do not respond adequately to aspirin and who are at risk for death or MI.

Authors
Voora, D; Cyr, D; Lucas, J; Chi, J-T; Dungan, J; McCaffrey, TA; Katz, R; Newby, LK; Kraus, WE; Becker, RC; Ortel, TL; Ginsburg, GS
MLA Citation
Voora, Deepak, et al. “Aspirin exposure reveals novel genes associated with platelet function and cardiovascular events..” J Am Coll Cardiol, vol. 62, no. 14, Oct. 2013, pp. 1267–76. Pubmed, doi:10.1016/j.jacc.2013.05.073.
PMID
23831034
Source
pubmed
Published In
J Am Coll Cardiol
Volume
62
Issue
14
Publish Date
2013
Start Page
1267
End Page
1276
DOI
10.1016/j.jacc.2013.05.073

Overcoming barriers in the implementation of personalized medicine into clinical practice.

Authors
Cohen, MJ; Ginsburg, GS; Abrahams, E; Bitterman, H; Karnieli, E
MLA Citation
Cohen, Matan J., et al. “Overcoming barriers in the implementation of personalized medicine into clinical practice..” Isr Med Assoc J, vol. 15, no. 10, Oct. 2013, pp. 599–601.
PMID
24266084
Source
pubmed
Published In
The Israel Medical Association Journal : Imaj
Volume
15
Issue
10
Publish Date
2013
Start Page
599
End Page
601

A host-based RT-PCR gene expression signature to identify acute respiratory viral infection.

Improved ways to diagnose acute respiratory viral infections could decrease inappropriate antibacterial use and serve as a vital triage mechanism in the event of a potential viral pandemic. Measurement of the host response to infection is an alternative to pathogen-based diagnostic testing and may improve diagnostic accuracy. We have developed a host-based assay with a reverse transcription polymerase chain reaction (RT-PCR) TaqMan low-density array (TLDA) platform for classifying respiratory viral infection. We developed the assay using two cohorts experimentally infected with influenza A H3N2/Wisconsin or influenza A H1N1/Brisbane, and validated the assay in a sample of adults presenting to the emergency department with fever (n = 102) and in healthy volunteers (n = 41). Peripheral blood RNA samples were obtained from individuals who underwent experimental viral challenge or who presented to the emergency department and had microbiologically proven viral respiratory infection or systemic bacterial infection. The selected gene set on the RT-PCR TLDA assay classified participants with experimentally induced influenza H3N2 and H1N1 infection with 100 and 87% accuracy, respectively. We validated this host gene expression signature in a cohort of 102 individuals arriving at the emergency department. The sensitivity of the RT-PCR test was 89% [95% confidence interval (CI), 72 to 98%], and the specificity was 94% (95% CI, 86 to 99%). These results show that RT-PCR-based detection of a host gene expression signature can classify individuals with respiratory viral infection and sets the stage for prospective evaluation of this diagnostic approach in a clinical setting.

Authors
Zaas, AK; Burke, T; Chen, M; McClain, M; Nicholson, B; Veldman, T; Tsalik, EL; Fowler, V; Rivers, EP; Otero, R; Kingsmore, SF; Voora, D; Lucas, J; Hero, AO; Carin, L; Woods, CW; Ginsburg, GS
MLA Citation
Zaas, Aimee K., et al. “A host-based RT-PCR gene expression signature to identify acute respiratory viral infection..” Sci Transl Med, vol. 5, no. 203, Sept. 2013. Pubmed, doi:10.1126/scitranslmed.3006280.
PMID
24048524
Source
pubmed
Published In
Sci Transl Med
Volume
5
Issue
203
Publish Date
2013
Start Page
203ra126
DOI
10.1126/scitranslmed.3006280

Implementing Genomic Medicine in the Clinic: The Future Is Here EDITORIAL COMMENT

Authors
Manolio, TA; Chisholm, RL; Ozenberger, B; Roden, DM; Williams, MS; Wilson, R; Bick, D; Bottinger, EP; Brilliant, MH; Eng, C; Frazer, KA; Korf, B; Ledbetter, DH; Lupski, JR; Marsh, C; Mrazek, D; Murray, MF; O'Donnell, PH; Rader, DJ; Relling, MV; Shuldiner, AR; Valle, D; Weinshilboum, R; Green, ED; Ginsburg, GS
MLA Citation
Manolio, Teri A., et al. “Implementing Genomic Medicine in the Clinic: The Future Is Here EDITORIAL COMMENT.” Obstetrical & Gynecological Survey, vol. 68, no. 9, LIPPINCOTT WILLIAMS & WILKINS, Sept. 2013, pp. 621–23.
Source
wos
Published In
Obstetrical & Gynecological Survey
Volume
68
Issue
9
Publish Date
2013
Start Page
621
End Page
623

Preface

Authors
Ginsburg, GS; Willard, HF
MLA Citation
Ginsburg, G. S., and H. F. Willard. “Preface.” Genomic and Personalized Medicine, vol. 1, Aug. 2013. Scopus, doi:10.1016/B978-0-12-382227-7.00125-7.
Source
scopus
Published In
Genomic and Personalized Medicine
Volume
1
Publish Date
2013
DOI
10.1016/B978-0-12-382227-7.00125-7

Application of Human Genome Information to Clinical Practice

Authors
Ginsburg, GS
MLA Citation
Ginsburg, G. S. Application of Human Genome Information to Clinical Practice. Vol. 1, Aug. 2013, pp. 204–15. Scopus, doi:10.1016/B978-0-12-382227-7.00017-3.
Source
scopus
Volume
1
Publish Date
2013
Start Page
204
End Page
215
DOI
10.1016/B978-0-12-382227-7.00017-3

Sepsis

Authors
Kingsmore, SF; Woods, CW; Saunders, CJ
MLA Citation
Kingsmore, S. F., et al. Sepsis. Vol. 2, Aug. 2013, pp. 1155–72. Scopus, doi:10.1016/B978-0-12-382227-7.00098-7.
Source
scopus
Volume
2
Publish Date
2013
Start Page
1155
End Page
1172
DOI
10.1016/B978-0-12-382227-7.00098-7

Genomic and Personalized Medicine

With advancing knowledge of the genome across and outside protein-coding regions of DNA, new comprehension of genomic variation and frequencies across populations, the elucidation of advanced strategic approaches to genomic study, and above all in the elaboration of next-generation sequencing, genomic medicine has begun to achieve the much-vaunted transformative health outcomes of the Human Genome Project, almost a decade after its official completion in April 2003. Genomic and Personalized Medicine 2nd edition is a major discussion of the structure, history, and applications of the field, as it emerges from the campus and lab into clinical action. As with the first edition, leading experts review the development of the new science, the current opportunities for genome-based analysis in healthcare, and the potential of genomic medicine in future healthcare. The inclusion of the latest information on diagnostic testing, population screening, disease susceptability, and pharmacogenomics makes this work an ideal companion for the many stakeholders of genomic and personalized medicine. Over 100 chapters, from leading researchers, review the many impacts of genomic discoveries in clinical action, including 63 chapters new to this edition Discusses state-of-the-art genome technologies, including population screening, novel diagnostics, and gene-based therapeutics Wide and inclusive discussion encompasses the formidable ethical, legal, regulatory and social challenges related to the evolving practice of genomic medicine Clearly and beautifully illustrated with 280 color figures, and many thousands of references for further reading and deeper analysis. © 2013 Elsevier Inc. All rights reserved.

Authors
Ginsburg, G; Willard, H
MLA Citation
Ginsburg, G., and H. Willard. “Genomic and Personalized Medicine.” Genomic and Personalized Medicine, vol. 1–2, Aug. 2013.
Source
scopus
Published In
Genomic and Personalized Medicine
Volume
1-2
Publish Date
2013

Patient and primary care provider experience using a family health history collection, risk stratification, and clinical decision support tool: a type 2 hybrid controlled implementation-effectiveness trial.

BACKGROUND: Family health history (FHH) is the single strongest predictor of disease risk and yet is significantly underutilized in primary care. We developed a patient facing FHH collection tool, MeTree, that uses risk stratification to generate clinical decision support for breast cancer, colorectal cancer, ovarian cancer, hereditary cancer syndromes, and thrombosis. Here we present data on the experience of patients and providers after integration of MeTree into 2 primary care practices. METHODS: This was a Type 2 hybrid controlled implementation-effectiveness study in 3 community-based primary care clinics in Greensboro, NC. All non-adopted adult English speaking patients with upcoming routine appointments were invited. Patients were recruited from December 2009 to the present and followed for one year. Ease of integration of MeTree into clinical practice at the two intervention clinics was evaluated through patient surveys after their appointment and at 3 months post-visit, and physician surveys 3 months after tool integration. RESULTS: Total enrollment =1,184. Average time to complete MeTree = 27 minutes. Patients found MeTree: easy to use (93%), easy to understand (97%), useful (98%), raised awareness of disease risk (85%), and changed how they think about their health (86%). Of the 26% (N = 311) asking for assistance to complete the tool, age (65 sd 9.4 vs. 57 sd 11.8, p-value < 0.00) and large pedigree size (24.4 sd 9.81 vs. 22.2 sd 8.30, p-value < 0.00) were the only significant factors; 77% of those requiring assistance were over the age of 60. Providers (N = 14) found MeTree: improved their practice (86%), improved their understanding of FHH (64%), made practice easier (79%), and worthy of recommending to their peers (93%). CONCLUSIONS: Our study shows that MeTree has broad acceptance and support from both patients and providers and can be implemented without disruption to workflow.

Authors
Wu, RR; Orlando, LA; Himmel, TL; Buchanan, AH; Powell, KP; Hauser, ER; Agbaje, AB; Henrich, VC; Ginsburg, GS
MLA Citation
Wu, R. Ryanne, et al. “Patient and primary care provider experience using a family health history collection, risk stratification, and clinical decision support tool: a type 2 hybrid controlled implementation-effectiveness trial..” Bmc Fam Pract, vol. 14, Aug. 2013. Pubmed, doi:10.1186/1471-2296-14-111.
PMID
23915256
Source
pubmed
Published In
Bmc Family Practice
Volume
14
Publish Date
2013
Start Page
111
DOI
10.1186/1471-2296-14-111

Clinical utility of genetic risk testing in primary care: the example of Type 2 diabetes.

Genetic advances in Type 2 diabetes (T2D) have led to the discovery and validation of multiple markers for this complex disease. Despite low predictive value of current T2D markers beyond clinical risk factors and family history, researchers are exploring the clinical utility and outcomes of implementation in practice, and testing is available via direct-to-consumer markets. Clinical utility research demonstrates high hypothetical utility to patients for motivating behavior change and potentially reducing risk. However, trials to date have not demonstrated improvements in behavioral and clinical outcomes over and above counseling based on traditional risk factors. Ongoing research in T2D genetics and associated risk-prediction models is necessary to refine genetic risk pathways, algorithms for risk prediction and use of this information in clinical care. Further research is also needed to explore care models and support interventions that address the needs of personalized risk information and sustainable preventive behaviors to reduce the rising prevalence of T2D.

Authors
Vorderstrasse, AA; Cho, A; Voils, CI; Orlando, LA; Ginsburg, GS
MLA Citation
Vorderstrasse, Allison A., et al. “Clinical utility of genetic risk testing in primary care: the example of Type 2 diabetes..” Per Med, vol. 10, no. 6, Aug. 2013, pp. 549–63. Pubmed, doi:10.2217/pme.13.47.
PMID
29776196
Source
pubmed
Published In
Personalized Medicine
Volume
10
Issue
6
Publish Date
2013
Start Page
549
End Page
563
DOI
10.2217/pme.13.47

Quantitative models of the dose-response and time course of inhalational anthrax in humans.

Anthrax poses a community health risk due to accidental or intentional aerosol release. Reliable quantitative dose-response analyses are required to estimate the magnitude and timeline of potential consequences and the effect of public health intervention strategies under specific scenarios. Analyses of available data from exposures and infections of humans and non-human primates are often contradictory. We review existing quantitative inhalational anthrax dose-response models in light of criteria we propose for a model to be useful and defensible. To satisfy these criteria, we extend an existing mechanistic competing-risks model to create a novel Exposure-Infection-Symptomatic illness-Death (EISD) model and use experimental non-human primate data and human epidemiological data to optimize parameter values. The best fit to these data leads to estimates of a dose leading to infection in 50% of susceptible humans (ID50) of 11,000 spores (95% confidence interval 7,200-17,000), ID10 of 1,700 (1,100-2,600), and ID1 of 160 (100-250). These estimates suggest that use of a threshold to human infection of 600 spores (as suggested in the literature) underestimates the infectivity of low doses, while an existing estimate of a 1% infection rate for a single spore overestimates low dose infectivity. We estimate the median time from exposure to onset of symptoms (incubation period) among untreated cases to be 9.9 days (7.7-13.1) for exposure to ID50, 11.8 days (9.5-15.0) for ID10, and 12.1 days (9.9-15.3) for ID1. Our model is the first to provide incubation period estimates that are independently consistent with data from the largest known human outbreak. This model refines previous estimates of the distribution of early onset cases after a release and provides support for the recommended 60-day course of prophylactic antibiotic treatment for individuals exposed to low doses.

Authors
Toth, DJA; Gundlapalli, AV; Schell, WA; Bulmahn, K; Walton, TE; Woods, CW; Coghill, C; Gallegos, F; Samore, MH; Adler, FR
MLA Citation
Toth, Damon J. A., et al. “Quantitative models of the dose-response and time course of inhalational anthrax in humans..” Plos Pathog, vol. 9, no. 8, Aug. 2013. Pubmed, doi:10.1371/journal.ppat.1003555.
PMID
24058320
Source
pubmed
Published In
Plos Pathog
Volume
9
Issue
8
Publish Date
2013
Start Page
e1003555
DOI
10.1371/journal.ppat.1003555

An integrated clinico-metabolomic model improves prediction of death in sepsis.

Sepsis is a common cause of death, but outcomes in individual patients are difficult to predict. Elucidating the molecular processes that differ between sepsis patients who survive and those who die may permit more appropriate treatments to be deployed. We examined the clinical features and the plasma metabolome and proteome of patients with and without community-acquired sepsis, upon their arrival at hospital emergency departments and 24 hours later. The metabolomes and proteomes of patients at hospital admittance who would ultimately die differed markedly from those of patients who would survive. The different profiles of proteins and metabolites clustered into the following groups: fatty acid transport and β-oxidation, gluconeogenesis, and the citric acid cycle. They differed consistently among several sets of patients, and diverged more as death approached. In contrast, the metabolomes and proteomes of surviving patients with mild sepsis did not differ from survivors with severe sepsis or septic shock. An algorithm derived from clinical features together with measurements of five metabolites predicted patient survival. This algorithm may help to guide the treatment of individual patients with sepsis.

Authors
Langley, RJ; Tsalik, EL; van Velkinburgh, JC; Glickman, SW; Rice, BJ; Wang, C; Chen, B; Carin, L; Suarez, A; Mohney, RP; Freeman, DH; Wang, M; You, J; Wulff, J; Thompson, JW; Moseley, MA; Reisinger, S; Edmonds, BT; Grinnell, B; Nelson, DR; Dinwiddie, DL; Miller, NA; Saunders, CJ; Soden, SS; Rogers, AJ; Gazourian, L; Fredenburgh, LE; Massaro, AF; Baron, RM; Choi, AMK; Corey, GR; Ginsburg, GS; Cairns, CB; Otero, RM; Fowler, VG; Rivers, EP; Woods, CW; Kingsmore, SF
MLA Citation
Langley, Raymond J., et al. “An integrated clinico-metabolomic model improves prediction of death in sepsis..” Sci Transl Med, vol. 5, no. 195, July 2013. Pubmed, doi:10.1126/scitranslmed.3005893.
PMID
23884467
Source
pubmed
Published In
Sci Transl Med
Volume
5
Issue
195
Publish Date
2013
Start Page
195ra95
DOI
10.1126/scitranslmed.3005893

Surface-enhanced Raman scattering molecular sentinel nanoprobes for viral infection diagnostics.

In this paper, we describe a surface-enhanced Raman scattering (SERS)-based detection approach, referred to as "molecular sentinel" (MS) plasmonic nanoprobes, to detect an RNA target related to viral infection. The MS method is essentially a label-free technique incorporating the SERS effect modulation scheme associated with silver nanoparticles and Raman dye-labeled DNA hairpin probes. Hybridization with target sequences opens the hairpin and spatially separates the Raman label from the silver surface thus reducing the SERS signal of the label. Herein, we have developed a MS nanoprobe to detect the human radical S-adenosyl methionine domain containing 2 (RSAD2) RNA target as a model system for method demonstration. The human RSAD2 gene has recently emerged as a novel host-response biomarker for diagnosis of respiratory infections. Our results showed that the RSAD2 MS nanoprobes exhibits high specificity and can detect as low as 1 nM target sequences. With the use of a portable Raman spectrometer and total RNA samples, we have also demonstrated for the first time the potential of the MS nanoprobe technology for detection of host-response RNA biomarkers for infectious disease diagnostics.

Authors
Wang, H-N; Fales, AM; Zaas, AK; Woods, CW; Burke, T; Ginsburg, GS; Vo-Dinh, T
MLA Citation
Wang, Hsin-Neng, et al. “Surface-enhanced Raman scattering molecular sentinel nanoprobes for viral infection diagnostics..” Anal Chim Acta, vol. 786, July 2013, pp. 153–58. Pubmed, doi:10.1016/j.aca.2013.05.017.
PMID
23790305
Source
pubmed
Published In
Anal Chim Acta
Volume
786
Publish Date
2013
Start Page
153
End Page
158
DOI
10.1016/j.aca.2013.05.017

Comparative effectiveness research in cancer genomics and precision medicine: current landscape and future prospects.

A major promise of genomic research is information that can transform health care and public health through earlier diagnosis, more effective prevention and treatment of disease, and avoidance of drug side effects. Although there is interest in the early adoption of emerging genomic applications in cancer prevention and treatment, there are substantial evidence gaps that are further compounded by the difficulties of designing adequately powered studies to generate this evidence, thus limiting the uptake of these tools into clinical practice. Comparative effectiveness research (CER) is intended to generate evidence on the "real-world" effectiveness compared with existing standards of care so informed decisions can be made to improve health care. Capitalizing on funding opportunities from the American Recovery and Reinvestment Act of 2009, the National Cancer Institute funded seven research teams to conduct CER in genomic and precision medicine and sponsored a workshop on CER on May 30, 2012, in Bethesda, Maryland. This report highlights research findings from those research teams, challenges to conducting CER, the barriers to implementation in clinical practice, and research priorities and opportunities in CER in genomic and precision medicine. Workshop participants strongly emphasized the need for conducting CER for promising molecularly targeted therapies, developing and supporting an integrated clinical network for open-access resources, supporting bioinformatics and computer science research, providing training and education programs in CER, and conducting research in economic and decision modeling.

Authors
Simonds, NI; Khoury, MJ; Schully, SD; Armstrong, K; Cohn, WF; Fenstermacher, DA; Ginsburg, GS; Goddard, KAB; Knaus, WA; Lyman, GH; Ramsey, SD; Xu, J; Freedman, AN
MLA Citation
Simonds, Naoko I., et al. “Comparative effectiveness research in cancer genomics and precision medicine: current landscape and future prospects..” J Natl Cancer Inst, vol. 105, no. 13, July 2013, pp. 929–36. Pubmed, doi:10.1093/jnci/djt108.
PMID
23661804
Source
pubmed
Published In
J Natl Cancer Inst
Volume
105
Issue
13
Publish Date
2013
Start Page
929
End Page
936
DOI
10.1093/jnci/djt108

Collection of family health history for assessment of chronic disease risk in primary care.

BACKGROUND: Family health history can predict a patient's risk for common complex diseases. This project assessed the completeness of family health history data in medical charts and evaluated the utility of these data for performing risk assessments in primary care. METHODS: Family health history data were collected and analyzed to determine the presence of quality indicators that are necessary for effective and accurate assessment of disease risk. RESULTS: More than 99% of the 390 paper charts analyzed contained information about family health history, which was usually scattered throughout the chart. Information on the health of the patient's parents was collected more often than information on the health of other relatives. Key information that was often not collected included age of disease onset, affected side of the family, and second-degree relatives affected. Less than 4% of patient charts included family health histories that were informative enough to accurately assess risk for common complex diseases. LIMITATIONS: Limitations of this study include the small number of charts reviewed per provider, the fact that the sample consisted of primary care providers in a single geographic location, and the inability to assess ethnicity, consanguinity, and other indicators of the informativeness of family health history. CONCLUSIONS: The family health histories collected in primary care are usually not complete enough to assess the patient's risk for common complex diseases. This situation could be improved with use of tools that analyze the family health history information collected and provide risk-stratified decision support recommendations for primary care.

Authors
Powell, KP; Christianson, CA; Hahn, SE; Dave, G; Evans, LR; Blanton, SH; Hauser, E; Agbaje, A; Orlando, LA; Ginsburg, GS; Henrich, VC
MLA Citation
Powell, Karen P., et al. “Collection of family health history for assessment of chronic disease risk in primary care..” N C Med J, vol. 74, no. 4, July 2013, pp. 279–86.
PMID
24044144
Source
pubmed
Published In
North Carolina Medical Journal
Volume
74
Issue
4
Publish Date
2013
Start Page
279
End Page
286

Development and validation of a primary care-based family health history and decision support program (MeTree).

INTRODUCTION: Family health history is a strong predictor of disease risk. To reduce the morbidity and mortality of many chronic diseases, risk-stratified evidence-based guidelines strongly encourage the collection and synthesis of family health history to guide selection of primary prevention strategies. However, the collection and synthesis of such information is not well integrated into clinical practice. To address barriers to collection and use of family health histories, the Genomedical Connection developed and validated MeTree, a Web-based, patient-facing family health history collection and clinical decision support tool. MeTree is designed for integration into primary care practices as part of the genomic medicine model for primary care. METHODS: We describe the guiding principles, operational characteristics, algorithm development, and coding used to develop MeTree. Validation was performed through stakeholder cognitive interviewing, a genetic counseling pilot program, and clinical practice pilot programs in 2 community-based primary care clinics. RESULTS: Stakeholder feedback resulted in changes to MeTree's interface and changes to the phrasing of clinical decision support documents. The pilot studies resulted in the identification and correction of coding errors and the reformatting of clinical decision support documents. MeTree's strengths in comparison with other tools are its seamless integration into clinical practice and its provision of action-oriented recommendations guided by providers' needs. LIMITATIONS: The tool was validated in a small cohort. CONCLUSION: MeTree can be integrated into primary care practices to help providers collect and synthesize family health history information from patients with the goal of improving adherence to risk-stratified evidence-based guidelines.

Authors
Orlando, LA; Buchanan, AH; Hahn, SE; Christianson, CA; Powell, KP; Skinner, CS; Chesnut, B; Blach, C; Due, B; Ginsburg, GS; Henrich, VC
MLA Citation
Orlando, Lori A., et al. “Development and validation of a primary care-based family health history and decision support program (MeTree)..” N C Med J, vol. 74, no. 4, July 2013, pp. 287–96.
PMID
24044145
Source
pubmed
Published In
North Carolina Medical Journal
Volume
74
Issue
4
Publish Date
2013
Start Page
287
End Page
296

Genomic medicine: a decade of successes, challenges, and opportunities.

Genomic medicine--an aspirational term 10 years ago--is gaining momentum across the entire clinical continuum from risk assessment in healthy individuals to genome-guided treatment in patients with complex diseases. We review the latest achievements in genome research and their impact on medicine, primarily in the past decade. In most cases, genomic medicine tools remain in the realm of research, but some tools are crossing over into clinical application, where they have the potential to markedly alter the clinical care of patients. In this State of the Art Review, we highlight notable examples including the use of next-generation sequencing in cancer pharmacogenomics, in the diagnosis of rare disorders, and in the tracking of infectious disease outbreaks. We also discuss progress in dissecting the molecular basis of common diseases, the role of the host microbiome, the identification of drug response biomarkers, and the repurposing of drugs. The significant challenges of implementing genomic medicine are examined, along with the innovative solutions being sought. These challenges include the difficulty in establishing clinical validity and utility of tests, how to increase awareness and promote their uptake by clinicians, a changing regulatory and coverage landscape, the need for education, and addressing the ethical aspects of genomics for patients and society. Finally, we consider the future of genomics in medicine and offer a glimpse of the forces shaping genomic medicine, such as fundamental shifts in how we define disease, how medicine is delivered to patients, and how consumers are managing their own health and affecting change.

Authors
McCarthy, JJ; McLeod, HL; Ginsburg, GS
MLA Citation
McCarthy, Jeanette J., et al. “Genomic medicine: a decade of successes, challenges, and opportunities..” Sci Transl Med, vol. 5, no. 189, June 2013. Pubmed, doi:10.1126/scitranslmed.3005785.
PMID
23761042
Source
pubmed
Published In
Sci Transl Med
Volume
5
Issue
189
Publish Date
2013
Start Page
189sr4
DOI
10.1126/scitranslmed.3005785

IMPACT OF A FAMILY HISTORY COLLECTION TOOL, METREE (c), IN IDENTIFYING INDIVIDUALS AT HIGH-RISK FOR CANCER AND THROMBOSIS

Authors
Wu, RR; Himmel, T; Buchanan, A; Powell, K; Hauser, E; Agbaje, AB; Ginsburg, GS; Henrich, V; Orlando, LA
MLA Citation
Wu, Rebekah R., et al. “IMPACT OF A FAMILY HISTORY COLLECTION TOOL, METREE (c), IN IDENTIFYING INDIVIDUALS AT HIGH-RISK FOR CANCER AND THROMBOSIS.” Journal of General Internal Medicine, vol. 28, SPRINGER, 2013, pp. S101–S101.
Source
wos
Published In
Journal of General Internal Medicine
Volume
28
Publish Date
2013
Start Page
S101
End Page
S101

USABILITY OF A FAMILY HEALTH HISTORY AND CLINICAL DECISION SUPPORT TOOL FOR PATIENTS AND PRIMARY CARE PROVIDERS

Authors
Wu, RR; Himmel, T; Powell, K; Hauser, E; Agbaje, AB; Henrich, V; Ginsburg, GS; Orlando, LA
MLA Citation
Wu, Rebekah R., et al. “USABILITY OF A FAMILY HEALTH HISTORY AND CLINICAL DECISION SUPPORT TOOL FOR PATIENTS AND PRIMARY CARE PROVIDERS.” Journal of General Internal Medicine, vol. 28, SPRINGER, 2013, pp. S233–S233.
Source
wos
Published In
Journal of General Internal Medicine
Volume
28
Publish Date
2013
Start Page
S233
End Page
S233

Latent protein trees

Unbiased, label-free proteomics is becoming a powerful technique for measuring protein expression in almost any biological sample. The output of these measurements after preprocessing is a collection of features and their associated intensities for each sample. Subsets of features within the data are from the same peptide, subsets of peptides are from the same protein, and subsets of proteins are in the same biological pathways, therefore, there is the potential for very complex and informative correlational structure inherent in these data. Recent attempts to utilize this data often focus on the identification of single features that are associated with a particular phenotype that is relevant to the experiment. However, to date, there have been no published approaches that directly model what we know to be multiple different levels of correlation structure. Here we present a hierarchical Bayesian model which is specifically designed to model such correlation structure in unbiased, label-free proteomics. This model utilizes partial identification information from peptide sequencing and database lookup as well as the observed correlation in the data to appropriately compress features into latent proteins and to estimate their correlation structure. We demonstrate the effectiveness of the model using artificial/benchmark data and in the context of a series of proteomics measurements of blood plasma from a collection of volunteers who were infected with two different strains of viral influenza. © Institute of Mathematical Statistics, 2013.

Authors
Henao, R; Thompson, JW; Moseley, MA; Ginsburg, GS; Carin, L; Lucas, JE
MLA Citation
Henao, R., et al. “Latent protein trees.” Annals of Applied Statistics, vol. 7, no. 2, June 2013, pp. 691–713. Scopus, doi:10.1214/13-AOAS639.
Website
http://hdl.handle.net/10161/8948
Source
scopus
Published In
The Annals of Applied Statistics
Volume
7
Issue
2
Publish Date
2013
Start Page
691
End Page
713
DOI
10.1214/13-AOAS639

The Impact of Personalized Medicine

Authors
Tenenbaum, JMM; Abernethy, AP; Mazumder, AR; Ginsburg, GS
MLA Citation
Tenenbaum, Jay M. Marty, et al. “The Impact of Personalized Medicine.” Scientist, vol. 27, no. 6, LABX MEDIA GROUP, June 2013, pp. 64–65.
Source
wos
Published In
Scientist
Volume
27
Issue
6
Publish Date
2013
Start Page
64
End Page
65

Health coaching and genomics-potential avenues to elicit behavior change in those at risk for chronic disease: protocol for personalized medicine effectiveness study in air force primary care.

BACKGROUND: Type 2 diabetes (T2D) and coronary heart disease (CHD) are prevalent chronic diseases from which military personnel are not exempt. While many genetic markers for these diseases have been identified, the clinical utility of genetic risk testing for multifactorial diseases such as these has not been established. The need for a behavioral intervention such as health coaching following a risk counseling intervention for T2D or CHD also has not been explored. Here we present the rationale, design, and protocol for evaluating the clinical utility of genetic risk testing and health coaching for active duty US Air Force (AF) retirees and beneficiaries. PRIMARY STUDY OBJECTIVES: Determine the direct and interactive effects of health coaching and providing genetic risk information when added to standard risk counseling for CHD and T2D on health behaviors and clinical risk markers. DESIGN: Four-group (2 X 2 factorial) randomized controlled trial. SETTING: Two AF primary care clinical settings on the west coast of the United States. PARTICIPANTS: Adult AF primary care patients. INTERVENTION: All participants will have a risk counseling visit with a clinic provider to discuss personal risk factors for T2D and CHD. Half of the participants (two groups) will also learn of their genetic risk testing results for T2D and CHD in this risk counseling session. Participants randomized to the two groups receiving health coaching will then receive telephonic health coaching over 6 months. MAIN OUTCOME MEASURES: Behavioral measures (self-reported dietary intake, physical activity, smoking cessation, medication adherence); clinical outcomes (AF composite fitness scores, weight, waist circumference, blood pressure, fasting glucose, lipids, T2D/CHD risk scores) and psychosocial measures (self-efficacy, worry, perceived risk) will be collected at baseline and 6 weeks, and 3, 6, and 12 months. CONCLUSION: This study tests novel strategies deployed within existing AF primary care to increase adherence to evidence-based diet, physical activity, smoking cessation, and medication recommendations for CHD and T2D risk reduction through methods of patient engagement and self-management support.

Authors
Vorderstrasse, AA; Ginsburg, GS; Kraus, WE; Maldonado, MCJ; Wolever, RQ
MLA Citation
Vorderstrasse, Allison A., et al. “Health coaching and genomics-potential avenues to elicit behavior change in those at risk for chronic disease: protocol for personalized medicine effectiveness study in air force primary care..” Glob Adv Health Med, vol. 2, no. 3, May 2013, pp. 26–38. Pubmed, doi:10.7453/gahmj.2013.035.
PMID
24416670
Source
pubmed
Published In
Global Advances in Health and Medicine
Volume
2
Issue
3
Publish Date
2013
Start Page
26
End Page
38
DOI
10.7453/gahmj.2013.035

The genomic medicine model: an integrated approach to implementation of family health history in primary care.

As an essential tool for risk stratification, family health history (FHH) is a central component of personalized medicine; yet, despite its widespread acceptance among professional societies and its established place in the medical interview, its widespread adoption is hindered by three major barriers: quality of FHH collection, risk stratification capabilities and interpretation of risk stratification for clinical care. To overcome these barriers and bring FHH to the forefront of the personalized medicine effort, we developed the genomic medicine model (GMM) for primary care. The GMM, founded upon the principles of the Health Belief Model, Adult Learning Theory and the implementation sciences, shifts responsibility for FHH onto the patient, uses information technology (MeTree©) for risk stratification and interpretation, and provides education across multiple levels for each stakeholder, freeing up the clinical encounter for discussion around personalized preventive healthcare plans. The GMM has been implemented and optimized as part of an implementation-effectiveness hybrid pilot study for breast/ovarian cancer, colon cancer and thrombosis, and risk for hereditary cancer syndromes in two primary care clinics in NC, USA. This paper describes the conceptual development of the model and key findings relevant for broader uptake and sustainability in the primary care community.

Authors
Orlando, LA; Henrich, VC; Hauser, ER; Wilson, C; Ginsburg, GS; Genomedical Connection,
MLA Citation
Orlando, Lori A., et al. “The genomic medicine model: an integrated approach to implementation of family health history in primary care..” Per Med, vol. 10, no. 3, May 2013, pp. 295–306. Pubmed, doi:10.2217/pme.13.20.
PMID
29768748
Source
pubmed
Published In
Personalized Medicine
Volume
10
Issue
3
Publish Date
2013
Start Page
295
End Page
306
DOI
10.2217/pme.13.20

Realizing the opportunities of genomics in health care.

Authors
Ginsburg, GS
MLA Citation
Ginsburg, Geoffrey S. “Realizing the opportunities of genomics in health care..” Jama, vol. 309, no. 14, Apr. 2013, pp. 1463–64. Pubmed, doi:10.1001/jama.2013.1465.
PMID
23571581
Source
pubmed
Published In
Jama
Volume
309
Issue
14
Publish Date
2013
Start Page
1463
End Page
1464
DOI
10.1001/jama.2013.1465

Public knowledge of and attitudes toward genetics and genetic testing.

BACKGROUND: Variable health literacy and genetic knowledge may pose significant challenges to engaging the general public in personal genomics, specifically with respect to promoting risk comprehension and healthy behaviors. METHODS: We are conducting a multistage study of individual responses to genomic risk information for Type 2 diabetes mellitus. A total of 300 individuals were recruited from the general public in Durham, North Carolina: 60% self-identified as White; 70% female; and 65% have a college degree. As part of the baseline survey, we assessed genetic knowledge and attitudes toward genetic testing. RESULTS: Scores of factual knowledge of genetics ranged from 50% to 100% (average=84%), with significant differences in relation to racial groups, the education level, and age. Scores were significantly higher on questions pertaining to the inheritance and causes of disease (mean score 90%) compared to scientific questions (mean score 77.4%). Scores on the knowledge survey were significantly higher than scores from European populations. Participants' perceived knowledge of the social consequences of genetic testing was significantly lower than their perceived knowledge of the medical uses of testing. More than half agreed with the statement that testing may affect a person's ability to obtain health insurance (51.3%) and 16% were worried about the consequences of testing for chances of finding a job. CONCLUSIONS: Despite the relatively high educational status and genetic knowledge of the study population, we find an imbalance of knowledge between scientific and medical concepts related to genetics as well as between the medical applications and societal consequences of testing, suggesting that more effort is needed to present the benefits, risks, and limitations of genetic testing, particularly, at the social and personal levels, to ensure informed decision making.

Authors
Haga, SB; Barry, WT; Mills, R; Ginsburg, GS; Svetkey, L; Sullivan, J; Willard, HF
MLA Citation
Haga, Susanne B., et al. “Public knowledge of and attitudes toward genetics and genetic testing..” Genet Test Mol Biomarkers, vol. 17, no. 4, Apr. 2013, pp. 327–35. Pubmed, doi:10.1089/gtmb.2012.0350.
PMID
23406207
Source
pubmed
Published In
Genet Test Mol Biomarkers
Volume
17
Issue
4
Publish Date
2013
Start Page
327
End Page
335
DOI
10.1089/gtmb.2012.0350

Implementing genomic medicine in the clinic: the future is here.

Although the potential for genomics to contribute to clinical care has long been anticipated, the pace of defining the risks and benefits of incorporating genomic findings into medical practice has been relatively slow. Several institutions have recently begun genomic medicine programs, encountering many of the same obstacles and developing the same solutions, often independently. Recognizing that successful early experiences can inform subsequent efforts, the National Human Genome Research Institute brought together a number of these groups to describe their ongoing projects and challenges, identify common infrastructure and research needs, and outline an implementation framework for investigating and introducing similar programs elsewhere. Chief among the challenges were limited evidence and consensus on which genomic variants were medically relevant; lack of reimbursement for genomically driven interventions; and burden to patients and clinicians of assaying, reporting, intervening, and following up genomic findings. Key infrastructure needs included an openly accessible knowledge base capturing sequence variants and their phenotypic associations and a framework for defining and cataloging clinically actionable variants. Multiple institutions are actively engaged in using genomic information in clinical care. Much of this work is being done in isolation and would benefit from more structured collaboration and sharing of best practices.Genet Med 2013:15(4):258-267.

Authors
Manolio, TA; Chisholm, RL; Ozenberger, B; Roden, DM; Williams, MS; Wilson, R; Bick, D; Bottinger, EP; Brilliant, MH; Eng, C; Frazer, KA; Korf, B; Ledbetter, DH; Lupski, JR; Marsh, C; Mrazek, D; Murray, MF; O'Donnell, PH; Rader, DJ; Relling, MV; Shuldiner, AR; Valle, D; Weinshilboum, R; Green, ED; Ginsburg, GS
MLA Citation
Manolio, Teri A., et al. “Implementing genomic medicine in the clinic: the future is here..” Genet Med, vol. 15, no. 4, Apr. 2013, pp. 258–67. Pubmed, doi:10.1038/gim.2012.157.
PMID
23306799
Source
pubmed
Published In
Genet Med
Volume
15
Issue
4
Publish Date
2013
Start Page
258
End Page
267
DOI
10.1038/gim.2012.157

Transforming epidemiology for 21st century medicine and public health.

In 2012, the National Cancer Institute (NCI) engaged the scientific community to provide a vision for cancer epidemiology in the 21st century. Eight overarching thematic recommendations, with proposed corresponding actions for consideration by funding agencies, professional societies, and the research community emerged from the collective intellectual discourse. The themes are (i) extending the reach of epidemiology beyond discovery and etiologic research to include multilevel analysis, intervention evaluation, implementation, and outcomes research; (ii) transforming the practice of epidemiology by moving toward more access and sharing of protocols, data, metadata, and specimens to foster collaboration, to ensure reproducibility and replication, and accelerate translation; (iii) expanding cohort studies to collect exposure, clinical, and other information across the life course and examining multiple health-related endpoints; (iv) developing and validating reliable methods and technologies to quantify exposures and outcomes on a massive scale, and to assess concomitantly the role of multiple factors in complex diseases; (v) integrating "big data" science into the practice of epidemiology; (vi) expanding knowledge integration to drive research, policy, and practice; (vii) transforming training of 21st century epidemiologists to address interdisciplinary and translational research; and (viii) optimizing the use of resources and infrastructure for epidemiologic studies. These recommendations can transform cancer epidemiology and the field of epidemiology, in general, by enhancing transparency, interdisciplinary collaboration, and strategic applications of new technologies. They should lay a strong scientific foundation for accelerated translation of scientific discoveries into individual and population health benefits.

Authors
Khoury, MJ; Lam, TK; Ioannidis, JPA; Hartge, P; Spitz, MR; Buring, JE; Chanock, SJ; Croyle, RT; Goddard, KA; Ginsburg, GS; Herceg, Z; Hiatt, RA; Hoover, RN; Hunter, DJ; Kramer, BS; Lauer, MS; Meyerhardt, JA; Olopade, OI; Palmer, JR; Sellers, TA; Seminara, D; Ransohoff, DF; Rebbeck, TR; Tourassi, G; Winn, DM; Zauber, A; Schully, SD
MLA Citation
Khoury, Muin J., et al. “Transforming epidemiology for 21st century medicine and public health..” Cancer Epidemiol Biomarkers Prev, vol. 22, no. 4, Apr. 2013, pp. 508–16. Pubmed, doi:10.1158/1055-9965.EPI-13-0146.
PMID
23462917
Source
pubmed
Published In
Cancer Epidemiol Biomarkers Prev
Volume
22
Issue
4
Publish Date
2013
Start Page
508
End Page
516
DOI
10.1158/1055-9965.EPI-13-0146

Unsupervised Bayesian linear unmixing of gene expression microarrays.

BACKGROUND: This paper introduces a new constrained model and the corresponding algorithm, called unsupervised Bayesian linear unmixing (uBLU), to identify biological signatures from high dimensional assays like gene expression microarrays. The basis for uBLU is a Bayesian model for the data samples which are represented as an additive mixture of random positive gene signatures, called factors, with random positive mixing coefficients, called factor scores, that specify the relative contribution of each signature to a specific sample. The particularity of the proposed method is that uBLU constrains the factor loadings to be non-negative and the factor scores to be probability distributions over the factors. Furthermore, it also provides estimates of the number of factors. A Gibbs sampling strategy is adopted here to generate random samples according to the posterior distribution of the factors, factor scores, and number of factors. These samples are then used to estimate all the unknown parameters. RESULTS: Firstly, the proposed uBLU method is applied to several simulated datasets with known ground truth and compared with previous factor decomposition methods, such as principal component analysis (PCA), non negative matrix factorization (NMF), Bayesian factor regression modeling (BFRM), and the gradient-based algorithm for general matrix factorization (GB-GMF). Secondly, we illustrate the application of uBLU on a real time-evolving gene expression dataset from a recent viral challenge study in which individuals have been inoculated with influenza A/H3N2/Wisconsin. We show that the uBLU method significantly outperforms the other methods on the simulated and real data sets considered here. CONCLUSIONS: The results obtained on synthetic and real data illustrate the accuracy of the proposed uBLU method when compared to other factor decomposition methods from the literature (PCA, NMF, BFRM, and GB-GMF). The uBLU method identifies an inflammatory component closely associated with clinical symptom scores collected during the study. Using a constrained model allows recovery of all the inflammatory genes in a single factor.

Authors
Bazot, C; Dobigeon, N; Tourneret, J-Y; Zaas, AK; Ginsburg, GS; Hero, AO
MLA Citation
Bazot, Cécile, et al. “Unsupervised Bayesian linear unmixing of gene expression microarrays..” Bmc Bioinformatics, vol. 14, Mar. 2013. Pubmed, doi:10.1186/1471-2105-14-99.
PMID
23506672
Source
pubmed
Published In
Bmc Bioinformatics
Volume
14
Publish Date
2013
Start Page
99
DOI
10.1186/1471-2105-14-99

Primary care physicians' knowledge of and experience with pharmacogenetic testing

Authors
Haga, SB; Burke, W; Ginsburg, GS; Mills, R; Agans, R
MLA Citation
Haga, S. B., et al. “Primary care physicians' knowledge of and experience with pharmacogenetic testing.” Obstetrical and Gynecological Survey, vol. 68, no. 2, Feb. 2013, pp. 91–93. Scopus, doi:10.1097/01.ogx.0000427617.89027.ca.
Source
scopus
Published In
Obstetrical & Gynecological Survey
Volume
68
Issue
2
Publish Date
2013
Start Page
91
End Page
93
DOI
10.1097/01.ogx.0000427617.89027.ca

Personalized medicine in women's obesity prevention and treatment: implications for research, policy and practice.

The prevalence of obesity in America has reached epidemic proportions, and obesity among women is particularly concerning. Severe obesity (body mass index ≥35 kg m(-2) ) is more prevalent in women than men. Further, women have sex-specific risk factors that must be considered when developing preventive and therapeutic interventions. This review presents personalized medicine as a dynamic approach to obesity prevention, management and treatment for women. First, we review obesity as a complex health issue, with contributing sex-specific, demographic, psychosocial, behavioural, environmental, epigenetic and genetic/genomic risk factors. Second, we present personalized medicine as a rapidly advancing field of health care that seeks to quantify these complex risk factors to develop more targeted and effective strategies that can improve disease management and/or better minimize an individual's likelihood of developing obesity. Third, we discuss how personalized medicine can be applied in a clinical setting with current and emerging tools, including health risk assessments, personalized health plans, and strategies for increasing patient engagement. Finally, we discuss the need for additional research, training and policy that can enhance the practice of personalized medicine in women's obesity, including further advancements in the '-omics' sciences, physician training in personalized medicine, and additional development and standardization of innovative targeted therapies and clinical tools.

Authors
Yang, N; Ginsburg, GS; Simmons, LA
MLA Citation
Yang, N., et al. “Personalized medicine in women's obesity prevention and treatment: implications for research, policy and practice..” Obes Rev, vol. 14, no. 2, Feb. 2013, pp. 145–61. Pubmed, doi:10.1111/j.1467-789X.2012.01048.x.
PMID
23114034
Source
pubmed
Published In
Obes Rev
Volume
14
Issue
2
Publish Date
2013
Start Page
145
End Page
161
DOI
10.1111/j.1467-789X.2012.01048.x

Blood Gene Expression Profiling Reveals An Association Between Viral Infection, Platelet Function, And Acute Myocardial Infarction

Authors
Rose, JJ; Voora, D; Cyr, DD; Lucas, JE; Zaas, AK; Newby, LK; Kraus, WE; Ginsburg, GS
MLA Citation
Rose, J. J., et al. “Blood Gene Expression Profiling Reveals An Association Between Viral Infection, Platelet Function, And Acute Myocardial Infarction.” American Journal of Respiratory and Critical Care Medicine, vol. 187, AMER THORACIC SOC, Jan. 2013.
Source
wos
Published In
American Journal of Respiratory and Critical Care Medicine
Volume
187
Publish Date
2013

Pneumococcal Pneumonia And Sepsis In Baboons Mirrors The Human Disease

Authors
Kraft, B; Piantadosi, CA; Suliman, HB; Ginsburg, GS; Bartz, RR; Zaas, A; Betancourt, M; Welty-Wolf, KE
MLA Citation
Kraft, B., et al. “Pneumococcal Pneumonia And Sepsis In Baboons Mirrors The Human Disease.” American Journal of Respiratory and Critical Care Medicine, vol. 187, AMER THORACIC SOC, 2013.
Source
wos
Published In
American Journal of Respiratory and Critical Care Medicine
Volume
187
Publish Date
2013

Chikungunya as a cause of acute febrile illness in southern Sri Lanka.

BACKGROUND: Chikungunya virus (CHIKV) re-emerged in Sri Lanka in late 2006 after a 40-year hiatus. We sought to identify and characterize acute chikungunya infection (CHIK) in patients presenting with acute undifferentiated febrile illness in unstudied rural and semi-urban southern Sri Lanka in 2007. METHODOLOGY/PRINCIPAL FINDINGS: We enrolled febrile patients ≥ 2 years of age, collected uniform epidemiologic and clinical data, and obtained serum samples for serology, virus isolation, and real-time reverse-transcriptase PCR (RT-PCR). Serology on paired acute and convalescent samples identified acute chikungunya infection in 3.5% (28/797) patients without acute dengue virus (DENV) infection, 64.3% (18/28) of which were confirmed by viral isolation and/or real-time RT-PCR. No CHIKV/DENV co-infections were detected among 54 patients with confirmed acute DENV. Sequencing of the E1 coding region of six temporally distinct CHIKV isolates (April through October 2007) showed that all isolates posessed the E1-226A residue and were most closely related to Sri Lankan and Indian isolates from the same time period. Except for more frequent and persistent musculoskeletal symptoms, acute chikungunya infections mimicked DENV and other acute febrile illnesses. Only 12/797 (1.5%) patients had serological evidence of past chikungunya infection. CONCLUSIONS/SIGNIFICANCE: Our findings suggest CHIKV is a prominent cause of non-specific acute febrile illness in southern Sri Lanka.

Authors
Reller, ME; Akoroda, U; Nagahawatte, A; Devasiri, V; Kodikaarachchi, W; Strouse, JJ; Chua, R; Hou, Y; Chow, A; Sessions, OM; Østbye, T; Gubler, DJ; Woods, CW; Bodinayake, C
MLA Citation
Reller, Megan E., et al. “Chikungunya as a cause of acute febrile illness in southern Sri Lanka..” Plos One, vol. 8, no. 12, 2013. Pubmed, doi:10.1371/journal.pone.0082259.
Website
http://hdl.handle.net/10161/12505
PMID
24312651
Source
pubmed
Published In
Plos One
Volume
8
Issue
12
Publish Date
2013
Start Page
e82259
DOI
10.1371/journal.pone.0082259

Bayesian modeling of temporal properties of infectious disease in a college student population

Authors
Xing, Z; Nicholson, B; Jimenez, M; Veldman, T; Hudson, L; Lucas, J; Dunson, D; Zaas, AK; Woods, CW; Ginsburg, GS; Carin, L
MLA Citation
Xing, Z., et al. “Bayesian modeling of temporal properties of infectious disease in a college student population.” Journal of Applied Statistics, 2013.
Source
scopus
Published In
Journal of Applied Statistics
Publish Date
2013

Comparing influenza and RSV viral and disease dynamics in experimentally infected adults predicts clinical effectiveness of RSV antivirals.

BACKGROUND: Antivirals reduce influenza viral replication and illness measures, particularly if initiated early, within 48 h of symptom onset. Whether experimental antivirals that reduce respiratory syncytial virus (RSV) load would also reduce disease is unknown. This study compares viral and disease dynamics in humans experimentally infected with influenza or RSV. METHODS: Clinical strains of RSV-A and influenza A were inoculated intranasally into 20 and 17 healthy volunteers, respectively, on day 0. Symptom scores and nasal washes were performed twice daily, and daily mucus weights were collected. Viral loads in nasal washes were quantified by culture (plaque assay in HEp-2 cells for RSV and by end point dilution in Madin-Darby canine kidney cells for influenza). RESULTS: After influenza inoculation, influenza viral load and illness markers increased simultaneously until day 2. Within individual subjects, peak influenza load occurred 0.4 days (95% CI -0.4, 1.3) before peak symptoms. Influenza viral load and disease declined thereafter. After RSV inoculation, a longer incubation period occurred prior to viral detection and symptom onset. RSV load and disease increased together until day 5. Within individual subjects, peak RSV loads occurred 0.2 days (95% CI -0.7, 1.05) before peak symptoms, after which both illness measures and viral load declined together. CONCLUSIONS: Viral and disease dynamics in experimental human infections suggest that reducing RSV load, if timed similarly to clinically-effective influenza antivirals, might be expected to have a similar or greater window of opportunity for reducing clinical RSV disease.

Authors
Bagga, B; Woods, CW; Veldman, TH; Gilbert, A; Mann, A; Balaratnam, G; Lambkin-Williams, R; Oxford, JS; McClain, MT; Wilkinson, T; Nicholson, BP; Ginsburg, GS; Devincenzo, JP
MLA Citation
Bagga, Bindiya, et al. “Comparing influenza and RSV viral and disease dynamics in experimentally infected adults predicts clinical effectiveness of RSV antivirals..” Antivir Ther, vol. 18, no. 6, 2013, pp. 785–91. Pubmed, doi:10.3851/IMP2629.
PMID
23714753
Source
pubmed
Published In
Antivir Ther
Volume
18
Issue
6
Publish Date
2013
Start Page
785
End Page
791
DOI
10.3851/IMP2629

Patient clustering with uncoded text in electronic medical records.

We propose a mixture model for text data designed to capture underlying structure in the history of present illness section of electronic medical records data. Additionally, we propose a method to induce bias that leads to more homogeneous sets of diagnoses for patients in each cluster. We apply our model to a collection of electronic records from an emergency department and compare our results to three other relevant models in order to assess performance. Results using standard metrics demonstrate that patient clusters from our model are more homogeneous when compared to others, and qualitative analyses suggest that our approach leads to interpretable patient sub-populations when applied to real data. Finally, we demonstrate an example of our patient clustering model to identify adverse drug events.

Authors
Henao, R; Murray, J; Ginsburg, G; Carin, L; Lucas, JE
MLA Citation
Henao, Ricardo, et al. “Patient clustering with uncoded text in electronic medical records..” Amia Annu Symp Proc, vol. 2013, 2013, pp. 592–99.
PMID
24551361
Source
pubmed
Published In
Amia ... Annual Symposium Proceedings. Amia Symposium
Volume
2013
Publish Date
2013
Start Page
592
End Page
599

A host transcriptional signature for presymptomatic detection of infection in humans exposed to influenza H1N1 or H3N2.

There is great potential for host-based gene expression analysis to impact the early diagnosis of infectious diseases. In particular, the influenza pandemic of 2009 highlighted the challenges and limitations of traditional pathogen-based testing for suspected upper respiratory viral infection. We inoculated human volunteers with either influenza A (A/Brisbane/59/2007 (H1N1) or A/Wisconsin/67/2005 (H3N2)), and assayed the peripheral blood transcriptome every 8 hours for 7 days. Of 41 inoculated volunteers, 18 (44%) developed symptomatic infection. Using unbiased sparse latent factor regression analysis, we generated a gene signature (or factor) for symptomatic influenza capable of detecting 94% of infected cases. This gene signature is detectable as early as 29 hours post-exposure and achieves maximal accuracy on average 43 hours (p = 0.003, H1N1) and 38 hours (p-value = 0.005, H3N2) before peak clinical symptoms. In order to test the relevance of these findings in naturally acquired disease, a composite influenza A signature built from these challenge studies was applied to Emergency Department patients where it discriminates between swine-origin influenza A/H1N1 (2009) infected and non-infected individuals with 92% accuracy. The host genomic response to Influenza infection is robust and may provide the means for detection before typical clinical symptoms are apparent.

Authors
Woods, CW; McClain, MT; Chen, M; Zaas, AK; Nicholson, BP; Varkey, J; Veldman, T; Kingsmore, SF; Huang, Y; Lambkin-Williams, R; Gilbert, AG; Hero, AO; Ramsburg, E; Glickman, S; Lucas, JE; Carin, L; Ginsburg, GS
MLA Citation
Woods, Christopher W., et al. “A host transcriptional signature for presymptomatic detection of infection in humans exposed to influenza H1N1 or H3N2..” Plos One, vol. 8, no. 1, 2013. Pubmed, doi:10.1371/journal.pone.0052198.
Website
http://hdl.handle.net/10161/8944
PMID
23326326
Source
pubmed
Published In
Plos One
Volume
8
Issue
1
Publish Date
2013
Start Page
e52198
DOI
10.1371/journal.pone.0052198

Gene expression-based classifiers identify Staphylococcus aureus infection in mice and humans.

Staphylococcus aureus causes a spectrum of human infection. Diagnostic delays and uncertainty lead to treatment delays and inappropriate antibiotic use. A growing literature suggests the host's inflammatory response to the pathogen represents a potential tool to improve upon current diagnostics. The hypothesis of this study is that the host responds differently to S. aureus than to E. coli infection in a quantifiable way, providing a new diagnostic avenue. This study uses Bayesian sparse factor modeling and penalized binary regression to define peripheral blood gene-expression classifiers of murine and human S. aureus infection. The murine-derived classifier distinguished S. aureus infection from healthy controls and Escherichia coli-infected mice across a range of conditions (mouse and bacterial strain, time post infection) and was validated in outbred mice (AUC>0.97). A S. aureus classifier derived from a cohort of 94 human subjects distinguished S. aureus blood stream infection (BSI) from healthy subjects (AUC 0.99) and E. coli BSI (AUC 0.84). Murine and human responses to S. aureus infection share common biological pathways, allowing the murine model to classify S. aureus BSI in humans (AUC 0.84). Both murine and human S. aureus classifiers were validated in an independent human cohort (AUC 0.95 and 0.92, respectively). The approach described here lends insight into the conserved and disparate pathways utilized by mice and humans in response to these infections. Furthermore, this study advances our understanding of S. aureus infection; the host response to it; and identifies new diagnostic and therapeutic avenues.

Authors
Ahn, SH; Tsalik, EL; Cyr, DD; Zhang, Y; van Velkinburgh, JC; Langley, RJ; Glickman, SW; Cairns, CB; Zaas, AK; Rivers, EP; Otero, RM; Veldman, T; Kingsmore, SF; Lucas, J; Woods, CW; Ginsburg, GS; Fowler, VG
MLA Citation
Ahn, Sun Hee, et al. “Gene expression-based classifiers identify Staphylococcus aureus infection in mice and humans..” Plos One, vol. 8, no. 1, 2013. Pubmed, doi:10.1371/journal.pone.0048979.
Website
http://hdl.handle.net/10161/13321
PMID
23326304
Source
pubmed
Published In
Plos One
Volume
8
Issue
1
Publish Date
2013
Start Page
e48979
DOI
10.1371/journal.pone.0048979

Implementing genomic medicine in the clinic: The future is here

Authors
Manolio, TA; Chisholm, RL; Ozenberger, B; Roden, DM; Williams, MS; Wilson, R; Bick, D; Bottinger, EP; Brilliant, MH; Eng, C; Frazer, KA; Korf, B; Ledbetter, DH; Lupski, JR; Marsh, C; Mrazek, D; Murray, MF; O'Donnell, PH; Rader, DJ; Relling, MV; Shuldiner, AR; Valle, D; Weinshilboum, R; Green, ED; Ginsburg, GS
MLA Citation
Manolio, T. A., et al. “Implementing genomic medicine in the clinic: The future is here.” Obstetrical and Gynecological Survey, vol. 68, no. 9, 2013, pp. 621–23. Scival, doi:10.1097/01.ogx.0000435523.89711.77.
Source
scival
Published In
Obstetrical & Gynecological Survey
Volume
68
Issue
9
Publish Date
2013
Start Page
621
End Page
623
DOI
10.1097/01.ogx.0000435523.89711.77

Abstract P2-10-03: A cross-platform comparison of genomic signatures and OncotypeDx score to discover potential prognostic/predictive genes and pathways

Authors
Kuderer, NM; Barry, WT; Geradts, J; Ginsburg, GS; Lyman, GH; Datto, M; Liotcheva, V; Isner, P; Veldman, T; Agarwal, P; Hwang, S; Ready, N; Marcom, PK
MLA Citation
Kuderer, N. M., et al. “Abstract P2-10-03: A cross-platform comparison of genomic signatures and OncotypeDx score to discover potential prognostic/predictive genes and pathways.” Poster Session Abstracts, American Association for Cancer Research, Dec. 2012. Crossref, doi:10.1158/0008-5472.sabcs12-p2-10-03.
Source
crossref
Published In
Poster Session Abstracts
Publish Date
2012
DOI
10.1158/0008-5472.sabcs12-p2-10-03

Abstract P3-06-07: Ki67 as a Predictive Marker of Response to Neoadjuvant Chemotherapy in Patients with Early-Stage Breast Cancer (ESBC): A Systematic Review and Evidence Summary

Authors
Lyman, GH; Culakova, E; Poniewierski, MS; Wogu, AF; Barry, W; Ginsburg, GS; Marcom, PK; Ready, N; Abernethy, A; Geradts, J; Hwang, S; Kuderer, NM
MLA Citation
Lyman, G. H., et al. “Abstract P3-06-07: Ki67 as a Predictive Marker of Response to Neoadjuvant Chemotherapy in Patients with Early-Stage Breast Cancer (ESBC): A Systematic Review and Evidence Summary.” Poster Session Abstracts, American Association for Cancer Research, Dec. 2012. Crossref, doi:10.1158/0008-5472.sabcs12-p3-06-07.
Source
crossref
Published In
Poster Session Abstracts
Publish Date
2012
DOI
10.1158/0008-5472.sabcs12-p3-06-07

Comparative effectiveness research, genomics-enabled personalized medicine, and rapid learning health care: a common bond.

Despite stunning advances in our understanding of the genetics and the molecular basis for cancer, many patients with cancer are not yet receiving therapy tailored specifically to their tumor biology. The translation of these advances into clinical practice has been hindered, in part, by the lack of evidence for biomarkers supporting the personalized medicine approach. Most stakeholders agree that the translation of biomarkers into clinical care requires evidence of clinical utility. The highest level of evidence comes from randomized controlled clinical trials (RCTs). However, in many instances, there may be no RCTs that are feasible for assessing the clinical utility of potentially valuable genomic biomarkers. In the absence of RCTs, evidence generation will require well-designed cohort studies for comparative effectiveness research (CER) that link detailed clinical information to tumor biology and genomic data. CER also uses systematic reviews, evidence-quality appraisal, and health outcomes research to provide a methodologic framework for assessing biologic patient subgroups. Rapid learning health care (RLHC) is a model in which diverse data are made available, ideally in a robust and real-time fashion, potentially facilitating CER and personalized medicine. Nonetheless, to realize the full potential of personalized care using RLHC requires advances in CER and biostatistics methodology and the development of interoperable informatics systems, which has been recognized by the National Cancer Institute's program for CER and personalized medicine. The integration of CER methodology and genomics linked to RLHC should enhance, expedite, and expand the evidence generation required for fully realizing personalized cancer care.

Authors
Ginsburg, GS; Kuderer, NM
MLA Citation
Ginsburg, Geoffrey S., and Nicole M. Kuderer. “Comparative effectiveness research, genomics-enabled personalized medicine, and rapid learning health care: a common bond..” J Clin Oncol, vol. 30, no. 34, Dec. 2012, pp. 4233–42. Pubmed, doi:10.1200/JCO.2012.42.6114.
PMID
23071236
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
30
Issue
34
Publish Date
2012
Start Page
4233
End Page
4242
DOI
10.1200/JCO.2012.42.6114

Clinical Implementation of Genomic Medicine in Primary Care

This two-volume set provides an in-depth look at one of the most promising avenues for advances in the diagnosis, prevention and treatment of human disease.

Authors
Orlando, LA; cho, AH
MLA Citation
Orlando, L. A., and A. H. cho. “Clinical Implementation of Genomic Medicine in Primary Care.” Genomic and Personalized Medicine, edited by G. S. ginsburg and H. willard, Academic Press, 2012.
Source
manual
Publish Date
2012

The host response to infection: advancing a novel diagnostic paradigm.

Capturing the host response by using genomic technologies such as transcriptional profiling provides a new paradigm for classifying and diagnosing infectious disease and for potentially distinguishing infection from other causes of serious respiratory illness. This strategy has been used to define a blood-based RNA signature as a classifier for pandemic H1N1 influenza infection that is distinct from bacterial pneumonia and other inflammatory causes of respiratory disease. To realize the full potential of this approach as a diagnostic test will require additional independent validation of the results and studies to examine the specificity of this signature for viral versus bacterial infection or co-infection.

Authors
Ginsburg, GS; Woods, CW
MLA Citation
Ginsburg, Geoffrey S., and Christopher W. Woods. “The host response to infection: advancing a novel diagnostic paradigm..” Crit Care, vol. 16, no. 6, Nov. 2012. Pubmed, doi:10.1186/cc11685.
PMID
23134694
Source
pubmed
Published In
Crit Care
Volume
16
Issue
6
Publish Date
2012
Start Page
168
DOI
10.1186/cc11685

Primary care physicians' knowledge of and experience with pharmacogenetic testing.

It is anticipated that as the range of drugs for which pharmacogenetic testing becomes available expands, primary care physicians (PCPs) will become major users of these tests. To assess their training, familiarity, and attitudes toward pharmacogenetic testing in order to identify barriers to uptake that may be addressed at this early stage of test use, we conducted a national survey of a sample of PCPs. Respondents were mostly white (79%), based primarily in community-based primary care (81%) and almost evenly divided between family medicine and internal medicine. The majority of respondents had heard of PGx testing and anticipated that these tests are or would soon become a valuable tool to inform drug response. However, only a minority of respondents (13%) indicated they felt comfortable ordering PGx tests and almost a quarter reported not having any education about pharmacogenetics. Our results indicate that primary care practitioners envision a major role for themselves in the delivery of PGx testing but recognize their lack of adequate knowledge and experience about these tests. Development of effective tools for guiding PCPs in the use of PGx tests should be a high priority.

Authors
Haga, SB; Burke, W; Ginsburg, GS; Mills, R; Agans, R
MLA Citation
Haga, S. B., et al. “Primary care physicians' knowledge of and experience with pharmacogenetic testing..” Clin Genet, vol. 82, no. 4, Oct. 2012, pp. 388–94. Pubmed, doi:10.1111/j.1399-0004.2012.01908.x.
PMID
22698141
Source
pubmed
Published In
Clin Genet
Volume
82
Issue
4
Publish Date
2012
Start Page
388
End Page
394
DOI
10.1111/j.1399-0004.2012.01908.x

Examining the impact of genetic testing for type 2 diabetes on health behaviors: study protocol for a randomized controlled trial.

BACKGROUND: We describe the study design, procedures, and development of the risk counseling protocol used in a randomized controlled trial to evaluate the impact of genetic testing for diabetes mellitus (DM) on psychological, health behavior, and clinical outcomes. METHODS/DESIGN: Eligible patients are aged 21 to 65 years with body mass index (BMI) ≥27 kg/m(2) and no prior diagnosis of DM. At baseline, conventional DM risk factors are assessed, and blood is drawn for possible genetic testing. Participants are randomized to receive conventional risk counseling for DM with eye disease counseling or with genetic test results. The counseling protocol was pilot tested to identify an acceptable graphical format for conveying risk estimates and match the length of the eye disease to genetic counseling. Risk estimates are presented with a vertical bar graph denoting risk level with colors and descriptors. After receiving either genetic counseling regarding risk for DM or control counseling on eye disease, brief lifestyle counseling for prevention of DM is provided to all participants. DISCUSSION: A standardized risk counseling protocol is being used in a randomized trial of 600 participants. Results of this trial will inform policy about whether risk counseling should include genetic counseling. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT01060540.

Authors
Voils, CI; Coffman, CJ; Edelman, D; Maciejewski, ML; Grubber, JM; Sadeghpour, A; Cho, A; McKenzie, J; Blanpain, F; Scheuner, M; Sandelowski, M; Gallagher, MP; Ginsburg, GS; Yancy, WS
MLA Citation
Voils, Corrine I., et al. “Examining the impact of genetic testing for type 2 diabetes on health behaviors: study protocol for a randomized controlled trial..” Trials, vol. 13, Aug. 2012. Pubmed, doi:10.1186/1745-6215-13-121.
PMID
22852560
Source
pubmed
Published In
Trials
Volume
13
Publish Date
2012
Start Page
121
DOI
10.1186/1745-6215-13-121

Genetic testing: clinical and personal utility.

Authors
Mills, RA; Haga, SB; Ginsburg, GS
MLA Citation
Mills, Rachel A., et al. “Genetic testing: clinical and personal utility..” Virtual Mentor, vol. 14, no. 8, Aug. 2012, pp. 604–09. Pubmed, doi:10.1001/virtualmentor.2012.14.8.ecas1-1208.
PMID
23351313
Source
pubmed
Published In
The Virtual Mentor : Vm
Volume
14
Issue
8
Publish Date
2012
Start Page
604
End Page
609
DOI
10.1001/virtualmentor.2012.14.8.ecas1-1208

Clinical application of cardiovascular pharmacogenetics.

Pharmacogenetics primarily uses genetic variation to identify subgroups of patients who may respond differently to a certain medication. Since its first description, the field of pharmacogenetics has expanded to study a broad range of cardiovascular drugs and has become a mainstream research discipline. Three principle classes of pharmacogenetic markers have emerged: 1) pharmacokinetic; 2) pharmacodynamic; and 3) underlying disease mechanism. In the realm of cardiovascular pharmacogenetics, significant advances have identified markers in each class for a variety of therapeutics, some with a potential for improving patient outcomes. While ongoing clinical trials will determine if routine use of pharmacogenetic testing may be beneficial, the data today support pharmacogenetic testing for certain variants on an individualized, case-by-case basis. Our primary goal is to review the association data for the major pharmacogenetic variants associated with commonly used cardiovascular medications: antiplatelet agents, warfarin, statins, beta-blockers, diuretics, and antiarrhythmic drugs. In addition, we highlight which variants and in which contexts pharmacogenetic testing can be implemented by practicing clinicians. The pace of genetic discovery has outstripped the generation of the evidence justifying its clinical adoption. Until the evidentiary gaps are filled, however, clinicians may choose to target therapeutics to individual patients whose genetic background indicates that they stand to benefit the most from pharmacogenetic testing.

Authors
Voora, D; Ginsburg, GS
MLA Citation
Voora, Deepak, and Geoffrey S. Ginsburg. “Clinical application of cardiovascular pharmacogenetics..” J Am Coll Cardiol, vol. 60, no. 1, July 2012, pp. 9–20. Pubmed, doi:10.1016/j.jacc.2012.01.067.
PMID
22742397
Source
pubmed
Published In
J Am Coll Cardiol
Volume
60
Issue
1
Publish Date
2012
Start Page
9
End Page
20
DOI
10.1016/j.jacc.2012.01.067

PRELIMINARY OUTCOMES OF GENETIC RISK TESTING IN PRIMARY CARE FOR COMMON DNA VARIANTS ASSOCIATED WITH TYPE 2 DIABETES

Authors
Cho, AH; Killeya-Jones, LA; Suchindran, S; O'Daniel, JM; Kawamoto, K; Haga, S; Lucas, JE; Trujillo, GM; Joy, S; Ginsburg, GS
MLA Citation
Cho, Alex H., et al. “PRELIMINARY OUTCOMES OF GENETIC RISK TESTING IN PRIMARY CARE FOR COMMON DNA VARIANTS ASSOCIATED WITH TYPE 2 DIABETES.” Journal of General Internal Medicine, vol. 27, SPRINGER, July 2012, pp. S278–S278.
Source
wos
Published In
Journal of General Internal Medicine
Volume
27
Publish Date
2012
Start Page
S278
End Page
S278

Discriminative value of inflammatory biomarkers for suspected sepsis.

BACKGROUND: Circulating biomarkers can facilitate sepsis diagnosis, enabling early management and improved outcomes. Procalcitonin (PCT) has been suggested to have superior diagnostic utility compared to other biomarkers. STUDY OBJECTIVES: To define the discriminative value of PCT, interleukin-6 (IL-6), and C-reactive protein (CRP) for suspected sepsis. METHODS: PCT, CRP, and IL-6 were correlated with infection likelihood, sepsis severity, and septicemia. Multivariable models were constructed for length-of-stay and discharge to a higher level of care. RESULTS: Of 336 enrolled subjects, 60% had definite infection, 13% possible infection, and 27% no infection. Of those with infection, 202 presented with sepsis, 28 with severe sepsis, and 17 with septic shock. Overall, 21% of subjects were septicemic. PCT, IL6, and CRP levels were higher in septicemia (median PCT 2.3 vs. 0.2 ng/mL; IL-6 178 vs. 72 pg/mL; CRP 106 vs. 62 mg/dL; p < 0.001). Biomarker concentrations increased with likelihood of infection and sepsis severity. Using receiver operating characteristic analysis, PCT best predicted septicemia (0.78 vs. IL-6 0.70 and CRP 0.67), but CRP better identified clinical infection (0.75 vs. PCT 0.71 and IL-6 0.69). A PCT cutoff of 0.5 ng/mL had 72.6% sensitivity and 69.5% specificity for bacteremia, as well as 40.7% sensitivity and 87.2% specificity for diagnosing infection. A combined clinical-biomarker model revealed that CRP was marginally associated with length of stay (p = 0.015), but no biomarker independently predicted discharge to a higher level of care. CONCLUSIONS: In adult emergency department patients with suspected sepsis, PCT, IL-6, and CRP highly correlate with several infection parameters, but are inadequately discriminating to be used independently as diagnostic tools.

Authors
Tsalik, EL; Jaggers, LB; Glickman, SW; Langley, RJ; van Velkinburgh, JC; Park, LP; Fowler, VG; Cairns, CB; Kingsmore, SF; Woods, CW
MLA Citation
Tsalik, Ephraim L., et al. “Discriminative value of inflammatory biomarkers for suspected sepsis..” J Emerg Med, vol. 43, no. 1, July 2012, pp. 97–106. Pubmed, doi:10.1016/j.jemermed.2011.05.072.
PMID
22056545
Source
pubmed
Published In
Journal of Emergency Medicine
Volume
43
Issue
1
Publish Date
2012
Start Page
97
End Page
106
DOI
10.1016/j.jemermed.2011.05.072

Conference Scene: Is personalized medicine ready for prime time?

This article provides a meeting report from the Duke Center for Personalized Medicine 2012 Symposium, which took place in Durham, NC, USA, on 29 March 2012. The event titled 'At the Interface of Clinical Research and Clinical Medicine', focused on many of the issues that arise as personalized medicine becomes integrated into clinical care. In particular, we summarize presentations on various topics: the future of genomic medicine, opportunities in pharmacogenomics and genetic testing; challenges in the clinical implementation of personalized medicine; systems medicine and biomedical informatics; the policy and education strategies for adopting personalized medicine; the common bond between comparative effectiveness and personalized medicine; and the value of personalized medicine.

Authors
Kraus, WE; Haga, SB; McLeod, HL; Staples, J; Ginsburg, GS
MLA Citation
Kraus, William E., et al. “Conference Scene: Is personalized medicine ready for prime time?.” Per Med, vol. 9, no. 5, July 2012, pp. 475–78. Pubmed, doi:10.2217/pme.12.57.
PMID
29768766
Source
pubmed
Published In
Personalized Medicine
Volume
9
Issue
5
Publish Date
2012
Start Page
475
End Page
478
DOI
10.2217/pme.12.57

Hierarchical factor modeling of proteomics data

This paper presents a hierarchical bayesian factor model specifically designed to model the known correlation structure of both peptides and proteins in unbiased, label free proteomics. The model utilizes partial identification information from peptide sequencing and database lookup as well as observed correlation in the data set in order to appropriately compress features into metaproteins and to estimate correlation structure. Although peptide to phenotype associations may be computed from hypothesis testing or multiple regression summaries, to date, there have been no published approaches that directly model what we know to be multiple different levels of correlation structure. We test the the proposed model using publicly available benchmark data and a recent study based on a collection of volunteers who were infected with two different strands of viral influenza. © 2012 IEEE.

Authors
Henao, R; Thompson, JW; Moseley, MA; Ginsburg, GS; Carin, L; Lucas, JE
MLA Citation
Henao, R., et al. “Hierarchical factor modeling of proteomics data.” 2012 Ieee 2nd International Conference on Computational Advances in Bio and Medical Sciences, Iccabs 2012, May 2012. Scopus, doi:10.1109/ICCABS.2012.6182638.
Source
scopus
Published In
2012 Ieee 2nd International Conference on Computational Advances in Bio and Medical Sciences, Iccabs 2012
Publish Date
2012
DOI
10.1109/ICCABS.2012.6182638

Unsuspected rickettsioses among patients with acute febrile illness, Sri Lanka, 2007.

We studied rickettsioses in southern Sri Lanka. Of 883 febrile patients with paired serum samples, 156 (17.7%) had acute rickettsioses; rickettsioses were unsuspected at presentation. Additionally, 342 (38.7%) had exposure to spotted fever and/or typhus group rickettsioses and 121 (13.7%) scrub typhus. Increased awareness of rickettsioses and better tests are needed.

Authors
Reller, ME; Bodinayake, C; Nagahawatte, A; Devasiri, V; Kodikara-Arachichi, W; Strouse, JJ; Flom, JE; Østbye, T; Woods, CW; Dumler, JS
MLA Citation
Reller, Megan E., et al. “Unsuspected rickettsioses among patients with acute febrile illness, Sri Lanka, 2007..” Emerg Infect Dis, vol. 18, no. 5, May 2012, pp. 825–29. Pubmed, doi:10.3201/eid1805.111563.
PMID
22516455
Source
pubmed
Published In
Emerging Infectious Diseases
Volume
18
Issue
5
Publish Date
2012
Start Page
825
End Page
829
DOI
10.3201/eid1805.111563

Time-dependent changes in non-COX-1-dependent platelet function with daily aspirin therapy.

To develop an integrated metric of non-COX-1-dependent platelet function (NCDPF) to measure the temporal response to aspirin in healthy volunteers and diabetics. NCDPF on aspirin demonstrates wide variability, despite suppression of COX-1. Although a variety of NCDPF assays are available, no standard exists and their reproducibility is not established. We administered 325 mg/day aspirin to two cohorts of volunteers (HV1, n = 52, and HV2, n = 96) and diabetics (DM, n = 74) and measured NCDPF using epinephrine, collagen, and ADP aggregometry and PFA100 (collagen/epi) before (Pre), after one dose (Post), and after several weeks (Final). COX-1 activity was assessed with arachidonic acid aggregometry (AAA). The primary outcome of the study, the platelet function score (PFS), was derived from a principal components analysis of NCDPF measures. The PFS strongly correlated with each measure of NCDPF in each cohort. After 2 or 4 weeks of daily aspirin the Final PFS strongly correlated (r > 0.7, P < 0.0001) and was higher (P < 0.01) than the Post PFS. The magnitude and direction of the change in PFS (Final–Post) in an individual subject was moderately inversely proportional to the Post PFS in HV1 (r = -0.45), HV2 (r = -0.54), DM (r = -0.68), P < 0.0001 for all. AAA remained suppressed during aspirin therapy. The PFS summarizes multiple measures of NCDPF. Despite suppression of COX-1 activity, NCDPF during aspirin therapy is predictably dynamic: those with heightened NCDPF continue to decline whereas those with low/normal NCDPF return to pre-aspirin levels over time.

Authors
Voora, D; Ortel, TL; Lucas, JE; Chi, J-T; Becker, RC; Ginsburg, GS
MLA Citation
Voora, Deepak, et al. “Time-dependent changes in non-COX-1-dependent platelet function with daily aspirin therapy..” J Thromb Thrombolysis, vol. 33, no. 3, Apr. 2012, pp. 246–57. Pubmed, doi:10.1007/s11239-012-0683-0.
PMID
22294277
Source
pubmed
Published In
Journal of Thrombosis and Thrombolysis
Volume
33
Issue
3
Publish Date
2012
Start Page
246
End Page
257
DOI
10.1007/s11239-012-0683-0

Genome technologies and personalized dental medicine.

The addition of genomic information to our understanding of oral disease is driving important changes in oral health care. It is anticipated that genome-derived information will promote a deeper understanding of disease etiology and permit earlier diagnosis, allowing for preventative measures prior to disease onset rather than treatment that attempts to repair the diseased state. Advances in genome technologies have fueled expectations for this proactive healthcare approach. Application of genomic testing is expanding and has already begun to find its way into the practice of clinical dentistry. To take full advantage of the information and technologies currently available, it is vital that dental care providers, consumers, and policymakers be aware of genomic approaches to understanding of oral diseases and the application of genomic testing to disease diagnosis and treatment. Ethical, legal, clinical, and educational initiatives are also required to responsibly incorporate genomic information into the practice of dentistry. This article provides an overview of the application of genomic technologies to oral health care and introduces issues that require consideration if we are to realize the full potential of genomics to enable the practice of personalized dental medicine.

Authors
Eng, G; Chen, A; Vess, T; Ginsburg, GS
MLA Citation
Eng, G., et al. “Genome technologies and personalized dental medicine..” Oral Diseases, vol. 18, no. 3, Apr. 2012, pp. 223–35. Epmc, doi:10.1111/j.1601-0825.2011.01876.x.
PMID
22129463
Source
epmc
Published In
Oral Diseases
Volume
18
Issue
3
Publish Date
2012
Start Page
223
End Page
235
DOI
10.1111/j.1601-0825.2011.01876.x

The oral microbiome in health and disease and the potential impact on personalized dental medicine.

Every human body contains a personalized microbiome that is essential to maintaining health but capable of eliciting disease. The oral microbiome is particularly imperative to health because it can cause both oral and systemic disease. The oral microbiome rests within biofilms throughout the oral cavity, forming an ecosystem that maintains health when in equilibrium. However, certain ecological shifts in the microbiome allow pathogens to manifest and cause disease. Severe forms of oral disease may result in systemic disease at different body sites. Microbiomics and metagenomics are two fields of research that have emerged to identify the presence of specific microbes in the body and understand the nature of the microbiome activity during both health and disease. The analysis of the microbiome and its genomes will pave the way for more effective therapeutic and diagnostic techniques and, ultimately, contribute to the development of personalized medicine and personalized dental medicine.

Authors
Zarco, MF; Vess, TJ; Ginsburg, GS
MLA Citation
Zarco, M. F., et al. “The oral microbiome in health and disease and the potential impact on personalized dental medicine..” Oral Dis, vol. 18, no. 2, Mar. 2012, pp. 109–20. Pubmed, doi:10.1111/j.1601-0825.2011.01851.x.
PMID
21902769
Source
pubmed
Published In
Oral Dis
Volume
18
Issue
2
Publish Date
2012
Start Page
109
End Page
120
DOI
10.1111/j.1601-0825.2011.01851.x

Southeastern Center for Emerging Biologic Threats tabletop exercise: foodborne toxoplasmosis outbreak on college campuses.

The use of tabletop exercises as a tool in emergency preparedness and response has proven to be an effective means of assessing readiness for unexpected events. Whereas most exercise developers target a population in a defined space (eg, state, county, metropolitan area, hospital), the Southeastern Center for Emerging Biologic Threats (SECEBT) conducted an innovative tabletop exercise involving an unusual foodborne outbreak pathogen, targeting public health agencies and academic institutions in 7 southeastern states. The exercise tested the ability of participants to respond to a simulated foodborne disease outbreak affecting the region. The attendees represented 4 federal agencies, 9 state agencies, 6 universities, 1 nonprofit organization, and 1 private corporation. The goals were to promote collaborative relationships among the players, identify gaps in plans and policies, and identify the unique contributions of each organization-and notably academic institutions-to outbreak recognition, investigation, and control. Participants discussed issues and roles related to outbreak detection and management, risk communication, and coordination of policies and responsibilities before, during, and after an emergency, with emphasis on assets of universities that could be mobilized during an outbreak response. The exercise generated several lessons and recommendations identified by participants and evaluators. Key recommendations included a need to establish trigger points and protocols for information sharing and alerts among public health, academic, and law enforcement; to establish relationships with local, state, and federal stakeholders to facilitate communications during an emergency; and to catalogue and leverage strengths, assets, and priorities of academic institutions to add value to outbreak responses.

Authors
Morris, JG; Greenspan, A; Howell, K; Gargano, LM; Mitchell, J; Jones, JL; Potter, M; Isakov, A; Woods, C; Hughes, JM
MLA Citation
Morris, J. Glenn, et al. “Southeastern Center for Emerging Biologic Threats tabletop exercise: foodborne toxoplasmosis outbreak on college campuses..” Biosecur Bioterror, vol. 10, no. 1, Mar. 2012, pp. 89–97. Pubmed, doi:10.1089/bsp.2011.0040.
PMID
22283568
Source
pubmed
Published In
Biosecur Bioterror
Volume
10
Issue
1
Publish Date
2012
Start Page
89
End Page
97
DOI
10.1089/bsp.2011.0040

Unsuspected dengue and acute febrile illness in rural and semi-urban southern Sri Lanka.

Dengue virus (DENV), a globally emerging cause of undifferentiated fever, has been documented in the heavily urbanized western coast of Sri Lanka since the 1960s. New areas of Sri Lanka are now being affected, and the reported number and severity of cases have increased. To study emerging DENV in southern Sri Lanka, we obtained epidemiologic and clinical data and acute- and convalescent-phase serum samples from patients >2 years old with febrile illness. We tested paired serum samples for DENV IgG and IgM and serotyped virus by using isolation and reverse transcription PCR. We identified acute DENV infection (serotypes 2, 3, and 4) in 54 (6.3%) of 859 patients. Only 14% of patients had clinically suspected dengue; however, 54% had serologically confirmed acute or past DENV infection. DENV is a major and largely unrecognized cause of fever in southern Sri Lanka, especially in young adults.

Authors
Reller, ME; Bodinayake, C; Nagahawatte, A; Devasiri, V; Kodikara-Arachichi, W; Strouse, JJ; Broadwater, A; Østbye, T; de Silva, A; Woods, CW
MLA Citation
Reller, Megan E., et al. “Unsuspected dengue and acute febrile illness in rural and semi-urban southern Sri Lanka..” Emerg Infect Dis, vol. 18, no. 2, Feb. 2012, pp. 256–63. Pubmed, doi:10.3201/eid1802.110962.
PMID
22304972
Source
pubmed
Published In
Emerging Infectious Diseases
Volume
18
Issue
2
Publish Date
2012
Start Page
256
End Page
263
DOI
10.3201/eid1802.110962

Effect of genetic testing for risk of type 2 diabetes mellitus on health behaviors and outcomes: study rationale, development and design.

BACKGROUND: Type 2 diabetes is a prevalent chronic condition globally that results in extensive morbidity, decreased quality of life, and increased health services utilization. Lifestyle changes can prevent the development of diabetes, but require patient engagement. Genetic risk testing might represent a new tool to increase patients' motivation for lifestyle changes. Here we describe the rationale, development, and design of a randomized controlled trial (RCT) assessing the clinical and personal utility of incorporating type 2 diabetes genetic risk testing into comprehensive diabetes risk assessments performed in a primary care setting. METHODS/DESIGN: Patients are recruited in the laboratory waiting areas of two primary care clinics and enrolled into one of three study arms. Those interested in genetic risk testing are randomized to receive either a standard risk assessment (SRA) for type 2 diabetes incorporating conventional risk factors plus upfront disclosure of the results of genetic risk testing ("SRA+G" arm), or the SRA alone ("SRA" arm). Participants not interested in genetic risk testing will not receive the test, but will receive SRA (forming a third, "no-test" arm). Risk counseling is provided by clinic staff (not study staff external to the clinic). Fasting plasma glucose, insulin levels, body mass index (BMI), and waist circumference are measured at baseline and 12 months, as are patients' self-reported behavioral and emotional responses to diabetes risk information. Primary outcomes are changes in insulin resistance and BMI after 12 months; secondary outcomes include changes in diet patterns, physical activity, waist circumference, and perceived risk of developing diabetes. DISCUSSION: The utility, feasibility, and efficacy of providing patients with genetic risk information for common chronic diseases in primary care remain unknown. The study described here will help to establish whether providing type 2 diabetes genetic risk information in a primary care setting can help improve patients' clinical outcomes, risk perceptions, and/or their engagement in healthy behavior change. In addition, study design features such as the use of existing clinic personnel for risk counseling could inform the future development and implementation of care models for the use of individual genetic risk information in primary care. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00849563.

Authors
Cho, AH; Killeya-Jones, LA; O'Daniel, JM; Kawamoto, K; Gallagher, P; Haga, S; Lucas, JE; Trujillo, GM; Joy, SV; Ginsburg, GS
MLA Citation
Cho, Alex H., et al. “Effect of genetic testing for risk of type 2 diabetes mellitus on health behaviors and outcomes: study rationale, development and design..” Bmc Health Serv Res, vol. 12, Jan. 2012. Pubmed, doi:10.1186/1472-6963-12-16.
Website
http://hdl.handle.net/10161/13545
PMID
22257365
Source
pubmed
Published In
Bmc Health Services Research
Volume
12
Publish Date
2012
Start Page
16
DOI
10.1186/1472-6963-12-16

High-Dimensional Longitudinal Genomic Data: An analysis used for monitoring viral infections.

Authors
Carin, L; Hero, A; Lucas, J; Dunson, D; Chen, M; Heñao, R; Tibau-Puig, A; Zaas, A; Woods, CW; Ginsburg, GS
MLA Citation
Carin, Lawrence, et al. “High-Dimensional Longitudinal Genomic Data: An analysis used for monitoring viral infections..” Ieee Signal Process Mag, vol. 29, no. 1, Jan. 2012, pp. 108–23. Pubmed, doi:10.1109/MSP.2011.943009.
PMID
24678238
Source
pubmed
Published In
Ieee Signal Processing Magazine
Volume
29
Issue
1
Publish Date
2012
Start Page
108
End Page
123
DOI
10.1109/MSP.2011.943009

The MURDOCK Study: a long-term initiative for disease reclassification through advanced biomarker discovery and integration with electronic health records.

BACKGROUND: Facing critically low return per dollar invested on clinical research and clinical care, the American biomedical enterprise is in need of a significant transformation. A confluence of high-throughput "omic" technologies and increasing adoption of the electronic health record has fueled excitement for a new paradigm for biomedical research and practice. The ability to simultaneously measure thousands of molecular variables and assess their relationships with clinical data collected during the course of care could enable reclassification of disease not only by gross phenotypic observation but according to underlying molecular mechanism and influence of social determinants.In turn, this reclassification could enable development of targeted therapeutic interventions as well as disease prevention strategies at the individual and population levels. METHODS/DESIGN: The MURDOCK Study consists of distinct project "horizons" or stages. Horizon 1 entailed the generation and analysis of molecular data for existing large,clinically well-annotated cohorts in four disease areas. Horizon 1.5 involves creating and maintaining a 50,000-person,community volunteer registry for biomarker signature validation and prospective studies, including integration of environmental and social data. Horizon 2 leverages and prospectively recruits Horizon 1.5 volunteers, and extends the study to additional disease areas of interest. Horizon 3 will expand the study through regional, national,and international partnerships. DISCUSSION: The MURDOCK Study embodies a new model of team science investigation and represents a significant resource for translational research. The study team invites inquiries to form new collaborations to exploit the rich resources provided by these biospecimens and associated study data.

Authors
Tenenbaum, JD; Christian, V; Cornish, MA; Dolor, RJ; Dunham, AA; Ginsburg, GS; Kraus, VB; McHutchison, JG; Nahm, ML; Newby, LK; Svetkey, LP; Udayakumar, K; Califf, RM
MLA Citation
Tenenbaum, Jessica D., et al. “The MURDOCK Study: a long-term initiative for disease reclassification through advanced biomarker discovery and integration with electronic health records..” Am J Transl Res, vol. 4, no. 3, 2012, pp. 291–301.
PMID
22937207
Source
pubmed
Published In
American Journal of Translational Research
Volume
4
Issue
3
Publish Date
2012
Start Page
291
End Page
301

The Measurement to Understand Reclassification of Disease of Cabarrus/Kannapolis (MURDOCK) Study Community Registry and Biorepository.

Current understanding of chronic diseases is based on crude clinical characterization, imaging studies, and laboratory testing that has evolved over decades. The Measurement to Understand Reclassification of Disease of Cabarrus/Kannapolis (MURDOCK) Study is a multi-tiered, longitudinal study designed to enable classification of chronic diseases using clinically annotated biospecimen collections, -omic technologies, electronic health records, and standard epidemiological methods. We expect that detailed molecular classification will improve mechanistic understanding of chronic diseases, augmenting discovery and testing of new treatments, and allowing refined selection of prevention and treatment strategies. The MURDOCK Study Community Registry and Biorepository will serve as a bridge for validation of initial exploratory studies, a platform for future prospective studies in targeted populations, and a resource of both data (analytical and clinical) and samples for cross-registry meta-analyses and comparative population studies. Participation of local health care providers and the Cabarrus County/Kannapolis, NC, community will facilitate future medical research and provide the opportunity to educate and inform the public about genomic research, actively engaging them in shaping the future of medical discovery and treatment of chronic diseases. We present the rationale and study design for the MURDOCK Community Registry and Biorepository and baseline characteristics of the first 6000 participants.

Authors
Bhattacharya, S; Dunham, AA; Cornish, MA; Christian, VA; Ginsburg, GS; Tenenbaum, JD; Nahm, ML; Miranda, ML; Califf, RM; Dolor, RJ; Newby, LK
MLA Citation
Bhattacharya, Sayanti, et al. “The Measurement to Understand Reclassification of Disease of Cabarrus/Kannapolis (MURDOCK) Study Community Registry and Biorepository..” Am J Transl Res, vol. 4, no. 4, 2012, pp. 458–70.
PMID
23145214
Source
pubmed
Published In
American Journal of Translational Research
Volume
4
Issue
4
Publish Date
2012
Start Page
458
End Page
470

P3-14-04: Assessment of Genomic Prognostic Signatures as Predictors of Response to Neoadjuvant Chemotherapy in Patients with Early Stage Breast Cancer.

Authors
Culakova, E; Poniewierski, MS; Huang, M; Kuderer, NM; Ginsburg, GS; Barry, W; Marcom, PK; Ready, N; Abernethy, A; Lyman, GH
MLA Citation
Culakova, E., et al. “P3-14-04: Assessment of Genomic Prognostic Signatures as Predictors of Response to Neoadjuvant Chemotherapy in Patients with Early Stage Breast Cancer..” Poster Session Abstracts, American Association for Cancer Research, Dec. 2011. Crossref, doi:10.1158/0008-5472.sabcs11-p3-14-04.
Source
crossref
Published In
Poster Session Abstracts
Publish Date
2011
DOI
10.1158/0008-5472.sabcs11-p3-14-04

Whole blood gene expression analyses in patients with single versus recurrent venous thromboembolism.

INTRODUCTION: Venous thromboembolism may recur in up to 30% of patients with a spontaneous venous thromboembolism after a standard course of anticoagulation. Identification of patients at risk for recurrent venous thromboembolism would facilitate decisions concerning the duration of anticoagulant therapy. OBJECTIVES: In this exploratory study, we investigated whether whole blood gene expression data could distinguish subjects with single venous thromboembolism from subjects with recurrent venous thromboembolism. METHODS: 40 adults with venous thromboembolism (23 with single event and 17 with recurrent events) on warfarin were recruited. Individuals with antiphospholipid syndrome or cancer were excluded. Plasma and serum samples were collected for biomarker testing, and PAXgene tubes were used to collect whole blood RNA samples. RESULTS: D-dimer levels were significantly higher in patients with recurrent venous thromboembolism, but P-selectin and thrombin-antithrombin complex levels were similar in the two groups. Comparison of gene expression data from the two groups provided us with a 50 gene probe model that distinguished these two groups with good receiver operating curve characteristics (AUC 0.75). This model includes genes involved in mRNA splicing and platelet aggregation. Pathway analysis between subjects with single and recurrent venous thromboembolism revealed that the Akt pathway was up-regulated in the recurrent venous thromboembolism group compared to the single venous thromboembolism group. CONCLUSIONS: In this exploratory study, gene expression profiles of whole blood appear to be a useful strategy to distinguish subjects with single venous thromboembolism from those with recurrent venous thromboembolism. Prospective studies with additional patients are needed to validate these results.

Authors
Lewis, DA; Stashenko, GJ; Akay, OM; Price, LI; Owzar, K; Ginsburg, GS; Chi, J-T; Ortel, TL
MLA Citation
Lewis, Deborah A., et al. “Whole blood gene expression analyses in patients with single versus recurrent venous thromboembolism..” Thromb Res, vol. 128, no. 6, Dec. 2011, pp. 536–40. Pubmed, doi:10.1016/j.thromres.2011.06.003.
PMID
21737128
Source
pubmed
Published In
Thromb Res
Volume
128
Issue
6
Publish Date
2011
Start Page
536
End Page
540
DOI
10.1016/j.thromres.2011.06.003

Protocol for implementation of family health history collection and decision support into primary care using a computerized family health history system.

BACKGROUND: The CDC's Family History Public Health Initiative encourages adoption and increase awareness of family health history. To meet these goals and develop a personalized medicine implementation science research agenda, the Genomedical Connection is using an implementation research (T3 research) framework to develop and integrate a self-administered computerized family history system with built-in decision support into 2 primary care clinics in North Carolina. METHODS/DESIGN: The family health history system collects a three generation family history on 48 conditions and provides decision support (pedigree and tabular family history, provider recommendation report and patient summary report) for 4 pilot conditions: breast cancer, ovarian cancer, colon cancer, and thrombosis. All adult English-speaking, non-adopted, patients scheduled for well-visits are invited to complete the family health system prior to their appointment. Decision support documents are entered into the medical record and available to provider's prior to the appointment. In order to optimize integration, components were piloted by stakeholders prior to and during implementation. Primary outcomes are change in appropriate testing for hereditary thrombophilia and screening for breast cancer, colon cancer, and ovarian cancer one year after study enrollment. Secondary outcomes include implementation measures related to the benefits and burdens of the family health system and its impact on clinic workflow, patients' risk perception, and intention to change health related behaviors. Outcomes are assessed through chart review, patient surveys at baseline and follow-up, and provider surveys. Clinical validity of the decision support is calculated by comparing its recommendations to those made by a genetic counselor reviewing the same pedigree; and clinical utility is demonstrated through reclassification rates and changes in appropriate screening (the primary outcome). DISCUSSION: This study integrates a computerized family health history system within the context of a routine well-visit appointment to overcome many of the existing barriers to collection and use of family history information by primary care providers. Results of the implementation process, its acceptability to patients and providers, modifications necessary to optimize the system, and impact on clinical care can serve to guide future implementation projects for both family history and other tools of personalized medicine, such as health risk assessments.

Authors
Orlando, LA; Hauser, ER; Christianson, C; Powell, KP; Buchanan, AH; Chesnut, B; Agbaje, AB; Henrich, VC; Ginsburg, G
MLA Citation
Orlando, Lori A., et al. “Protocol for implementation of family health history collection and decision support into primary care using a computerized family health history system..” Bmc Health Serv Res, vol. 11, Oct. 2011. Pubmed, doi:10.1186/1472-6963-11-264.
Website
http://hdl.handle.net/10161/13544
PMID
21989281
Source
pubmed
Published In
Bmc Health Services Research
Volume
11
Publish Date
2011
Start Page
264
DOI
10.1186/1472-6963-11-264

Consideration of patient preferences and challenges in storage and access of pharmacogenetic test results.

PURPOSE: Pharmacogenetic testing is one of the primary drivers of personalized medicine. The use of pharmacogenetic testing may provide a lifetime of benefits through tailoring drug dosing and selection of multiple medications to improve therapeutic outcomes and reduce adverse responses. We aimed to assess public interest and concerns regarding sharing and storage of pharmacogenetic test results that would facilitate the reuse of pharmacogenetic data across a lifetime of care. METHODS: We conducted a random-digit-dial phone survey of a sample of the US public. RESULTS: We achieved an overall response rate of 42% (n = 1139). Most respondents indicated that they were extremely or somewhat comfortable allowing their pharmacogenetic test results to be shared with other doctors involved in their care management (90% ± 2.18%); significantly fewer respondents (74% ± 3.27%) indicated that they were extremely or somewhat comfortable sharing results with their pharmacist (P < 0.0001). CONCLUSION: Patients, pharmacists, and physicians will all be critical players in the pharmacotherapy process. Patients are supportive of sharing pharmacogenetic test results with physicians and pharmacists and personally maintaining their test results. However, further study is needed to understand which options are needed for sharing, appropriate storage, and patient education about the relevance of pharmacogenetic test results to promote consideration of this information by other prescribing practitioners.

Authors
Haga, SB; Kawamoto, K; Agans, R; Ginsburg, GS
MLA Citation
Haga, Susanne B., et al. “Consideration of patient preferences and challenges in storage and access of pharmacogenetic test results..” Genet Med, vol. 13, no. 10, Oct. 2011, pp. 887–90. Pubmed, doi:10.1097/GIM.0b013e31822077a5.
PMID
21673581
Source
pubmed
Published In
Genet Med
Volume
13
Issue
10
Publish Date
2011
Start Page
887
End Page
890
DOI
10.1097/GIM.0b013e31822077a5

Academic medical centers: ripe for rapid-learning personalized health care.

In an attempt to reduce the lengthy process of translating scientific findings into clinical practice, the United States and several European governments are making substantial investments in health information technology, comparative effectiveness research, and increased access to quality health care. New technologies--genomics in particular--are expected to usher in more cost-effective personalized health care. Academic medical centers can play a central role in this transformation through the development of rapid learning environments, evidence generation, implementation research, and education of health professionals and the public.

Authors
Ginsburg, GS; Staples, J; Abernethy, AP
MLA Citation
Ginsburg, Geoffrey S., et al. “Academic medical centers: ripe for rapid-learning personalized health care..” Sci Transl Med, vol. 3, no. 101, Sept. 2011. Pubmed, doi:10.1126/scitranslmed.3002386.
PMID
21937754
Source
pubmed
Published In
Sci Transl Med
Volume
3
Issue
101
Publish Date
2011
Start Page
101cm27
DOI
10.1126/scitranslmed.3002386

Methicillin-susceptible Staphylococcus aureus endocarditis isolates are associated with clonal complex 30 genotype and a distinct repertoire of enterotoxins and adhesins.

BACKGROUND: Using multinational collections of methicillin-susceptible Staphylococcus aureus (MSSA) isolates from infective endocarditis (IE) and soft tissue infections (STIs), we sought to (1) validate the finding that S. aureus in clonal complex (CC) 30 is associated with hematogenous complications and (2) test the hypothesis that specific genetic characteristics in S. aureus are associated with infection severity. METHODS: IE and STI isolates from 2 cohorts were frequency matched by geographic origin. Isolates underwent spa typing to infer CC and multiplex polymerase chain reaction for presence of virulence genes. RESULTS: 114 isolate pairs were genotyped. IE isolates were more likely to be CC30 (19.5% vs 6.2%; P = .005) and to contain 3 adhesins (clfB, cna, map/eap; P < .0001 for all) and 5 enterotoxins (tst, sea, sed, see, and sei; P ≤ .005 for all). CC30 isolates were more likely to contain cna, tst, sea, see, seg, and chp (P < .05 for all). CONCLUSIONS: MSSA IE isolates were significantly more likely to be CC30 and to possess a distinct repertoire of virulence genes than MSSA STI isolates from the same region. The genetic basis of this association requires further study.

Authors
Nienaber, JJC; Sharma Kuinkel, BK; Clarke-Pearson, M; Lamlertthon, S; Park, L; Rude, TH; Barriere, S; Woods, CW; Chu, VH; Marín, M; Bukovski, S; Garcia, P; Corey, GR; Korman, T; Doco-Lecompte, T; Murdoch, DR; Reller, LB; Fowler, VG; International Collaboration on Endocarditis-Microbiology Investigators,
MLA Citation
Nienaber, Juhsien J. C., et al. “Methicillin-susceptible Staphylococcus aureus endocarditis isolates are associated with clonal complex 30 genotype and a distinct repertoire of enterotoxins and adhesins..” J Infect Dis, vol. 204, no. 5, Sept. 2011, pp. 704–13. Pubmed, doi:10.1093/infdis/jir389.
PMID
21844296
Source
pubmed
Published In
J Infect Dis
Volume
204
Issue
5
Publish Date
2011
Start Page
704
End Page
713
DOI
10.1093/infdis/jir389

Hallucinations, sensory neuropathy, and peripheral visual deficits in a young woman infected with Bartonella koehlerae.

A young woman experiencing depression, anxiety, mood swings, severe headaches, muscle spasms, interphalangeal joint stiffness, decreased peripheral vision, diminished tactile sensation, and hallucinations was persistently Bartonella koehlerae seroreactive and bacteremic. Following antibiotic treatment, B. koehlerae antibodies and DNA were not detected and all symptoms resolved.

Authors
Breitschwerdt, EB; Mascarelli, PE; Schweickert, LA; Maggi, RG; Hegarty, BC; Bradley, JM; Woods, CW
MLA Citation
Breitschwerdt, Edward B., et al. “Hallucinations, sensory neuropathy, and peripheral visual deficits in a young woman infected with Bartonella koehlerae..” J Clin Microbiol, vol. 49, no. 9, Sept. 2011, pp. 3415–17. Pubmed, doi:10.1128/JCM.00833-11.
PMID
21734026
Source
pubmed
Published In
J Clin Microbiol
Volume
49
Issue
9
Publish Date
2011
Start Page
3415
End Page
3417
DOI
10.1128/JCM.00833-11

Leptospirosis as frequent cause of acute febrile illness in southern Sri Lanka.

To determine the proportion of fevers caused by leptospirosis, we obtained serum specimens and epidemiologic and clinical data from patients in Galle, Sri Lanka, March-October 2007. Immunoglobulin M ELISA was performed on paired serum specimens to diagnose acute (seroconversion or 4-fold titer rise) or past (titer without rise) leptospirosis and seroprevalence (acute). We compared (individually) the diagnostic yield of acute-phase specimens and clinical impression with paired specimens for acute leptospirosis. Of 889 patients with paired specimens, 120 had acute leptosoirosis and 241 had past leptospirosis. The sensitivity and specificity of acute-phase serum specimens were 17.5% (95% confidence interval [CI] 11.2%-25.5%) and 69.2% (95% CI 65.5%-72.7%), respectively, and of clinical impression 22.9% (95% CI 15.4%-32.0%) and 91.7% (95% CI 89.2%-93.8%), respectively. For identifying acute leptospirosis, clinical impression is insensitive, and immunoglobulin M results are more insensitive and costly. Rapid, pathogen-based tests for early diagnosis are needed.

Authors
Reller, ME; Bodinayake, C; Nagahawatte, A; Devasiri, V; Kodikara-Arachichi, W; Strouse, JJ; Flom, JE; Dumler, JS; Woods, CW
MLA Citation
Reller, Megan E., et al. “Leptospirosis as frequent cause of acute febrile illness in southern Sri Lanka..” Emerg Infect Dis, vol. 17, no. 9, Sept. 2011, pp. 1678–84. Pubmed, doi:10.3201/eid1709.100915.
PMID
21888794
Source
pubmed
Published In
Emerging Infectious Diseases
Volume
17
Issue
9
Publish Date
2011
Start Page
1678
End Page
1684
DOI
10.3201/eid1709.100915

Genomic risk profiling: attitudes and use in personal and clinical care of primary care physicians who offer risk profiling.

BACKGROUND: Genomic risk profiling involves the analysis of genetic variations linked through statistical associations to a range of disease states. There is considerable controversy as to how, and even whether, to incorporate these tests into routine medical care. OBJECTIVE: To assess physician attitudes and uptake of genomic risk profiling among an 'early adopter' practice group. DESIGN: We surveyed members of MDVIP, a national group of primary care physicians (PCPs), currently offering genomic risk profiling as part of their practice. POPULATION: All physicians in the MDVIP network (N = 356) RESULTS: We obtained a 44% response rate. One third of respondents had ordered a test for themselves and 42% for a patient. The odds of having ordered personal testing were 10.51-fold higher for those who felt well-informed about genomic risk testing (p < 0.0001). Of those who had not ordered a test for themselves, 60% expressed concerns for patients regarding discrimination by life and long-term/disability insurers, 61% about test cost, and 62% about clinical utility. The odds of ordering testing for their patients was 8.29-fold higher among respondents who had ordered testing for themselves (p < 0.0001). Of those who had ordered testing for patients, concerns about insurance coverage (p = 0.014) and uncertain clinical utility (p = 0.034) were associated with a lower relative frequency of intention to order testing again in the future. CONCLUSIONS: Our findings demonstrate that respondent familiarity was a key predictor of physician ordering behavior and clinical utility was a primary concern for genomic risk profiling. Educational and interpretive support may enhance uptake of genomic risk profiling.

Authors
Haga, SB; Carrig, MM; O'Daniel, JM; Orlando, LA; Killeya-Jones, LA; Ginsburg, GS; Cho, A
MLA Citation
Haga, Susanne B., et al. “Genomic risk profiling: attitudes and use in personal and clinical care of primary care physicians who offer risk profiling..” J Gen Intern Med, vol. 26, no. 8, Aug. 2011, pp. 834–40. Pubmed, doi:10.1007/s11606-011-1651-7.
PMID
21311998
Source
pubmed
Published In
J Gen Intern Med
Volume
26
Issue
8
Publish Date
2011
Start Page
834
End Page
840
DOI
10.1007/s11606-011-1651-7

Temporal dynamics of host molecular responses differentiate symptomatic and asymptomatic influenza a infection.

Exposure to influenza viruses is necessary, but not sufficient, for healthy human hosts to develop symptomatic illness. The host response is an important determinant of disease progression. In order to delineate host molecular responses that differentiate symptomatic and asymptomatic Influenza A infection, we inoculated 17 healthy adults with live influenza (H3N2/Wisconsin) and examined changes in host peripheral blood gene expression at 16 timepoints over 132 hours. Here we present distinct transcriptional dynamics of host responses unique to asymptomatic and symptomatic infections. We show that symptomatic hosts invoke, simultaneously, multiple pattern recognition receptors-mediated antiviral and inflammatory responses that may relate to virus-induced oxidative stress. In contrast, asymptomatic subjects tightly regulate these responses and exhibit elevated expression of genes that function in antioxidant responses and cell-mediated responses. We reveal an ab initio molecular signature that strongly correlates to symptomatic clinical disease and biomarkers whose expression patterns best discriminate early from late phases of infection. Our results establish a temporal pattern of host molecular responses that differentiates symptomatic from asymptomatic infections and reveals an asymptomatic host-unique non-passive response signature, suggesting novel putative molecular targets for both prognostic assessment and ameliorative therapeutic intervention in seasonal and pandemic influenza.

Authors
Huang, Y; Zaas, AK; Rao, A; Dobigeon, N; Woolf, PJ; Veldman, T; Øien, NC; McClain, MT; Varkey, JB; Nicholson, B; Carin, L; Kingsmore, S; Woods, CW; Ginsburg, GS; Hero, AO
MLA Citation
Huang, Yongsheng, et al. “Temporal dynamics of host molecular responses differentiate symptomatic and asymptomatic influenza a infection..” Plos Genet, vol. 7, no. 8, Aug. 2011. Pubmed, doi:10.1371/journal.pgen.1002234.
Website
http://hdl.handle.net/10161/8945
PMID
21901105
Source
pubmed
Published In
Plos Genet
Volume
7
Issue
8
Publish Date
2011
Start Page
e1002234
DOI
10.1371/journal.pgen.1002234

A hub for bench-to-bedside pharmacogenomic-based research.

In 2003 Duke University (Durham, NC, USA) launched the Institute for Genome Sciences & Policy (IGSP) as an interdisciplinary network of centers comprised of scientists, engineers and physicians, as well as experts in law, business, economics public policy and ethics. Within this environment, the IGSP and its Center for Genomic Medicine form the hub for pharmacogenomic research discovery initiatives through collaborations with other scientific and clinical units at the Duke University Medical Center. The Center for Genomic Medicine specifically focuses on developing strategies for translating and implementing pharmacogenomic discoveries into the clinical arena; therefore, by harnessing the resources of the IGSP as well as other complementary centers on campus, Duke University is poised to accelerate the development of novel pharmacgenomic paradigms for the prevention and treatment of disease. These new treatment paradigms can, potentially, ensure that the right dose of the right drug is prescribed to the right individual - an often stated goal of personalized medicine and pharmacogenomics.

Authors
Voora, D; Ginsburg, GS
MLA Citation
Voora, Deepak, and Geoffrey S. Ginsburg. “A hub for bench-to-bedside pharmacogenomic-based research..” Pharmacogenomics, vol. 12, no. 8, Aug. 2011, pp. 1095–98. Pubmed, doi:10.2217/pgs.11.62.
PMID
21843063
Source
pubmed
Published In
Pharmacogenomics
Volume
12
Issue
8
Publish Date
2011
Start Page
1095
End Page
1098
DOI
10.2217/pgs.11.62

Application of Molecular Technologies to Clinical Medicine

Authors
Ginsburg, GS
MLA Citation
Ginsburg, G. S. Application of Molecular Technologies to Clinical Medicine. Vol. 1, July 2011, pp. 199–203. Scopus, doi:10.1016/B978-1-4377-1604-7.00042-7.
Source
scopus
Volume
1
Publish Date
2011
Start Page
199
End Page
203
DOI
10.1016/B978-1-4377-1604-7.00042-7

Discovery of biomarker candidates for coronary artery disease from an APOE-knock out mouse model using iTRAQ-based multiplex quantitative proteomics.

Due to the lack of precise markers indicative of its occurrence and progression, coronary artery disease (CAD), the most common type of heart diseases, is currently associated with high mortality in the United States. To systemically identify novel protein biomarkers associated with CAD progression for early diagnosis and possible therapeutic intervention, we employed an iTRAQ-based quantitative proteomic approach to analyze the proteome changes in the plasma collected from a pair of wild-type versus apolipoprotein E knockout (APOE(-/-) ) mice which were fed with a high fat diet. In a multiplex manner, iTRAQ serves as the quantitative 'in-spectra' marker for 'cross-sample' comparisons to determine the differentially expressed/secreted proteins caused by APOE knock-out. To obtain the most comprehensive proteomic data sets from this CAD-associated mouse model, we applied both MALDI and ESI-based mass spectrometric (MS) platforms coupled with two different schemes of multidimensional liquid chromatography (2-D LC) separation. We then comparatively analyzed a series of the plasma samples collected at 6 and 12 wk of age after the mice were fed with fat diets, where the 6- or 12-wk time point represents the early or intermediate phase of the fat-induced CAD, respectively. We then categorized those proteins showing abundance changes in accordance with APOE depletion. Several proteins such as the γ and β chains of fibrinogen, apolipoprotein B, apolipoprotein C-I, and thrombospondin-4 were among the previously known CAD markers identified by other methods. Our results suggested that these unbiased proteomic methods are both feasible and a practical means of discovering potential biomarkers associated with CAD progression.

Authors
Jing, L; Parker, CE; Seo, D; Hines, MW; Dicheva, N; Yu, Y; Schwinn, D; Ginsburg, GS; Chen, X
MLA Citation
Jing, Linhong, et al. “Discovery of biomarker candidates for coronary artery disease from an APOE-knock out mouse model using iTRAQ-based multiplex quantitative proteomics..” Proteomics, vol. 11, no. 14, July 2011, pp. 2763–76. Pubmed, doi:10.1002/pmic.201000202.
PMID
21681990
Source
pubmed
Published In
Proteomics
Volume
11
Issue
14
Publish Date
2011
Start Page
2763
End Page
2776
DOI
10.1002/pmic.201000202

High predictive accuracy of an unbiased proteomic profile for sustained virologic response in chronic hepatitis C patients.

UNLABELLED: Chronic hepatitis C (CHC) infection is a leading cause of endstage liver disease. Current standard-of-care (SOC) interferon-based therapy results in sustained virological response (SVR) in only one-half of patients, and is associated with significant side effects. Accurate host predictors of virologic response are needed to individualize treatment regimens. We applied a label-free liquid chromatography mass spectrometry (LC-MS)-based proteomics discovery platform to pretreatment sera from a well-characterized and matched training cohort of 55 CHC patients, and an independent validation set of 41 CHC genotype 1 patients with characterized IL28B genotype. Accurate mass and retention time methods aligned samples to generate quantitative peptide data, with predictive modeling using Bayesian sparse latent factor regression. We identified 105 proteins of interest with two or more peptides, and a total of 3,768 peptides. Regression modeling selected three identified metaproteins, vitamin D binding protein, alpha 2 HS glycoprotein, and Complement C5, with a high predictive area under the receiver operator characteristic curve (AUROC) of 0.90 for SVR in the training cohort. A model averaging approach for identified peptides resulted in an AUROC of 0.86 in the validation cohort, and correctly identified virologic response in 71% of patients without the favorable IL28B "responder" genotype. CONCLUSION: Our preliminary data indicate that a serum-based protein signature can accurately predict treatment response to current SOC in most CHC patients.

Authors
Patel, K; Lucas, JE; Thompson, JW; Dubois, LG; Tillmann, HL; Thompson, AJ; Uzarski, D; Califf, RM; Moseley, MA; Ginsburg, GS; McHutchison, JG; McCarthy, JJ; MURDOCK Horizon 1 Study Team,
MLA Citation
Patel, Keyur, et al. “High predictive accuracy of an unbiased proteomic profile for sustained virologic response in chronic hepatitis C patients..” Hepatology, vol. 53, no. 6, June 2011, pp. 1809–18. Pubmed, doi:10.1002/hep.24284.
PMID
21381069
Source
pubmed
Published In
Hepatology
Volume
53
Issue
6
Publish Date
2011
Start Page
1809
End Page
1818
DOI
10.1002/hep.24284

Quality appraisal of clinical validation studies for multigene prediction assays of chemotherapy response in early-stage breast cancer.

Authors
Kuderer, NM; Culakova, E; Huang, M; Poniewierski, MS; Ginsburg, GS; Barry, WT; Marcom, PK; Ready, N; Abernethy, AP; Lyman, GH
MLA Citation
Kuderer, N. M., et al. “Quality appraisal of clinical validation studies for multigene prediction assays of chemotherapy response in early-stage breast cancer..” Journal of Clinical Oncology, vol. 29, no. 15_suppl, American Society of Clinical Oncology (ASCO), May 2011, pp. 3082–3082. Crossref, doi:10.1200/jco.2011.29.15_suppl.3082.
Source
crossref
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
29
Issue
15_suppl
Publish Date
2011
Start Page
3082
End Page
3082
DOI
10.1200/jco.2011.29.15_suppl.3082

Quality appraisal of clinical validation studies for multigene prediction assays of chemotherapy response in early-stage breast cancer.

3082 Background: Despite enthusiasm concerning the potential for genomic predictors of chemotherapy response, considerable uncertainty about optimal research methodology remain. A comprehensive literature search and quality appraisal of multigene signatures predictive of response to chemotherapy in breast cancer were initiated as part of NIH ARRA grant funding. METHODS: Validation studies of multigene signatures for prediction of chemotherapy response in breast cancer were sought. A priori inclusion/exclusion criteria and data extraction were applied in a dual blinded fashion. Conflict resolution was based on consensus among three reviewers. Detailed information on the genomic assay, patient population, specific chemotherapeutic agents, clinical prognostic measures, and study outcomes were extracted. In addition, a formal quality appraisal was conducted, utilizing a modified quality scoring system from EGAPP, REMARK, and the STREGA Statements. RESULTS: A total of 37 fully eligible studies were identified. These papers present results on 68 multigene predictors. The primary outcome is treatment response in 51 (75%) analyses and time to recurrence or survival in 17 (25%). A high percentage of studies fail to report the following quality measures: sample size rationale (95%), patient selection (49%), study protocol (81%), quantity/quality of specimen tumor content (33%), assessment of prognostic subgroups (70%), adjustment for false discovery rate (63%), blinding of assay results to clinical outcome (95%), model ROC (56%), complete model specification (96%) or source code for analysis (96%), and clinical utility assessment in univariate (59%) or multivariate (62%) analysis. On a 3-point scale from poor to good, studies were graded as poor to fair for patient characteristics (41%), study endpoints (30%), tissue handling (65%), statistical methods (76%), and statistical model development (81%). CONCLUSIONS: Validation studies of multigene signatures of chemotherapy response in patients with early-stage breast cancer vary substantially in terms of study design, methodology, and most studies exhibit major reporting and quality limitations.

Authors
Kuderer, NM; Culakova, E; Huang, M; Poniewierski, MS; Ginsburg, GS; Barry, WT; Marcom, PK; Ready, N; Abernethy, AP; Lyman, GH
MLA Citation
Kuderer, N. M., et al. “Quality appraisal of clinical validation studies for multigene prediction assays of chemotherapy response in early-stage breast cancer..” J Clin Oncol, vol. 29, no. 15_suppl, May 2011.
PMID
28022514
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
29
Issue
15_suppl
Publish Date
2011
Start Page
3082

Automated detection of influenza-like illness using clinical surveillance markers at a Department of Veterans Affairs Medical Center.

BACKGROUND: Using demographic and clinical measures from emergency department evaluations, we developed an automated surveillance system for influenza-like illness (ILI). METHODS: We selected a random sample of patients who were seen at the Durham, NC Veterans Affairs Medical Center between May 2002 and October 2009 with fever or a respiratory ICD-9 diagnosis code and divided this into subsets for system development and validation. Comprehensive chart reviews identified patients who met a standard case definition for ILI. Logistic regression models predicting ILI were fit in the development sample. We applied the parameter estimates from these models to the validation sample and evaluated their utility using receiver-operator characteristic analysis. RESULTS: The models discriminated ILI very well in the validation sample; the C-statistics were >0.89. CONCLUSIONS: Risk estimates based on statistical models can be incorporated into electronic medical records systems to assist clinicians and could be used in real-time surveillance for disease outbreaks.

Authors
Park, LP; Rao, S; Nabity, SA; Abbott, D; Frederick, J; Woods, CW
MLA Citation
Park, Lawrence P., et al. “Automated detection of influenza-like illness using clinical surveillance markers at a Department of Veterans Affairs Medical Center..” Emerg Health Threats J, vol. 4, Apr. 2011. Pubmed, doi:10.3402/ehtj.v4i0.7108.
PMID
24149026
Source
pubmed
Published In
Emerging Health Threats Journal
Volume
4
Publish Date
2011
Start Page
7108
DOI
10.3402/ehtj.v4i0.7108

Development of a blood-based gene expression algorithm for assessment of obstructive coronary artery disease in non-diabetic patients.

BACKGROUND: Alterations in gene expression in peripheral blood cells have been shown to be sensitive to the presence and extent of coronary artery disease (CAD). A non-invasive blood test that could reliably assess obstructive CAD likelihood would have diagnostic utility. RESULTS: Microarray analysis of RNA samples from a 195 patient Duke CATHGEN registry case:control cohort yielded 2,438 genes with significant CAD association (p < 0.05), and identified the clinical/demographic factors with the largest effects on gene expression as age, sex, and diabetic status. RT-PCR analysis of 88 CAD classifier genes confirmed that diabetic status was the largest clinical factor affecting CAD associated gene expression changes. A second microarray cohort analysis limited to non-diabetics from the multi-center PREDICT study (198 patients; 99 case: control pairs matched for age and sex) evaluated gene expression, clinical, and cell population predictors of CAD and yielded 5,935 CAD genes (p < 0.05) with an intersection of 655 genes with the CATHGEN results. Biological pathway (gene ontology and literature) and statistical analyses (hierarchical clustering and logistic regression) were used in combination to select 113 genes for RT-PCR analysis including CAD classifiers, cell-type specific markers, and normalization genes.RT-PCR analysis of these 113 genes in a PREDICT cohort of 640 non-diabetic subject samples was used for algorithm development. Gene expression correlations identified clusters of CAD classifier genes which were reduced to meta-genes using LASSO. The final classifier for assessment of obstructive CAD was derived by Ridge Regression and contained sex-specific age functions and 6 meta-gene terms, comprising 23 genes. This algorithm showed a cross-validated estimated AUC = 0.77 (95% CI 0.73-0.81) in ROC analysis. CONCLUSIONS: We have developed a whole blood classifier based on gene expression, age and sex for the assessment of obstructive CAD in non-diabetic patients from a combination of microarray and RT-PCR data derived from studies of patients clinically indicated for invasive angiography. CLINICAL TRIAL REGISTRATION INFORMATION: PREDICT, Personalized Risk Evaluation and Diagnosis in the Coronary Tree, http://www.clinicaltrials.gov, NCT00500617.

Authors
Elashoff, MR; Wingrove, JA; Beineke, P; Daniels, SE; Tingley, WG; Rosenberg, S; Voros, S; Kraus, WE; Ginsburg, GS; Schwartz, RS; Ellis, SG; Tahirkheli, N; Waksman, R; McPherson, J; Lansky, AJ; Topol, EJ
MLA Citation
Elashoff, Michael R., et al. “Development of a blood-based gene expression algorithm for assessment of obstructive coronary artery disease in non-diabetic patients..” Bmc Med Genomics, vol. 4, Mar. 2011. Pubmed, doi:10.1186/1755-8794-4-26.
Website
http://hdl.handle.net/10161/13547
PMID
21443790
Source
pubmed
Published In
Bmc Medical Genomics
Volume
4
Publish Date
2011
Start Page
26
DOI
10.1186/1755-8794-4-26

Detection of viruses via statistical gene expression analysis.

We develop a new bayesian construction of the elastic net (ENet), with variational bayesian analysis. This modeling framework is motivated by analysis of gene expression data for viruses, with a focus on H3N2 and H1N1 influenza, as well as Rhino virus and RSV (respiratory syncytial virus). Our objective is to understand the biological pathways responsible for the host response to such viruses, with the ultimate objective of developing a clinical test to distinguish subjects infected by such viruses from subjects with other symptom causes (e.g., bacteria). In addition to analyzing these new datasets, we provide a detailed analysis of the bayesian ENet and compare it to related models.

Authors
Chen, M; Carlson, D; Zaas, A; Woods, CW; Ginsburg, GS; Hero, A; Lucas, J; Carin, L
MLA Citation
Chen, Minhua, et al. “Detection of viruses via statistical gene expression analysis..” Ieee Trans Biomed Eng, vol. 58, no. 3, Mar. 2011, pp. 468–79. Pubmed, doi:10.1109/TBME.2010.2059702.
PMID
20643599
Source
pubmed
Published In
Ieee Trans Biomed Eng
Volume
58
Issue
3
Publish Date
2011
Start Page
468
End Page
479
DOI
10.1109/TBME.2010.2059702

A case-control study of community-associated Clostridium difficile infection: no role for proton pump inhibitors.

BACKGROUND: The epidemiology of community-associated Clostridium difficile infection is not well known. We performed a multicenter, case-control study to further describe community-associated C. difficile infection and assess novel risk factors. METHODS: We conducted this study at 5 sites from October 2006 through November 2007. Community-associated C. difficile infection included individuals with diarrhea, a positive C. difficile toxin, and no recent (12 weeks) discharge from a health care facility. We selected controls from the same clinics attended by cases. We collected clinical and exposure data at the time of illness and cultured residual stool samples and performed ribotyping. RESULTS: Of 1041 adult C. difficile infections, 162 (15.5%) met criteria for community-associated: 66 case and 114 control patients were enrolled. Case patients were relatively young (median 64 years), female (56%), and frequently required hospitalization (38%). Antimicrobials, malignancy, exposure to high-risk persons, and remote health care exposure were independently associated with community-associated C. difficile infection. In 40% of cases, we could not confirm recent antibiotic exposure. Stomach-acid suppressants were not associated with community-associated infection, and 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors appeared protective. Prevalence of the hypervirulent NAP-1/027 strain was infrequent (17%). CONCLUSIONS: Community-associated C. difficile infection resulted in a substantial health care burden. Antimicrobials are a significant risk factor for community-associated infection. However, other unique factors also may contribute, including person-to-person transmission, remote health care exposures, and 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors. A role for stomach-acid suppressants in community-associated C. difficile infection is not supported.

Authors
Naggie, S; Miller, BA; Zuzak, KB; Pence, BW; Mayo, AJ; Nicholson, BP; Kutty, PK; McDonald, LC; Woods, CW
MLA Citation
Naggie, Susanna, et al. “A case-control study of community-associated Clostridium difficile infection: no role for proton pump inhibitors..” Am J Med, vol. 124, no. 3, Mar. 2011, pp. 276.e1-276.e7. Pubmed, doi:10.1016/j.amjmed.2010.10.013.
PMID
21396512
Source
pubmed
Published In
Am J Med
Volume
124
Issue
3
Publish Date
2011
Start Page
276.e1
End Page
276.e7
DOI
10.1016/j.amjmed.2010.10.013

The Biomedical Resource Ontology (BRO) to enable resource discovery in clinical and translational research.

The biomedical research community relies on a diverse set of resources, both within their own institutions and at other research centers. In addition, an increasing number of shared electronic resources have been developed. Without effective means to locate and query these resources, it is challenging, if not impossible, for investigators to be aware of the myriad resources available, or to effectively perform resource discovery when the need arises. In this paper, we describe the development and use of the Biomedical Resource Ontology (BRO) to enable semantic annotation and discovery of biomedical resources. We also describe the Resource Discovery System (RDS) which is a federated, inter-institutional pilot project that uses the BRO to facilitate resource discovery on the Internet. Through the RDS framework and its associated Biositemaps infrastructure, the BRO facilitates semantic search and discovery of biomedical resources, breaking down barriers and streamlining scientific research that will improve human health.

Authors
Tenenbaum, JD; Whetzel, PL; Anderson, K; Borromeo, CD; Dinov, ID; Gabriel, D; Kirschner, B; Mirel, B; Morris, T; Noy, N; Nyulas, C; Rubenson, D; Saxman, PR; Singh, H; Whelan, N; Wright, Z; Athey, BD; Becich, MJ; Ginsburg, GS; Musen, MA; Smith, KA; Tarantal, AF; Rubin, DL; Lyster, P
MLA Citation
Tenenbaum, Jessica D., et al. “The Biomedical Resource Ontology (BRO) to enable resource discovery in clinical and translational research..” J Biomed Inform, vol. 44, no. 1, Feb. 2011, pp. 137–45. Pubmed, doi:10.1016/j.jbi.2010.10.003.
PMID
20955817
Source
pubmed
Published In
J Biomed Inform
Volume
44
Issue
1
Publish Date
2011
Start Page
137
End Page
145
DOI
10.1016/j.jbi.2010.10.003

Predicting Viral Infection From High-Dimensional Biomarker Trajectories.

There is often interest in predicting an individual's latent health status based on high-dimensional biomarkers that vary over time. Motivated by time-course gene expression array data that we have collected in two influenza challenge studies performed with healthy human volunteers, we develop a novel time-aligned Bayesian dynamic factor analysis methodology. The time course trajectories in the gene expressions are related to a relatively low-dimensional vector of latent factors, which vary dynamically starting at the latent initiation time of infection. Using a nonparametric cure rate model for the latent initiation times, we allow selection of the genes in the viral response pathway, variability among individuals in infection times, and a subset of individuals who are not infected. As we demonstrate using held-out data, this statistical framework allows accurate predictions of infected individuals in advance of the development of clinical symptoms, without labeled data and even when the number of biomarkers vastly exceeds the number of individuals under study. Biological interpretation of several of the inferred pathways (factors) is provided.

Authors
Chen, M; Zaas, A; Woods, C; Ginsburg, GS; Lucas, J; Dunson, D; Carin, L
MLA Citation
Chen, Minhua, et al. “Predicting Viral Infection From High-Dimensional Biomarker Trajectories..” J Am Stat Assoc, vol. 106, no. 496, Jan. 2011, pp. 1259–79. Pubmed, doi:10.1198/jasa.2011.ap10611.
PMID
23704802
Source
pubmed
Published In
Journal of the American Statistical Association
Volume
106
Issue
496
Publish Date
2011
Start Page
1259
End Page
1279
DOI
10.1198/jasa.2011.ap10611

Order-preserving factor analysis-application to longitudinal gene expression

We present a novel factor analysis method that can be applied to the discovery of common factors shared among trajectories in multivariate time series data. These factors satisfy a precedence-ordering property: certain factors are recruited only after some other factors are activated. Precedence-ordering arise in applications where variables are activated in a specific order, which is unknown. The proposed method is based on a linear model that accounts for each factor's inherent delays and relative order. We present an algorithm to fit the model in an unsupervised manner using techniques from convex and nonconvex optimization that enforce sparsity of the factor scores and consistent precedence-order of the factor loadings. We illustrate the order-preserving factor analysis (OPFA) method for the problem of extracting precedence-ordered factors from a longitudinal (time course) study of gene expression data. © 2011 IEEE.

Authors
Puig, AT; Wiesel, A; Zaas, AK; Woods, CW; Ginsburg, GS; Fleury, G; Hero, AO
MLA Citation
Puig, A. T., et al. “Order-preserving factor analysis-application to longitudinal gene expression.” Ieee Transactions on Signal Processing, vol. 59, no. 9, Jan. 2011, pp. 4447–58. Scopus, doi:10.1109/TSP.2011.2157146.
Source
scopus
Published In
Ieee Transactions on Signal Processing
Volume
59
Issue
9
Publish Date
2011
Start Page
4447
End Page
4458
DOI
10.1109/TSP.2011.2157146

Academic consortia: Untapped resources for preparedness, response, and recovery-examining the cholera outbreak in Haiti

Authors
Gargano, LM; Gallagher, PF; Freeman, AS; Morris, JG; Cookson, ST; Greenwald, I; Lichtenberger, P; Milhous, WK; Williams-Johnson, M; Wolfe, C; Isakov, A; Woods, CW; Hughes, JM
MLA Citation
Gargano, L. M., et al. “Academic consortia: Untapped resources for preparedness, response, and recovery-examining the cholera outbreak in Haiti.” Emerging Infectious Diseases, vol. 17, no. 11, Jan. 2011. Scopus, doi:10.3201/eid1711.110727.
Source
scopus
Published In
Emerging Infectious Diseases
Volume
17
Issue
11
Publish Date
2011
DOI
10.3201/eid1711.110727

An Infection Control Program for a 2009 influenza A H1N1 outbreak in a university-based summer camp.

OBJECTIVES: Describe two 2009-H1N1 influenza outbreaks in university-based summer camps and the implementation of an infection control program. PARTICIPANTS: 7,906 campers across 73 residential camps from May 21-August 2, 2009. METHODS: Influenza-like-illness (ILI) was defined as fever with cough and/or sore throat. Influenza A was identified using PCR or rapid-antigen testing. We implemented an infection control program consisting of education, hand hygiene, disinfection, symptom screening, and ILI case management. RESULTS: An initial ILI cluster involved 60 cases across 3 camps from June 17-July 2. Academic Camp-1 had the most cases (n = 45, 14.9% attack rate); influenza A was identified in 84% of those tested. Despite implementation of an infection control program, a second ILI cluster began on July 12 in Academic Camp-2 (n = 47, 15.0% attack rate). CONCLUSIONS: ILI can spread rapidly in a university-based residential camp. Infection control is an important aspect of the medical response but is challenging to implement.

Authors
Tsalik, EL; Cunningham, CK; Cunningham, HM; Lopez-Marti, MG; Sangvai, DG; Purdy, WK; Anderson, DJ; Thompson, JR; Brown, M; Woods, CW; Jaggers, LB; Hendershot, EF
MLA Citation
Tsalik, Ephraim L., et al. “An Infection Control Program for a 2009 influenza A H1N1 outbreak in a university-based summer camp..” J Am Coll Health, vol. 59, no. 5, 2011, pp. 419–26. Pubmed, doi:10.1080/07448481.2010.534215.
PMID
21500062
Source
pubmed
Published In
J Am Coll Health
Volume
59
Issue
5
Publish Date
2011
Start Page
419
End Page
426
DOI
10.1080/07448481.2010.534215

H3N2 influenza infection elicits more cross-reactive and less clonally expanded anti-hemagglutinin antibodies than influenza vaccination.

BACKGROUND: During the recent H1N1 influenza pandemic, excess morbidity and mortality was seen in young but not older adults suggesting that prior infection with influenza strains may have protected older subjects. In contrast, a history of recent seasonal trivalent vaccine in younger adults was not associated with protection. METHODS AND FINDINGS: To study hemagglutinin (HA) antibody responses in influenza immunization and infection, we have studied the day 7 plasma cell repertoires of subjects immunized with seasonal trivalent inactivated influenza vaccine (TIV) and compared them to the plasma cell repertoires of subjects experimentally infected (EI) with influenza H3N2 A/Wisconsin/67/2005. The majority of circulating plasma cells after TIV produced influenza-specific antibodies, while most plasma cells after EI produced antibodies that did not react with influenza HA. While anti-HA antibodies from TIV subjects were primarily reactive with single or few HA strains, anti-HA antibodies from EI subjects were isolated that reacted with multiple HA strains. Plasma cell-derived anti-HA antibodies from TIV subjects showed more evidence of clonal expansion compared with antibodies from EI subjects. From an H3N2-infected subject, we isolated a 4-member clonal lineage of broadly cross-reactive antibodies that bound to multiple HA subtypes and neutralized both H1N1 and H3N2 viruses. This broad reactivity was not detected in post-infection plasma suggesting this broadly reactive clonal lineage was not immunodominant in this subject. CONCLUSION: The presence of broadly reactive subdominant antibody responses in some EI subjects suggests that improved vaccine designs that make broadly reactive antibody responses immunodominant could protect against novel influenza strains.

Authors
Moody, MA; Zhang, R; Walter, EB; Woods, CW; Ginsburg, GS; McClain, MT; Denny, TN; Chen, X; Munshaw, S; Marshall, DJ; Whitesides, JF; Drinker, MS; Amos, JD; Gurley, TC; Eudailey, JA; Foulger, A; DeRosa, KR; Parks, R; Meyerhoff, RR; Yu, J-S; Kozink, DM; Barefoot, BE; Ramsburg, EA; Khurana, S; Golding, H; Vandergrift, NA; Alam, SM; Tomaras, GD; Kepler, TB; Kelsoe, G; Liao, H-X; Haynes, BF
MLA Citation
Moody, M. Anthony, et al. “H3N2 influenza infection elicits more cross-reactive and less clonally expanded anti-hemagglutinin antibodies than influenza vaccination..” Plos One, vol. 6, no. 10, 2011. Pubmed, doi:10.1371/journal.pone.0025797.
PMID
22039424
Source
pubmed
Published In
Plos One
Volume
6
Issue
10
Publish Date
2011
Start Page
e25797
DOI
10.1371/journal.pone.0025797

Personalized medicine: progress and promise.

Personalized medicine is a broad and rapidly advancing field of health care that is informed by each person's unique clinical, genetic, genomic, and environmental information. Personalized medicine depends on multidisciplinary health care teams and integrated technologies (e.g., clinical decision support) to utilize our molecular understanding of disease in order to optimize preventive health care strategies. Human genome information now allows providers to create optimized care plans at every stage of a disease, shifting the focus from reactive to preventive health care. The further integration of personalized medicine into the clinical workflow requires overcoming several barriers in education, accessibility, regulation, and reimbursement. This review focuses on providing a comprehensive understanding of personalized medicine, from scientific discovery at the laboratory bench to integration of these novel ways of understanding human biology at the bedside.

Authors
Chan, IS; Ginsburg, GS
MLA Citation
Chan, Isaac S., and Geoffrey S. Ginsburg. “Personalized medicine: progress and promise..” Annu Rev Genomics Hum Genet, vol. 12, 2011, pp. 217–44. Pubmed, doi:10.1146/annurev-genom-082410-101446.
PMID
21721939
Source
pubmed
Published In
Annu Rev Genomics Hum Genet
Volume
12
Publish Date
2011
Start Page
217
End Page
244
DOI
10.1146/annurev-genom-082410-101446

Order-preserving factor discovery from misaligned data

We present a factor analysis method that accounts for possible temporal misalignment of the factor loadings across the population of samples. Our main hypothesis is that the data contains a subset of variables with similar but delayed profiles obeying a consistent precedence ordering relationship. Our model is motivated by the difficulty of gene expression analysis across subjects who have common patterns of immune response but show different onset times after a uniform innoculation time of a viral pathogen. The proposed method is based on a linear model with additional degrees of freedom that account for each subject's inherent delays. We present an algorithm to fit this model in a totally unsupervised manner and demonstrate its effectiveness on extracting gene expression factors affecting host response using a flu-virus human challenge study dataset. © 2010 IEEE.

Authors
Puig, AT; Wiesel, A; Zaas, A; Ginsburg, GS; Fleury, G; Hero, AO
MLA Citation
Puig, A. T., et al. “Order-preserving factor discovery from misaligned data.” 2010 Ieee Sensor Array and Multichannel Signal Processing Workshop, Sam 2010, Dec. 2010, pp. 209–12. Scopus, doi:10.1109/SAM.2010.5606736.
Source
scopus
Published In
2010 Ieee Sensor Array and Multichannel Signal Processing Workshop, Sam 2010
Publish Date
2010
Start Page
209
End Page
212
DOI
10.1109/SAM.2010.5606736

Translational Genomics. From Discovery to Clinical Practice.

This chapter focuses on paradigms for translational genomics that enables effective translation of human genome information to clinically relevant actions and outcomes. New knowledge from the study of genomes and their by-products permits the development of predictors of disease predisposition, prognosis, and therapeutic response in individual patients, providing an opportunity to employ these predictors in present day practice. An astounding number of genome-based discoveries are defined with the potential to fundamentally alter how medicine is practiced in cardiovascular disease, oncology, metabolic disease, neuropsychiatric disorders, infectious disease, and diseases with a basic inflammatory component. Despite the vast amount of genomic information available, the translation of basic scientific findings from the genome and its derivative products, RNA, and protein, to daily use in medical practice is slow. Personal genomics and direct-to-consumer avenues are bringing genomics directly to the public, thus circumventing the traditional health care delivery and regulatory channels. © 2010 Copyright © 2010 Elsevier Inc. All rights reserved.

Authors
Ginsburg, GS
MLA Citation
Ginsburg, G. S. Translational Genomics. From Discovery to Clinical Practice.. Dec. 2010, pp. 163–74. Scopus, doi:10.1016/B978-0-12-374934-5.00014-3.
Source
scopus
Publish Date
2010
Start Page
163
End Page
174
DOI
10.1016/B978-0-12-374934-5.00014-3

The Foundations of Genomic and Personalized Medicine

This chapter presents the principles and applications underlying genomic and personalized medicine. Genomics is the scientific study of a genome or genomes. A genome is the complete DNA sequence containing the entire genetic information of a gamete, an individual, a population, or a species. Personalized medicine refers to a rapidly advancing field of health care that is informed by each person's unique clinical, genetic, genomic, and environmental information. Personalized medicine aims to take advantage of the molecular understanding of disease. This is done to optimize preventive health care strategies and drug therapies while people are still well or at the earliest stages of disease. These factors are different for every person. Therefore the nature of disease, its onset, its course, and its response to drug or other interventions are as individual as the people who have them. In order for personalized medicine to be used by health care providers and their patients, the findings must be translated into precision diagnostic tests and targeted therapies. Since the overarching goal is to optimize medical care and outcomes for each individual, treatments, medication types and dosages, and/or prevention strategies may differ from person to person, resulting in unprecedented customization of patient care. © 2010 Copyright © 2010 Elsevier Inc. All rights reserved.

Authors
Ginsburg, GS; Willard, HF
MLA Citation
Ginsburg, G. S., and H. F. Willard. The Foundations of Genomic and Personalized Medicine. Dec. 2010, pp. 1–10. Scopus, doi:10.1016/B978-0-12-374934-5.00001-5.
Source
scopus
Publish Date
2010
Start Page
1
End Page
10
DOI
10.1016/B978-0-12-374934-5.00001-5

A Whole Blood RNA Signature Accurately Classifies Multiple Measures of Platelet Function on Aspirin in Healthy Volunteers and Highlights a Common Underlying Pathway

Authors
Voora, D; Ortel, TL; Lucas, JE; Chi, J-T; Becker, RC; Ginsburg, GS
MLA Citation
Voora, Deepak, et al. “A Whole Blood RNA Signature Accurately Classifies Multiple Measures of Platelet Function on Aspirin in Healthy Volunteers and Highlights a Common Underlying Pathway.” Circulation, vol. 122, no. 21, LIPPINCOTT WILLIAMS & WILKINS, Nov. 2010.
Source
wos
Published In
Circulation
Volume
122
Issue
21
Publish Date
2010

Cancer pharmacogenomics and pharmacoepidemiology: setting a research agenda to accelerate translation.

Recent advances in genomic research have demonstrated a substantial role for genomic factors in predicting response to cancer therapies. Researchers in the fields of cancer pharmacogenomics and pharmacoepidemiology seek to understand why individuals respond differently to drug therapy, in terms of both adverse effects and treatment efficacy. To identify research priorities as well as the resources and infrastructure needed to advance these fields, the National Cancer Institute (NCI) sponsored a workshop titled "Cancer Pharmacogenomics: Setting a Research Agenda to Accelerate Translation" on July 21, 2009, in Bethesda, MD. In this commentary, we summarize and discuss five science-based recommendations and four infrastructure-based recommendations that were identified as a result of discussions held during this workshop. Key recommendations include 1) supporting the routine collection of germline and tumor biospecimens in NCI-sponsored clinical trials and in some observational and population-based studies; 2) incorporating pharmacogenomic markers into clinical trials; 3) addressing the ethical, legal, social, and biospecimen- and data-sharing implications of pharmacogenomic and pharmacoepidemiologic research; and 4) establishing partnerships across NCI, with other federal agencies, and with industry. Together, these recommendations will facilitate the discovery and validation of clinical, sociodemographic, lifestyle, and genomic markers related to cancer treatment response and adverse events, and they will improve both the speed and efficiency by which new pharmacogenomic and pharmacoepidemiologic information is translated into clinical practice.

Authors
Freedman, AN; Sansbury, LB; Figg, WD; Potosky, AL; Weiss Smith, SR; Khoury, MJ; Nelson, SA; Weinshilboum, RM; Ratain, MJ; McLeod, HL; Epstein, RS; Ginsburg, GS; Schilsky, RL; Liu, G; Flockhart, DA; Ulrich, CM; Davis, RL; Lesko, LJ; Zineh, I; Randhawa, G; Ambrosone, CB; Relling, MV; Rothman, N; Xie, H; Spitz, MR; Ballard-Barbash, R; Doroshow, JH; Minasian, LM
MLA Citation
Freedman, Andrew N., et al. “Cancer pharmacogenomics and pharmacoepidemiology: setting a research agenda to accelerate translation..” J Natl Cancer Inst, vol. 102, no. 22, Nov. 2010, pp. 1698–705. Pubmed, doi:10.1093/jnci/djq390.
PMID
20944079
Source
pubmed
Published In
J Natl Cancer Inst
Volume
102
Issue
22
Publish Date
2010
Start Page
1698
End Page
1705
DOI
10.1093/jnci/djq390

Bayesian inference of the number of factors in gene-expression analysis: application to human virus challenge studies.

BACKGROUND: Nonparametric Bayesian techniques have been developed recently to extend the sophistication of factor models, allowing one to infer the number of appropriate factors from the observed data. We consider such techniques for sparse factor analysis, with application to gene-expression data from three virus challenge studies. Particular attention is placed on employing the Beta Process (BP), the Indian Buffet Process (IBP), and related sparseness-promoting techniques to infer a proper number of factors. The posterior density function on the model parameters is computed using Gibbs sampling and variational Bayesian (VB) analysis. RESULTS: Time-evolving gene-expression data are considered for respiratory syncytial virus (RSV), Rhino virus, and influenza, using blood samples from healthy human subjects. These data were acquired in three challenge studies, each executed after receiving institutional review board (IRB) approval from Duke University. Comparisons are made between several alternative means of per-forming nonparametric factor analysis on these data, with comparisons as well to sparse-PCA and Penalized Matrix Decomposition (PMD), closely related non-Bayesian approaches. CONCLUSIONS: Applying the Beta Process to the factor scores, or to the singular values of a pseudo-SVD construction, the proposed algorithms infer the number of factors in gene-expression data. For real data the "true" number of factors is unknown; in our simulations we consider a range of noise variances, and the proposed Bayesian models inferred the number of factors accurately relative to other methods in the literature, such as sparse-PCA and PMD. We have also identified a "pan-viral" factor of importance for each of the three viruses considered in this study. We have identified a set of genes associated with this pan-viral factor, of interest for early detection of such viruses based upon the host response, as quantified via gene-expression data.

Authors
Chen, B; Chen, M; Paisley, J; Zaas, A; Woods, C; Ginsburg, GS; Hero, A; Lucas, J; Dunson, D; Carin, L
MLA Citation
Chen, Bo, et al. “Bayesian inference of the number of factors in gene-expression analysis: application to human virus challenge studies..” Bmc Bioinformatics, vol. 11, Nov. 2010. Pubmed, doi:10.1186/1471-2105-11-552.
Website
http://hdl.handle.net/10161/8946
PMID
21062443
Source
pubmed
Published In
Bmc Bioinformatics
Volume
11
Publish Date
2010
Start Page
552
DOI
10.1186/1471-2105-11-552

Opening up to precompetitive collaboration.

In order to enhance biomedical research and development efficiency and innovation, nontraditional research collaborations have emerged that feature the sharing of information, resources, and capabilities. Although many of these so-called precompetitive collaborations are in the field of oncology, the lessons they offer are broadly applicable to other subfields of translational medicine.

Authors
Altshuler, JS; Balogh, E; Barker, AD; Eck, SL; Friend, SH; Ginsburg, GS; Herbst, RS; Nass, SJ; Streeter, CM; Wagner, JA
MLA Citation
Altshuler, Jill S., et al. “Opening up to precompetitive collaboration..” Sci Transl Med, vol. 2, no. 52, Oct. 2010. Pubmed, doi:10.1126/scitranslmed.3001515.
PMID
20926831
Source
pubmed
Published In
Sci Transl Med
Volume
2
Issue
52
Publish Date
2010
Start Page
52cm26
DOI
10.1126/scitranslmed.3001515

A stick-breaking construction of the beta process

We present and derive a new stick-breaking construction of the beta process. The construction is closely related to a special case of the stick-breaking construction of the Dirich-let process (Sethuraman, 1994) applied to the beta distribution. We derive an inference procedure that relies on Monte Carlo integration to reduce the number of parameters to be inferred, and present results on synthetic data, the MNIST handwritten digits data set and a time-evolving gene expression data set. Copyright 2010 by the author(s)/owner(s).

Authors
Paisley, J; Zaas, A; Woods, CW; Ginsburg, GS; Carin, L
MLA Citation
Paisley, J., et al. “A stick-breaking construction of the beta process.” Icml 2010  Proceedings, 27th International Conference on Machine Learning, Sept. 2010, pp. 847–54.
Source
scopus
Published In
Icml 2010 Proceedings, 27th International Conference on Machine Learning
Publish Date
2010
Start Page
847
End Page
854

The clinical and prognostic importance of positive blood cultures in adults.

BACKGROUND: Bloodstream infections are a major cause of morbidity and mortality in adults. Bloodstream infections should be reassessed periodically because of increased antibiotic resistance, more patients receiving immunomodulatory therapy, improved antiretroviral therapy, and acquisition of infection in health care settings other than hospitals. METHODS: We conducted retrospective assessment by infectious disease physicians of hospitalized adults with positive blood cultures at 3 academic medical centers. RESULTS: Two thousand two hundred seventy positive blood culture episodes occurred in 1706 patients. Of 2669 isolates, 51% represented true infection, 41% contamination, and 8% unknown clinical significance. Although coagulase-negative staphylococci were most common, only 10% were clinically significant. Among 1225 true bloodstream infections, the most frequent isolates were Staphylococcus aureus, Escherichia coli, Enterococcus spp., Klebsiella pneumoniae, coagulase-negative staphylococci, Pseudomonas aeruginosa, Candida albicans, Enterobacter cloacae, and Serratia marcescens. Intravenous catheters were the most common primary source of bloodstream infection (23% of episodes). Most (81%) bloodstream infections were acquired in the hospital or other health care settings. Crude and attributable in-hospital case-fatality ratios were 20% and 12%, respectively, lower than in previous studies. Increasing age, hypotension, absence of fever, hospital acquisition, extreme white blood cell count values, and the presence of the acquired immunodeficiency syndrome, malignancy, or renal disease were significantly associated with an increased risk of in-hospital attributable death in multivariable analysis. CONCLUSIONS: The proportion of bloodstream infections due to intravenous catheters is continuing to increase. Most episodes were acquired in the hospital or other health care setting. In-hospital case-fatality ratios have decreased compared with previous studies. Several previously identified factors associated with an increased mortality remain statistically significant.

Authors
Pien, BC; Sundaram, P; Raoof, N; Costa, SF; Mirrett, S; Woods, CW; Reller, LB; Weinstein, MP
MLA Citation
Pien, Brian C., et al. “The clinical and prognostic importance of positive blood cultures in adults..” Am J Med, vol. 123, no. 9, Sept. 2010, pp. 819–28. Pubmed, doi:10.1016/j.amjmed.2010.03.021.
PMID
20800151
Source
pubmed
Published In
Am J Med
Volume
123
Issue
9
Publish Date
2010
Start Page
819
End Page
828
DOI
10.1016/j.amjmed.2010.03.021

Performance of diagnostic tests to detect respiratory viruses in older adults.

The performance of 4 laboratory methods for diagnosis of viral respiratory tract infections (RTI) in older adults was evaluated. Seventy-four nasopharyngeal (NP) swab specimens were obtained from 60 patients with RTI at a long-term care facility over 2 respiratory seasons. Sixteen specimens were positive for a respiratory virus by at least 1 method. Multiplex reverse transcriptase polymerase chain reaction (RT-PCR) by the Luminex xTAG Respiratory Viral Panel (RVP) detected 16 (100%) of the positive specimens, RVP of 24-h culture supernatant detected 8 (50%), direct fluorescent antibody testing detected 4 (25%), rapid culture detected 2 (12.5%), and rapid antigen testing detected none. For a comparison group, RVP was performed on NP swabs from 20 outpatient children with RTI. The mean fluorescence intensity by RVP was significantly lower for positive adult patients than pediatric patients (P = 0.0373). Our data suggest that older adult patients shed lower titers of viruses, necessitating a highly sensitive assay such as RT-PCR to reliably detect respiratory viral pathogens.

Authors
She, RC; Polage, CR; Caram, LB; Taggart, EW; Hymas, WC; Woods, CW; Schmader, K; Petti, CA
MLA Citation
She, Rosemary C., et al. “Performance of diagnostic tests to detect respiratory viruses in older adults..” Diagn Microbiol Infect Dis, vol. 67, no. 3, July 2010, pp. 246–50. Pubmed, doi:10.1016/j.diagmicrobio.2010.02.020.
PMID
20542205
Source
pubmed
Published In
Diagn Microbiol Infect Dis
Volume
67
Issue
3
Publish Date
2010
Start Page
246
End Page
250
DOI
10.1016/j.diagmicrobio.2010.02.020

The long and winding road to warfarin pharmacogenetic testing.

Authors
Ginsburg, GS; Voora, D
MLA Citation
Ginsburg, Geoffrey S., and Deepak Voora. “The long and winding road to warfarin pharmacogenetic testing..” J Am Coll Cardiol, vol. 55, no. 25, June 2010, pp. 2813–15. Pubmed, doi:10.1016/j.jacc.2010.04.006.
PMID
20579536
Source
pubmed
Published In
J Am Coll Cardiol
Volume
55
Issue
25
Publish Date
2010
Start Page
2813
End Page
2815
DOI
10.1016/j.jacc.2010.04.006

Intratumor heterogeneity and precision of microarray-based predictors of breast cancer biology and clinical outcome.

PURPOSE: Identifying sources of variation in expression microarray data and the effect of variance in gene expression measurements on complex predictive and diagnostic models is essential when translating microarray-based experimental approaches into clinical assays. The technical reproducibility of microarray platforms is well established. Here, we investigate the additional impact of intratumor heterogeneity, a largely unstudied component of variance, on the performance of several microarray-based assays in breast cancer. PATIENTS AND METHODS: Genome-wide expression profiling was performed on 50 core needle biopsies from 18 breast cancer patients using Affymetrix GeneChip Human Genome U133 Plus 2.0 arrays. Global profiles of expression were characterized using unsupervised clustering methods and variance components models. Array-based measures of estrogen receptor (ER) and progesterone receptor (PR) status were compared with immunohistochemistry. The precision of genomic predictors of ER pathway status, recurrence risk, and sensitivity to chemotherapeutics was evaluated by interclass correlation. RESULTS: Global patterns of gene expression demonstrated that intratumor variation was substantially less than the total variation observed across the patient population. Nevertheless, a fraction of genes exhibited significant intratumor heterogeneity in expression. A high degree of reproducibility was observed in single-gene predictors of ER (intraclass correlation coefficient [ICC] = 0.94) and PR expression (ICC = 0.90), and in a multigene predictor of ER pathway activation (ICC = 0.98) with high concordance with immunohistochemistry. Substantial agreement was also observed for multigene signatures of cancer recurrence (ICC = 0.71) and chemotherapeutic sensitivity (ICC = 0.72 and 0.64). CONCLUSION: Intratumor heterogeneity, although present at the level of individual gene expression, does not preclude precise microarray-based predictions of tumor behavior or clinical outcome in breast cancer patients.

Authors
Barry, WT; Kernagis, DN; Dressman, HK; Griffis, RJ; Hunter, JD; Olson, JA; Marks, JR; Ginsburg, GS; Marcom, PK; Nevins, JR; Geradts, J; Datto, MB
MLA Citation
Barry, William T., et al. “Intratumor heterogeneity and precision of microarray-based predictors of breast cancer biology and clinical outcome..” J Clin Oncol, vol. 28, no. 13, May 2010, pp. 2198–206. Pubmed, doi:10.1200/JCO.2009.26.7245.
PMID
20368555
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
28
Issue
13
Publish Date
2010
Start Page
2198
End Page
2206
DOI
10.1200/JCO.2009.26.7245

Genome-wide association study of Lp-PLA(2) activity and mass in the Framingham Heart Study.

Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) is an emerging risk factor and therapeutic target for cardiovascular disease. The activity and mass of this enzyme are heritable traits, but major genetic determinants have not been explored in a systematic, genome-wide fashion. We carried out a genome-wide association study of Lp-PLA(2) activity and mass in 6,668 Caucasian subjects from the population-based Framingham Heart Study. Clinical data and genotypes from the Affymetrix 550K SNP array were obtained from the open-access Framingham SHARe project. Each polymorphism that passed quality control was tested for associations with Lp-PLA(2) activity and mass using linear mixed models implemented in the R statistical package, accounting for familial correlations, and controlling for age, sex, smoking, lipid-lowering-medication use, and cohort. For Lp-PLA(2) activity, polymorphisms at four independent loci reached genome-wide significance, including the APOE/APOC1 region on chromosome 19 (p = 6 x 10(-24)); CELSR2/PSRC1 on chromosome 1 (p = 3 x 10(-15)); SCARB1 on chromosome 12 (p = 1x10(-8)) and ZNF259/BUD13 in the APOA5/APOA1 gene region on chromosome 11 (p = 4 x 10(-8)). All of these remained significant after accounting for associations with LDL cholesterol, HDL cholesterol, or triglycerides. For Lp-PLA(2) mass, 12 SNPs achieved genome-wide significance, all clustering in a region on chromosome 6p12.3 near the PLA2G7 gene. Our analyses demonstrate that genetic polymorphisms may contribute to inter-individual variation in Lp-PLA(2) activity and mass.

Authors
Suchindran, S; Rivedal, D; Guyton, JR; Milledge, T; Gao, X; Benjamin, A; Rowell, J; Ginsburg, GS; McCarthy, JJ
MLA Citation
Suchindran, Sunil, et al. “Genome-wide association study of Lp-PLA(2) activity and mass in the Framingham Heart Study..” Plos Genet, vol. 6, no. 4, Apr. 2010. Pubmed, doi:10.1371/journal.pgen.1000928.
Website
http://hdl.handle.net/10161/13543
PMID
20442857
Source
pubmed
Published In
Plos Genet
Volume
6
Issue
4
Publish Date
2010
Start Page
e1000928
DOI
10.1371/journal.pgen.1000928

Association of a peripheral blood metabolic profile with coronary artery disease and risk of subsequent cardiovascular events.

BACKGROUND: Molecular tools may provide insight into cardiovascular risk. We assessed whether metabolites discriminate coronary artery disease (CAD) and predict risk of cardiovascular events. METHODS AND RESULTS: We performed mass-spectrometry-based profiling of 69 metabolites in subjects from the CATHGEN biorepository. To evaluate discriminative capabilities of metabolites for CAD, 2 groups were profiled: 174 CAD cases and 174 sex/race-matched controls ("initial"), and 140 CAD cases and 140 controls ("replication"). To evaluate the capability of metabolites to predict cardiovascular events, cases were combined ("event" group); of these, 74 experienced death/myocardial infarction during follow-up. A third independent group was profiled ("event-replication" group; n=63 cases with cardiovascular events, 66 controls). Analysis included principal-components analysis, linear regression, and Cox proportional hazards. Two principal components analysis-derived factors were associated with CAD: 1 comprising branched-chain amino acid metabolites (factor 4, initial P=0.002, replication P=0.01), and 1 comprising urea cycle metabolites (factor 9, initial P=0.0004, replication P=0.01). In multivariable regression, these factors were independently associated with CAD in initial (factor 4, odds ratio [OR], 1.36; 95% CI, 1.06 to 1.74; P=0.02; factor 9, OR, 0.67; 95% CI, 0.52 to 0.87; P=0.003) and replication (factor 4, OR, 1.43; 95% CI, 1.07 to 1.91; P=0.02; factor 9, OR, 0.66; 95% CI, 0.48 to 0.91; P=0.01) groups. A factor composed of dicarboxylacylcarnitines predicted death/myocardial infarction (event group hazard ratio 2.17; 95% CI, 1.23 to 3.84; P=0.007) and was associated with cardiovascular events in the event-replication group (OR, 1.52; 95% CI, 1.08 to 2.14; P=0.01). CONCLUSIONS: Metabolite profiles are associated with CAD and subsequent cardiovascular events.

Authors
Shah, SH; Bain, JR; Muehlbauer, MJ; Stevens, RD; Crosslin, DR; Haynes, C; Dungan, J; Newby, LK; Hauser, ER; Ginsburg, GS; Newgard, CB; Kraus, WE
MLA Citation
Shah, Svati H., et al. “Association of a peripheral blood metabolic profile with coronary artery disease and risk of subsequent cardiovascular events..” Circ Cardiovasc Genet, vol. 3, no. 2, Apr. 2010, pp. 207–14. Pubmed, doi:10.1161/CIRCGENETICS.109.852814.
Website
http://hdl.handle.net/10161/5964
PMID
20173117
Source
pubmed
Published In
Circ Cardiovasc Genet
Volume
3
Issue
2
Publish Date
2010
Start Page
207
End Page
214
DOI
10.1161/CIRCGENETICS.109.852814

Identifying patients at high risk of a cardiovascular event in the near future: current status and future directions: report of a national heart, lung, and blood institute working group.

Authors
Eagle, KA; Ginsburg, GS; Musunuru, K; Aird, WC; Balaban, RS; Bennett, SK; Blumenthal, RS; Coughlin, SR; Davidson, KW; Frohlich, ED; Greenland, P; Jarvik, GP; Libby, P; Pepine, CJ; Ruskin, JN; Stillman, AE; Van Eyk, JE; Tolunay, HE; McDonald, CL; Smith, SC
MLA Citation
Eagle, Kim A., et al. “Identifying patients at high risk of a cardiovascular event in the near future: current status and future directions: report of a national heart, lung, and blood institute working group..” Circulation, vol. 121, no. 12, Mar. 2010, pp. 1447–54. Pubmed, doi:10.1161/CIRCULATIONAHA.109.904029.
PMID
20351302
Source
pubmed
Published In
Circulation
Volume
121
Issue
12
Publish Date
2010
Start Page
1447
End Page
1454
DOI
10.1161/CIRCULATIONAHA.109.904029

Blood gene expression signatures predict invasive candidiasis.

Candidemia is the fourth most common bloodstream infection, with Candida albicans being the most common causative species. Success in reducing the associated morbidity and mortality has been limited by the inadequacy and time delay of currently available diagnostic modalities. Focusing on host response to infection, we used a murine model to develop a blood gene expression signature that accurately classified mice with candidemia and distinguished candidemia from Staphylococcus aureus bacteremia. Validation of the signature was achieved in an independent cohort of mice. Genes represented in the signature have known associations with host defense against Candida and other microorganisms. Our results demonstrate a temporal pattern of host molecular responses that distinguish candidemia from S. aureus-induced bacteremia and establish a novel paradigm for infectious disease diagnosis.

Authors
Zaas, AK; Aziz, H; Lucas, J; Perfect, JR; Ginsburg, GS
MLA Citation
Zaas, Aimee K., et al. “Blood gene expression signatures predict invasive candidiasis..” Sci Transl Med, vol. 2, no. 21, Mar. 2010. Pubmed, doi:10.1126/scitranslmed.3000715.
PMID
20374997
Source
pubmed
Published In
Sci Transl Med
Volume
2
Issue
21
Publish Date
2010
Start Page
21ra17
DOI
10.1126/scitranslmed.3000715

Clinical presentation and response to treatment of novel influenza A H1N1 in a university-based summer camp population.

BACKGROUND: Little is known about the clinical presentation and course of novel H1N1 influenza in summer camps. OBJECTIVES: To describe the clinical course and evaluate the effect of influenza treatment in a summer camp population. STUDY DESIGN: Two large influenza outbreaks occurred in university-based residential camps between May 21 and August 2, 2009. Through active daily surveillance, medical evaluation at symptom onset, and data collection during isolation, we describe the clinical course of a large outbreak of novel H1N1 influenza. RESULTS: Influenza-like illness (ILI) was documented in 119 individuals. Influenza A was confirmed in 66 (79%) of 84 samples tested. Three early samples were identified as novel H1N1. ILI cases had an average age of 15.7 years and 52% were male. Sixty-three were treated with oseltamivir or zanamivir, which was initiated within 24h of diagnosis. Cough, myalgia and sore throat occurred in 69, 64 and 63% of cases, respectively. The highest temperature over the course of illness (T(max)) occurred within 48h after symptom onset in 87.5% of individuals. Average T(max) was 38.4 degrees C (range 36.1-40.2 degrees C). Among confirmed influenza cases, 69% defervesced by 72h and 95% defervesced by 96h. Defervescence at 72h was not different in the treated and untreated groups (p=0.12). CONCLUSIONS: Novel H1N1 generally has a mild, self-limited course in healthy adolescent campers. Defervescence occurred within 72h and was unaffected by treatment.

Authors
Tsalik, EL; Hendershot, EF; Sangvai, DG; Cunningham, HM; Cunningham, CK; Lopez-Marti, MG; Purdy, WK; Woods, CW; Caram, LB
MLA Citation
Tsalik, Ephraim L., et al. “Clinical presentation and response to treatment of novel influenza A H1N1 in a university-based summer camp population..” J Clin Virol, vol. 47, no. 3, Mar. 2010, pp. 286–88. Pubmed, doi:10.1016/j.jcv.2009.12.012.
PMID
20064740
Source
pubmed
Published In
J Clin Virol
Volume
47
Issue
3
Publish Date
2010
Start Page
286
End Page
288
DOI
10.1016/j.jcv.2009.12.012

Response: Improving Development of the Molecular Signature for Diagnosis of Acute Respiratory Viral Infections

Authors
Zaas, AK; Chen, M; Hero, AO; Lucas, J; Carin, L; Ginsburg, GS
MLA Citation
Zaas, A. K., et al. “Response: Improving Development of the Molecular Signature for Diagnosis of Acute Respiratory Viral Infections.” Cell Host and Microbe, vol. 7, no. 2, Feb. 2010. Scopus, doi:10.1016/j.chom.2010.02.002.
Source
scopus
Published In
Cell Host & Microbe
Volume
7
Issue
2
Publish Date
2010
Start Page
102
DOI
10.1016/j.chom.2010.02.002

Preface

Authors
Burt, TP; Allison, RJ
MLA Citation
Burt, T. P., and R. J. Allison. “Preface.” Sediment Cascades: An Integrated Approach, Feb. 2010. Scopus, doi:10.1002/9780470682876.
Source
scopus
Published In
Sediment Cascades: an Integrated Approach
Publish Date
2010
DOI
10.1002/9780470682876

Risk factors for and estimated incidence of community-associated Clostridium difficile infection, North Carolina, USA.

We determined estimated incidence of and risk factors for community-associated Clostridium difficile infection (CA-CDI) among patients treated at 6 North Carolina hospitals. CA-CDI case-patients were defined as adults (>18 years of age) with a positive stool test result for C. difficile toxin and no hospitalization within the prior 8 weeks. CA-CDI incidence was 21 and 46 per 100,000 person-years in Veterans Affairs (VA) outpatients and Durham County populations, respectively. VA case-patients were more likely than controls to have received antimicrobial drugs (adjusted odds ratio [aOR] 17.8, 95% confidence interval [CI] 6.6-48] and to have had a recent outpatient visit (aOR 5.1, 95% CI 1.5-17.9). County case-patients were more likely than controls to have received antimicrobial drugs (aOR 9.1, 95% CI 2.9-28.9), to have gastroesophageal reflux disease (aOR 11.2, 95% CI 1.9-64.2), and to have cardiac failure (aOR 3.8, 95% CI 1.1-13.7). Risk factors for CA-CDI overlap with those for healthcare-associated infection.

Authors
Kutty, PK; Woods, CW; Sena, AC; Benoit, SR; Naggie, S; Frederick, J; Evans, S; Engel, J; McDonald, LC
MLA Citation
Kutty, Preeta K., et al. “Risk factors for and estimated incidence of community-associated Clostridium difficile infection, North Carolina, USA..” Emerg Infect Dis, vol. 16, no. 2, Feb. 2010, pp. 197–204. Pubmed, doi:10.3201/eid1602.090953.
Website
http://hdl.handle.net/10161/6345
PMID
20113547
Source
pubmed
Published In
Emerging Infectious Diseases
Volume
16
Issue
2
Publish Date
2010
Start Page
197
End Page
204
DOI
10.3201/eid1602.090953

Impact of gene variants on sex-specific regulation of human Scavenger receptor class B type 1 (SR-BI) expression in liver and association with lipid levels in a population-based study.

BACKGROUND: Several studies have noted that genetic variants of SCARB1, a lipoprotein receptor involved in reverse cholesterol transport, are associated with serum lipid levels in a sex-dependent fashion. However, the mechanism underlying this gene by sex interaction has not been explored. METHODS: We utilized both epidemiological and molecular methods to study how estrogen and gene variants interact to influence SCARB1 expression and lipid levels. Interaction between 35 SCARB1 haplotype-tagged polymorphisms and endogenous estradiol levels was assessed in 498 postmenopausal Caucasian women from the population-based Rancho Bernardo Study. We further examined associated variants with overall and SCARB1 splice variant (SR-BI and SR-BII) expression in 91 human liver tissues using quantitative real-time PCR. RESULTS: Several variants on a haplotype block spanning intron 11 to intron 12 of SCARB1 showed significant gene by estradiol interaction affecting serum lipid levels, the strongest for rs838895 with HDL-cholesterol (p=9.2x10(-4)) and triglycerides (p=1.3x10(-3)) and the triglyceride:HDL cholesterol ratio (p=2.7x10(-4)). These same variants were associated with expression of the SR-BI isoform in a sex-specific fashion, with the strongest association found among liver tissue from 52 young women<45 years old (p=0.002). CONCLUSIONS: Estrogen and SCARB1 genotype may act synergistically to regulate expression of SCARB1 isoforms and impact serum levels of HDL cholesterol and triglycerides. This work highlights the importance of considering sex-dependent effects of gene variants on serum lipid levels.

Authors
Chiba-Falek, O; Nichols, M; Suchindran, S; Guyton, J; Ginsburg, GS; Barrett-Connor, E; McCarthy, JJ
MLA Citation
Chiba-Falek, Ornit, et al. “Impact of gene variants on sex-specific regulation of human Scavenger receptor class B type 1 (SR-BI) expression in liver and association with lipid levels in a population-based study..” Bmc Med Genet, vol. 11, Jan. 2010. Pubmed, doi:10.1186/1471-2350-11-9.
Website
http://hdl.handle.net/10161/4353
PMID
20085651
Source
pubmed
Published In
Bmc Medical Genetics
Volume
11
Publish Date
2010
Start Page
9
DOI
10.1186/1471-2350-11-9

Pharmacogenetics of the response to statins

Statins (inhibitors of the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase) are widely prescribed medications for the prevention of incident and recurrent cardiovascular disease events and death. They are powerful assets in the current arsenal of cardiovascular medications, with high efficacy and minimal toxicity. However, heterogeneity exists with respect to the response to statin medications, and there has been considerable investigation into the genetic determinants of the statin response. In this review, we separate the response to statins into 1) measures of efficacy (low-density lipoprotein cholesterol lowering and protection from cardiovascular events) and 2) effects of toxicity (musculoskeletal adverse effects and nonadherence to statin therapy). The current data suggest that prospective genotyping for certain variants may be of use in tailoring statin therapy to reduce cardiovascular events and to avoid statin-induced adverse effects. © 2009 Current Medicine Group, LLC.

Authors
Voora, D; Ginsburg, GS
MLA Citation
Voora, D., and G. S. Ginsburg. “Pharmacogenetics of the response to statins.” Current Cardiovascular Risk Reports, vol. 3, no. 6, Dec. 2009, pp. 434–40. Scopus, doi:10.1007/s12170-009-0064-1.
Source
scopus
Published In
Current Cardiovascular Risk Reports
Volume
3
Issue
6
Publish Date
2009
Start Page
434
End Page
440
DOI
10.1007/s12170-009-0064-1

Preface

Authors
Lendlein, A; Shastri, VP; Gall, K
MLA Citation
Lendlein, A., et al. “Preface.” Materials Research Society Symposium Proceedings, vol. 1190, Dec. 2009.
Source
scopus
Published In
Materials Research Society Symposium Proceedings
Volume
1190
Publish Date
2009

Genomic and Personalized Medicine, Two-Vol Set

This two-volume set provides an in-depth look at one of the most promising avenues for advances in the diagnosis, prevention and treatment of human disease. The inclusion of the latest information on diagnostic testing, population screening, predicting disease susceptibility, pharmacogenomics and more presents this book as an essential tool for both students and specialists across many biological and medical disciplines, including human genetics and genomics, oncology, neuroscience, cardiology, infectious disease, molecular medicine, and biomedical science, as well as health policy disciplines focusing on ethical, legal, regulatory and economic aspects of genomics and medicine. Volume One Includes: Principles, Methodology and Translational Approaches, takes readers on the journey from principles of human genomics to technology, informatic and computational platforms for genomic medicine, as well as strategies for translating genomic discoveries into advances in personalized clinical care. Volume Two Includes: Genome Discoveries and Clinical Applications presents the latest developments in disease-based genomic and personalized medicine. With chapters dedicated to cardiovascular disease, oncology, inflammatory disease, metabolic disease, neuropsychiatric disease, and infectious disease, this work provides the most comprehensive guide to the principles and practice of genomic and personalized medicine. * Contributions from leaders in the field provide unparalleled insight into current technologies and applications in clinical medicine. * Full colour throughout enhances the utility of this work as the only available comprehensive reference for genomic and personalized medicine. * Discusses scientific foundations and practical applications of new discoveries, as well as ethical, legal/regulatory, and social issues related to the practice of genomic medicine. © 2009 Elsevier Inc. All rights reserved.

Authors
Ginsburg, GS; Willard, HF
MLA Citation
Ginsburg, G. S., and H. F. Willard. “Genomic and Personalized Medicine, Two-Vol Set.” Genomic and Personalized Medicine, Two Vol Set, Dec. 2009.
Source
scopus
Published In
Genomic and Personalized Medicine, Two Vol Set
Publish Date
2009

Translational Genomics: From Discovery to Clinical Practice

Authors
Ginsburg, GS
MLA Citation
Ginsburg, G. S. Translational Genomics: From Discovery to Clinical Practice. Dec. 2009, pp. 242–51. Scopus, doi:10.1016/B978-0-12-369420-1.00022-6.
Source
scopus
Publish Date
2009
Start Page
242
End Page
251
DOI
10.1016/B978-0-12-369420-1.00022-6

Preface

Authors
Willard, HF; Ginsburg, GS
MLA Citation
Willard, H. F., and G. S. Ginsburg. “Preface.” Genomic and Personalized Medicine, Two Vol Set, Dec. 2009.
Source
scopus
Published In
Genomic and Personalized Medicine, Two Vol Set
Publish Date
2009

Genomic and personalized medicine: foundations and applications.

The last decade has witnessed a steady embrace of genomic and personalized medicine by senior government officials, industry leadership, health care providers, and the public. Genomic medicine, which is the use of information from genomes and their derivatives (RNA, proteins, and metabolites) to guide medical decision making-is a key component of personalized medicine, which is a rapidly advancing field of health care that is informed by each person's unique clinical, genetic, genomic, and environmental information. As medicine begins to embrace genomic tools that enable more precise prediction and treatment disease, which include "whole genome" interrogation of sequence variation, transcription, proteins, and metabolites, the fundamentals of genomic and personalized medicine will require the development, standardization, and integration of several important tools into health systems and clinical workflows. These tools include health risk assessment, family health history, and clinical decision support for complex risk and predictive information. Together with genomic information, these tools will enable a paradigm shift to a comprehensive approach that will identify individual risks and guide clinical management and decision making, all of which form the basis for a more informed and effective approach to patient care. DNA-based risk assessment for common complex disease, molecular signatures for cancer diagnosis and prognosis, and genome-guided therapy and dose selection are just among the few important examples for which genome information has already enabled personalized health care along the continuum from health to disease. In addition, information from individual genomes, which is a fast-moving area of technological development, is spawning a social and information revolution among consumers that will undoubtedly affect health care decision making. Although these and other scientific findings are making their way from the genome to the clinic, the full application of genomic and personalized medicine in health care will require dramatic changes in regulatory and reimbursement policies as well as legislative protections for privacy for system-wide adoption. Thus, there are challenges from both a scientific and a policy perspective to personalized health care; however, they will be confronted and solved with the certainty that the science behind genomic medicine is sound and the practice of medicine that it informs is evidence based.

Authors
Ginsburg, GS; Willard, HF
MLA Citation
Ginsburg, Geoffrey S., and Huntington F. Willard. “Genomic and personalized medicine: foundations and applications..” Transl Res, vol. 154, no. 6, Dec. 2009, pp. 277–87. Pubmed, doi:10.1016/j.trsl.2009.09.005.
PMID
19931193
Source
pubmed
Published In
Transl Res
Volume
154
Issue
6
Publish Date
2009
Start Page
277
End Page
287
DOI
10.1016/j.trsl.2009.09.005

Evaluation of the PharmGKB knowledge base as a resource for efficiently assessing the clinical validity and utility of pharmacogenetic assays.

Prior to clinical use, pharmacogenetic tests should be systematically evaluated for their clinical validity and utility. Here, we evaluated whether the publicly available, online Pharmacogenomics Knowledge Base (PharmGKB) could facilitate such assessments by efficiently identifying relevant peer-reviewed manuscripts. The search targets were 55 manuscripts regarding clinical validity and utility included in systematic reviews of warfarin, antidepressant, and irinotecan pharmacogenetics. When direct inclusion in PharmGKB was the search criterion, recall was 33% and precision was 16%. However, recall increased to 78% when citation within a PharmGKB-identified manuscript was added as a search criterion. These recalled manuscripts accounted for 87% of the study subjects, and domain experts determined that the omission of the remaining manuscripts was unlikely to have changed the conclusions of the reviews. Thus, we conclude that PharmGKB can facilitate the systematic assessment of pharmacogenetic assays through the efficient identification of relevant peer-reviewed manuscripts.

Authors
Kawamoto, K; Orlando, LA; Voora, D; Lobach, DF; Joy, S; Cho, A; Ginsburg, GS
MLA Citation
Kawamoto, Kensaku, et al. “Evaluation of the PharmGKB knowledge base as a resource for efficiently assessing the clinical validity and utility of pharmacogenetic assays..” Amia Annu Symp Proc, vol. 2009, Nov. 2009, pp. 307–11.
PMID
20351870
Source
pubmed
Published In
Amia ... Annual Symposium Proceedings. Amia Symposium
Volume
2009
Publish Date
2009
Start Page
307
End Page
311

The SLCO1B1*5 genetic variant is associated with statin-induced side effects.

OBJECTIVES: We sought to identify single nucleotide polymorphisms associated with mild statin-induced side effects. BACKGROUND: Statin-induced side effects can interfere with therapy. Single nucleotide polymorphisms in cytochrome P450 enzymes impair statin metabolism; the reduced function SLCO1B1*5 allele impairs statin clearance and is associated with simvastatin-induced myopathy with creatine kinase (CK) elevation. METHODS: The STRENGTH (Statin Response Examined by Genetic Haplotype Markers) study was a pharmacogenetics study of statin efficacy and safety. Subjects (n = 509) were randomized to atorvastatin 10 mg, simvastatin 20 mg, or pravastatin 10 mg followed by 80 mg, 80 mg, and 40 mg, respectively. We defined a composite adverse event (CAE) as discontinuation for any side effect, myalgia, or CK >3x upper limit of normal during follow-up. We sequenced CYP2D6, CYP2C8, CYP2C9, CYP3A4, and SLCO1B1 and tested 7 reduced function alleles for association with the CAE. RESULTS: The CAE occurred in 99 subjects (54 discontinuations, 49 myalgias, and 9 CK elevations). Sex was associated with CAE (percent female in CAE vs. no CAE groups, 66% vs. 50%, p < 0.01). SLCO1B1*5 was associated with CAE (percent with > or = 1 allele in CAE vs. no CAE groups, 37% vs. 25%, p = 0.03) and those with CAE with no significant CK elevation (p < or = 0.03). Furthermore, there was evidence for a gene-dose effect (percent with CAE in those with 0, 1, or 2 alleles: 19%, 27%, and 50%, trend p = 0.01). Finally, the CAE risk appeared to be greatest in those carriers assigned to simvastatin. CONCLUSIONS: SLCO1B1*5 genotype and female sex were associated mild statin-induced side effects. These findings expand the results of a recent genome-wide association study of statin myopathy with CK >3x normal to milder, statin-induced, muscle side effects.

Authors
Voora, D; Shah, SH; Spasojevic, I; Ali, S; Reed, CR; Salisbury, BA; Ginsburg, GS
MLA Citation
Voora, Deepak, et al. “The SLCO1B1*5 genetic variant is associated with statin-induced side effects..” J Am Coll Cardiol, vol. 54, no. 17, Oct. 2009, pp. 1609–16. Pubmed, doi:10.1016/j.jacc.2009.04.053.
PMID
19833260
Source
pubmed
Published In
J Am Coll Cardiol
Volume
54
Issue
17
Publish Date
2009
Start Page
1609
End Page
1616
DOI
10.1016/j.jacc.2009.04.053

Gene expression signatures diagnose influenza and other symptomatic respiratory viral infections in humans.

Acute respiratory infections (ARIs) are a common reason for seeking medical attention, and the threat of pandemic influenza will likely add to these numbers. Using human viral challenge studies with live rhinovirus, respiratory syncytial virus, and influenza A, we developed peripheral blood gene expression signatures that distinguish individuals with symptomatic ARIs from uninfected individuals with >95% accuracy. We validated this "acute respiratory viral" signature-encompassing genes with a known role in host defense against viral infections-across each viral challenge. We also validated the signature in an independently acquired data set for influenza A and classified infected individuals from healthy controls with 100% accuracy. In the same data set, we could also distinguish viral from bacterial ARIs (93% accuracy). These results demonstrate that ARIs induce changes in human peripheral blood gene expression that can be used to diagnose a viral etiology of respiratory infection and triage symptomatic individuals.

Authors
Zaas, AK; Chen, M; Varkey, J; Veldman, T; Hero, AO; Lucas, J; Huang, Y; Turner, R; Gilbert, A; Lambkin-Williams, R; Øien, NC; Nicholson, B; Kingsmore, S; Carin, L; Woods, CW; Ginsburg, GS
MLA Citation
Zaas, Aimee K., et al. “Gene expression signatures diagnose influenza and other symptomatic respiratory viral infections in humans..” Cell Host Microbe, vol. 6, no. 3, Sept. 2009, pp. 207–17. Pubmed, doi:10.1016/j.chom.2009.07.006.
PMID
19664979
Source
pubmed
Published In
Cell Host Microbe
Volume
6
Issue
3
Publish Date
2009
Start Page
207
End Page
217
DOI
10.1016/j.chom.2009.07.006

Gene expression patterns in peripheral blood correlate with the extent of coronary artery disease.

Systemic and local inflammation plays a prominent role in the pathogenesis of atherosclerotic coronary artery disease, but the relationship of whole blood gene expression changes with coronary disease remains unclear. We have investigated whether gene expression patterns in peripheral blood correlate with the severity of coronary disease and whether these patterns correlate with the extent of atherosclerosis in the vascular wall. Patients were selected according to their coronary artery disease index (CADi), a validated angiographical measure of the extent of coronary atherosclerosis that correlates with outcome. RNA was extracted from blood of 120 patients with at least a stenosis greater than 50% (CADi > or = 23) and from 121 controls without evidence of coronary stenosis (CADi = 0). 160 individual genes were found to correlate with CADi (rho > 0.2, P<0.003). Prominent differential expression was observed especially in genes involved in cell growth, apoptosis and inflammation. Using these 160 genes, a partial least squares multivariate regression model resulted in a highly predictive model (r(2) = 0.776, P<0.0001). The expression pattern of these 160 genes in aortic tissue also predicted the severity of atherosclerosis in human aortas, showing that peripheral blood gene expression associated with coronary atherosclerosis mirrors gene expression changes in atherosclerotic arteries. In conclusion, the simultaneous expression pattern of 160 genes in whole blood correlates with the severity of coronary artery disease and mirrors expression changes in the atherosclerotic vascular wall.

Authors
Sinnaeve, PR; Donahue, MP; Grass, P; Seo, D; Vonderscher, J; Chibout, S-D; Kraus, WE; Sketch, M; Nelson, C; Ginsburg, GS; Goldschmidt-Clermont, PJ; Granger, CB
MLA Citation
Sinnaeve, Peter R., et al. “Gene expression patterns in peripheral blood correlate with the extent of coronary artery disease..” Plos One, vol. 4, no. 9, Sept. 2009. Pubmed, doi:10.1371/journal.pone.0007037.
PMID
19750006
Source
pubmed
Published In
Plos One
Volume
4
Issue
9
Publish Date
2009
Start Page
e7037
DOI
10.1371/journal.pone.0007037

The Scientific Foundation for personal genomics: recommendations from a National Institutes of Health-Centers for Disease Control and Prevention multidisciplinary workshop.

The increasing availability of personal genomic tests has led to discussions about the validity and utility of such tests and the balance of benefits and harms. A multidisciplinary workshop was convened by the National Institutes of Health and the Centers for Disease Control and Prevention to review the scientific foundation for using personal genomics in risk assessment and disease prevention and to develop recommendations for targeted research. The clinical validity and utility of personal genomics is a moving target with rapidly developing discoveries but little translation research to close the gap between discoveries and health impact. Workshop participants made recommendations in five domains: (1) developing and applying scientific standards for assessing personal genomic tests; (2) developing and applying a multidisciplinary research agenda, including observational studies and clinical trials to fill knowledge gaps in clinical validity and utility; (3) enhancing credible knowledge synthesis and information dissemination to clinicians and consumers; (4) linking scientific findings to evidence-based recommendations for use of personal genomics; and (5) assessing how the concept of personal utility can affect health benefits, costs, and risks by developing appropriate metrics for evaluation. To fulfill the promise of personal genomics, a rigorous multidisciplinary research agenda is needed.

Authors
Khoury, MJ; McBride, CM; Schully, SD; Ioannidis, JPA; Feero, WG; Janssens, ACJW; Gwinn, M; Simons-Morton, DG; Bernhardt, JM; Cargill, M; Chanock, SJ; Church, GM; Coates, RJ; Collins, FS; Croyle, RT; Davis, BR; Downing, GJ; Duross, A; Friedman, S; Gail, MH; Ginsburg, GS; Green, RC; Greene, MH; Greenland, P; Gulcher, JR; Hsu, A; Hudson, KL; Kardia, SLR; Kimmel, PL; Lauer, MS; Miller, AM; Offit, K; Ransohoff, DF; Roberts, JS; Rasooly, RS; Stefansson, K; Terry, SF; Teutsch, SM; Trepanier, A; Wanke, KL; Witte, JS; Xu, J; Centers for Disease Control and Prevention,
MLA Citation
Khoury, Muin J., et al. “The Scientific Foundation for personal genomics: recommendations from a National Institutes of Health-Centers for Disease Control and Prevention multidisciplinary workshop..” Genet Med, vol. 11, no. 8, Aug. 2009, pp. 559–67. Pubmed, doi:10.1097/GIM.0b013e3181b13a6c.
PMID
19617843
Source
pubmed
Published In
Genet Med
Volume
11
Issue
8
Publish Date
2009
Start Page
559
End Page
567
DOI
10.1097/GIM.0b013e3181b13a6c

Genomic and Personalized Medicine: Happening now

Authors
Ginsburg, G
MLA Citation
Ginsburg, G. “Genomic and Personalized Medicine: Happening now.” Personalized Medicine, vol. 6, no. 1, July 2009, pp. 15–18. Scopus, doi:10.2217/17410541.6.1.15.
Source
scopus
Published In
Personalized Medicine
Volume
6
Issue
1
Publish Date
2009
Start Page
15
End Page
18
DOI
10.2217/17410541.6.1.15

Development and Validation of a Peripheral Blood-Based Gene Expression Algorithm for the Detection of Coronary Artery Disease (CAD)

Authors
Wingrove, JA; Elashoff, M; Tingley, WG; Sehnert, AJ; Daniels, SE; Rosenberg, S; Kraus, WE; Newby, LK; Ginsburg, GS
MLA Citation
Wingrove, James A., et al. “Development and Validation of a Peripheral Blood-Based Gene Expression Algorithm for the Detection of Coronary Artery Disease (CAD).” Arteriosclerosis Thrombosis and Vascular Biology, vol. 29, no. 7, LIPPINCOTT WILLIAMS & WILKINS, July 2009, pp. E24–E24.
Source
wos
Published In
Arteriosclerosis, Thrombosis, and Vascular Biology
Volume
29
Issue
7
Publish Date
2009
Start Page
E24
End Page
E24

The Center for Genomic Medicine at the Duke Institute for Genome Sciences & Policy: propelling genomics into clinical practice.

Until now, advances in the genomic sciences have had a minor impact on the practice of medicine. But genomic medicine has the potential to radically alter healthcare in the USA and around the world. By understanding the predictive power of patients' genomes, it should be possible to identify individuals at risk of disease and to create smarter, more effective treatments for those who are already ill. It is the mission of the Center for Genomic Medicine at the Duke Institute for Genome Sciences & Policy (NC, USA) to harness information from the human genome in order to optimize efficiency, effectiveness and success in bringing the right therapy to the right patient at the right time. In doing so, the Center has focused on the development and implementation of translational models for delivery of genomic healthcare, exploring the nature and breadth of genomic tests, novel approaches to pre- and post‑analytical care, and the design of an optimal healthcare delivery team.

Authors
Broadfoot, MV; Ginsburg, GS
MLA Citation
Broadfoot, Marla Vacek, and Geoffrey S. Ginsburg. “The Center for Genomic Medicine at the Duke Institute for Genome Sciences & Policy: propelling genomics into clinical practice..” Personalized Medicine, vol. 6, no. 3, May 2009, pp. 255–61. Epmc, doi:10.2217/pme.09.9.
PMID
29783502
Source
epmc
Published In
Personalized Medicine
Volume
6
Issue
3
Publish Date
2009
Start Page
255
End Page
261
DOI
10.2217/pme.09.9

Erratum: A genomic approach to colon cancer risk stratification yields biologic insights into therapeutic opportunities (Proceedings of the National Academy of Sciences of the United States of America (2008) 105:49 (19432-19437) Doi: 10.1073/pnas.0806674105)

Authors
Garman, KS; Acharya, CR; Edelman, E; Grade, M; Gaedcke, J; Sud, S; Barry, W; Diehl, AM; Provenzale, D; Ginsburg, GS; Ghadimi, BM; Ried, T; Nevins, JR; Mukherjee, S; Hsu, D; Potti, A
MLA Citation
Garman, K. S., et al. “Erratum: A genomic approach to colon cancer risk stratification yields biologic insights into therapeutic opportunities (Proceedings of the National Academy of Sciences of the United States of America (2008) 105:49 (19432-19437) Doi: 10.1073/pnas.0806674105).” Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 16, Apr. 2009. Scopus, doi:10.1073/pnas.0902004106.
Source
scopus
Published In
Proceedings of the National Academy of Sciences of the United States of America
Volume
106
Issue
16
Publish Date
2009
Start Page
6878
DOI
10.1073/pnas.0902004106

A national clinical decision support infrastructure to enable the widespread and consistent practice of genomic and personalized medicine.

BACKGROUND: In recent years, the completion of the Human Genome Project and other rapid advances in genomics have led to increasing anticipation of an era of genomic and personalized medicine, in which an individual's health is optimized through the use of all available patient data, including data on the individual's genome and its downstream products. Genomic and personalized medicine could transform healthcare systems and catalyze significant reductions in morbidity, mortality, and overall healthcare costs. DISCUSSION: Critical to the achievement of more efficient and effective healthcare enabled by genomics is the establishment of a robust, nationwide clinical decision support infrastructure that assists clinicians in their use of genomic assays to guide disease prevention, diagnosis, and therapy. Requisite components of this infrastructure include the standardized representation of genomic and non-genomic patient data across health information systems; centrally managed repositories of computer-processable medical knowledge; and standardized approaches for applying these knowledge resources against patient data to generate and deliver patient-specific care recommendations. Here, we provide recommendations for establishing a national decision support infrastructure for genomic and personalized medicine that fulfills these needs, leverages existing resources, and is aligned with the Roadmap for National Action on Clinical Decision Support commissioned by the U.S. Office of the National Coordinator for Health Information Technology. Critical to the establishment of this infrastructure will be strong leadership and substantial funding from the federal government. SUMMARY: A national clinical decision support infrastructure will be required for reaping the full benefits of genomic and personalized medicine. Essential components of this infrastructure include standards for data representation; centrally managed knowledge repositories; and standardized approaches for leveraging these knowledge repositories to generate patient-specific care recommendations at the point of care.

Authors
Kawamoto, K; Lobach, DF; Willard, HF; Ginsburg, GS
MLA Citation
Kawamoto, Kensaku, et al. “A national clinical decision support infrastructure to enable the widespread and consistent practice of genomic and personalized medicine..” Bmc Med Inform Decis Mak, vol. 9, Mar. 2009. Pubmed, doi:10.1186/1472-6947-9-17.
PMID
19309514
Source
pubmed
Published In
Bmc Medical Informatics and Decision Making
Volume
9
Publish Date
2009
Start Page
17
DOI
10.1186/1472-6947-9-17

Genomic and Personalized Medicine, Two-Vol Set

This two-volume set provides an in-depth look at one of the most promising avenues for advances in the diagnosis, prevention and treatment of human disease. The inclusion of the latest information on diagnostic testing, population screening, predicting disease susceptibility, pharmacogenomics and more presents this book as an essential tool for both students and specialists across many biological and medical disciplines, including human genetics and genomics, oncology, neuroscience, cardiology, infectious disease, molecular medicine, and biomedical science, as well as health policy disciplines focusing on ethical, legal, regulatory and economic aspects of genomics and medicine. Volume One Includes: Principles, Methodology and Translational Approaches, takes readers on the journey from principles of human genomics to technology, informatic and computational platforms for genomic medicine, as well as strategies for translating genomic discoveries into advances in personalized clinical care. Volume Two Includes: Genome Discoveries and Clinical Applications presents the latest developments in disease-based genomic and personalized medicine. With chapters dedicated to cardiovascular disease, oncology, inflammatory disease, metabolic disease, neuropsychiatric disease, and infectious disease, this work provides the most comprehensive guide to the principles and practice of genomic and personalized medicine. * Contributions from leaders in the field provide unparalleled insight into current technologies and applications in clinical medicine. * Full colour throughout enhances the utility of this work as the only available comprehensive reference for genomic and personalized medicine. * Discusses scientific foundations and practical applications of new discoveries, as well as ethical, legal/regulatory, and social issues related to the practice of genomic medicine. © 2009 Elsevier Inc. All rights reserved.

Authors
Ginsburg, GS; Willard, HF
MLA Citation
Ginsburg, G. S., and H. F. Willard. Genomic and Personalized Medicine, Two-Vol Set. 2009. Scopus, doi:10.1016/B978-0-12-369420-1.X0001-7.
Source
scopus
Publish Date
2009
DOI
10.1016/B978-0-12-369420-1.X0001-7

Neuropeptide Y gene polymorphisms confer risk of early-onset atherosclerosis.

Neuropeptide Y (NPY) is a strong candidate gene for coronary artery disease (CAD). We have previously identified genetic linkage to familial CAD in the genomic region of NPY. We performed follow-up genetic, biostatistical, and functional analysis of NPY in early-onset CAD. In familial CAD (GENECARD, N = 420 families), we found increased microsatellite linkage to chromosome 7p14 (OSA LOD = 4.2, p = 0.004) in 97 earliest age-of-onset families. Tagged NPY SNPs demonstrated linkage to CAD of a 6-SNP block (LOD = 1.58-2.72), family-based association of this block with CAD (p = 0.02), and stronger linkage to CAD in the earliest age-of-onset families. Association of this 6-SNP block with CAD was validated in: (a) 556 non-familial early-onset CAD cases and 256 controls (OR 1.46-1.65, p = 0.01-0.05), showing stronger association in youngest cases (OR 1.84-2.20, p = 0.0004-0.09); and (b) GENECARD probands versus non-familial controls (OR 1.79-2.06, p = 0.003-0.02). A promoter SNP (rs16147) within this 6-SNP block was associated with higher plasma NPY levels (p = 0.04). To assess a causal role of NPY in atherosclerosis, we applied the NPY1-receptor-antagonist BIBP-3226 adventitially to endothelium-denuded carotid arteries of apolipoprotein E-deficient mice; treatment reduced atherosclerotic neointimal area by 50% (p = 0.03). Thus, NPY variants associate with atherosclerosis in two independent datasets (with strong age-of-onset effects) and show allele-specific expression with NPY levels, while NPY receptor antagonism reduces atherosclerosis in mice. We conclude that NPY contributes to atherosclerosis pathogenesis.

Authors
Shah, SH; Freedman, NJ; Zhang, L; Crosslin, DR; Stone, DH; Haynes, C; Johnson, J; Nelson, S; Wang, L; Connelly, JJ; Muehlbauer, M; Ginsburg, GS; Crossman, DC; Jones, CJH; Vance, J; Sketch, MH; Granger, CB; Newgard, CB; Gregory, SG; Goldschmidt-Clermont, PJ; Kraus, WE; Hauser, ER
MLA Citation
Shah, Svati H., et al. “Neuropeptide Y gene polymorphisms confer risk of early-onset atherosclerosis..” Plos Genet, vol. 5, no. 1, Jan. 2009. Pubmed, doi:10.1371/journal.pgen.1000318.
Website
http://hdl.handle.net/10161/16064
PMID
19119412
Source
pubmed
Published In
Plos Genet
Volume
5
Issue
1
Publish Date
2009
Start Page
e1000318
DOI
10.1371/journal.pgen.1000318

Transforming the practice of medicine using genomics.

Recent studies have demonstrated the use of genomic data, particularly gene expression signatures, as clinical prognostic factors in complex diseases. Such studies herald the future for genomic medicine and the opportunity for personalized prognosis in a variety of clinical contexts that utilize genomescale molecular information. Several key areas represent logical and critical next steps in the use of complex genomic profiling data towards the goal of personalized medicine. First, analyses should be geared toward the development of molecular profiles that predict future events - such as major clinical events or the response, resistance, or adverse reaction to therapy. Secondly, these must move into actual clinical practice by forming the basis for the next generation of clinical trials that will employ these methodologies to stratify patients. Lastly, there remain formidable challenges is in the translation of genomic technologies into clinical medicine that will need to be addressed: professional and public education, health outcomes research, reimbursement, regulatory oversight and privacy protection.

Authors
Ginsburg, GS; J McCarthy, J
MLA Citation
Ginsburg, Geoffrey S., and Jeanette J McCarthy. “Transforming the practice of medicine using genomics..” Clinical Cases in Mineral and Bone Metabolism : The Official Journal of the Italian Society of Osteoporosis, Mineral Metabolism, and Skeletal Diseases, vol. 6, no. 1, Jan. 2009, pp. 25–28.
PMID
22461094
Source
epmc
Published In
Clinical Cases in Mineral and Bone Metabolism : the Official Journal of the Italian Society of Osteoporosis, Mineral Metabolism, and Skeletal Diseases
Volume
6
Issue
1
Publish Date
2009
Start Page
25
End Page
28

High heritability of metabolomic profiles in families burdened with premature cardiovascular disease.

Integration of genetic and metabolic profiling holds promise for providing insight into human disease. Coronary artery disease (CAD) is strongly heritable, but the heritability of metabolomic profiles has not been evaluated in humans. We performed quantitative mass spectrometry-based metabolic profiling in 117 individuals within eight multiplex families from the GENECARD study of premature CAD. Heritabilities were calculated using variance components. We found high heritabilities for amino acids (arginine, ornithine, alanine, proline, leucine/isoleucine, valine, glutamate/glutamine, phenylalanine and glycine; h(2)=0.33-0.80, P=0.005-1.9 x 10(-16)), free fatty acids (arachidonic, palmitic, linoleic; h(2)=0.48-0.59, P=0.002-0.00005) and acylcarnitines (h(2)=0.23-0.79, P=0.05-0.0000002). Principal components analysis was used to identify metabolite clusters. Reflecting individual metabolites, several components were heritable, including components comprised of ketones, beta-hydroxybutyrate and C2-acylcarnitine (h(2)=0.61); short- and medium-chain acylcarnitines (h(2)=0.39); amino acids (h(2)=0.44); long-chain acylcarnitines (h(2)=0.39) and branched-chain amino acids (h(2)=0.27). We report a novel finding of high heritabilities of metabolites in premature CAD, establishing a possible genetic basis for these profiles. These results have implications for understanding CAD pathophysiology and genetics.

Authors
Shah, SH; Hauser, ER; Bain, JR; Muehlbauer, MJ; Haynes, C; Stevens, RD; Wenner, BR; Dowdy, ZE; Granger, CB; Ginsburg, GS; Newgard, CB; Kraus, WE
MLA Citation
Shah, Svati H., et al. “High heritability of metabolomic profiles in families burdened with premature cardiovascular disease..” Mol Syst Biol, vol. 5, 2009. Pubmed, doi:10.1038/msb.2009.11.
PMID
19357637
Source
pubmed
Published In
Molecular Systems Biology
Volume
5
Publish Date
2009
Start Page
258
DOI
10.1038/msb.2009.11

A genomic approach to colon cancer risk stratification yields biologic insights into therapeutic opportunities.

Gene expression profiles provide an opportunity to dissect the heterogeneity of solid tumors, including colon cancer, to improve prognosis and predict response to therapies. Bayesian binary regression methods were used to generate a signature of disease recurrence in patients with resected early stage colon cancer validated in an independent cohort. A 50-gene signature was developed that effectively distinguished early stage colon cancer patients with a low or high risk of disease recurrence. RT-PCR analysis of the 50-gene signature validated 9 of the top 10 differentially expressed genes. When applied to two independent validation cohorts of 55 and 73 patients, the 50-gene model accurately predicted recurrence. Standard Kaplan-Meier survival analysis confirmed the prognostic accuracy (P < 0.01, log rank), as did multivariate Cox proportional hazard models. We tested potential targeted therapeutic options for patients at high risk for disease recurrence and found a clinically important relationship between sensitivity to celecoxib, LY-294002 (PI3kinase inhibitor), retinol, and sulindac in colon cancer cell lines expressing the poor prognostic phenotype (P < 0.01, t test), which performed better than standard chemotherapy (5-FU and oxaliplatin). We present a genomic strategy in early stage colon cancer to identify patients at highest risk of recurrence. An ability to move beyond current staging by refining the estimation of prognosis in early stage colon cancer also has implications for individualized therapy.

Authors
Garman, KS; Acharya, CR; Edelman, E; Grade, M; Gaedcke, J; Sud, S; Barry, W; Diehl, AM; Provenzale, D; Ginsburg, GS; Ghadimi, BM; Ried, T; Nevins, JR; Mukherjee, S; Hsu, D; Potti, A
MLA Citation
Garman, Katherine S., et al. “A genomic approach to colon cancer risk stratification yields biologic insights into therapeutic opportunities..” Proc Natl Acad Sci U S A, vol. 105, no. 49, Dec. 2008, pp. 19432–37. Pubmed, doi:10.1073/pnas.0806674105.
PMID
19050079
Source
pubmed
Published In
Proc Natl Acad Sci U S A
Volume
105
Issue
49
Publish Date
2008
Start Page
19432
End Page
19437
DOI
10.1073/pnas.0806674105

Pharmacogenetic predictors of statin-mediated low-density lipoprotein cholesterol reduction and dose response.

BACKGROUND: There is interindividual variation in low-density lipoprotein cholesterol (LDLc) lowering by statins and limited study into the genetic associations of the dose dependant LDLc lowering by statins. METHODS AND RESULTS: Five hundred nine patients with hyperlipidemia were randomly assigned atorvastatin 10 mg, simvastatin 20 mg, or pravastatin 10 mg (low-dose phase) followed by 80 mg, 80 mg, and 40 mg (high-dose phase), respectively. Thirty-one genes in statin, cholesterol, and lipoprotein metabolism were sequenced and 489 single nucleotide polymorphisms with minor allele frequencies >2% were tested for associations with percentage LDLc lowering at low doses using multivariable adjusted general linear regression. Significant associations from the analysis at low dose were then repeated at high-dose statins. At low doses, only 1 single nucleotide polymorphism met our experiment-wide significance level, ABCA1 rs12003906. Twenty-six subjects carried the minor allele of rs12003906, which was associated with an attenuated LDLc reduction (LDLc reduction in carriers versus noncarriers -24.1+/-2.6% versus -32.2+/-1.5%; P=0.0001). In addition, we replicated the association with the APOE epsilon3 allele and a reduced LDLc reduction. At high doses, carriers of the minor allele of ABCA1 rs12003906 and the APOE epsilon3 allele improved their LDLc reduction but continued to have a diminished LDLc reduction compared with noncarriers (-30.5+/-4.0% versus -42.0+/-2.4%; P=0.005) and (-38.5+/-1.9% versus -45.3+/-2.8%; P=0.009), respectively. CONCLUSIONS: An intronic single nucleotide polymorphism in ABCA1 and the APOE epsilon3 allele are associated with reduced LDLc lowering by statins and identify individuals who may be resistant to maximal LDLc lowering by statins.

Authors
Voora, D; Shah, SH; Reed, CR; Zhai, J; Crosslin, DR; Messer, C; Salisbury, BA; Ginsburg, GS
MLA Citation
Voora, Deepak, et al. “Pharmacogenetic predictors of statin-mediated low-density lipoprotein cholesterol reduction and dose response..” Circ Cardiovasc Genet, vol. 1, no. 2, Dec. 2008, pp. 100–06. Pubmed, doi:10.1161/CIRCGENETICS.108.795013.
PMID
20031551
Source
pubmed
Published In
Circ Cardiovasc Genet
Volume
1
Issue
2
Publish Date
2008
Start Page
100
End Page
106
DOI
10.1161/CIRCGENETICS.108.795013

Organizational improvements to enhance modern clinical epidemiology.

Authors
Califf, RM; Ginsburg, GS
MLA Citation
Califf, Robert M., and Geoffrey S. Ginsburg. “Organizational improvements to enhance modern clinical epidemiology..” Jama, vol. 300, no. 19, Nov. 2008, pp. 2300–02. Pubmed, doi:10.1001/jama.2008.638.
PMID
19017917
Source
pubmed
Published In
Jama
Volume
300
Issue
19
Publish Date
2008
Start Page
2300
End Page
2302
DOI
10.1001/jama.2008.638

Discovery of Genes Expressed in Whole Blood which Identity Patients with Coronary Artery Disease

Authors
Wingrove, JA; Elashoff, M; Tingley, WG; Sehnert, AJ; Daniels, SE; Paoni, NF; Rosenberg, S; Kraus, WE; Newby, LK; Ginsburg, GS
MLA Citation
Wingrove, James A., et al. “Discovery of Genes Expressed in Whole Blood which Identity Patients with Coronary Artery Disease.” Circulation, vol. 118, no. 18, LIPPINCOTT WILLIAMS & WILKINS, Oct. 2008, pp. S389–S389.
Source
wos
Published In
Circulation
Volume
118
Issue
18
Publish Date
2008
Start Page
S389
End Page
S389

Association of Statin-Induced Musculoskeletal Side Effects with Sex and a Hepatic Uptake Transporter Reduced Function Allele, SLC01B1*5

Authors
Voora, D; Ali, S; Shah, SH; Reed, CR; Salisbury, B; Ginsburg, GS
MLA Citation
Voora, Deepak, et al. “Association of Statin-Induced Musculoskeletal Side Effects with Sex and a Hepatic Uptake Transporter Reduced Function Allele, SLC01B1*5.” Circulation, vol. 118, no. 18, LIPPINCOTT WILLIAMS & WILKINS, Oct. 2008, pp. S326–S326.
Source
wos
Published In
Circulation
Volume
118
Issue
18
Publish Date
2008
Start Page
S326
End Page
S326

Gene Expression in Peripheral Blood Reflects the Presence and Extent of Coronary Artery Stenosis

Authors
Tingley, WG; Wingrove, JA; Sehnert, AJ; Elashoff, M; Daniels, SE; Rosenberg, S; Buellesfeld, L; Grube, E; Newby, LK; Ginsburg, GS; Kraus, WE
MLA Citation
Tingley, Whittemore G., et al. “Gene Expression in Peripheral Blood Reflects the Presence and Extent of Coronary Artery Stenosis.” American Journal of Cardiology, vol. 102, no. 8A, EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC, 2008, pp. 55I-55I.
Source
wos
Published In
The American Journal of Cardiology
Volume
102
Issue
8A
Publish Date
2008
Start Page
55I
End Page
55I

Correlation of peripheral-blood gene expression with the extent of coronary artery stenosis.

BACKGROUND: The molecular pathophysiology of coronary artery disease (CAD) includes cytokine release and a localized inflammatory response within the vessel wall. The extent to which CAD and its severity is reflected by gene expression in circulating cells is unknown. METHODS AND RESULTS: From an initial coronary catheterization cohort we identified 41 patients, comprising 27 cases with angiographically significant CAD and 14 controls without coronary stenosis. Whole-genome microarray analysis performed on peripheral-blood mononuclear cells yielded 526 genes with >1.3-fold differential expression (P<0.05) between cases and controls. Real-time polymerase chain reaction on 106 genes (the 50 most significant microarray genes and 56 additional literature genes) in an independent subset of 95 patients (63 cases, 32 controls) from the same cohort yielded 14 genes (P<0.05) that independently discriminated CAD state in a multivariable analysis that included clinical and demographic factors. From an independent second catheterization cohort, 215 patients were selected for real-time polymerase chain reaction-based replication. A case:control subset of 107 patients (86 cases, 21 controls) replicated 11 of the 14 multivariably significant genes from the first cohort. An analysis of the 14 genes in the entire set of 215 patients demonstrated that gene expression was proportional to maximal coronary artery stenosis (P<0.001 by ANOVA). CONCLUSIONS: Gene expression in peripheral-blood cells reflects the presence and extent of CAD in patients undergoing angiography.

Authors
Wingrove, JA; Daniels, SE; Sehnert, AJ; Tingley, W; Elashoff, MR; Rosenberg, S; Buellesfeld, L; Grube, E; Newby, LK; Ginsburg, GS; Kraus, WE
MLA Citation
Wingrove, James A., et al. “Correlation of peripheral-blood gene expression with the extent of coronary artery stenosis..” Circ Cardiovasc Genet, vol. 1, no. 1, Oct. 2008, pp. 31–38. Pubmed, doi:10.1161/CIRCGENETICS.108.782730.
PMID
20031539
Source
pubmed
Published In
Circ Cardiovasc Genet
Volume
1
Issue
1
Publish Date
2008
Start Page
31
End Page
38
DOI
10.1161/CIRCGENETICS.108.782730

Corrigendum: Genomic signatures to guide the use of chemotherapeutics (Nature Medicine (2006) 12, (1294-1300))

Authors
Potti, A; Dressman, HK; Bild, A; Riedel, RF; Chan, G; Sayer, R; Cragun, J; Cottrill, H; Kelley, MJ; Petersen, R; Harpole, D; Marks, J; Berchuck, A; Ginsburg, GS; Febbo, P; Lancaster, J; Nevins, JR
MLA Citation
Potti, A., et al. “Corrigendum: Genomic signatures to guide the use of chemotherapeutics (Nature Medicine (2006) 12, (1294-1300)).” Nature Medicine, vol. 14, no. 8, 1 Aug. 2008. Scopus, doi:10.1038/nm0808-889.
Source
scopus
Published In
Nature Medicine
Volume
14
Issue
8
Publish Date
2008
Start Page
889
DOI
10.1038/nm0808-889

Genomic Medicine: 'grand challenges' in the translation of genomics to human health.

Authors
Ginsburg, GS
MLA Citation
Ginsburg, Geoffrey S. “Genomic Medicine: 'grand challenges' in the translation of genomics to human health..” European Journal of Human Genetics : Ejhg, vol. 16, no. 8, Aug. 2008, pp. 873–74. Epmc, doi:10.1038/ejhg.2008.115.
PMID
18560443
Source
epmc
Published In
European Journal of Human Genetics : Ejhg
Volume
16
Issue
8
Publish Date
2008
Start Page
873
End Page
874
DOI
10.1038/ejhg.2008.115

Challenges in enrollment of minority, pediatric, and geriatric patients in emergency and acute care clinical research.

STUDY OBJECTIVE: Emergency department (ED) -based clinical research has the potential to include patient populations that are typically underrepresented in clinical research. The objective of this study is to assess how emergency clinical care and research processes, informed consent, and patient demographic factors (age, sex, and ethnicity/race) affect enrollment and consent in clinical research in the ED. METHODS: This was an analysis of prospectively collected data of all patients (aged 2 to 101 years) eligible for one of 7 clinical research studies from February 2005 to April 2007 in an academic ED. We measured rates of enrollment and consent in the clinical studies. RESULTS: One thousand two hundred two of the 4418 patients screened for participation in 7 clinical studies were clinically eligible for enrollment. Of the 868 patients who were able to provide a voluntary decision regarding consent, 639 (73.6%) agreed to participate; an overall enrollment rate of 53.2%. The mean age of patients enrolled was 51.8 years (range 3 to 98 years). Black patients (49.2% enrollment) and Latino patients (18.4% enrollment) were less likely to be enrolled in comparison with white patients (58.3% enrollment) (adjusted odds ratio [OR] of enrollment for blacks=0.64; 95% confidence interval [CI] 0.50 to 0.82; adjusted OR of enrollment for Latinos=0.16; 95% CI 0.08 to 0.33). Enrollment rates were lower among pediatric (40.0%) and geriatric patients (49.1%) in comparison with adult patients ages 18 to 64 years (55.5%) (adjusted OR of enrollment for pediatric patients=0.70, 95% CI 0.34 to 1.43; adjusted OR of enrollment for geriatric patients=0.69, 95% CI 0.53 to 0.90). Unique issues contributing to underenrollment included challenges in consent among pediatric and elderly patients, language issues in Latino patients, reduced voluntary consent rates among black patients, and perhaps underuse of minimal risk waivers. CONCLUSION: In a large academic ED, minority, pediatric, and geriatric patients were less likely to be enrolled in acute care clinical research studies than middle-aged whites. Enrollment and consent strategies designed to enhance research participation in these important patient populations may be necessary to address disparities in the development and application of evidence-based emergency and acute care.

Authors
Glickman, SW; Anstrom, KJ; Lin, L; Chandra, A; Laskowitz, DT; Woods, CW; Freeman, DH; Kraft, M; Beskow, LM; Weinfurt, KP; Schulman, KA; Cairns, CB
MLA Citation
Glickman, Seth W., et al. “Challenges in enrollment of minority, pediatric, and geriatric patients in emergency and acute care clinical research..” Ann Emerg Med, vol. 51, no. 6, June 2008, pp. 775-780.e3. Pubmed, doi:10.1016/j.annemergmed.2007.11.002.
PMID
18191297
Source
pubmed
Published In
Annals of Emergency Medicine
Volume
51
Issue
6
Publish Date
2008
Start Page
775
End Page
780.e3
DOI
10.1016/j.annemergmed.2007.11.002

Gene expression signatures, clinicopathological features, and individualized therapy in breast cancer.

CONTEXT: Gene expression profiling may be useful for prognostic and therapeutic strategies in breast carcinoma. OBJECTIVES: To demonstrate the value in integrating genomic information with clinical and pathological risk factors, to refine prognosis, and to improve therapeutic strategies for early stage breast cancer. DESIGN, SETTING, AND PATIENTS: Retrospective study of patients with early stage breast carcinoma who were candidates for adjuvant chemotherapy; 964 clinically annotated breast tumor samples (573 in the initial discovery set and 391 in the validation cohort) with corresponding microarray data were used. All patients were assigned relapse risk scores based on their respective clinicopathological features. Signatures representing oncogenic pathway activation and tumor biology/microenvironment status were applied to these samples to obtain patterns of deregulation that correspond with relapse risk scores to refine prognosis with the clinicopathological prognostic model alone. Predictors of chemotherapeutic response were also applied to further characterize clinically relevant heterogeneity in early stage breast cancer. MAIN OUTCOME MEASURES: Gene expression signatures and clinicopathological variables in early stage breast cancer to determine a refined estimation of relapse-free survival and sensitivity to chemotherapy. RESULTS: In the initial data set of 573 patients, prognostically significant clusters representing patterns of oncogenic pathway activation and tumor biology/microenvironment states were identified within the low-risk (log-rank P = .004), intermediate-risk (log-rank P = .01), and high-risk (log-rank P = .003) model cohorts, representing clinically important genomic subphenotypes of breast cancer. As an example, in the low-risk cohort, of 6 prognostically significant clusters, patients in cluster 4 had an inferior relapse-free survival vs patients in cluster 1 (log-rank P = .004) and cluster 5 (log-rank P = .03). Median relapse-free survival for patients in cluster 4 was 16 months less than for patients in cluster 1 (95% CI, 7.5-24.5 months) and 19 months less than for patients in cluster 5 (95% CI, 10.5-27.5 months). Multivariate analyses confirmed the independent prognostic value of the genomic clusters (low risk, P = .05; high risk, P = .02). The reproducibility and validity of these patterns of pathway deregulation in predicting relapse risk was established using related but not identical clusters in the independent validation cohort. The prognostic clinicogenomic clusters also have unique sensitivity patterns to commonly used cytotoxic therapies. CONCLUSIONS: These results provide preliminary evidence that incorporation of gene expression signatures into clinical risk stratification can refine prognosis. Prospective studies are needed to determine the value of this approach for individualizing therapeutic strategies.

Authors
Acharya, CR; Hsu, DS; Anders, CK; Anguiano, A; Salter, KH; Walters, KS; Redman, RC; Tuchman, SA; Moylan, CA; Mukherjee, S; Barry, WT; Dressman, HK; Ginsburg, GS; Marcom, KP; Garman, KS; Lyman, GH; Nevins, JR; Potti, A
MLA Citation
Acharya, Chaitanya R., et al. “Gene expression signatures, clinicopathological features, and individualized therapy in breast cancer..” Jama, vol. 299, no. 13, Apr. 2008, pp. 1574–87. Pubmed, doi:10.1001/jama.299.13.1574.
PMID
18387932
Source
pubmed
Published In
Jama
Volume
299
Issue
13
Publish Date
2008
Start Page
1574
End Page
1587
DOI
10.1001/jama.299.13.1574

Gene expression signatures of radiation response are specific, durable and accurate in mice and humans.

BACKGROUND: Previous work has demonstrated the potential for peripheral blood (PB) gene expression profiling for the detection of disease or environmental exposures. METHODS AND FINDINGS: We have sought to determine the impact of several variables on the PB gene expression profile of an environmental exposure, ionizing radiation, and to determine the specificity of the PB signature of radiation versus other genotoxic stresses. Neither genotype differences nor the time of PB sampling caused any lessening of the accuracy of PB signatures to predict radiation exposure, but sex difference did influence the accuracy of the prediction of radiation exposure at the lowest level (50 cGy). A PB signature of sepsis was also generated and both the PB signature of radiation and the PB signature of sepsis were found to be 100% specific at distinguishing irradiated from septic animals. We also identified human PB signatures of radiation exposure and chemotherapy treatment which distinguished irradiated patients and chemotherapy-treated individuals within a heterogeneous population with accuracies of 90% and 81%, respectively. CONCLUSIONS: We conclude that PB gene expression profiles can be identified in mice and humans that are accurate in predicting medical conditions, are specific to each condition and remain highly accurate over time.

Authors
Meadows, SK; Dressman, HK; Muramoto, GG; Himburg, H; Salter, A; Wei, Z; Ginsburg, GS; Chao, NJ; Nevins, JR; Chute, JP
MLA Citation
Meadows, Sarah K., et al. “Gene expression signatures of radiation response are specific, durable and accurate in mice and humans..” Plos One, vol. 3, no. 4, Apr. 2008. Pubmed, doi:10.1371/journal.pone.0001912.
Website
http://hdl.handle.net/10161/13546
PMID
18382685
Source
pubmed
Published In
Plos One
Volume
3
Issue
4
Publish Date
2008
Start Page
e1912
DOI
10.1371/journal.pone.0001912

Centralized biorepositories for genetic and genomic research.

Authors
Ginsburg, GS; Burke, TW; Febbo, P
MLA Citation
Ginsburg, Geoffrey S., et al. “Centralized biorepositories for genetic and genomic research..” Jama, vol. 299, no. 11, Mar. 2008, pp. 1359–61. Pubmed, doi:10.1001/jama.299.11.1359.
PMID
18349099
Source
pubmed
Published In
Jama
Volume
299
Issue
11
Publish Date
2008
Start Page
1359
End Page
1361
DOI
10.1001/jama.299.11.1359

Peripheral blood metabolic signatures are markers of coronary artery disease and myocardial infarction

Authors
Shah, SH; Bain, J; Muehlbauer, MJ; Stevens, RD; Wenner, BR; Naliboff, LC; Haynes, C; Ginsburg, GS; Hauser, ER; Newgard, CB; Kraus, WE
MLA Citation
Shah, Svati H., et al. “Peripheral blood metabolic signatures are markers of coronary artery disease and myocardial infarction.” Circulation, vol. 117, no. 11, LIPPINCOTT WILLIAMS & WILKINS, 2008.
Source
wos
Published In
Circulation
Volume
117
Issue
11
Publish Date
2008

Clinical genomic testing: getting it right.

Authors
Douglas, PS; Ginsburg, GS
MLA Citation
Douglas, Pamela S., and Geoffrey S. Ginsburg. “Clinical genomic testing: getting it right..” J Cardiovasc Transl Res, vol. 1, no. 1, Mar. 2008, pp. 17–20. Pubmed, doi:10.1007/s12265-007-9004-y.
PMID
20559953
Source
pubmed
Published In
J Cardiovasc Transl Res
Volume
1
Issue
1
Publish Date
2008
Start Page
17
End Page
20
DOI
10.1007/s12265-007-9004-y

Highlights of the year in JACC 2007.

Authors
DeMaria, AN; Bax, JJ; Ben-Yehuda, O; Clopton, P; Feld, GK; Ginsburg, GS; Greenberg, BH; Knoke, JD; Lew, WYW; Lima, JAC; Maisel, AS; Narayan, SM; Narula, J; Sahn, DJ; Tsimikas, S
MLA Citation
DeMaria, Anthony N., et al. “Highlights of the year in JACC 2007..” J Am Coll Cardiol, vol. 51, no. 4, Jan. 2008, pp. 490–512. Pubmed, doi:10.1016/j.jacc.2007.12.003.
PMID
18222362
Source
pubmed
Published In
J Am Coll Cardiol
Volume
51
Issue
4
Publish Date
2008
Start Page
490
End Page
512
DOI
10.1016/j.jacc.2007.12.003

Regression of atherosclerosis with therapeutic antibodies pipe cleaner or pipe dream?

Authors
Ginsburg, GS
MLA Citation
Ginsburg, Geoffrey S. “Regression of atherosclerosis with therapeutic antibodies pipe cleaner or pipe dream?.” J Am Coll Cardiol, vol. 50, no. 24, Dec. 2007, pp. 2319–21. Pubmed, doi:10.1016/j.jacc.2007.08.039.
PMID
18068041
Source
pubmed
Published In
J Am Coll Cardiol
Volume
50
Issue
24
Publish Date
2007
Start Page
2319
End Page
2321
DOI
10.1016/j.jacc.2007.08.039

Genetic profiling and tailored therapy in asthma: are we there yet?

Asthma is characterized by reversible bronchial hyper-responsiveness and airway inflammation, and encompasses a wide variety of patients with different clinical phenotypes that display variable responses to therapy. The definition of genomic variation presented in the Human Genome Project has facilitated the development of genetic-guided therapy in various diseases, including asthma. Tailored therapy is a reality in many types of malignancies where specific gene mutations or molecular profiles are identified and used to make critical therapeutic decisions. Despite the identification of beta-adrenergic receptor polymorphisms by Liggett and colleagues during the 1990s, the pharmacogenetics of asthma is still in its infancy. There have been great advances in asthma pharmacogenetics and pharmacotherapy with the completion of several large trials highlighting the effects of genotype on response to asthma therapy. This review focuses on research articles that serve to emphasize the potential role of using genotyping as a tool to develop individualized patient treatment regimens for asthma, thus improving outcomes and limiting adverse effects of certain therapies.

Authors
Lugogo, NL; Ginsburg, GS; Que, LG
MLA Citation
Lugogo, Njira L., et al. “Genetic profiling and tailored therapy in asthma: are we there yet?.” Curr Opin Mol Ther, vol. 9, no. 6, Dec. 2007, pp. 528–37.
PMID
18041663
Source
pubmed
Published In
Current Opinion in Molecular Therapeutics
Volume
9
Issue
6
Publish Date
2007
Start Page
528
End Page
537

Erratum: Genomic signatures to guide the use of chemotherapeutics (Nature (2006) 12, (1294-1300))

Authors
Potti, A; Dressman, HK; Bild, A; Riedel, RF; Chan, G; Sayer, R; Cragun, J; Cottrill, H; Kelley, MJ; Petersen, R; Harpole, D; Marks, J; Berchuck, A; Ginsburg, GS; Febbo, P; Lancaster, J; Nevins, JR
MLA Citation
Potti, A., et al. “Erratum: Genomic signatures to guide the use of chemotherapeutics (Nature (2006) 12, (1294-1300)).” Nature Medicine, vol. 13, no. 11, 1 Nov. 2007. Scopus, doi:10.1038/nm1107-1388.
Source
scopus
Published In
Nature Medicine
Volume
13
Issue
11
Publish Date
2007
Start Page
1388
DOI
10.1038/nm1107-1388

Corrigenda: Genomic signatures to guide the use of chemotherapeutics.

Authors
Potti, A; Dressman, HK; Bild, A; Riedel, RF; Chan, G; Sayer, R; Cragun, J; Cottrill, H; Kelley, MJ; Petersen, R; Harpole, D; Marks, J; Berchuck, A; Ginsburg, GS; Febbo, P; Lancaster, J; Nevins, JR
MLA Citation
Potti, A., et al. “Corrigenda: Genomic signatures to guide the use of chemotherapeutics..” Nature Medicine, vol. 13, no. 11, Nov. 2007.
Source
manual
Published In
Nature Medicine
Volume
13
Issue
11
Publish Date
2007
Start Page
1388

Opposing effects of the D70 mutation and the shared epitope in HLA-DR4 on disease activity and certain disease phenotypes in rheumatoid arthritis.

Certain sequences present in the hypervariable region of human leucocyte antigen (HLA)-DRB1 known as the shared epitope (SE) are hypothesised to increase the risk of rheumatoid arthritis (RA), whereas alleles encoding aspartic acid at position 70 (D70 alleles) may have a protective effect.Patient HLA-DRB1 serotypes were assessed and the genotypes encoding the SE motif or the putatively protective D70 motif identified in a large RA cohort. Logistic regression was used to analyse associations of genotype with presence of disease, comorbidities and disease severity, and association between genotype and change in disease activity over time.The 689 patients enrolled had a mean (SD) age of 57.9 (13.7) years and mean (SD) disease duration of 15.3 (12.7) years. In a comparison with 482 ethnicity matched population-based controls, the D70 sequence exerted a strong protective effect (OR = 0.52, p<0.001) that remained significant when the SE at the same locus was accounted for (OR = 0.72, 95% CI 0.60 to 0.86, p<0.001). The SE assessed on all HLA-DRB1 serotypic backgrounds except DR1 was associated with RA susceptibility (additive OR = 2.43, p<0.001). Associations were found between SE and serum levels of rheumatoid factor (p<0.001, with correlation of 0.18) and anti-cyclic citrullinated peptide antibodies (p<0.001, with correlation of 0.25) but not with serum C-reactive protein.The D70 allele has a significant protective effect that is mitigated but still significant when the risk effect of the SE at the same locus is taken into account. The presence of the SE on DR4 is associated with greater RA susceptibility and certain disease-activity measures.

Authors
Shadick, NA; Heller, JE; Weinblatt, ME; Maher, NE; Cui, J; Ginsburg, G; Coblyn, J; Anderson, R; Solomon, DH; Roubenoff, R; Parker, A
MLA Citation
Shadick, N. A., et al. “Opposing effects of the D70 mutation and the shared epitope in HLA-DR4 on disease activity and certain disease phenotypes in rheumatoid arthritis..” Annals of the Rheumatic Diseases, vol. 66, no. 11, Nov. 2007, pp. 1497–502. Epmc, doi:10.1136/ard.2006.067603.
PMID
17491100
Source
epmc
Published In
Annals of the Rheumatic Diseases
Volume
66
Issue
11
Publish Date
2007
Start Page
1497
End Page
1502
DOI
10.1136/ard.2006.067603

Polymorphisms in ABCA1 predict statin mediated LDL cholesterol lowering and suggest an interaction with CETP

Authors
Voora, D; Reed, CR; Zhai, J; Salisbury, BA; Shah, SH; Ginsburg, GS
MLA Citation
Voora, Deepalk, et al. “Polymorphisms in ABCA1 predict statin mediated LDL cholesterol lowering and suggest an interaction with CETP.” Circulation, vol. 116, no. 16, LIPPINCOTT WILLIAMS & WILKINS, Oct. 2007, pp. 178–178.
Source
wos
Published In
Circulation
Volume
116
Issue
16
Publish Date
2007
Start Page
178
End Page
178

Taking cardiovascular genetic association studies to the next level.

Genetic information is beginning to have a direct impact on patient care and it is important that cardiologists appreciate the value and approaches to associating genetic variation and health outcomes. Genetic associations should be based on compelling genetic and biological hypotheses and should be statistically sound so as to reduce the possibility of "false discovery" in the setting of testing multiple hypotheses. Study designs should clearly define cases and controls and measurement of phenotypes. Finally, findings should be replicated in at least 1 independent cohort. Consideration of these principles should provide insight into disease biology based on genetic findings and encourage their meaningful adoption into clinical practice.

Authors
Ginsburg, GS; Shah, SH; McCarthy, JJ
MLA Citation
Ginsburg, Geoffrey S., et al. “Taking cardiovascular genetic association studies to the next level..” J Am Coll Cardiol, vol. 50, no. 10, Sept. 2007, pp. 930–32. Pubmed, doi:10.1016/j.jacc.2007.05.025.
PMID
17765118
Source
pubmed
Published In
J Am Coll Cardiol
Volume
50
Issue
10
Publish Date
2007
Start Page
930
End Page
932
DOI
10.1016/j.jacc.2007.05.025

Peripheral blood expression of nuclear factor-kappab-regulated genes is associated with rheumatoid arthritis disease activity and responds differentially to anti-tumor necrosis factor-alpha versus methotrexate.

OBJECTIVE: To evaluate peripheral blood expression of genes regulated by nuclear factor-kappaB (NF-kappaB), a key mediator of tumor necrosis factor-alpha (TNF-alpha) signaling, in patients with rheumatoid arthritis (RA) before and during treatment with anti-TNF-alpha or methotrexate (MTX). We analyzed association of gene expression with disease activity, rheumatoid factor (RF), age, sex, disease duration, treatment modality, and clinical response. METHODS: Sixty patients consented for RNA analysis at baseline and after 2 and 6 weeks of treatment. Disease activity was quantified using Disease Activity Score (DAS28) and C-reactive protein (CRP). Expression of 67 TNF-alpha-responsive, NF-kappaB-regulated genes was measured using Affymetrix arrays and RT-PCR. RESULTS: Expression of 34 genes was associated with DAS28-CRP, notably S100A12/calgranulin C, IL7R, and aquaporin 3. No association was observed with age, sex, RF, or disease duration. Expression of 16 genes changed in a manner that differed significantly between treatment groups. Eleven were reduced in anti-TNF-alpha-treated patients relative to MTX, while 5 were increased. The majority of these observations were confirmed using RT-PCR. Gene expression was not associated significantly with change in disease activity. CONCLUSION: NF-kappaB-dependent gene expression in peripheral leukocytes is highly correlated with RA activity as measured by DAS28-CRP. Expression of many genes responds differentially to anti-TNF-alpha versus MTX, suggesting fundamentally different effects on the NF-kappaB pathway. This peripheral blood expression signature provides candidate markers that could lead to development of a simple, minimally invasive pharmacodynamic assay for RA treatments directed at the NF-kappaB pathway. Combination of gene expression data with clinical scores and serum markers may provide more sensitive and predictive measures of RA disease activity.

Authors
Parker, A; Izmailova, ES; Narang, J; Badola, S; Le, T; Roubenoff, R; Ginsburg, GS; Maier, A; Coblyn, JS; Shadick, NA; Weinblatt, ME
MLA Citation
Parker, Alex, et al. “Peripheral blood expression of nuclear factor-kappab-regulated genes is associated with rheumatoid arthritis disease activity and responds differentially to anti-tumor necrosis factor-alpha versus methotrexate..” J Rheumatol, vol. 34, no. 9, Sept. 2007, pp. 1817–22.
PMID
17696278
Source
pubmed
Published In
The Journal of Rheumatology
Volume
34
Issue
9
Publish Date
2007
Start Page
1817
End Page
1822

Gene expression signatures that predict radiation exposure in mice and humans.

BACKGROUND: The capacity to assess environmental inputs to biological phenotypes is limited by methods that can accurately and quantitatively measure these contributions. One such example can be seen in the context of exposure to ionizing radiation. METHODS AND FINDINGS: We have made use of gene expression analysis of peripheral blood (PB) mononuclear cells to develop expression profiles that accurately reflect prior radiation exposure. We demonstrate that expression profiles can be developed that not only predict radiation exposure in mice but also distinguish the level of radiation exposure, ranging from 50 cGy to 1,000 cGy. Likewise, a molecular signature of radiation response developed solely from irradiated human patient samples can predict and distinguish irradiated human PB samples from nonirradiated samples with an accuracy of 90%, sensitivity of 85%, and specificity of 94%. We further demonstrate that a radiation profile developed in the mouse can correctly distinguish PB samples from irradiated and nonirradiated human patients with an accuracy of 77%, sensitivity of 82%, and specificity of 75%. Taken together, these data demonstrate that molecular profiles can be generated that are highly predictive of different levels of radiation exposure in mice and humans. CONCLUSIONS: We suggest that this approach, with additional refinement, could provide a method to assess the effects of various environmental inputs into biological phenotypes as well as providing a more practical application of a rapid molecular screening test for the diagnosis of radiation exposure.

Authors
Dressman, HK; Muramoto, GG; Chao, NJ; Meadows, S; Marshall, D; Ginsburg, GS; Nevins, JR; Chute, JP
MLA Citation
Dressman, Holly K., et al. “Gene expression signatures that predict radiation exposure in mice and humans..” Plos Med, vol. 4, no. 4, Apr. 2007. Pubmed, doi:10.1371/journal.pmed.0040106.
Website
http://hdl.handle.net/10161/11574
PMID
17407386
Source
pubmed
Published In
Plos Medicine
Volume
4
Issue
4
Publish Date
2007
Start Page
e106
DOI
10.1371/journal.pmed.0040106

Challenges in the phenotypic characterisation of patients in genetic studies of coronary artery disease.

Coronary artery disease and acute myocardial infarction are complex traits in which there has been recent research to identify the principal genes that engender susceptibility or provide protection. Although there has been exceptional progress in the technology, which now allows genotyping of hundreds of thousands of single-nucleotide polymorphisms in each individual, there remains a pattern of inconsistency in the studies performed to date, in part owing to the difficulties in defining cases and controls. In this paper, salient issues to facilitate research in this important field are reviewed.

Authors
Luo, AK; Jefferson, BK; Garcia, MJ; Ginsburg, GS; Topol, EJ
MLA Citation
Luo, Albert K., et al. “Challenges in the phenotypic characterisation of patients in genetic studies of coronary artery disease..” J Med Genet, vol. 44, no. 3, Mar. 2007, pp. 161–65. Pubmed, doi:10.1136/jmg.2006.045732.
PMID
17158593
Source
pubmed
Published In
Journal of Medical Genetics
Volume
44
Issue
3
Publish Date
2007
Start Page
161
End Page
165
DOI
10.1136/jmg.2006.045732

An integrated genomic-based approach to individualized treatment of patients with advanced-stage ovarian cancer.

PURPOSE: The purpose of this study was to develop an integrated genomic-based approach to personalized treatment of patients with advanced-stage ovarian cancer. We have used gene expression profiles to identify patients likely to be resistant to primary platinum-based chemotherapy and also to identify alternate targeted therapeutic options for patients with de novo platinum-resistant disease. PATIENTS AND METHODS: A gene expression model that predicts response to platinum-based therapy was developed using a training set of 83 advanced-stage serous ovarian cancers and tested on a 36-sample external validation set. In parallel, expression signatures that define the status of oncogenic signaling pathways were evaluated in 119 primary ovarian cancers and 12 ovarian cancer cell lines. In an effort to increase chemotherapy sensitivity, pathways shown to be activated in platinum-resistant cancers were subject to targeted therapy in ovarian cancer cell lines. RESULTS: Gene expression profiles identified patients with ovarian cancer likely to be resistant to primary platinum-based chemotherapy with greater than 80% accuracy. In patients with platinum-resistant disease, we identified expression signatures consistent with activation of Src and Rb/E2F pathways, components of which were successfully targeted to increase response in ovarian cancer cell lines. CONCLUSION: We have defined a strategy for treatment of patients with advanced-stage ovarian cancer that uses therapeutic stratification based on predictions of response to chemotherapy, coupled with prediction of oncogenic pathway deregulation, as a method to direct the use of targeted agents.

Authors
Dressman, HK; Berchuck, A; Chan, G; Zhai, J; Bild, A; Sayer, R; Cragun, J; Clarke, J; Whitaker, RS; Li, L; Gray, J; Marks, J; Ginsburg, GS; Potti, A; West, M; Nevins, JR; Lancaster, JM
MLA Citation
Dressman, Holly K., et al. “An integrated genomic-based approach to individualized treatment of patients with advanced-stage ovarian cancer..” J Clin Oncol, vol. 25, no. 5, 10 Feb. 2007, pp. 517–25. Pubmed, doi:10.1200/JCO.2006.06.3743.
PMID
17290060
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
25
Issue
5
Publish Date
2007
Start Page
517
End Page
525
DOI
10.1200/JCO.2006.06.3743

Highlights of the Year in JACC 2006.

Authors
DeMaria, AN; Ben-Yehuda, O; Feld, GK; Ginsburg, GS; Greenberg, BH; Lew, WYW; Lima, JAC; Maisel, AS; Narula, J; Sahn, DJ; Tsimikas, S
MLA Citation
DeMaria, Anthony N., et al. “Highlights of the Year in JACC 2006..” J Am Coll Cardiol, vol. 49, no. 4, Jan. 2007, pp. 509–27. Pubmed, doi:10.1016/j.jacc.2006.12.008.
PMID
17258099
Source
pubmed
Published In
J Am Coll Cardiol
Volume
49
Issue
4
Publish Date
2007
Start Page
509
End Page
527
DOI
10.1016/j.jacc.2006.12.008

Peripheral blood gene expression profiling for cardiovascular disease assessment.

Whole blood gene expression profiling has the potential to be informative about dynamic changes in disease states and to provide information on underlying disease mechanisms. Having demonstrated proof of concept in animal models, a number of studies have now tried to tackle the complexity of cardiovascular disease in human hosts to develop better diagnostic and prognostic indicators. These studies show that genomic signatures are capable of classifying patients with cardiovascular diseases into finer categories based on the molecular architecture of a patient's disease and more accurately predict the likelihood of a cardiovascular event than current techniques. To highlight the spectrum of potential applications of whole blood gene expression profiling approach in cardiovascular science, we have chosen to review the findings in a number of complex cardiovascular diseases such as atherosclerosis, hypertension and myocardial infarction as well as thromboembolism, aortic aneurysm, and heart transplant.

Authors
Aziz, H; Zaas, A; Ginsburg, GS
MLA Citation
Aziz, Hamza, et al. “Peripheral blood gene expression profiling for cardiovascular disease assessment..” Genomic Med, vol. 1, no. 3–4, 2007, pp. 105–12. Pubmed, doi:10.1007/s11568-008-9017-x.
PMID
18923935
Source
pubmed
Published In
Genomic Medicine
Volume
1
Issue
3-4
Publish Date
2007
Start Page
105
End Page
112
DOI
10.1007/s11568-008-9017-x

Erratum: Genomics and medicine at a crossroads in chernobyl (Science (62))

Authors
Ginsburg, GS
MLA Citation
Ginsburg, G. S. “Erratum: Genomics and medicine at a crossroads in chernobyl (Science (62)).” Science, vol. 314, no. 5806, Dec. 2006.
Source
scopus
Published In
Science (New York, N.Y.)
Volume
314
Issue
5806
Publish Date
2006
Start Page
1683

Genomic signatures to guide the use of chemotherapeutics.

Using in vitro drug sensitivity data coupled with Affymetrix microarray data, we developed gene expression signatures that predict sensitivity to individual chemotherapeutic drugs. Each signature was validated with response data from an independent set of cell line studies. We further show that many of these signatures can accurately predict clinical response in individuals treated with these drugs. Notably, signatures developed to predict response to individual agents, when combined, could also predict response to multidrug regimens. Finally, we integrated the chemotherapy response signatures with signatures of oncogenic pathway deregulation to identify new therapeutic strategies that make use of all available drugs. The development of gene expression profiles that can predict response to commonly used cytotoxic agents provides opportunities to better use these drugs, including using them in combination with existing targeted therapies.

Authors
Potti, A; Dressman, HK; Bild, A; Riedel, RF; Chan, G; Sayer, R; Cragun, J; Cottrill, H; Kelley, MJ; Petersen, R; Harpole, D; Marks, J; Berchuck, A; Ginsburg, GS; Febbo, P; Lancaster, J; Nevins, JR
MLA Citation
Potti, Anil, et al. “Genomic signatures to guide the use of chemotherapeutics..” Nat Med, vol. 12, no. 11, Nov. 2006, pp. 1294–300. Pubmed, doi:10.1038/nm1491.
PMID
17057710
Source
pubmed
Published In
Nature Medicine
Volume
12
Issue
11
Publish Date
2006
Start Page
1294
End Page
1300
DOI
10.1038/nm1491

High heritabilities of serum metabolites and differential metabolomic profiles in families burdened with early onset coronary artery disease

Authors
Shah, SH; Newgard, CB; Bain, J; Stevens, R; Wenner, B; Muehlbauer, M; Dowdy, E; Haynes, C; Ginsburg, GS; Hauser, ER; Kraus, WE
MLA Citation
Shah, Svati H., et al. “High heritabilities of serum metabolites and differential metabolomic profiles in families burdened with early onset coronary artery disease.” Circulation, vol. 114, no. 18, LIPPINCOTT WILLIAMS & WILKINS, 2006, pp. 677–677.
Source
wos
Published In
Circulation
Volume
114
Issue
18
Publish Date
2006
Start Page
677
End Page
677

Public health. Genomics and medicine at a crossroads in Chernobyl.

Authors
Ginsburg, GS; Angrist, M; Cook-Deegan, R
MLA Citation
Ginsburg, Geoffrey S., et al. “Public health. Genomics and medicine at a crossroads in Chernobyl..” Science, vol. 314, no. 5796, Oct. 2006, pp. 62–63. Pubmed, doi:10.1126/science.1130274.
PMID
17023637
Source
pubmed
Published In
Science
Volume
314
Issue
5796
Publish Date
2006
Start Page
62
End Page
63
DOI
10.1126/science.1130274

Novel--and "neu"--therapeutic possibilities for heart failure.

Authors
Freedman, NJ; Ginsburg, GS
MLA Citation
Freedman, Neil J., and Geoffrey S. Ginsburg. “Novel--and "neu"--therapeutic possibilities for heart failure..” J Am Coll Cardiol, vol. 48, no. 7, Oct. 2006, pp. 1448–50. Pubmed, doi:10.1016/j.jacc.2006.07.005.
PMID
17010809
Source
pubmed
Published In
J Am Coll Cardiol
Volume
48
Issue
7
Publish Date
2006
Start Page
1448
End Page
1450
DOI
10.1016/j.jacc.2006.07.005

Microarrays coming of age in cardiovascular medicine: standards, predictions, and biology.

Authors
Ginsburg, GS; Seo, D; Frazier, C
MLA Citation
Ginsburg, Geoffrey S., et al. “Microarrays coming of age in cardiovascular medicine: standards, predictions, and biology..” Journal of the American College of Cardiology, vol. 48, no. 8, Oct. 2006, pp. 1618–20. Epmc, doi:10.1016/j.jacc.2006.07.025.
PMID
17045897
Source
epmc
Published In
Journal of the American College of Cardiology
Volume
48
Issue
8
Publish Date
2006
Start Page
1618
End Page
1620
DOI
10.1016/j.jacc.2006.07.025

A framework to evaluate the economic impact of pharmacogenomics.

INTRODUCTION: Pharmacogenomics and personalized medicine promise to improve healthcare by increasing drug efficacy and minimizing side effects. There may also be substantial savings realized by eliminating costs associated with failed treatment. This paper describes a framework using health claims data for analyzing the potential value of pharmacogenomic testing in clinical practice. METHODS: We evaluated a model of alternate clinical strategies using asthma patients' data from a retrospective health claims database to determine a potential cost offset. We estimated the likely cost impact of using a hypothetical pharmacogenomic test to determine a preferred initial therapy. We compared the annualized per patient costs distributions under two clinical strategies: testing all patients for a nonresponse genotype prior to treating and testing none. RESULTS: In the Test All strategy, more patients fall into lower cost ranges of the distribution. In our base case (15% phenotype prevalence, 200 US dollars test, 74% overall first-line treatment efficacy and 60% second-line therapy efficacy) the cost savings per patient for a typical run of the testing strategy simulation ranged from 200 US dollars to 767 US dollars (5th and 95th percentile). Genetic variant prevalence, test cost and the cost of choosing the wrong treatment are key parameters in the economic viability of pharmacogenomics in clinical practice. CONCLUSIONS: A general tool for predicting the impact of pharmacogenomic-based diagnostic tests on healthcare costs in asthma patients suggests that upfront testing costs are likely offset by avoided nonresponse costs. We suggest that similar analyses for decision making could be undertaken using claims data in which a population can be stratified by response to a drug.

Authors
Stallings, SC; Huse, D; Finkelstein, SN; Crown, WH; Witt, WP; Maguire, J; Hiller, AJ; Sinskey, AJ; Ginsburg, GS
MLA Citation
Stallings, Sarah C., et al. “A framework to evaluate the economic impact of pharmacogenomics..” Pharmacogenomics, vol. 7, no. 6, Sept. 2006, pp. 853–62. Pubmed, doi:10.2217/14622416.7.6.853.
PMID
16981846
Source
pubmed
Published In
Pharmacogenomics
Volume
7
Issue
6
Publish Date
2006
Start Page
853
End Page
862
DOI
10.2217/14622416.7.6.853

A genomic strategy to refine prognosis in early-stage non-small-cell lung cancer.

BACKGROUND: Clinical trials have indicated a benefit of adjuvant chemotherapy for patients with stage IB, II, or IIIA--but not stage IA--non-small-cell lung cancer (NSCLC). This classification scheme is probably an imprecise predictor of the prognosis of an individual patient. Indeed, approximately 25 percent of patients with stage IA disease have a recurrence after surgery, suggesting the need to identify patients in this subgroup for more effective therapy. METHODS: We identified gene-expression profiles that predicted the risk of recurrence in a cohort of 89 patients with early-stage NSCLC (the lung metagene model). We evaluated the predictor in two independent groups of 25 patients from the American College of Surgeons Oncology Group (ACOSOG) Z0030 study and 84 patients from the Cancer and Leukemia Group B (CALGB) 9761 study. RESULTS: The lung metagene model predicted recurrence for individual patients significantly better than did clinical prognostic factors and was consistent across all early stages of NSCLC. Applied to the cohorts from the ACOSOG Z0030 trial and the CALGB 9761 trial, the lung metagene model had an overall predictive accuracy of 72 percent and 79 percent, respectively. The predictor also identified a subgroup of patients with stage IA disease who were at high risk for recurrence and who might be best treated by adjuvant chemotherapy. CONCLUSIONS: The lung metagene model provides a potential mechanism to refine the estimation of a patient's risk of disease recurrence and, in principle, to alter decisions regarding the use of adjuvant chemotherapy in early-stage NSCLC.

Authors
Potti, A; Mukherjee, S; Petersen, R; Dressman, HK; Bild, A; Koontz, J; Kratzke, R; Watson, MA; Kelley, M; Ginsburg, GS; West, M; Harpole, DH; Nevins, JR
MLA Citation
Potti, Anil, et al. “A genomic strategy to refine prognosis in early-stage non-small-cell lung cancer..” N Engl J Med, vol. 355, no. 6, Aug. 2006, pp. 570–80. Pubmed, doi:10.1056/NEJMoa060467.
PMID
16899777
Source
pubmed
Published In
The New England Journal of Medicine
Volume
355
Issue
6
Publish Date
2006
Start Page
570
End Page
580
DOI
10.1056/NEJMoa060467

Gene expression analysis of cardiovascular diseases: novel insights into biology and clinical applications.

Although the contribution of genetics to complex cardiovascular diseases such as atherosclerosis has been accepted for quite some time, full and detailed knowledge of the individual causative genes has been elusive. With the advent of genomic technologies and methods, the necessary tools are now available to begin pinpointing the genes that contribute to disease susceptibility and progression. One approach being applied extensively in candidate gene discovery is gene expression analysis of human and animal tissues using microarrays. The genes identified by these genomic studies provide valuable insight into disease biology and represent the initial steps toward the development of diagnostic tests and therapeutic strategies that will substantially improve human health. This paper highlights the progress that has been made in using gene expression analysis cardiovascular genomic research and the potential for applying these findings in clinical medicine.

Authors
Seo, D; Ginsburg, GS; Goldschmidt-Clermont, PJ
MLA Citation
Seo, David, et al. “Gene expression analysis of cardiovascular diseases: novel insights into biology and clinical applications..” J Am Coll Cardiol, vol. 48, no. 2, July 2006, pp. 227–35. Pubmed, doi:10.1016/j.jacc.2006.02.070.
PMID
16843168
Source
pubmed
Published In
J Am Coll Cardiol
Volume
48
Issue
2
Publish Date
2006
Start Page
227
End Page
235
DOI
10.1016/j.jacc.2006.02.070

Prescribing BiDil: is it black and white?

The approval of BiDil as an adjunct treatment in self-identified blacks with heart failure raises questions regarding the underlying etiology of drug response in this target population and the ability to accurately identify patients who are most likely to benefit. Preliminary data have indicated that differences in nitric oxide synthesis between groups may account for differences in response to BiDil and genetic studies have begun to elucidate the mechanism of these differences. Until more accurate selection criteria are developed to identify patients who are most likely to benefit, both clinicians and the general public will need to consider the unique issues raised by BiDil.

Authors
Haga, SB; Ginsburg, GS
MLA Citation
Haga, Susanne B., and Geoffrey S. Ginsburg. “Prescribing BiDil: is it black and white?.” J Am Coll Cardiol, vol. 48, no. 1, July 2006, pp. 12–14. Pubmed, doi:10.1016/j.jacc.2006.04.017.
PMID
16814642
Source
pubmed
Published In
J Am Coll Cardiol
Volume
48
Issue
1
Publish Date
2006
Start Page
12
End Page
14
DOI
10.1016/j.jacc.2006.04.017

Increased case-fatality rate associated with outbreaks of Neisseria meningitidis infection, compared with sporadic meningococcal disease, in the United States, 1994-2002.

BACKGROUND: Outbreaks of meningococcal disease are infrequent but important public health events. We characterize outbreak-associated cases in the United States and compare them with sporadic disease. METHODS: Outbreaks of meningococcal disease that occurred during the period of 1 July 1994 through 30 June 2002 were identified through state health departments, Centers for Disease Control and Prevention records, and a review of newspapers and the medical literature. Cases associated with outbreaks were compared with sporadic cases identified through population-based surveillance. RESULTS: We identified 69 outbreaks of Neisseria meningitidis infection (median, 9.5 outbreaks per year; range, 3-14 outbreaks per year), which involved 229 patients from 30 states. Forty-three (62%) of the outbreaks involved N. meningitidis serogroup C, 17 (25%) involved serogroup B, and 9 (13%) involved serogroup Y. Twenty-five outbreaks (36%) occurred in communities, and 44 (64%) were organization based, including 12 that occurred in colleges and universities, 19 that occurred in primary and secondary schools, and 8 that occurred in nursing homes. Vaccination campaigns (with the A/C/Y/W-135 meningococcal polysaccharide vaccine) were conducted for 31 outbreaks (28 involving serogroup C and 3 involving serogroup Y). After controlling for age, serogroup, and clinical presentation, outbreak-associated cases were associated with a higher case-fatality rate than were sporadic cases (21% vs. 11%; odds ratio, 3.3; 95% confidence interval, 2.0-5.5). CONCLUSIONS: Outbreaks remain an important but infrequent public health issue, representing <2% of all cases of meningococcal disease. However, given the increased case-fatality rate found among outbreak-related cases of N. meningitidis infection, additional investigation of factors that favor the transmission and virulence of outbreak-related strains is warranted.

Authors
Brooks, R; Woods, CW; Benjamin, DK; Rosenstein, NE
MLA Citation
Brooks, Richard, et al. “Increased case-fatality rate associated with outbreaks of Neisseria meningitidis infection, compared with sporadic meningococcal disease, in the United States, 1994-2002..” Clin Infect Dis, vol. 43, no. 1, July 2006, pp. 49–54. Pubmed, doi:10.1086/504804.
PMID
16758417
Source
pubmed
Published In
Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America
Volume
43
Issue
1
Publish Date
2006
Start Page
49
End Page
54
DOI
10.1086/504804

Genomic analyses: a neonatology perspective.

Authors
Cotten, CM; Ginsburg, GS; Goldberg, RN; Speer, MC
MLA Citation
Cotten, C. Michael, et al. “Genomic analyses: a neonatology perspective..” J Pediatr, vol. 148, no. 6, June 2006, pp. 720–26. Pubmed, doi:10.1016/j.jpeds.2006.01.006.
PMID
16769375
Source
pubmed
Published In
The Journal of Pediatrics
Volume
148
Issue
6
Publish Date
2006
Start Page
720
End Page
726
DOI
10.1016/j.jpeds.2006.01.006

Prosthetic valve endocarditis due to coagulase-negative staphylococci: findings from the International Collaboration on Endocarditis Merged Database.

Infective endocarditis due to coagulase-negative staphylococci is increasingly recognized as a difficult-to-treat disease associated with poor outcome. The aim of this report is to describe the characteristics and outcome of patients with prosthetic valve endocarditis (PVE) due to coagulase-negative staphylococci versus those of patients with PVE due to Staphylococcus aureus and viridans streptococci. Patients were identified through the International Collaboration on Endocarditis Merged Database. A total of 54 cases of coagulase-negative staphylococci PVE, 58 cases of S. aureus PVE, and 63 cases of viridans-streptococci-related PVE were available for analysis. There was no difference between the three groups with respect to the type of valve involved or the rate of embolization. However, heart failure was encountered more frequently with coagulase-negative staphylococci (54%) than with either S. aureus (33%; p=0.03) or viridans streptococci (32%; p=0.02). In addition, valvular abscesses complicated 39% of infections due to coagulase-negative staphylococci compared with 22% of those due to S. aureus (p=0.06) and 6% of those due to viridans streptococci (p<0.001). Mortality was highest in patients with S. aureus and coagulase-negative staphylococcal endocarditis (47 and 36%, respectively; p=0.22) and was considerably lower in patients with viridans streptococcal endocarditis (p=0.002 compared to patients with coagulase-negative staphylococcal endocarditis). The results of this analysis demonstrate the aggressive nature of coagulase-negative staphylococcal PVE and the substantially greater morbidity and mortality associated with this infection compared to PVE caused by other pathogens.

Authors
Lalani, T; Kanafani, ZA; Chu, VH; Moore, L; Corey, GR; Pappas, P; Woods, CW; Cabell, CH; Hoen, B; Selton-Suty, C; Doco-Lecompte, T; Chirouze, C; Raoult, D; Miro, JM; Mestres, CA; Olaison, L; Eykyn, S; Abrutyn, E; Fowler, VG; International Collaboration on Endocarditis Merged Database Study Group,
MLA Citation
Lalani, T., et al. “Prosthetic valve endocarditis due to coagulase-negative staphylococci: findings from the International Collaboration on Endocarditis Merged Database..” Eur J Clin Microbiol Infect Dis, vol. 25, no. 6, June 2006, pp. 365–68. Pubmed, doi:10.1007/s10096-006-0141-z.
PMID
16767483
Source
pubmed
Published In
European Journal of Clinical Microbiology & Infectious Diseases : Official Publication of the European Society of Clinical Microbiology
Volume
25
Issue
6
Publish Date
2006
Start Page
365
End Page
368
DOI
10.1007/s10096-006-0141-z

Use of sentinel laboratories by clinicians to evaluate potential bioterrorism and emerging infections.

With the persistent threat of emerging infectious diseases and bioterrorism, it has become increasingly important that clinicians be able to identify the diseases that might signal the occurrence of these unusual events. Essential to a thoughtful diagnostic approach is understanding when to initiate a public health investigation and how to appropriately use commonly performed microbiology procedures in the sentinel laboratory to evaluate potential pathogens. Although diagnostic test development is evolving rapidly, recognizing many of these pathogens continues to challenge the capabilities of most sentinel laboratories. Therefore, effective, ongoing communication and education among clinicians, infection control personnel, sentinel laboratorians, public health authorities, and Laboratory Response Network reference laboratorians is the key to preparedness.

Authors
Pien, BC; Saah, JR; Miller, SE; Woods, CW
MLA Citation
Pien, Brian C., et al. “Use of sentinel laboratories by clinicians to evaluate potential bioterrorism and emerging infections..” Clin Infect Dis, vol. 42, no. 9, May 2006, pp. 1311–24. Pubmed, doi:10.1086/503260.
PMID
16586392
Source
pubmed
Published In
Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America
Volume
42
Issue
9
Publish Date
2006
Start Page
1311
End Page
1324
DOI
10.1086/503260

Embracing the complexity of genomic data for personalized medicine.

Numerous recent studies have demonstrated the use of genomic data, particularly gene expression signatures, as clinical prognostic factors in cancer and other complex diseases. Such studies herald the future of genomic medicine and the opportunity for personalized prognosis in a variety of clinical contexts that utilizes genome-scale molecular information. The scale, complexity, and information content of high-throughput gene expression data, as one example of complex genomic information, is often under-appreciated as many analyses continue to focus on defining individual rather than multiplex biomarkers for patient stratification. Indeed, this complexity of genomic data is often--rather paradoxically--viewed as a barrier to its utility. To the contrary, the complexity and scale of global genomic data, as representing the many dimensions of biology, must be embraced for the development of more precise clinical prognostics. The need is for integrated analyses--approaches that embrace the complexity of genomic data, including multiple forms of genomic data, and aim to explore and understand multiple, interacting, and potentially conflicting predictors of risk, rather than continuing on the current and traditional path that oversimplifies and ignores the information content in the complexity. All forms of potentially relevant data should be examined, with particular emphasis on understanding the interactions, complementarities, and possible conflicts among gene expression, genetic, and clinical markers of risk.

Authors
West, M; Ginsburg, GS; Huang, AT; Nevins, JR
MLA Citation
West, Mike, et al. “Embracing the complexity of genomic data for personalized medicine..” Genome Res, vol. 16, no. 5, May 2006, pp. 559–66. Pubmed, doi:10.1101/gr.3851306.
PMID
16651662
Source
pubmed
Published In
Genome Research
Volume
16
Issue
5
Publish Date
2006
Start Page
559
End Page
566
DOI
10.1101/gr.3851306

The future may be closer than you think: a response from the Personalized Medicine Coalition to the Royal Society's report on personalized medicine.

A recent report from the British Royal Society on the prospects for personalized medicine provides a sobering assessment of the field and its prospects. The report contends that pharmacogenetics has little clinical relevance at the moment and will only progress with the completion of large, cumbersome clinical trials. The report goes on to note that the regulatory infrastructure, medical education initiatives and public deliberation necessary to make personalized medicine a reality are essentially nonexistent, at least so far. In our view, personalized medicine is much more than a hypothetical protocol designed to correlate genotypes with prescriptions. We argue that the development of personalized medicine is a broader phenomenon that is already being practiced in one form or another in many contexts. Both academic medicine and the pharmaceutical industry have a huge stake in bringing pharmacogenetic-based personalized medicine to fruition; we expect both entities to act as drivers of what will be a long-term, iterative process.

Authors
Ginsburg, GS; Angrist, M
MLA Citation
Ginsburg, Geoffrey S., and Misha Angrist. “The future may be closer than you think: a response from the Personalized Medicine Coalition to the Royal Society's report on personalized medicine..” Per Med, vol. 3, no. 2, May 2006, pp. 119–23. Pubmed, doi:10.2217/17410541.3.2.119.
PMID
29793285
Source
pubmed
Published In
Personalized Medicine
Volume
3
Issue
2
Publish Date
2006
Start Page
119
End Page
123
DOI
10.2217/17410541.3.2.119

Translating genomic biomarkers into clinically useful diagnostics.

The landmark sequencing of the human genome has ushered in a new field of large-scale research. Advances in understanding the molecular basis of disease have opened up new opportunities to develop genomics-based tools to diagnose, predict disease onset or recurrence, tailor treatment options, and assess treatment response. Although still in the early stages of research and development, genomic biomarker research has the capability of providing a comprehensive insight into pathophysiological processes as well as more precise predictors of outcome not previously attainable with traditional biomarkers. Before genomic biomarkers are incorporated into clinical practice, several issues will need to be addressed in order to generate the necessary levels of evidence to demonstrate analytical and clinical validity and utility. In addition, efforts will be needed to educate health professionals and the public about genomics-based tools, revise regulatory oversight mechanisms, and ensure privacy safeguards of the information generated from these new tests.

Authors
Ginsburg, GS; Haga, SB
MLA Citation
Ginsburg, Geoffrey S., and Susanne B. Haga. “Translating genomic biomarkers into clinically useful diagnostics..” Expert Rev Mol Diagn, vol. 6, no. 2, Mar. 2006, pp. 179–91. Pubmed, doi:10.1586/14737159.6.2.179.
PMID
16512778
Source
pubmed
Published In
Expert Rev Mol Diagn
Volume
6
Issue
2
Publish Date
2006
Start Page
179
End Page
191
DOI
10.1586/14737159.6.2.179

Highlights of the Year in JACC 2005.

Authors
Demaria, AN; Ben-Yehuda, O; Berman, D; Feld, GK; Ginsberg, J; Greenberg, BH; Lew, WYW; Sahn, D; Tsimikas, S
MLA Citation
Demaria, Anthony N., et al. “Highlights of the Year in JACC 2005..” J Am Coll Cardiol, vol. 47, no. 1, Jan. 2006, pp. 184–202. Pubmed, doi:10.1016/j.jacc.2005.11.020.
PMID
16386685
Source
pubmed
Published In
J Am Coll Cardiol
Volume
47
Issue
1
Publish Date
2006
Start Page
184
End Page
202
DOI
10.1016/j.jacc.2005.11.020

Optimizing biomarker development for clinical studies at the lead optimization stage of drug development

Authors
Ginsburg, GS; Lekstrom-Himes, J; Trepicchio, W
MLA Citation
Ginsburg, Geoffrey S., et al. “Optimizing biomarker development for clinical studies at the lead optimization stage of drug development.” Optimizing the Drug Like Properties of Leads in Drug Discovery, edited by R. T. Borchardt et al., vol. 4, SPRINGER, 2006, pp. 411-+.
Source
wos
Published In
Optimizing the Drug Like Properties of Leads in Drug Discovery
Volume
4
Publish Date
2006
Start Page
411
End Page
+

Implications of pharmacogenomics for drug development and clinical practice.

Pharmacogenomics is likely to be among the first clinical applications of the Human Genome Project and is certain to have an enormous impact on the clinical practice of medicine. Herein, we discuss the potential implications of pharmacogenomics on the drug development process, including drug safety, productivity, market segmentation, market expansion, differentiation, and personalized health care. We also review 3 challenges facing the translation of pharmacogenomics into clinical practice: dependence on information technology, limited health care financing, and the scientific uncertainty surrounding validation of specific applications of the technology. To our knowledge, there is currently no formal agenda to promote and cultivate innovation, to develop progressive information technology, or to obtain the financing that would be required to advance the use of pharmacogenomic technologies in patient care. Although the potential of these technologies is driving change in the development of clinical sciences, it remains to be seen which health care systems level needs will be addressed.

Authors
Ginsburg, GS; Konstance, RP; Allsbrook, JS; Schulman, KA
MLA Citation
Ginsburg, Geoffrey S., et al. “Implications of pharmacogenomics for drug development and clinical practice..” Arch Intern Med, vol. 165, no. 20, Nov. 2005, pp. 2331–36. Pubmed, doi:10.1001/archinte.165.20.2331.
PMID
16287761
Source
pubmed
Published In
Archives of Internal Medicine
Volume
165
Issue
20
Publish Date
2005
Start Page
2331
End Page
2336
DOI
10.1001/archinte.165.20.2331

Prospects for personalized cardiovascular medicine: the impact of genomics.

Sequencing of the human genome has ushered in prospects for individualizing cardiovascular health care. There is growing evidence that the practice of cardiovascular medicine might soon have a new toolbox to predict and treat disease more effectively. The Human Genome Project has spawned several important "omic" technologies that allow "whole genome" interrogation of sequence variation (re-sequencing, genotyping, comparative genome hybridization), transcription (expression profiling, tissue arrays), proteins (gas or liquid chromatography and tandem mass spectroscopy [MS]), and metabolites (MS or nuclear magnetic resonance profiling); deoxyribonucleic acid, ribonucleic acid, protein, and metabolic approaches all provide more exacting detail of cardiovascular disease mechanisms and, in some cases, are redefining its taxonomy. Pharmacogenomic approaches are emerging across broad classes of cardiovascular therapeutics to assist practitioners in making more precise decisions about which drugs to give to which patients to optimize the benefit-to-risk ratio. Molecular imaging is developing chemical and biological probes that can sense molecular pathway mechanisms that will allow us to monitor health and disease. Together, these tools will enable a paradigm shift from genetic medicine--on the basis of the study of individual inherited characteristics, most often single genes--to genomic medicine, which by its nature is comprehensive and focuses on the functions and interactions of multiple genes and gene products, among themselves and with their environment. The information gained from such analyses, in combination with clinical data, is now allowing us to assess individual risks and guide clinical management and decision-making, all of which form the basis for cardiovascular genomic medicine.

Authors
Ginsburg, GS; Donahue, MP; Newby, LK
MLA Citation
Ginsburg, Geoffrey S., et al. “Prospects for personalized cardiovascular medicine: the impact of genomics..” J Am Coll Cardiol, vol. 46, no. 9, Nov. 2005, pp. 1615–27. Pubmed, doi:10.1016/j.jacc.2005.06.075.
PMID
16256859
Source
pubmed
Published In
J Am Coll Cardiol
Volume
46
Issue
9
Publish Date
2005
Start Page
1615
End Page
1627
DOI
10.1016/j.jacc.2005.06.075

Genomic medicine: genetic variation and its impact on the future of health care.

Advances in genome technology and other fruits of the Human Genome Project are playing a growing role in the delivery of health care. With the development of new technologies and opportunities for large-scale analysis of the genome, transcriptome, proteome and metabolome, the genome sciences are poised to have a profound impact on clinical medicine. Cancer prognostics will be among the first major test cases for a genomic medicine paradigm, given that all cancer is caused by genomic instability, and microarrays allow assessment of patients' entire expressed genomes. Analysis of breast cancer patients' expression patterns can already be highly correlated with recurrence risks. By integrating clinical data with gene expression profiles, imaging, metabolomic profiles and proteomic data, the prospect for developing truly individualized care becomes ever more real. Notwithstanding these promises, daunting challenges remain for genomic medicine. Success will require planning robust prospective trials, analysing health care economic and outcome data, assuaging insurance and privacy concerns, developing health delivery models that are commercially viable and scaling up to meet the needs of the whole population.

Authors
Willard, HF; Angrist, M; Ginsburg, GS
MLA Citation
Willard, Huntington F., et al. “Genomic medicine: genetic variation and its impact on the future of health care..” Philos Trans R Soc Lond B Biol Sci, vol. 360, no. 1460, Aug. 2005, pp. 1543–50. Pubmed, doi:10.1098/rstb.2005.1683.
PMID
16096102
Source
pubmed
Published In
Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences
Volume
360
Issue
1460
Publish Date
2005
Start Page
1543
End Page
1550
DOI
10.1098/rstb.2005.1683

Genomic medicine: bringing biomarkers to clinical medicine.

An important by-product of sequencing the human genome has been the development of a novel 'toolbox' for biomarker discovery and development. Genomic medicine is an emerging discipline in the genome sciences that integrates these tools to interrogate genomic variation in well-defined populations in order to develop predictors of disease susceptibility, progression and drug response. Several important classes of biomarkers result from these analyses which, when translated to clinical medicine and drug development, will have an important impact on human health and disease. This review highlights both the opportunities and challenges in bringing biomarkers into clinical medicine.

Authors
Seo, D; Ginsburg, GS
MLA Citation
Seo, David, and Geoffrey S. Ginsburg. “Genomic medicine: bringing biomarkers to clinical medicine..” Curr Opin Chem Biol, vol. 9, no. 4, Aug. 2005, pp. 381–86. Pubmed, doi:10.1016/j.cbpa.2005.06.009.
PMID
16006183
Source
pubmed
Published In
Current Opinion in Chemical Biology
Volume
9
Issue
4
Publish Date
2005
Start Page
381
End Page
386
DOI
10.1016/j.cbpa.2005.06.009

Aspirin resistance and a single gene.

This study examined the association of single nucleotide polymorphisms in 4 candidate genes in a cohort of subjects with aspirin resistance. Aspirin resistance was significantly associated with genetic variation in the platelet surface adenosine 5-diphosphate receptor gene P2Y1.

Authors
Jefferson, BK; Foster, JH; McCarthy, JJ; Ginsburg, G; Parker, A; Kottke-Marchant, K; Topol, EJ
MLA Citation
Jefferson, Brian K., et al. “Aspirin resistance and a single gene..” Am J Cardiol, vol. 95, no. 6, Mar. 2005, pp. 805–08. Pubmed, doi:10.1016/j.amjcard.2004.11.045.
PMID
15757620
Source
pubmed
Published In
The American Journal of Cardiology
Volume
95
Issue
6
Publish Date
2005
Start Page
805
End Page
808
DOI
10.1016/j.amjcard.2004.11.045

Controlled clinical comparison of plastic versus glass bottles of BacT/ALERT PF medium for culturing blood from children.

The plastic pediatric BacT/ALERT (bioMérieux, Durham, N.C.) PF (PPF) is a new nonvented aerobic culture medium in a clear plastic bottle designed to prevent breakage. We compared the performance of the new PPF bottle to that of the present glass BacT/ALERT PF bottle for the recovery of microorganisms as well as for the time to detection of growth in samples of blood obtained for culture from children. We found that the PPF and PF bottles were comparable for recovery of microorganisms and that the safety advantage of plastic bottles can be achieved without compromising performance.

Authors
Petti, CA; Mirrett, S; Woods, CW; Reller, LB
MLA Citation
Petti, Cathy A., et al. “Controlled clinical comparison of plastic versus glass bottles of BacT/ALERT PF medium for culturing blood from children..” J Clin Microbiol, vol. 43, no. 1, Jan. 2005, pp. 445–47. Pubmed, doi:10.1128/JCM.43.1.445-447.2005.
PMID
15635011
Source
pubmed
Published In
Journal of Clinical Microbiology
Volume
43
Issue
1
Publish Date
2005
Start Page
445
End Page
447
DOI
10.1128/JCM.43.1.445-447.2005

The Personalized Medicine Coalition: goals and strategies.

The concept of personalized medicine--that medical care can be tailored to the genomic and molecular profile of the individual--has repercussions that extend far beyond the technology that makes it possible. The adoption of personalized medicine will require changes in healthcare infrastructure, diagnostics and therapeutics business models, reimbursement policy from government and private payers, and a different approach to regulatory oversight. Personalized medicine will shift medical practices upstream from the reactive treatment of disease, to proactive healthcare management including screening, early treatment, and prevention, and will alter the roles of both physician and patient. It will create a greater reliance on electronic medical records and decision support systems in an industry that has a long history of resistance to information technology. Personalized medicine requires a systems approach to implementation. But in a healthcare economy that is highly decentralized and market driven, it is incumbent upon the stakeholders themselves to advocate for a consistent set of policies and legislation that pave the way for the adoption of personalized medicine. To address this need, the Personalized Medicine Coalition (PMC) was formed as a nonprofit umbrella organization of pharmaceutical, biotechnology, diagnostic, and information technology companies, healthcare providers and payers, patient advocacy groups, industry policy organizations, major academic institutions, and government agencies. The PMC provides a structure for achieving consensus positions among these stakeholders on crucial public policy issues, a role which will be vital to translating personalized medicine into widespread clinical practice. In this article, we outline the goals of the PMC, and the strategies it will take to foster communication, debate, and consensus on issues such as genetic discrimination, the reimbursement structures for pharmacogenomic drugs and diagnostics, regulation, physician training and medical school curricula, and public education.

Authors
Abrahams, E; Ginsburg, GS; Silver, M
MLA Citation
Abrahams, Edward, et al. “The Personalized Medicine Coalition: goals and strategies..” Am J Pharmacogenomics, vol. 5, no. 6, 2005, pp. 345–55.
PMID
16336000
Source
pubmed
Published In
American Journal of Pharmacogenomics : Genomics Related Research in Drug Development and Clinical Practice
Volume
5
Issue
6
Publish Date
2005
Start Page
345
End Page
355

Targeted therapies for cancer 2004.

The regulatory agency approvals in the United States and Europe of imatinib mesylate (Gleevec) for patients with bcr/abl-positive chronic myelogenous leukemia, cetuximab (Erbitux) for patients with epidermal growth factor receptor overexpressing metastatic colorectal cancer, the antiangiogenesis agent bevacizumab (Avastin), and the proteasome inhibitor bortezomib (Velcade)--and the considerable public interest in new anticancer drugs that take advantage of specific genetic defects that render the malignant cells more likely to respond to specific treatment--are driving a new era of integrated diagnostics and therapeutics. The recent discovery of a drug response predicting activating mutation in the epidermal growth factor receptor gene for patients with non-small cell lung cancer treated with gefitinib (Iressa) has intensified this interest. In this review, the history of targeted anticancer therapies is highlighted, with focus on the development of molecular diagnostics for hematologic malignancies and the emergence of trastuzumab (Herceptin), an antibody-based targeted therapy for HER-2/neu overexpressing metastatic breast cancer: The potential of pharmacogenomic strategies and the use of high-density genomic microarrays to classify and select therapy for cancer are briefly considered. This review also considers the widely held view that, in the next 5 to 10 years, the clinical application of molecular diagnostics will further revolutionize the drug discovery and development process; customize the selection, dosing, route of administration of existing and new therapeutic agents; and truly personalize medical care for cancer patients.

Authors
Ross, JS; Schenkein, DP; Pietrusko, R; Rolfe, M; Linette, GP; Stec, J; Stagliano, NE; Ginsburg, GS; Symmans, WF; Pusztai, L; Hortobagyi, GN
MLA Citation
Ross, Jeffrey S., et al. “Targeted therapies for cancer 2004..” Am J Clin Pathol, vol. 122, no. 4, Oct. 2004, pp. 598–609. Pubmed, doi:10.1309/5CWP-U41A-FR1V-YM3F.
PMID
15487459
Source
pubmed
Published In
American Journal of Clinical Pathology
Volume
122
Issue
4
Publish Date
2004
Start Page
598
End Page
609
DOI
10.1309/5CWP-U41A-FR1V-YM3F

Controlled clinical comparison of the BacT/ALERT FN and the standard anaerobic SN blood culture medium.

To determine the optimal anaerobic companion bottle to pair with the BacT/ALERT (bioMerieux, Durham, N.C.) nonvented aerobic FA (FA) medium for recovery of pathogenic microorganisms from adult patients with bacteremia and fungemia, we compared the BacT/ALERT FN (FN) anaerobic bottle with the standard BacT/ALERT SN (SN) anaerobic bottle. Each bottle, FA, FN, and SN, was filled with 8 to 12 ml of blood. Of 11,498 blood culture sets received in the clinical microbiology laboratories at two university medical centers, 7,945 sets had all three bottles filled adequately and 8,569 had both anaerobic bottles filled adequately. Of 686 clinically important (based on previously published criteria) isolates detected in one or both adequately filled anaerobic bottles, more staphylococci (P < 0.001), including Staphylococcus aureus (P < 0.001); members of the family Enterobacteriaceae (P < 0.001); and all microorganisms combined (P < 0.001) were detected in FN bottles. In contrast, more Pseudomonas aeruginosa isolates (P < 0.01) and yeasts (P < 0.001) were detected in SN bottles. More Bacteroides fragilis group bacteremias were detected only in the FN (six) than in the SN (one) anaerobic bottle (P = not significant). Overall, the mean time to detection was shorter with FN (16.8 h) than with SN (18.2 h). This difference in time to detection was greatest for the B. fragilis group: FN, 28 h, versus SN, 60.0 h. Many of the facultative microorganisms recovered in either FN or SN were also found in the companion FA. When microorganisms found in the companion FA bottle were omitted from the analysis, significantly more staphylococci (P < 0.001), including S. aureus (P < 0.001), and Enterobacteriaceae (P < 0.005) still were detected in FN bottles, whereas there were no significant differences for P. aeruginosa and yeasts, which were found as expected in FA bottles. We conclude that the companion anaerobic FN bottle detects more microorganisms than does the anaerobic SN bottle when used in conjunction with the nonvented aerobic FA bottle in the BacT/ALERT blood culture system.

Authors
Mirrett, S; Petti, CA; Woods, CW; Magadia, R; Weinstein, MP; Reller, LB
MLA Citation
Mirrett, S., et al. “Controlled clinical comparison of the BacT/ALERT FN and the standard anaerobic SN blood culture medium..” J Clin Microbiol, vol. 42, no. 10, Oct. 2004, pp. 4581–85. Pubmed, doi:10.1128/JCM.42.10.4581-4585.2004.
PMID
15472312
Source
pubmed
Published In
Journal of Clinical Microbiology
Volume
42
Issue
10
Publish Date
2004
Start Page
4581
End Page
4585
DOI
10.1128/JCM.42.10.4581-4585.2004

Adverse events in humans associated with accidental exposure to the livestock brucellosis vaccine RB51.

Brucella abortus strain RB51 vaccine, is an attenuated live bacterial vaccine that was licensed conditionally by the Center for Veterinary Biologics, Veterinary Services, Animal and Plant Health Inspection Service, USDA, on 23 February 1996, for vaccination of cattle in the United States. Accidental human inoculations can occur during vaccination of cattle, and previous live Brucella vaccines designed for cattle have been known to cause brucellosis in humans. The Centers for Disease Control and Prevention (CDC) established passive surveillance for accidental inoculation with the RB51 vaccine in the United States to determine if this veterinary vaccine is associated with human disease, to describe the circumstances of accidental inoculation, to evaluate the potential efficacy of post-exposure chemoprophylaxis, and to develop recommendations for post-exposure management following exposure to RB51. Reports were received from 26 individuals. Accidental exposure to RB51 occurred by needle stick injury in 21 people (81%), conjunctival spray exposure in four (15%), and spray exposure of an open wound in one (4%) individual. At least one systemic symptom was reported in 19 (73%) people, including three (12%) who reported persistent local reactions with systemic involvement. One case required surgery, and B. abortus strain RB51 was isolated from the wound of that individual. Seven cases reported no adverse event associated with accidental exposure. Nine cases reported previous exposure to Brucella vaccines, including one case who also reported a previous diagnosis of brucellosis following exposure to S19 vaccine. Accidental needle stick injuries and conjunctival or open wound exposures of humans with the RB51 vaccine are associated with both local and systemic adverse events in the United States that are consistent with brucellosis; however, it remains undetermined if strain RB51 vaccine can cause systemic brucellosis in humans. Early culture attempts on those exposed and developing disease in the future and serologic diagnostic assays for anti-RB-51 antibodies are needed to define if these adverse events are due to RB51 and to define appropriate prophylaxis regimens.

Authors
Ashford, DA; di Pietra, J; Lingappa, J; Woods, C; Noll, H; Neville, B; Weyant, R; Bragg, SL; Spiegel, RA; Tappero, J; Perkins, BA
MLA Citation
Ashford, David A., et al. “Adverse events in humans associated with accidental exposure to the livestock brucellosis vaccine RB51..” Vaccine, vol. 22, no. 25–26, Sept. 2004, pp. 3435–39. Pubmed, doi:10.1016/j.vaccine.2004.02.041.
PMID
15308369
Source
pubmed
Published In
Vaccine
Volume
22
Issue
25-26
Publish Date
2004
Start Page
3435
End Page
3439
DOI
10.1016/j.vaccine.2004.02.041

Antibacterial susceptibility testing in the clinical laboratory.

This article familiarizes the clinician with the principles of bacterial susceptibility testing and reporting to facilitate communication with the clinical microbiology laboratory. The emergence of resistance in nearly all commonly isolated bacterial organisms has highlighted the need for ongoing dialogue between the laboratory and those who use its services.

Authors
Joyce, M; Woods, CW
MLA Citation
Joyce, Maria, and Christopher W. Woods. “Antibacterial susceptibility testing in the clinical laboratory..” Infect Dis Clin North Am, vol. 18, no. 3, Sept. 2004, pp. 401–vii. Pubmed, doi:10.1016/j.idc.2004.04.001.
PMID
15308270
Source
pubmed
Published In
Infectious Disease Clinics of North America
Volume
18
Issue
3
Publish Date
2004
Start Page
401
End Page
vii
DOI
10.1016/j.idc.2004.04.001

Non-O1 Vibrio cholerae septicemia: case report, discussion of literature, and relevance to bioterrorism.

Non-O1 Vibrio cholerae (NOVC) is a rare cause of septicemia in the United States. We report a case of NOVC septicemia and discuss the literature pertaining to this organism. NOVC takes on new significance given that it can be confused with toxigenic V. cholerae, a Centers for Disease Control and Prevention category B bioterrorism agent.

Authors
Anderson, AML; Varkey, JB; Petti, CA; Liddle, RA; Frothingham, R; Woods, CW
MLA Citation
Anderson, Albert M. L., et al. “Non-O1 Vibrio cholerae septicemia: case report, discussion of literature, and relevance to bioterrorism..” Diagn Microbiol Infect Dis, vol. 49, no. 4, Aug. 2004, pp. 295–97. Pubmed, doi:10.1016/j.diagmicrobio.2004.04.016.
PMID
15313536
Source
pubmed
Published In
Diagnostic Microbiology and Infectious Disease
Volume
49
Issue
4
Publish Date
2004
Start Page
295
End Page
297
DOI
10.1016/j.diagmicrobio.2004.04.016

Risk factors for human anthrax among contacts of anthrax-infected livestock in Kazakhstan.

A retrospective cohort analysis was conducted in Kazakhstan to define modifiable risk factors during seven outbreaks of human anthrax. Fifty-three cases and 255 non-ill persons with an epidemiologic link to an infected animal were enrolled. Cases were 58% male and had a median age of 35 years (range = 5-71). Nearly all cases had cutaneous disease (96%). Two patients (4%) were diagnosed with gastrointestinal disease. Although all cases had some contact with an infected animal other than consumption, in multivariable analysis the act of butchering an animal (relative risk [RR] = 3.6, 95% confidence interval [CI] = 1.5-9.6) and the presence of visible cuts on the hands were associated with anthrax (RR = 3.0, 95% CI = 0.9-9.6). Contact with infected livestock, in particular butchering, is associated with developing anthrax. The risk may be exacerbated by the presence of cuts on the hands at the time of contact with the animal or animal products.

Authors
Woods, CW; Ospanov, K; Myrzabekov, A; Favorov, M; Plikaytis, B; Ashford, DA
MLA Citation
Woods, Christopher W., et al. “Risk factors for human anthrax among contacts of anthrax-infected livestock in Kazakhstan..” Am J Trop Med Hyg, vol. 71, no. 1, July 2004, pp. 48–52.
PMID
15238688
Source
pubmed
Published In
The American Journal of Tropical Medicine and Hygiene
Volume
71
Issue
1
Publish Date
2004
Start Page
48
End Page
52

The etiology of febrile illness in adults presenting to Patan hospital in Kathmandu, Nepal.

In Nepal, many infections remain poorly characterized, partly due to limited diagnostic facilities. We studied consecutive febrile adults presenting to a general hospital in Kathmandu, Nepal. Of the 876 patients enrolled, enteric fever and pneumonia were the most common clinical diagnoses. Putative pathogens were identified in 323 (37%) patients, the most common being Salmonella enterica serotype Typhi and S. enterica serotype Paratyphi A (117), Rickettsia typhi (97), Streptococcus pneumoniae (53), Leptospira spp. (36), and Orientia tsutsugamushi (28). Approximately half of the Salmonella isolates were resistant to nalidixic acid. No clinical predictors were identified to reliably distinguish between the different infections. These findings confirm the heavy burden of enteric fever and pneumonia in Kathmandu, and highlight the importance of murine typhus, scrub typhus, and leptospirosis. Given the lack of reliable clinical predictors, the development of cheap and accurate diagnostic tests are likely to be of great clinical utility in this setting.

Authors
Murdoch, DR; Woods, CW; Zimmerman, MD; Dull, PM; Belbase, RH; Keenan, AJ; Scott, RM; Basnyat, B; Archibald, LK; Reller, LB
MLA Citation
Murdoch, David R., et al. “The etiology of febrile illness in adults presenting to Patan hospital in Kathmandu, Nepal..” Am J Trop Med Hyg, vol. 70, no. 6, June 2004, pp. 670–75.
PMID
15211012
Source
pubmed
Published In
The American Journal of Tropical Medicine and Hygiene
Volume
70
Issue
6
Publish Date
2004
Start Page
670
End Page
675

Virulence associated with outbreak-related strains of Burkholderia cepacia complex among a cohort of patients with bacteremia.

The Burkholderia cepacia complex includes 9 genomovars. The relative virulence of each is unknown. Host and pathogen features associated with mortality were evaluated among patients with B. cepacia complex bacteremia. Cases were ascertained through review of blood culture results for the period of May 1996 through May 2002. Isolates were identified to species level with 16S rDNA and recA-based species-specific polymerase chain reaction analyses and recA restriction fragment-length polymorphism. Strain typing was performed with pulsed-field gel electrophoresis. Fifty-three patients with B. cepacia complex bacteremia were identified; only 9 (17%) had cystic fibrosis. Twenty-five patients (47%) died within 14 days of bacteremia. After controlling for comorbid conditions and therapeutic interventions, 2 outbreak-related strains of Burkholderia cenocepacia (genomovar III) were associated with 14-day mortality (odds ratio, 5.5; 95% confidence interval, 1.20-25.02). B. cenocepacia is an emerging nosocomial pathogen. Certain strains are associated with an enhanced capacity for interpatient spread and poor outcome.

Authors
Woods, CW; Bressler, AM; LiPuma, JJ; Alexander, BD; Clements, DA; Weber, DJ; Moore, CM; Reller, LB; Kaye, KS
MLA Citation
Woods, Christopher W., et al. “Virulence associated with outbreak-related strains of Burkholderia cepacia complex among a cohort of patients with bacteremia..” Clin Infect Dis, vol. 38, no. 9, May 2004, pp. 1243–50. Pubmed, doi:10.1086/383313.
PMID
15127335
Source
pubmed
Published In
Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America
Volume
38
Issue
9
Publish Date
2004
Start Page
1243
End Page
1250
DOI
10.1086/383313

Endocarditis caused by Staphylococcus aureus with reduced susceptibility to vancomycin.

Clinical management of infective endocarditis (IE) is expected to become more difficult with the emergence of Staphylococcus aureus with reduced susceptibility to vancomycin (SARV) in the United States and worldwide. We report the strain characterization and treatment of a patient with SARV IE.

Authors
Woods, CW; Cheng, AC; Fowler, VG; Moorefield, M; Frederick, J; Sakoulas, G; Meka, VG; Tenover, FC; Zwadyk, P; Wilson, KH
MLA Citation
Woods, Christopher W., et al. “Endocarditis caused by Staphylococcus aureus with reduced susceptibility to vancomycin..” Clin Infect Dis, vol. 38, no. 8, Apr. 2004, pp. 1188–91. Pubmed, doi:10.1086/383027.
PMID
15095227
Source
pubmed
Published In
Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America
Volume
38
Issue
8
Publish Date
2004
Start Page
1188
End Page
1191
DOI
10.1086/383027

Sacral tuberculosis: a case report and review of the literature.

BACKGROUND: We present a patient with a heterogeneously enhancing lesion within the body of the sacrum and the sacral canal. Sacral tuberculosis (TB) was suspected because of a history of familial exposure. Few cases isolated to the sacrum have been reported in the literature. The characteristic histopathologic and magnetic resonance imaging (MRI) findings are also presented. CASE DESCRIPTION: A 31-year-old African-American male presented with an 8-month history of lower back pain radiating into his legs as well as numbness and weakness of the right foot. His history revealed PPD conversion following an exposure to active pulmonary TB 3 years prior for which he received 6 months of isoniazid prophylaxis. An MRI scan revealed a large heterogeneously enhancing lesion involving the sacrum with extension into the sacral canal. The patient underwent computed tomography (CT)- guided needle biopsy of the sacral lesion. Cytopathologic examination revealed caseating granulomas. Acid-fast bacilli cultures were positive for Mycobacterium tuberculosis. He was placed on a 6-month course of isoniazid, rifampin, pyrazinamide, and ethambutol. At 3-month follow-up, his examination and symptoms had improved. CONCLUSIONS: Sacral TB is an extremely rare cause of lower back pain with radiation into the lower extremities. TB should always be considered in the differential diagnosis of isolated sacral masses, especially in light of today's increasing multidrug resistance and immunosuppressed population.

Authors
Wellons, JC; Zomorodi, AR; Villaviciencio, AT; Woods, CW; Lawson, WT; Eastwood, JD
MLA Citation
Wellons, John C., et al. “Sacral tuberculosis: a case report and review of the literature..” Surg Neurol, vol. 61, no. 2, Feb. 2004, pp. 136–39.
PMID
14751619
Source
pubmed
Published In
Surgical Neurology
Volume
61
Issue
2
Publish Date
2004
Start Page
136
End Page
139

Sp and GATA factors are critical for Apolipoprotein AI downstream enhancer activity in human HepG2 cells.

The factors that bind to the hepatic-specific human apolipoprotein AI (apoAI) 48-bp downstream enhancer (DSE) were identified and characterized by electrophoretic mobility shift assays. A significant homology was shown between the histone 4 (H4) promoters and the hepatic-specific human apoAI DSE at Sp1 and H4TF2 binding sites. Human HepG2 nuclear extracts were used to form four specific complexes with the DSE (referred to as apoAI DSE-1, -2, -3, and -4). The apoAI DSE-1 and -2 complexes showed similar binding specificity to the Sp/H4TF1 consensus site within the apoAI DSE. The apoAI DSE-1 complex was predominantly recognized by anti-Sp1 and Sp3 sera in gel shift assays, indicating that the DSE was recognized by multiple Sp family members. Nuclear extracts that were prepared from retinoic acid treated HepG2 cells showed increased levels of Sp factors in gel shift and Western blot assays. The apoAI DSE-2 complex was identified as H4TF1 and formed in the absence of magnesium chloride. The apoAI DSE-3 complex bound to a consensus GATA element within the DSE that was recognized by recombinant human GATA-6 as well. The apoAI DSE-3 complex was completely disrupted by a GATA-4 antibody in EMSA. GATA-4 and -6 were detected in nuclear extracts prepared from retinoic acid treated HepG2 cells using Western blot assays. The highest apoAI DSE-3 levels were observed with retinoic acid treated HepG2 cell nuclear extracts in EMSA. ApoAI DSE-4 is a multi-factor complex that includes an Sp/H4TF1 factor and either H4TF2 or apoAI DSE-3. Because apoAI DSE mutations revealed transcription defects in transient transfection assays, we conclude that the entire DSE sequence is required for full apoAI transcriptional activity in HepG2 cells.

Authors
Ivanov, GS; Kater, JM; Jha, SH; Stutius, EA; Sabharwal, R; Tricarico, MD; Ginsburg, GS; Ozer, JS
MLA Citation
Ivanov, Gleb S., et al. “Sp and GATA factors are critical for Apolipoprotein AI downstream enhancer activity in human HepG2 cells..” Gene, vol. 323, Dec. 2003, pp. 31–42.
PMID
14659877
Source
pubmed
Published In
Gene
Volume
323
Publish Date
2003
Start Page
31
End Page
42

Clinical identifiers of complicated Staphylococcus aureus bacteremia.

BACKGROUND: Complications of Staphylococcus aureus bacteremia (SAB) are often difficult to identify. The ability to accurately predict the likelihood of these complications would impact patient management. This investigation sought to define readily available clinical characteristics that could help identify patients at risk for complicated SAB. METHODS: A prospective, observational cohort study was conducted from September 1994 through December 1999. Patients were followed up for 12 weeks after the initial positive blood culture result. The primary end point was complicated SAB (attributable mortality, complicated infection, embolic stroke, or recurrent S aureus infection during the 12-week follow-up period). The predictive model was validated using bootstrap resampling. RESULTS: Complicated SAB was present in 43% of 724 consecutive adult hospitalized patients identified during the study period. The full predictive model had a high discriminative ability (bootstrap-corrected c index, 0.78). The strongest predictor of complicated SAB was a positive follow-up blood culture result at 48 to 96 hours. A scoring system based on the presence or absence of 4 risk factors (community acquisition, skin examination findings suggesting acute systemic infection, persistent fever at 72 hours, and positive follow-up blood culture results at 48-96 hours) accurately identified complicated SAB (bootstrap-corrected c index, 0.76). CONCLUSION: Readily available clinical variables can help identify patients at risk for complicated SAB.

Authors
Fowler, VG; Olsen, MK; Corey, GR; Woods, CW; Cabell, CH; Reller, LB; Cheng, AC; Dudley, T; Oddone, EZ
MLA Citation
Fowler, Vance G., et al. “Clinical identifiers of complicated Staphylococcus aureus bacteremia..” Arch Intern Med, vol. 163, no. 17, Sept. 2003, pp. 2066–72. Pubmed, doi:10.1001/archinte.163.17.2066.
PMID
14504120
Source
pubmed
Published In
Archives of Internal Medicine
Volume
163
Issue
17
Publish Date
2003
Start Page
2066
End Page
2072
DOI
10.1001/archinte.163.17.2066

Controlled clinical comparison of BacT/ALERT standard aerobic medium with BACTEC standard aerobic medium for culturing blood.

Standard aerobic media are widely used for culturing blood with the BacT/ALERT (BioMérieux, Inc., Durham, N.C.) (BM) and BACTEC 9240 (BD Diagnostic Systems, Sparks, Md.) (BD) automated continuously monitoring instrument systems. Although similarly composed of soybean-casein digest broths, the formulations of the standard aerobic media available for these instruments differ from each other in supplements and in sodium polyanetholesulfonate concentration. Therefore, we compared the standard aerobic media available for these systems at two university hospitals. Blood samples from adult patients with suspected bloodstream infection were inoculated at the bedside into nonvented BM and BD standard aerobic blood culture bottles and incubated in their respective instruments. The laboratories received 6,743 pairs of bottles that were each filled with 8 to 12 ml of blood. A total of 523 isolates representing true infections were recovered from 257 patients; of these isolates, 348 were recovered from both the BD and the BM bottles, 108 were recovered from the BM bottles only, and 67 were recovered from the BD bottles only (P < 0.005). More staphylococci (P < 0.05), especially coagulase-negative staphylococci (P < 0.05), and yeasts (P < 0.01) were recovered from BM bottles than from BD bottles. Of 291 unimicrobial episodes of bloodstream infection, 220 were detected with both bottles, 41 were detected with the BM bottles only, and 30 were detected with the BD bottles only (difference not significant). Among 335 cultures that were positive in both bottles within the first 72 h of incubation, the median times to detection were 14 h for BM bottles and 13 h for BD bottles. Rates for false-positive results were 0.5% for BM bottles and 0.1% for BD bottles. One BM bottle and seven BD bottles yielded false-negative results. We conclude that the BM medium provides improved recovery of microorganisms, especially staphylococci and yeasts, compared with that provided by the BD medium.

Authors
Mirrett, S; Reller, LB; Petti, CA; Woods, CW; Vazirani, B; Sivadas, R; Weinstein, MP
MLA Citation
Mirrett, Stanley, et al. “Controlled clinical comparison of BacT/ALERT standard aerobic medium with BACTEC standard aerobic medium for culturing blood..” J Clin Microbiol, vol. 41, no. 6, June 2003, pp. 2391–94. Pubmed, doi:10.1128/jcm.41.6.2391-2394.2003.
PMID
12791854
Source
pubmed
Published In
Journal of Clinical Microbiology
Volume
41
Issue
6
Publish Date
2003
Start Page
2391
End Page
2394
DOI
10.1128/jcm.41.6.2391-2394.2003

Evaluation of four commercially available rapid serologic tests for diagnosis of leptospirosis.

Four rapid tests for the serologic diagnosis of leptospirosis were evaluated, and the performance of each was compared with that of the current standard, the microscopic agglutination test (MAT). The four rapid tests were a microplate immunoglobulin M (IgM)-enzyme-linked immunosorbent assay (ELISA), an indirect hemagglutination assay (IHA), an IgM dipstick assay (LDS), and an IgM dot-ELISA dipstick test (DST). A panel of 276 sera from 133 cases of leptospirosis from four different geographic locations was tested as well as 642 sera from normal individuals or individuals with other infectious or autoimmune diseases. Acute-phase sera from cases (n = 148) were collected or=15 days after onset (median = 29.1). By a traditional method (two-by-two contingency table), the sensitivities for detection of leptospirosis cases were 93.2% by LDS, 92.5% by DST, 86.5% by ELISA, and 79.0% by IHA. Specificity was 98.8% by DST, 97% by ELISA and MAT, 95.8% by IHA, and 89.6% by LDS. With a latent class analysis (LCA) model that included all the rapid tests and the clinical case definition, sensitivity was 95.5% by DST, 94.5% by LDS, 89.9% by ELISA, and 81.1% by IHA. The sensitivity and specificity estimated by the traditional methods were quite close to the LCA estimates. However, LCA allowed estimation of the sensitivity of the MAT (98.2%), which traditional methods do not allow. For acute-phase sera, sensitivity was 52.7% by LDS, 50.0% by DST, 48.7% by MAT and ELISA, and 38.5% by IHA. The sensitivity for convalescent-phase sera was 93.8% by MAT, 84.4% by DST, 83.6% by LDS, 75.0% by ELISA, and 67.2% by IHA. A good overall correlation with the MAT was obtained for each of the assays, with the highest concordance being with the DST (kappa value, 0.85; 95% confidence interval [CI], 0.8 to 0.90). The best correlation was between ELISA and DST (kappa value, 0.86; 95% CI, 0.81 to 0.91). False-positive LDS results were frequent (>or=20%) in sera from individuals with Epstein-Barr virus, human immunodeficiency virus, and periodontal disease and from healthy volunteers. The ease of use and significantly high sensitivity and specificity of DST and ELISA make these good choices for diagnostic testing.

Authors
Bajani, MD; Ashford, DA; Bragg, SL; Woods, CW; Aye, T; Spiegel, RA; Plikaytis, BD; Perkins, BA; Phelan, M; Levett, PN; Weyant, RS
MLA Citation
Bajani, Mary D., et al. “Evaluation of four commercially available rapid serologic tests for diagnosis of leptospirosis..” J Clin Microbiol, vol. 41, no. 2, Feb. 2003, pp. 803–09. Pubmed, doi:10.1128/jcm.41.2.803-809.2003.
PMID
12574287
Source
pubmed
Published In
Journal of Clinical Microbiology
Volume
41
Issue
2
Publish Date
2003
Start Page
803
End Page
809
DOI
10.1128/jcm.41.2.803-809.2003

The integration of molecular diagnostics with therapeutics. Implications for drug development and pathology practice.

It is widely anticipated that during the next 5 years the molecular diagnostic industry will continue to grow at double-digit pace to meet increasing demand for personalized medicine. A wide variety of drugs in late preclinical and early clinical development are being targeted to disease-specific gene and protein defects that will require coapproval of diagnostic and therapeutic products by regulatory agencies. An increasingly educated public will demand more information about their predisposition for serious diseases and how these potential illnesses can be detected in an early stage when they can be arrested or cured with new therapies custom-designed for their individual clinical status. To respond to this demand, major pharmaceutical companies will partner with diagnostics companies or develop their own in-house capabilities that will permit efficient production of more effective and less toxic integrated personalized medicine drug and test products. For clinical laboratories and pathologists, this integration of diagnostics and therapeutics represents a major new opportunity to emerge as leaders of the new medicine, guiding the selection, dosage, route of administration, and multidrug combinations and producing increased efficacy and reduced toxicity of pharmaceutical products.

Authors
Ross, JS; Ginsburg, GS
MLA Citation
Ross, Jeffrey S., and Geoffrey S. Ginsburg. “The integration of molecular diagnostics with therapeutics. Implications for drug development and pathology practice..” Am J Clin Pathol, vol. 119, no. 1, Jan. 2003, pp. 26–36. Pubmed, doi:10.1309/VMLL-66Y5-KHQ3-5KUE.
PMID
12520694
Source
pubmed
Published In
American Journal of Clinical Pathology
Volume
119
Issue
1
Publish Date
2003
Start Page
26
End Page
36
DOI
10.1309/VMLL-66Y5-KHQ3-5KUE

Task Force on Strategic Research Direction: Basic Science Subgroup key science topics report.

Authors
Loscalzo, J; Balaban, R; Becker, LB; Ginsburg, GS; Hachinski, VC; Hall, JE; Heistad, DD; Leinwand, LA; Lenfant, CJ; Marban, E; Olson, EN; Schwartz, SM; American Heart Association. Task Force on Strategic Research Direction. Basic Science Subgroup,
MLA Citation
Loscalzo, Joseph, et al. “Task Force on Strategic Research Direction: Basic Science Subgroup key science topics report..” Circulation, vol. 106, no. 20, Nov. 2002, pp. e149–61. Pubmed, doi:10.1161/01.cir.0000040842.08331.4e.
PMID
12427670
Source
pubmed
Published In
Circulation
Volume
106
Issue
20
Publish Date
2002
Start Page
e149
End Page
e161
DOI
10.1161/01.cir.0000040842.08331.4e

Integration of molecular diagnostics with therapeutics: implications for drug discovery and patient care.

The Introduction of targeted therapeutics into clinical practice has created major opportunities for further development of the molecular diagnostics industry. Emerging genomic and proteomic technologies and information are now resulting in the molecular subclassification of disease as the basis for diagnosis, prognosis and therapeutic selection. The ultimate goals of personalized medicine are to take advantage of a molecular understanding of disease, both to optimize drug development and direct preventive resources and therapeutic agents at the right population of people while they are still well. Single nucleotide polymorphisms identification and genotyping have uncovered predisposition markers from cancer and heart disease as well in the prediction of both drug efficacy and toxicity. Pharmacogenomic and pharmacodynamic assays are being developed to enhance the speed and decrease the cost of drug development, as well as reduce side effects and increase response rates in a variety of diseases. The traditional trial and error practice of medicine is progressively eroding in favor of more precise marker-assisted diagnosis and safer and more effective molecularly guided treatment of disease. For the diagnostics industry this represents an unprecedented opportunity for integration, increased value and commercial opportunities for molecularly-derived tests.

Authors
Ross, JS; Ginsburg, GS
MLA Citation
Ross, Jeffrey S., and Geoffrey S. Ginsburg. “Integration of molecular diagnostics with therapeutics: implications for drug discovery and patient care..” Expert Rev Mol Diagn, vol. 2, no. 6, Nov. 2002, pp. 531–41. Pubmed, doi:10.1586/14737159.2.6.531.
PMID
12465450
Source
pubmed
Published In
Expert Review of Molecular Diagnostics
Volume
2
Issue
6
Publish Date
2002
Start Page
531
End Page
541
DOI
10.1586/14737159.2.6.531

Integrating diagnostics and therapeutics: revolutionizing drug discovery and patient care.

Over the next five years it is widely anticipated that the molecular diagnostics industry will continue to grow at double-digit pace to meet increasing demand for personalized medicine. A wide variety of drugs in late preclinical and early clinical development is now being targeted to disease-specific gene and protein defects that will require co-approval of diagnostic and therapeutic products by regulatory agencies. For clinical laboratories and pathologists, this integration of diagnostics and therapeutics represents a major new opportunity to emerge as leaders of the new medicine, guiding the selection, dosage, route of administration and multi-drug combinations, and producing increased efficacy and reduced toxicity of pharmaceutical products.

Authors
Ross, JS; Ginsburg, GS
MLA Citation
Ross, Jeffrey S., and Geoffrey S. Ginsburg. “Integrating diagnostics and therapeutics: revolutionizing drug discovery and patient care..” Drug Discov Today, vol. 7, no. 16, Aug. 2002, pp. 859–64.
PMID
12546952
Source
pubmed
Published In
Drug Discovery Today
Volume
7
Issue
16
Publish Date
2002
Start Page
859
End Page
864

The path to personalized medicine.

Advances in personalized medicine, or the use of an individual's molecular profile to direct the practice of medicine, have been greatly enabled through human genome research. This research is leading to the identification of a range of molecular markers for predisposition testing, disease screening and prognostic assessment, as well as markers used to predict and monitor drug response. Successful personalized medicine research programs will not only require strategies for developing and validating biomarkers, but also coordinating these efforts with drug discovery and clinical development.

Authors
Meyer, JM; Ginsburg, GS
MLA Citation
Meyer, Joanne M., and Geoffrey S. Ginsburg. “The path to personalized medicine..” Curr Opin Chem Biol, vol. 6, no. 4, Aug. 2002, pp. 434–38.
PMID
12133717
Source
pubmed
Published In
Current Opinion in Chemical Biology
Volume
6
Issue
4
Publish Date
2002
Start Page
434
End Page
438

Outbreak of leptospirosis among triathlon participants and community residents in Springfield, Illinois, 1998.

We investigated an outbreak of leptospirosis among athletes and community residents after a triathlon was held in Springfield, Illinois. A telephone survey was conducted to collect clinical information and data on possible risk factors, community surveillance was established, and animal specimens and lake water samples were collected to determine the source of the leptospiral contamination. A total of 834 of 876 triathletes were contacted; 98 (12%) reported being ill. Serum samples obtained from 474 athletes were tested; 52 of these samples (11%) tested positive for leptospirosis. Fourteen (6%) of 248 symptomatic community residents tested positive for leptospirosis. Heavy rains that preceded the triathlon are likely to have increased leptospiral contamination of Lake Springfield. Among athletes, ingestion of 1 or more swallows of lake water was a predominant risk factor for illness. This is the largest outbreak of leptospirosis that has been reported in the United States. Health care providers and occupational and recreational users of bodies of freshwater in the United States should be aware of the risk of contracting leptospirosis, particularly after heavy rains.

Authors
Morgan, J; Bornstein, SL; Karpati, AM; Bruce, M; Bolin, CA; Austin, CC; Woods, CW; Lingappa, J; Langkop, C; Davis, B; Graham, DR; Proctor, M; Ashford, DA; Bajani, M; Bragg, SL; Shutt, K; Perkins, BA; Tappero, JW; Leptospirosis Working Group,
MLA Citation
Morgan, Juliette, et al. “Outbreak of leptospirosis among triathlon participants and community residents in Springfield, Illinois, 1998..” Clin Infect Dis, vol. 34, no. 12, June 2002, pp. 1593–99. Pubmed, doi:10.1086/340615.
PMID
12032894
Source
pubmed
Published In
Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America
Volume
34
Issue
12
Publish Date
2002
Start Page
1593
End Page
1599
DOI
10.1086/340615

Surveillance for unexplained deaths and critical illnesses due to possibly infectious causes, United States, 1995-1998.

Population-based surveillance for unexplained death and critical illness possibly due to infectious causes (UNEX) was conducted in four U.S. Emerging Infections Program sites (population 7.7 million) from May 1, 1995, to December 31, 1998, to define the incidence, epidemiologic features, and etiology of this syndrome. A case was defined as death or critical illness in a hospitalized, previously healthy person, 1 to 49 years of age, with infection hallmarks but no cause identified after routine testing. A total of 137 cases were identified (incidence rate 0.5 per 100,000 per year). Patients' median age was 20 years, 72 (53%) were female, 112 (82%) were white, and 41 (30%) died. The most common clinical presentations were neurologic (29%), respiratory (27%), and cardiac (21%). Infectious causes were identified for 34 cases (28% of the 122 cases with clinical specimens); 23 (68%) were diagnosed by reference serologic tests, and 11 (32%) by polymerase chain reaction-based methods. The UNEX network model would improve U.S. diagnostic capacities and preparedness for emerging infections.

Authors
Hajjeh, RA; Relman, D; Cieslak, PR; Sofair, AN; Passaro, D; Flood, J; Johnson, J; Hacker, JK; Shieh, W-J; Hendry, RM; Nikkari, S; Ladd-Wilson, S; Hadler, J; Rainbow, J; Tappero, JW; Woods, CW; Conn, L; Reagan, S; Zaki, S; Perkins, BA
MLA Citation
Hajjeh, Rana A., et al. “Surveillance for unexplained deaths and critical illnesses due to possibly infectious causes, United States, 1995-1998..” Emerg Infect Dis, vol. 8, no. 2, Feb. 2002, pp. 145–53. Pubmed, doi:10.3201/eid0802.010165.
PMID
11897065
Source
pubmed
Published In
Emerging Infectious Diseases
Volume
8
Issue
2
Publish Date
2002
Start Page
145
End Page
153
DOI
10.3201/eid0802.010165

An outbreak of Rift Valley fever in Northeastern Kenya, 1997-98.

In December 1997, 170 hemorrhagic fever-associated deaths were reported in Garissa District, Kenya. Laboratory testing identified evidence of acute Rift Valley fever virus (RVFV). Of the 171 persons enrolled in a cross-sectional study, 31(18%) were anti-RVFV immunoglobulin (Ig) M positive. An age-adjusted IgM antibody prevalence of 14% was estimated for the district. We estimate approximately 27,500 infections occurred in Garissa District, making this the largest recorded outbreak of RVFV in East Africa. In multivariable analysis, contact with sheep body fluids and sheltering livestock in one s home were significantly associated with infection. Direct contact with animals, particularly contact with sheep body fluids, was the most important modifiable risk factor for RVFV infection. Public education during epizootics may reduce human illness and deaths associated with future outbreaks.

Authors
Woods, CW; Karpati, AM; Grein, T; McCarthy, N; Gaturuku, P; Muchiri, E; Dunster, L; Henderson, A; Khan, AS; Swanepoel, R; Bonmarin, I; Martin, L; Mann, P; Smoak, BL; Ryan, M; Ksiazek, TG; Arthur, RR; Ndikuyeze, A; Agata, NN; Peters, CJ; World Health Organization Hemorrhagic Fever Task Force,
MLA Citation
Woods, Christopher W., et al. “An outbreak of Rift Valley fever in Northeastern Kenya, 1997-98..” Emerg Infect Dis, vol. 8, no. 2, Feb. 2002, pp. 138–44. Pubmed, doi:10.3201/eid0802.010023.
PMID
11897064
Source
pubmed
Published In
Emerging Infectious Diseases
Volume
8
Issue
2
Publish Date
2002
Start Page
138
End Page
144
DOI
10.3201/eid0802.010023

Changing patient characteristics and the effect on mortality in endocarditis.

BACKGROUND: Limited data exist on recent demographic and microbiological changes in infective endocarditis (IE) and the impact of these changes on patient survival. METHODS: Data were collected from all patients with definite or possible IE at Duke University Medical Center, Durham, NC, from 1993 to 1999. Logistic regression analysis was used to identify demographic and microbiological changes that occurred in patients with IE over the study period. The impact of these changes on survival was evaluated using Cox proportional hazards modeling. RESULTS: Among the 329 study patients, rates of hemodialysis dependence, immunosuppression, and Staphylococcus aureus infection increased during the study period (P=.04, P=.008, and P<.001, respectively), while rates of infection due to viridans group streptococci decreased (P=.007). Hemodialysis was independently associated with S aureus infection (odds ratio, 3.1; 95% confidence interval, 1.6-5.9). Patients with S aureus IE had a higher 1-year mortality rate (43.9% vs 32.5%; P=.04) that persisted after adjustment for other illness severity characteristics (hazard ratio, 1.5; 95% confidence interval, 1.03-2.3). CONCLUSIONS: The demographic and microbiological characteristics of IE at our institution have changed over the past decade in ways that suggest a link between medical practice and IE characteristics. Staphylococcus aureus has emerged as a dominant cause of IE, and is an independent predictor of mortality. These findings identify clinical settings that may warrant closer surveillance and more aggressive measures in the identification and prevention of endocarditis.

Authors
Cabell, CH; Jollis, JG; Peterson, GE; Corey, GR; Anderson, DJ; Sexton, DJ; Woods, CW; Reller, LB; Ryan, T; Fowler, VG
MLA Citation
Cabell, Christopher H., et al. “Changing patient characteristics and the effect on mortality in endocarditis..” Arch Intern Med, vol. 162, no. 1, Jan. 2002, pp. 90–94.
PMID
11784225
Source
pubmed
Published In
Archives of Internal Medicine
Volume
162
Issue
1
Publish Date
2002
Start Page
90
End Page
94

Atherosclerosis: a cancer of the blood vessels?

A series of molecular pathways have in common a significant role in the pathogenesis and progression of atherosclerosis and cancer. Shared mechanisms implicated for both diseases include oxidative stress and the cellular damage that results from it, toxic metabolites produced by cigarette smoking, and increased dietary fat intake. Atherosclerosis may begin when an injury or infection mutates or transforms a single arterial smooth muscle cell in the progenitor of a proliferative clone, similar to the most widely held carcinogenesis theory. Cell proliferation regulatory pathways have been associated with plaque progression, stenosis, and restenosis after angioplasty and with cancer progression. Alterations in cell adhesion molecules have been linked to plaque formation and thrombosis and to tumor invasion and metastasis. Altered expression of proteases associated with thrombolysis has been implicated in atherosclerotic plaque expansion and hemorrhage and in the invasion and metastasis of malignant neoplasms. Ligand-growth factor receptor interactions have been associated with early atherosclerotic lesions and with cancer development and spread. Nuclear transcription factors have been associated with progression of both diseases. Angiogenesis modulators have been linked to plaque expansion and restenosis of atherosclerotic lesions and to local and metastatic tumor expansion.

Authors
Ross, JS; Stagliano, NE; Donovan, MJ; Breitbart, RE; Ginsburg, GS
MLA Citation
Ross, J. S., et al. “Atherosclerosis: a cancer of the blood vessels?.” Am J Clin Pathol, vol. 116 Suppl, Dec. 2001, pp. S97-107. Pubmed, doi:10.1309/YNCK-9R19-5JA3-K2K9.
PMID
11993705
Source
pubmed
Published In
American Journal of Clinical Pathology
Volume
116 Suppl
Publish Date
2001
Start Page
S97
End Page
107
DOI
10.1309/YNCK-9R19-5JA3-K2K9

Atherosclerosis and cancer: common molecular pathways of disease development and progression.

Recently, a series of shared molecular pathways have emerged that have in common a significant role in the pathogenesis and progression of both atherosclerosis and cancer. Oxidative stress and the cellular damage that results from it have been implicated in a wide variety of disease processes including atherogenesis and neoplasia. Toxic metabolites produced by cigarette smoking and increased dietary fat intake are implicated in the pathogenesis of both diseases. It has been hypothesized that atherosclerosis may begin when an injury or infection mutates or transforms a single arterial smooth muscle cell in the progenitor of a proliferative clone similar to the most widely held theory of carcinogenesis. Cell proliferation regulatory pathways including genes involved in the GIS checkpoint (p53, pRb, p15, p16, and cyclins A, D, E, and cdk 2,4) have been associated with plaque progression, stenosis and restenosis after angioplasty as well as in cancer progression. Alterations in cell adhesion molecules (integrins, cadherin-catenins) have been linked to plaque formation and thrombosis as well as to tumor invasion and metastasis. Altered expression of proteases associated with thrombolysis has been implicated in atherosclerotic plaque expansion and hemorrhage and in the invasion and metastasis of malignancy. Ligand-growth factor receptor interactions (tyrosine kinases) have been associated with early atherosclerotic lesions as well as cancer development and spread. Nuclear transcription factors such as NFkappaB have been associated with progression of both diseases. Angiogenesis modulators have recently been linked to plaque expansion and restenosis of atherosclerotic lesions as well as local and metastatic tumor expansion. Common disease treatments, such as the use of growth factor inhibitors and radiation treatment, established anticancer treatments, were recently introduced into atherosclerosis therapeutic strategies to prevent restenosis after angioplasty and endarterectomy. In conclusion, a series of molecular pathways of disease development and progression common to atherosclerosis and cancer support that the world's two most common diseases are far more closely aligned than previously believed and that emerging anti-inflammatory and antiproliferative therapeutic strategies may ultimately be efficacious in both conditions.

Authors
Ross, JS; Stagliano, NE; Donovan, MJ; Breitbart, RE; Ginsburg, GS
MLA Citation
Ross, J. S., et al. “Atherosclerosis and cancer: common molecular pathways of disease development and progression..” Ann N Y Acad Sci, vol. 947, Dec. 2001, pp. 271–92.
PMID
11795276
Source
pubmed
Published In
Annals of the New York Academy of Sciences
Volume
947
Publish Date
2001
Start Page
271
End Page
292

Personalized medicine: revolutionizing drug discovery and patient care.

Advances in human genome research are opening the door to a new paradigm for practising medicine that promises to transform healthcare. Personalized medicine, the use of marker-assisted diagnosis and targeted therapies derived from an individual's molecular profile, will impact the way drugs are developed and medicine is practiced. Knowledge of the molecular basis of disease will lead to novel target identification, toxicogenomic markers to screen compounds and improved selection of clinical trial patients, which will fundamentally change the pharmaceutical industry. The traditional linear process of drug discovery and development will be replaced by an integrated and heuristic approach. In addition, patient care will be revolutionized through the use of novel molecular predisposition, screening, diagnostic, prognostic, pharmacogenomic and monitoring markers. Although numerous challenges will need to be met to make personalized medicine a reality, with time, this approach will replace the traditional trial-and-error practice of medicine.

Authors
Ginsburg, GS; McCarthy, JJ
MLA Citation
Ginsburg, G. S., and J. J. McCarthy. “Personalized medicine: revolutionizing drug discovery and patient care..” Trends Biotechnol, vol. 19, no. 12, Dec. 2001, pp. 491–96.
PMID
11711191
Source
pubmed
Published In
Trends in Biotechnology
Volume
19
Issue
12
Publish Date
2001
Start Page
491
End Page
496

Mycobacterium bovis peritonitis mimicking ovarian cancer in a young woman.

We describe a 27-year-old woman with peritonitis due to Mycobacterium bovis that initially appeared to be ovarian cancer. Clinicians should include this disease in the differential diagnosis of ovarian cancer and should consider laparoscopic diagnosis in the appropriate epidemiologic setting.

Authors
Stout, JE; Woods, CW; Alvarez, AA; Berchuck, A; Dukes Hamilton, C
MLA Citation
Stout, J. E., et al. “Mycobacterium bovis peritonitis mimicking ovarian cancer in a young woman..” Clin Infect Dis, vol. 33, no. 4, Aug. 2001, pp. E14–16. Pubmed, doi:10.1086/321908.
PMID
11462205
Source
pubmed
Published In
Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America
Volume
33
Issue
4
Publish Date
2001
Start Page
E14
End Page
E16
DOI
10.1086/321908

Marijuana use and social networks in a community outbreak of meningococcal disease.

BACKGROUND: We examined the role of social networks and marijuana smoking in a community outbreak of infections due to Neisseria meningitidis. METHODS: We interviewed all patients and their contacts. Isolates were tested by pulsed field electrophoresis and multilocus enzyme electrophoresis. RESULTS: Nine cases of meningococcal disease occurred in the outbreak; isolates from seven cases with positive cultures were identical. Multiple overlapping social networks were found for case-patients and their contacts. All case-patients were linked by the marijuana-related activities of their contacts. CONCLUSION: Investigation of social networks and marijuana exposure might help identify close contacts of patients with meningococcal disease and help prevent secondary infections.

Authors
Krause, G; Blackmore, C; Wiersma, S; Lesneski, C; Woods, CW; Rosenstein, NE; Hopkins, RS
MLA Citation
Krause, G., et al. “Marijuana use and social networks in a community outbreak of meningococcal disease..” South Med J, vol. 94, no. 5, May 2001, pp. 482–85.
PMID
11372796
Source
pubmed
Published In
Southern Medical Journal
Volume
94
Issue
5
Publish Date
2001
Start Page
482
End Page
485

Gender differences in exercise-induced changes in sex hormone levels and lipid peroxidation in athletes participating in the Hawaii Ironman triathlon. Ginsburg-gender and exercise-induced lipid peroxidation.

BACKGROUND: Exercise reduces the risk of coronary heart disease in men and women but paradoxically, may promote free-radical formation, lipid peroxidation and vascular tissue injury. In this study, we assessed whether exercise-induced oxidative stress similarly affected men and women who participated in the Hawaii Ironman triathlon. METHODS AND RESULTS: Fifty-seven athletes (38 males) who completed the triathlon (3.9 km swim, 180.2 km bike, 42.2 km run) participated in this study. Blood samples were obtained 2 days before and immediately after the triathlon for the measurement of lipids, antioxidants and sex hormones and for the assessment of the susceptibility of plasma lipids to peroxidation. Lipid changes after exercise were similar for men and women. However, the susceptibility of plasma lipids to peroxidation was reduced by 61% (P < 0.001) in men and only 14% (P = NS) in women postrace. These changes were not associated with the supplemental use or levels of antioxidants. In addition, in men there was an increase of 58% in the antioxidant sex hormone estradiol and a decrease of 58% in testosterone (P < 0.001) postrace. No significant changes were noted for these two hormones in women. CONCLUSIONS: There are significant gender-specific differences in the susceptibility of lipids to peroxidation and in changes in estradiol and testosterone levels as a result of ultra-endurance exercise. These changes may in part explain the salutary effect of exercise on the development of vascular disease.

Authors
Ginsburg, GS; O'Toole, M; Rimm, E; Douglas, PS; Rifai, N
MLA Citation
Ginsburg, G. S., et al. “Gender differences in exercise-induced changes in sex hormone levels and lipid peroxidation in athletes participating in the Hawaii Ironman triathlon. Ginsburg-gender and exercise-induced lipid peroxidation..” Clin Chim Acta, vol. 305, no. 1–2, Mar. 2001, pp. 131–39. Pubmed, doi:10.1016/s0009-8981(00)00427-7.
PMID
11249932
Source
pubmed
Published In
Clinica Chimica Acta; International Journal of Clinical Chemistry
Volume
305
Issue
1-2
Publish Date
2001
Start Page
131
End Page
139
DOI
10.1016/s0009-8981(00)00427-7

Meningococcemia in a patient coinfected with hepatitis C virus and HIV.

We describe the first reported case of meningococcemia in a patient coinfected with hepatitis C virus and HIV. Hypocomplementemia secondary to hepatic dysfunction may have enhanced the patient's susceptibility to meningococcal infection.

Authors
Nelson, CG; Iler, MA; Woods, CW; Bartlett, JA; Fowler, VG
MLA Citation
Nelson, C. G., et al. “Meningococcemia in a patient coinfected with hepatitis C virus and HIV..” Emerg Infect Dis, vol. 6, no. 6, Nov. 2000, pp. 646–48. Pubmed, doi:10.3201/eid0606.000615.
Website
http://hdl.handle.net/10161/13327
PMID
11076725
Source
pubmed
Published In
Emerging Infectious Diseases
Volume
6
Issue
6
Publish Date
2000
Start Page
646
End Page
648
DOI
10.3201/eid0606.000615

Dyslipidemia in patients with CAD: Rational use of diets and drugs

In patients with established coronary artery disease (CAD), therapy to lower serum low-density lipoprotein (LDL) levels can halt the progression of atherosclerosis; it may also permit disease regression and improve endothelial function. Clinical trials have shown that aggressive lipid management can prevent cardiac events. In addition, lipid-altering medications have effects on endothelial function that may contribute to their preventive efficacy. The first steps in management are to measure serum lipid levels on at least 2 occasions and to identify and treat secondary causes of hyperlipidemia. Therapy should begin with dietary measures but escalate rapidly if necessary to include appropriate hypolipidemic agents. For most patients with established CAD (including those with 'normal' baseline LDL levels), lipid-lowering therapy with both diet and drugs is recommended.

Authors
Yu, HH; Pasternak, RC; Ginsburg, GS
MLA Citation
Yu, H. H., et al. “Dyslipidemia in patients with CAD: Rational use of diets and drugs.” Consultant, vol. 40, no. 10, Sept. 2000, pp. 1762–72.
Source
scopus
Published In
Consultant
Volume
40
Issue
10
Publish Date
2000
Start Page
1762
End Page
1772

Meningococcal immunisation in Ghana.

Authors
de Chabalier, F; Chippaux, JP; Massougbodji, A
MLA Citation
de Chabalier, F., et al. “Meningococcal immunisation in Ghana..” Lancet, vol. 355, no. 9222, June 2000. Pubmed, doi:10.1016/S0140-6736(05)72749-5.
PMID
10881917
Source
pubmed
Published In
Lancet (London, England)
Volume
355
Issue
9222
Publish Date
2000
Start Page
2252
DOI
10.1016/S0140-6736(05)72749-5

Control of meningococcal disease in west Africa.

Authors
Obaro, S
MLA Citation
Obaro, S. “Control of meningococcal disease in west Africa..” Lancet, vol. 355, no. 9210, Apr. 2000, pp. 1184–85. Pubmed, doi:10.1016/S0140-6736(05)72263-7.
PMID
10791403
Source
pubmed
Published In
Lancet (London, England)
Volume
355
Issue
9210
Publish Date
2000
Start Page
1184
End Page
1185
DOI
10.1016/S0140-6736(05)72263-7

Coccidioidomycosis in human immunodeficiency virus-infected persons in Arizona, 1994-1997: incidence, risk factors, and prevention.

From 1 January 1995 through 31 June 1997, 153 cases of coccidioidomycosis in human immunodeficiency virus (HIV)-infected persons were identified in Arizona (incidence, 41/1000 persons living with AIDS). A case-control study was conducted to evaluate risk factors for coccidioidomycosis in HIV-infected persons. A case was defined as laboratory-confirmed, incident coccidioidomycosis in a person infected with HIV for > or =3 months, and each case patient had 3 control patients matched by county, age group, sex, HIV/AIDS status, and CD4 lymphocyte count. Multivariable analysis identified black race and a history of oropharyngeal or esophageal candidiasis to be associated with increased risk of coccidioidomycosis; protease inhibitor therapy was associated with a reduced risk. In persons with previous history of oropharyngeal or esophageal candidiasis, having received an azole drug was associated with a reduced risk (odds ratio, 0.4; 95% confidence interval, 0.2-0.9; P=.04). Physicians may need to consider azole chemoprophylaxis for HIV-infected persons who live in areas of endemicity, have CD4 cell counts <200/microL, are black, or have a history of thrush.

Authors
Woods, CW; McRill, C; Plikaytis, BD; Rosenstein, NE; Mosley, D; Boyd, D; England, B; Perkins, BA; Ampel, NM; Hajjeh, RA
MLA Citation
Woods, C. W., et al. “Coccidioidomycosis in human immunodeficiency virus-infected persons in Arizona, 1994-1997: incidence, risk factors, and prevention..” J Infect Dis, vol. 181, no. 4, Apr. 2000, pp. 1428–34. Pubmed, doi:10.1086/315401.
PMID
10753734
Source
pubmed
Published In
The Journal of Infectious Diseases
Volume
181
Issue
4
Publish Date
2000
Start Page
1428
End Page
1434
DOI
10.1086/315401

Emergency vaccination against epidemic meningitis in Ghana: implications for the control of meningococcal disease in West Africa.

BACKGROUND: Recurrent epidemics of meningococcal disease have been reported throughout the African meningitis belt since description of the disease in 1912. Meningooccal polysaccharide vaccines can effectively prevent disease but the optimum strategy for their use in this setting has been controversial. We used data from an outbreak of meningococcal disease in northern Ghana in 1997 to assess the potential effect of different vaccination strategies. METHODS: We identified all reported cases of meningococcal meningitis and estimated the number of cases and deaths that could have been prevented by vaccination through use of a simple mathematical model. We then assessed the potential effect of different vaccination strategies and the burden of these strategies on the public-health system. FINDINGS: In the three affected regions in northern Ghana there were 18703 cases and 1356 deaths reported between November, 1996, and May, 1997. Vaccination began in the third week of February and continued to April, reaching 72% of the at-risk population and preventing an estimated 23% of cases and 18% of deaths. A strategy of routine childhood and adult immunisation would have prevented 61% of cases had this same rate of vaccine coverage been achieved and maintained before the epidemic. If vaccination had started after the onset of the epidemic in January, as currently advocated by WHO guidelines, a similar proportion (61%) of cases could have been prevented. INTERPRETATION: Prevention of epidemics of meningococal disease in west Africa will be difficult until long-lasting conjugate vaccines capable of interrupting transmission of Neisseria meningitidis can be incorporated into routine infant-immunisation schedules. Until then, the strategy of surveillance and response advocated by WHO is as effective and more practical than a strategy of routine childhood and adult vaccination with currently available polysaccharide vaccines.

Authors
Woods, CW; Armstrong, G; Sackey, SO; Tetteh, C; Bugri, S; Perkins, BA; Rosenstein, NE
MLA Citation
Woods, C. W., et al. “Emergency vaccination against epidemic meningitis in Ghana: implications for the control of meningococcal disease in West Africa..” Lancet, vol. 355, no. 9197, Jan. 2000, pp. 30–33. Pubmed, doi:10.1016/S0140-6736(99)03366-8.
PMID
10615888
Source
pubmed
Published In
Lancet (London, England)
Volume
355
Issue
9197
Publish Date
2000
Start Page
30
End Page
33
DOI
10.1016/S0140-6736(99)03366-8

Lipid management for patients with CAD, Part 2: A guide to drug therapy

The primary goal of lipid therapy is to reduce serum levels of low- density lipoprotein (LDL). However, lipid-altering agents variously affect multiple lipoprotein species and should be chosen to treat specific patterns of dyslipidemia. Available agents include bile acid resins, niacin, fibric acid derivatives, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, fish oil, and estrogens. Overall, the HMG-CoA reductase inhibitors have reduced the need for combination drug therapy. Nevertheless, certain patients still require treatment with more than 1 drug to achieve a lipid profile that permits regression of atherosclerosis and reduces mortality. Using drugs with different and complementary modes of action may provide the most effective treatment for 'mixed' dyslipidemias. Some combinations may increase the frequency of certain adverse effects; monitoring, especially of creatine kinase levels, may be required. Often, however, using lower dosages of more than 1 drug lessens side effects.

Authors
Yu, HH; Pasternak, RC; Ginsburg, GS
MLA Citation
Yu, H. H., et al. “Lipid management for patients with CAD, Part 2: A guide to drug therapy.” Journal of Critical Illness, vol. 15, no. 6, Jan. 2000, pp. 302–15.
Source
scopus
Published In
Journal of Critical Illness
Volume
15
Issue
6
Publish Date
2000
Start Page
302
End Page
315

Lipid management for patients with CAD, Part 1: What to expect, when to start. Consider an aggressive strategy for prevention of cardiac events

In patients with established coronary artery disease (CAD), therapy to lower serum low-density lipoprotein (LDL) levels can halt the progression of atherosclerosis; it may also permit disease regression and improve endothelial function. Clinical trials have shown that aggressive lipid management can prevent cardiac events. In addition, lipid-altering medications have effects on endothelial function that may contribute to their preventive efficacy. The first steps in management are to measure serum lipid levels on at least 2 occasions and to identify and treat secondary causes of hyperlipidemia. Therapy should begin with dietary measures but escalate rapidly if necessary to include appropriate hypolipidemic agents. For most patients with established CAD (including those with 'normal' baseline LDL levels), lipid-lowering therapy with both diet and drugs is recommended.

Authors
Yu, HH; Pasternak, RC; Ginsburg, GS
MLA Citation
Yu, H. H., et al. “Lipid management for patients with CAD, Part 1: What to expect, when to start. Consider an aggressive strategy for prevention of cardiac events.” Journal of Critical Illness, vol. 15, no. 5, Jan. 2000, pp. 247–64.
Source
scopus
Published In
Journal of Critical Illness
Volume
15
Issue
5
Publish Date
2000
Start Page
247
End Page
264

Dyslipidemia in patients with CAD: How to make best use of drug therapy

The primary goal of lipid therapy is to reduce serum levels of low-density lipoprotein (LDL). However, lipid-altering agents variously affect multiple lipoprotein species and should be chosen to treat specific patterns of dyslipidemia. Available agents include bile acid resins, niacin, fibric acid derivatives, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, fish oil, and estrogens. Overall, the HMG-CoA reductase inhibitors have reduced the need for combination drug therapy. Nevertheless, certain patients still require treatment with more than 1 drug to achieve a lipid profile that permits regression of atherosclerosis and reduces mortality. Using drugs with different and complementary modes of action may provide the most effective treatment for 'mixed' dyslipidemias. Some combinations may increase the frequency of certain adverse effects; monitoring, especially of creatine kinase levels, may be required. Often, however, using lower dosages lessens side effects.

Authors
Yu, HH; Pasternak, RC; Ginsburg, GS
MLA Citation
Yu, H. H., et al. “Dyslipidemia in patients with CAD: How to make best use of drug therapy.” Consultant, vol. 40, no. 12, Jan. 2000, pp. 2097–109.
Source
scopus
Published In
Consultant
Volume
40
Issue
12
Publish Date
2000
Start Page
2097
End Page
2109

Gender role orientation and fearfulness in children with anxiety disorders.

Research on gender differences in children's fears has generally shown that girls are more fearful than boys. A common hypothesis offered for this finding is that gender role orientations or expectations may be operating. However, this hypothesis has not been directly investigated in child samples. The present study examined the relation between a self-report measure of gender role orientation (i.e., masculinity/femininity) and the intensity of self-reported fears in a clinic sample of children (N = 66; ages 6-11; 41 boys and 25 girls) with anxiety disorders. Results revealed that masculinity was negatively related to overall levels of fearfulness as well as specific fears of failure and criticism, medical fears, and fears of the unknown. In contrast, no relation was found between femininity and fearfulness. These findings suggest that gender role orientation, especially masculinity, may play a role in the development and/or maintenance of fearfulness in children.

Authors
Ginsburg, GS; Silverman, WK
MLA Citation
Ginsburg, G. S., and W. K. Silverman. “Gender role orientation and fearfulness in children with anxiety disorders..” J Anxiety Disord, vol. 14, no. 1, Jan. 2000, pp. 57–67.
PMID
10770236
Source
pubmed
Published In
Journal of Anxiety Disorders
Volume
14
Issue
1
Publish Date
2000
Start Page
57
End Page
67

Acute changes in serum lipids and lipoprotein subclasses in triathletes as assessed by proton nuclear magnetic resonance spectroscopy.

Exercise is associated with changes in lipids that may protect against coronary heart disease (CHD). In this study of 28 triathletes, we analyzed acute changes in serum lipid and lipoprotein concentrations after completion of the 1995 World Championship Hawaii Ironman Triathlon. With standard laboratory assays, we demonstrate significant decreases in total cholesterol, VLDL cholesterol, ApoB100, and Lp(a). Total HDL cholesterol increased significantly immediately after the race. With a novel proton NMR spectroscopy assay, we demonstrate that smaller diameter LDL particles, corresponding to small, dense LDL, declined by 62%. Moreover, larger HDL subclasses, whose levels are inversely associated with CHD, increased significantly by 11%. Smaller HDL subclasses, which have been directly associated with CHD in some studies, acutely decreased by 16%. Therefore, exercise not only acutely induces changes in lipoprotein concentrations among the standard species in a manner that favorably affects CHD risk, but also induces favorable changes in specific lipoprotein subclass size distribution that also may alter CHD risk independently of the total lipoprotein serum concentration.

Authors
Yu, HH; Ginsburg, GS; O'Toole, ML; Otvos, JD; Douglas, PS; Rifai, N
MLA Citation
Yu, H. H., et al. “Acute changes in serum lipids and lipoprotein subclasses in triathletes as assessed by proton nuclear magnetic resonance spectroscopy..” Arterioscler Thromb Vasc Biol, vol. 19, no. 8, Aug. 1999, pp. 1945–49.
PMID
10446075
Source
pubmed
Published In
Arteriosclerosis, Thrombosis, and Vascular Biology
Volume
19
Issue
8
Publish Date
1999
Start Page
1945
End Page
1949

Characterization of a cholesterol response element (CRE) in the promoter of the cholesteryl ester transfer protein gene: functional role of the transcription factors SREBP-1a, -2, and YY1.

Cholesteryl ester transfer protein (CETP) is expressed in human adipocytes, where it acts to promote selective uptake of HDL-CE (Benoist, F., M. McDonnell, P. Lau, R. Milne, and R. McPherson. 1997. J. Biol. Chem. 272: 23572;-23577). In contrast to other major sterol-responsive genes such as 3-hydroxy-3-methylglutaryl coenzyme A reductase CETP expression is up-regulated rather than down-regulated in response to cholesterol. To define elements involved in cholesterol-mediated up-regulation of CETP gene expression, deletion derivatives of the CETP promoter were cloned into a luciferase reporter construct and transfected into the human liposarcoma cell line SW872, cultured in the presence or absence of lipoproteins. A fragment associated with a positive cholesterol response was identified between nucleotides -361 and -138 (relative to the initiation site of transcription) of the promoter. This region contains a tandem repeat of a sequence known to mediate sterol dependent regulation of the hamster HMG-CoA reductase gene. We have putatively denoted this region, the cholesterol response element (CRE). Using gel mobility shift assays we demonstrate that both YY1 and SREBP-1 interact with the CRE of CETP. Furthermore, in transient co-transfection experiments, both YY1 and SREBP-1a were found to trans-activate, in a dose-dependent manner, the luciferase activity of constructs harboring the CRE. We also demonstrate that SREBP-2, is able to trans-activate a luciferase construct harboring the CRE although much less effectively as compared to SREBP-1. Finally, functional analysis of the CRE confirms its regulatory role in modulating CETP gene expression through its interaction with YY1 and SREBP-1a.

Authors
Gauthier, B; Robb, M; Gaudet, F; Ginsburg, GS; McPherson, R
MLA Citation
Gauthier, B., et al. “Characterization of a cholesterol response element (CRE) in the promoter of the cholesteryl ester transfer protein gene: functional role of the transcription factors SREBP-1a, -2, and YY1..” J Lipid Res, vol. 40, no. 7, July 1999, pp. 1284–93.
PMID
10393213
Source
pubmed
Published In
Journal of Lipid Research
Volume
40
Issue
7
Publish Date
1999
Start Page
1284
End Page
1293

Cardiac troponin T and I, echocardiographic [correction of electrocardiographic] wall motion analyses, and ejection fractions in athletes participating in the Hawaii Ironman Triathlon.

Cardiac troponin T (cTnT) and troponin I (cTnI) are highly sensitive and specific for detecting myocardial damage even in the presence of skeletal muscle injury. In this study, we assessed whether ultraendurance exercise induced cardiomyocyte injury using plasma cTnT and cTnI measurements, quantitative echocardiographic wall-motion analysis, and ejection fraction measurement in athletes who participated in the Hawaii Ironman Triathlon. Twenty-three athletes (11 men) who completed the triathlon (3.9 km swim, 180.2 km bike, and 42.2 km run) participated in this study. Blood samples were obtained 2 days before and immediately after the triathlon for the determination of cTnT (Enzymun, Roche Diagnostics) and cTnI (Dade Behring) concentrations. Quantitative echocardiographic wall motion analysis and ejection fraction were obtained on 12 of the 23 participants before and immediately after the race. No subject had detectable cTnT or cTnI or abnormal echo score before the race. Following the race, 2 subjects (9%) had marked increases in both cTnT (0.15 and 0.33 microg/L) and cTnI (2.09 and 4.44 microg/L). Four additional subjects (17%) had moderate increases in cTnT (0.04 to 0.05 microg/L) but no detectable cTnI. Race time correlated inversely with cTnT (r = -0.65, p <0.01). Mean change in the number of abnormal echo segments after the race was 6.5 in those with a marked increase in cTnT and cTnI, 2.3 in those with a moderate increase in cTnT, and 1.7 in those with no increase. Ejection fraction decreased by an average of 24% after the race (p <0.002). Thus, ultraendurance exercise may cause myocardial damage as indicated by biochemical cardiac-specific markers and echocardiography. The cellular nature of this damage and whether it is transient or permanent is unclear at present.

Authors
Rifai, N; Douglas, PS; O'Toole, M; Rimm, E; Ginsburg, GS
MLA Citation
Rifai, N., et al. “Cardiac troponin T and I, echocardiographic [correction of electrocardiographic] wall motion analyses, and ejection fractions in athletes participating in the Hawaii Ironman Triathlon..” Am J Cardiol, vol. 83, no. 7, Apr. 1999, pp. 1085–89. Pubmed, doi:10.1016/s0002-9149(99)00020-x.
PMID
10190525
Source
pubmed
Published In
The American Journal of Cardiology
Volume
83
Issue
7
Publish Date
1999
Start Page
1085
End Page
1089
DOI
10.1016/s0002-9149(99)00020-x

Multiple different missense mutations in the pore region of HERG in patients with long QT syndrome.

Long QT syndrome (LQTS), is an inherited cardiac disorder in which ventricular tachyarrhythmias predispose affected individuals to syncope, seizures, and sudden death. Characteristic electrocardiographic findings include a prolonged QT interval, T wave alternans, and notched T waves. We have screened LQTS patients from 89 families for mutations in the pore region of HERG , the K+ channel gene previously associated with chromosome 7-linked LQT2. In six unrelated LQTS kindreds, single-strand conformation polymorphism analyses identified aberrant conformers in all affected family members. These conformers were not seen in over 100 unaffected, unrelated control individuals, suggesting that they represent pathogenic LQTS mutations. DNA sequence analyses of the aberrant conformers demonstrated that they reflect five different missense mutations: V612L, A614V, N629D, N629S, and N633S. The missense mutation A614V was found in two unrelated families. Further functional studies will be required to determine what effect each of these changes may have on HERG channel function.

Authors
Satler, CA; Vesely, MR; Duggal, P; Ginsburg, GS; Beggs, AH
MLA Citation
Satler, C. A., et al. “Multiple different missense mutations in the pore region of HERG in patients with long QT syndrome..” Hum Genet, vol. 102, no. 3, Mar. 1998, pp. 265–72. Pubmed, doi:10.1007/s004390050690.
PMID
9544837
Source
pubmed
Published In
Human Genetics
Volume
102
Issue
3
Publish Date
1998
Start Page
265
End Page
272
DOI
10.1007/s004390050690

Left ventricular hypertrophy in athletes.

Left ventricular wall thickness >1.3 cm, septal-to-posterior wall ratios > 1.5, diastolic left ventricular size >6.0 cm, and eccentric or concentric remodeling are rare in athletes. Values outside of these cutoffs in an athlete of any age probably represent a pathologic state.

Authors
Douglas, PS; O'Toole, ML; Katz, SE; Ginsburg, GS; Hiller, WD; Laird, RH
MLA Citation
Douglas, P. S., et al. “Left ventricular hypertrophy in athletes..” Am J Cardiol, vol. 80, no. 10, Nov. 1997, pp. 1384–88. Pubmed, doi:10.1016/s0002-9149(97)00693-0.
PMID
9388126
Source
pubmed
Published In
The American Journal of Cardiology
Volume
80
Issue
10
Publish Date
1997
Start Page
1384
End Page
1388
DOI
10.1016/s0002-9149(97)00693-0

Evaluation and clinical application of a direct low-density lipoprotein cholesterol assay in normolipidemic and hyperlipidemic adults.

This study examines the performance and clinical use of a commercial immunoseparation assay for low-density lipoprotein (LDL) cholesterol in a sample population of normolipidemic and hyperlipidemic adult volunteers. Using paired fasting and nonfasting samples, we compared the direct LDL assay with the beta quantification method and the Friedewald calculation. Overall, the direct LDL assay correctly classified 82% and 60% of fasting and nonfasting subjects, respectively, into National Cholesterol Education Program risk groups. The Friedewald method correctly classified 84% of subjects. The fasting direct LDL assay has comparable positive and negative predictive values to the Friedewald method, except at an LDL cholesterol of 100 mg/dl. The nonfasting direct LDL assay demonstrates unacceptable positive predictive values when LDL cholesterol decreases to the 130 to 159 and > or = 160 mg/dl categories. Overall, direct LDL assay demonstrates limitations in the nonfasting state and at the LDL cholesterol level of 100 mg/dl used for patients with established coronary heart disease.

Authors
Yu, HH; Ginsburg, GS; Harris, N; Rifai, N
MLA Citation
Yu, H. H., et al. “Evaluation and clinical application of a direct low-density lipoprotein cholesterol assay in normolipidemic and hyperlipidemic adults..” Am J Cardiol, vol. 80, no. 10, Nov. 1997, pp. 1295–99. Pubmed, doi:10.1016/s0002-9149(97)00668-1.
PMID
9388101
Source
pubmed
Published In
The American Journal of Cardiology
Volume
80
Issue
10
Publish Date
1997
Start Page
1295
End Page
1299
DOI
10.1016/s0002-9149(97)00668-1

Acquired dynamic left ventricular outflow tract obstruction complicating acute anterior myocardial infarction: serial echocardiographic and clinical evaluation.

We describe three cases of dynamic outflow obstruction complicating acute anterior myocardial infarction. Serial echocardiography suggests the intraventricular gradient results from basal hyperkinesis, the latter being a reciprocal response to the apical wall motion abnormality.

Authors
Joffe, II; Riley, MF; Katz, SE; Ginsburg, GS; Douglas, PS
MLA Citation
Joffe, I. I., et al. “Acquired dynamic left ventricular outflow tract obstruction complicating acute anterior myocardial infarction: serial echocardiographic and clinical evaluation..” J Am Soc Echocardiogr, vol. 10, no. 7, Sept. 1997, pp. 717–21.
PMID
9339422
Source
pubmed
Published In
Journal of the American Society of Echocardiography
Volume
10
Issue
7
Publish Date
1997
Start Page
717
End Page
721

Intestinal transcription and synthesis of apolipoprotein AI is regulated by five natural polymorphisms upstream of the apolipoprotein CIII gene.

To understand the factors contributing to the synthesis of human apolipoprotein AI (apoAI), relative apoAI synthesis was measured from endoscopic biopsy samples obtained from 18 healthy volunteers. The relative amount of apoAI synthesis was directly correlated with steady state intestinal apoAI mRNA levels and a 10-fold within-group variability was observed. Analysis of genomic DNA from the subjects revealed five polymorphic sites which defined two haplotypes in the intestinal enhancer region of the apoAI gene located upstream of the apolipoprotein CIII gene transcriptional start site (+ 1): (-641 C to A, -630 G to A, -625 T to deletion, -482 C to T, and -455 T to C). The population frequencies of the wild-type and mutant alleles were 0.53 and 0.44, respectively. Mean steady state apoAI mRNA levels and mean relative apoAI synthesis were 49 and 37% lower, respectively, in homozygotes for the mutant allele and 28 and 41% lower, respectively, in heterozygotes than in homozygotes for the wild-type allele (P < 0.05 for both). Site-directed mutants of apoAI gene promoter/reporter constructs containing the above mutations were transfected into Caco-2 cells and showed a 46% decrease in transcriptional activity compared with the wild type (P < 0.001); however, no significant differences were observed in HepG2 cells. Electrophoretic mobility shift assays showed that the mutated sequences from -655 to -610 bound Caco-2 cell nuclear protein(s) while the wild type did not. These results indicate that intestinal apoAI gene transcription and protein synthesis are genetically determined and are reduced in the presence of common mutations which induced binding of nuclear protein(s), possibly a transcriptional repressor.

Authors
Naganawa, S; Ginsberg, HN; Glickman, RM; Ginsburg, GS
MLA Citation
Naganawa, S., et al. “Intestinal transcription and synthesis of apolipoprotein AI is regulated by five natural polymorphisms upstream of the apolipoprotein CIII gene..” J Clin Invest, vol. 99, no. 8, Apr. 1997, pp. 1958–65. Pubmed, doi:10.1172/JCI119363.
PMID
9109440
Source
pubmed
Published In
The Journal of Clinical Investigation
Volume
99
Issue
8
Publish Date
1997
Start Page
1958
End Page
1965
DOI
10.1172/JCI119363

Novel missense mutation in the cyclic nucleotide-binding domain of HERG causes long QT syndrome

Autosomal-dominant long QT syndrome (LQT) is an inherited disorder, predisposing affected individuals to sudden death from tachyarrhythmias. To identify the gene(s) responsible for LQT, we identified and characterized an LQT family consisting of 48 individuals. DNA was screened with 150 microsatellite polymorphic markers encompassing approximately 70% of the genome. We found evidence for linkage of the LQT phenotype to chromosome 7(q35-36). Marker D7S636 yielded a maximum lod score of 6.93 at a recombination fraction (θ) of 0.00. Haplotype analysis further localized the LQT gene within a 6.2-cM interval. HERG encodes a potassium channel which has been mapped to this region. Single-strand conformational polymorphism analyses demonstrated aberrant bands that were unique to all affected individuals. DNA sequencing of the aberrant bands demonstrated a G to A substitution in all affected patients; this point mutation results in the substitution of a highly conserved valine residue with a methionine (V822M) in the cyclic nucleotide-binding domain of this potassium channel. The cosegregation of this distinct mutation with LQT demonstrates that HERG is the LQT gene in this pedigree. Furthermore, the location and character of this mutation suggests that the cyclic nucleotide-binding domain of the potassium channel encoded by HERG plays an important role in normal cardiac repolarization and may decrease susceptibility to ventricular tachyarrhythmias.

Authors
Satler, CA; Walsh, EP; Vesely, MR; Plummer, MH; Ginsburg, GS; Jacob, HJ
MLA Citation
Satler, C. A., et al. “Novel missense mutation in the cyclic nucleotide-binding domain of HERG causes long QT syndrome.” American Journal of Medical Genetics, vol. 65, no. 1, Oct. 1996, pp. 27–35. Scopus, doi:10.1002/(SICI)1096-8628(19961002)65:1<27::AID-AJMG4>3.0.CO;2-V.
Source
scopus
Published In
American Journal of Medical Genetics
Volume
65
Issue
1
Publish Date
1996
Start Page
27
End Page
35
DOI
10.1002/(SICI)1096-8628(19961002)65:1<27::AID-AJMG4>3.0.CO;2-V

Novel missense mutation in the cyclic nucleotide-binding domain of HERG causes long QT syndrome.

Autosomal-dominant long QT syndrome (LQT) is an inherited disorder, predisposing affected individuals to sudden death from tachyarrhythmias. To identify the gene(s) responsible for LQT, we identified and characterized an LQT family consisting of 48 individuals. DNA was screened with 150 microsatellite polymorphic markers encompassing approximately 70% of the genome. We found evidence for linkage of the LQT phenotype to chromosome 7(q35-36). Marker D7S636 yielded a maximum lod score of 6.93 at a recombination fraction (theta) of 0.00. Haplotype analysis further localized the LQT gene within a 6.2-cM interval. HERG encodes a potassium channel which has been mapped to this region. Single-strand conformational polymorphism analyses demonstrated aberrant bands that were unique to all affected individuals. DNA sequencing of the aberrant bands demonstrated a G to A substitution in all affected patients; this point mutation results in the substitution of a highly conserved valine residue with a methionine (V822M) in the cyclic nucleotide-binding domain of this potassium channel. The cosegregation of this distinct mutation with LQT demonstrates that HERG is the LQT gene in this pedigree. Furthermore, the location and character of this mutation suggests that the cyclic nucleotide-binding domain of the potassium channel encoded by HERG plays an important role in normal cardiac repolarization and may decrease susceptibility to ventricular tachyarrhythmias.

Authors
Satler, CA; Walsh, EP; Vesely, MR; Plummer, MH; Ginsburg, GS; Jacob, HJ
MLA Citation
Satler, C. A., et al. “Novel missense mutation in the cyclic nucleotide-binding domain of HERG causes long QT syndrome..” Am J Med Genet, vol. 65, no. 1, Oct. 1996, pp. 27–35. Pubmed, doi:10.1002/(SICI)1096-8628(19961002)65:1<27::AID-AJMG4>3.0.CO;2-V.
PMID
8914737
Source
pubmed
Published In
American Journal of Medical Genetics
Volume
65
Issue
1
Publish Date
1996
Start Page
27
End Page
35
DOI
10.1002/(SICI)1096-8628(19961002)65:1<27::AID-AJMG4>3.0.CO;2-V

Chest pain in women.

Authors
Auerbach, I; Chouraqui, P; Motro, M
MLA Citation
Auerbach, I., et al. “Chest pain in women..” N Engl J Med, vol. 335, no. 11, Sept. 1996. Pubmed, doi:10.1056/NEJM199609123351113.
PMID
8778591
Source
pubmed
Published In
The New England Journal of Medicine
Volume
335
Issue
11
Publish Date
1996
Start Page
820
DOI
10.1056/NEJM199609123351113

Why cardiologists should be interested in estrogen.

Authors
Ginsburg, GS; Douglas, PS
MLA Citation
Ginsburg, G. S., and P. S. Douglas. “Why cardiologists should be interested in estrogen..” Am J Cardiol, vol. 78, no. 5, Sept. 1996, pp. 559–61. Pubmed, doi:10.1016/s0002-9149(96)00365-7.
PMID
8806343
Source
pubmed
Published In
The American Journal of Cardiology
Volume
78
Issue
5
Publish Date
1996
Start Page
559
End Page
561
DOI
10.1016/s0002-9149(96)00365-7

Analytical performance and clinical utility of a direct LDL-cholesterol assay in a hyperlipidemic pediatric population

This study compares a new latex immunoseparation method for the direct determination of plasma low-density lipoprotein cholesterol (LDL-C) with the reference procedure for LDL-C (β-quantification) in a pediatric hyperlipidemic population. The direct LDL-C assay has a mean bias of -98 mg/L in a fasting group (n = 96) of patients (mean triglycerides 1057 ± 720 mg/L) and a bias of + 177 mg/L in a nonfasting group (n = 42, mean triglycerides 4854 ± 5457 mg/L). The mean total analytical error calculated from our data is 13.8%. The direct LDL-C assay and the commonly used Friedewald calculation respectively classified 81% and 84% of fasting patients correctly, according to the cutoffs of 1100 and 1300 mg/L for LDL-C set by the National Cholesterol Education Program for pediatric patients. Of combined fasting and nonfasting patients, 80% were correctly classified by the direct LDL-C assay. Therefore, despite several analytical shortcomings, the direct LDL-C assay may be useful in managing hyperlipidemic children without the need for a fasting specimen.

Authors
Harris, N; Neufeld, EJ; Newburger, JW; Ticho, B; Baker, A; Ginsburg, GS; Rimm, E; Rifai, N
MLA Citation
Harris, N., et al. “Analytical performance and clinical utility of a direct LDL-cholesterol assay in a hyperlipidemic pediatric population.” Clinical Chemistry, vol. 42, no. 8, Aug. 1996, pp. 1182–88.
Source
scopus
Published In
Clinical Chemistry
Volume
42
Issue
8
Publish Date
1996
Start Page
1182
End Page
1188

Analytical performance and clinical utility of a direct LDL-cholesterol assay in a hyperlipidemic pediatric population.

This study compares a new latex immunoseparation method for the direct determination of plasma low-density lipoprotein cholesterol (LDL-C) with the reference procedure for LDL-C (beta-quantification) in a pediatric hyperlipidemic population. The direct LDL-C assay has a mean bias of -98 mg/L in a fasting group (n = 96) of patients (mean triglycerides 1057 +/- 720 mg/L) and a bias of +177 mg/L in a nonfasting group (n = 42, mean triglycerides 4854 +/- 5457 mg/L). The mean total analytical error calculated from our data is 13.8%. The direct LDL-C assay and the commonly used Friedewald calculation respectively classified 81% and 84% of fasting patients correctly, according to the cutoffs of 1100 and 1300 mg/L for LDL-C set by the National Cholesterol Education Program for pediatric patients. Of combined fasting and nonfasting patients, 80% were correctly classified by the direct LDL-C assay. Therefore, despite several analytical shortcomings, the direct LDL-C assay may be useful in managing hyperlipidemic children without the need for a fasting specimen.

Authors
Harris, N; Neufeld, EJ; Newburger, JW; Ticho, B; Baker, A; Ginsburg, GS; Rimm, E; Rifai, N
MLA Citation
Harris, N., et al. “Analytical performance and clinical utility of a direct LDL-cholesterol assay in a hyperlipidemic pediatric population..” Clin Chem, vol. 42, no. 8 Pt 1, Aug. 1996, pp. 1182–88.
PMID
8697574
Source
pubmed
Published In
Clinical Chemistry
Volume
42
Issue
8 Pt 1
Publish Date
1996
Start Page
1182
End Page
1188

Effects of a single bout of ultraendurance exercise on lipid levels and susceptibility of lipids to peroxidation in triathletes.

OBJECTIVE: To determine the effects of a single bout of ultraendurance exercise, as a model for physiologic stress, on lipid and lipoprotein levels, and oxidative susceptibility of lipids in highly trained athletes. DESIGN: Observational trial. POPULATION AND SETTING: Thirty-nine volunteer subjects (26 mean, 13 women; mean age, 38 +/- 10 years) who competed in and completed the 1994 Hawaii Ironman World Championship Triathlon consisting of a consecutive 3.9-km (2.4-mi) swim, 180.2-km (112-mi) bike ride, and a 42.2-km (26.2-mi) run. Subjects answered questionnaires and had blood samples obtained 2 days prior to and within 15 minutes of completion of the triathlon. MAIN OUTCOME MEASURES: Prerace vs postrace changes in lipid and lipoprotein levels, and susceptibility of lipids to peroxidation. RESULTS: The mean duration of exercise was 753 +/- 128 minutes. With exercise, plasma volume-corrected levels of triglycerides decreased 39% from 1.58 +/- 0.83 to 0.97 +/- 0.68 mmol/L (139.6 +/- 73.6 to 85.8 +/- 60.5 mg/dL) (P < .001). Levels of total cholesterol decreased 9% from 4.94 +/- 0.88 to 4.50 +/- 0.79 mmol/L (190.8 +/- 33.8 to 173.8 +/- 30.6 mg/dL) (P < .001), low-density lipoprotein cholesterol decreased 11% from 2.59 +/- 0.77 to 2.30 +/- 0.86 mmol/L (100.1 +/- 29.9 to 88.7 +/- 33.3 mg/dL) (P = .02), and apolipoprotein B decreased 10% from 0.91 +/- 0.20 to 0.82 +/- 0.18 g/L (90.7 +/- 20.0 to 82.0 +/- 17.9 mg/dL) (P < .001). High-density lipoprotein cholesterol and apolipoprotein A-I increased with exercise but not significantly. The susceptibility of lipids to peroxidation decreased significantly (4.51 +/- 1.91 micromol/L, preexercise, vs 2.42 +/- 2.27 micromol/L, postexercise, P < .001), an effect that was not related to antioxidant use or levels of vitamins A, C, or E. Serum iron, a potential pro-oxidant, also decreased by 45% with exercise from 15.75 +/- 5.55 to 8.59 +/- 4.30 micromol/L (88 +/- 31 to 48 +/- 24 micrograms/dL) (P < .001), an effect that was weakly correlated with changes in lipid peroxidation (P = .05). CONCLUSIONS: These data suggest that a single bout of prolonged exercise can reduce lipid and lipoprotein risk factors for developing cardiovascular disease. Moreover, susceptibility of lipids to peroxidation is reduced by exercise, thereby adding to the benefits of physical activity. This effect appears to be independent of antioxidant supplement use and may be mediated by induction of endogenous antioxidants. These observations may explain in part the reduced risk of developing vascular and other diseases in individuals who are physically active.

Authors
Ginsburg, GS; Agil, A; O'Toole, M; Rimm, E; Douglas, PS; Rifai, N
MLA Citation
Ginsburg, G. S., et al. “Effects of a single bout of ultraendurance exercise on lipid levels and susceptibility of lipids to peroxidation in triathletes..” Jama, vol. 276, no. 3, July 1996, pp. 221–25.
PMID
8667567
Source
pubmed
Published In
Jama
Volume
276
Issue
3
Publish Date
1996
Start Page
221
End Page
225

The evaluation of chest pain in women.

Authors
Douglas, PS; Ginsburg, GS
MLA Citation
Douglas, P. S., and G. S. Ginsburg. “The evaluation of chest pain in women..” N Engl J Med, vol. 334, no. 20, May 1996, pp. 1311–15. Pubmed, doi:10.1056/NEJM199605163342007.
PMID
8609950
Source
pubmed
Published In
The New England Journal of Medicine
Volume
334
Issue
20
Publish Date
1996
Start Page
1311
End Page
1315
DOI
10.1056/NEJM199605163342007

Transcriptional regulation of the cholesteryl ester transfer protein gene by the orphan nuclear hormone receptor apolipoprotein AI regulatory protein-1.

We have defined a 105-base pair tissue-restricted promoter for the cholesteryl ester transfer protein (CETP) gene that contains a nuclear hormone receptor response element essential for transcriptional activity. DNaseI protection and electrophoretic mobility shift assays showed specific binding of nuclear extracts from HepG2 (hepatic) and Caco-2 (intestinal) cells (expressing cell types) to 3 sites (designated A (-26 to -57), B (-59 to -87), and C (-93 to -118)) within the 105-base pair minimal promoter element between -138 and -33. Mutagenesis studies indicated that the function of the promoter was dependent upon synergistic interactions between transcription factors bound to these sites. Mutation of site C reduced transcription by 50 and 80%, respectively, in HepG2 and Caco-2 cells, and electrophoretic mobility shift assays showed that nuclear hormone receptors, including ARP-1 and its homologue Ear-3/COUP-TF, were occupants of site C in both of these cell types. Overexpression of ARP-1 or Ear-3/COUP-TF with CETP promoter/chloramphenicol acetyltransferase gene reporter plasmids repressed transcriptional activity of the CETP promoter containing sequences up to -300, but activated transcription in the context of larger constructs containing sequences up to -636. Thus ARP-1 may assume a dichotomous role as both a transcriptional repressor and a transcriptional activator dependent on the promoter context. In addition, the architecture of the CETP gene promoter suggests that its expression is under the control of multiple transcriptional signaling pathways mediated by inducible transcription factors as well as nuclear hormone receptors.

Authors
Gaudet, F; Ginsburg, GS
MLA Citation
Gaudet, F., and G. S. Ginsburg. “Transcriptional regulation of the cholesteryl ester transfer protein gene by the orphan nuclear hormone receptor apolipoprotein AI regulatory protein-1..” J Biol Chem, vol. 270, no. 50, Dec. 1995, pp. 29916–22. Pubmed, doi:10.1074/jbc.270.50.29916.
PMID
8530390
Source
pubmed
Published In
The Journal of Biological Chemistry
Volume
270
Issue
50
Publish Date
1995
Start Page
29916
End Page
29922
DOI
10.1074/jbc.270.50.29916

Intestinal apolipoprotein AI gene transcription is regulated by multiple distinct DNA elements and is synergistically activated by the orphan nuclear receptor, hepatocyte nuclear factor 4.

We have used apolipoprotein genes to investigate the signal transduction mechanisms involved in the control of intestinal specific gene expression. The human apoAI, apoCIII, and apoAIV genes are tandemly organized within a 15-kb DNA segment and are expressed predominantly in the liver and intestine. Transient transfection of various human apoAI gene plasmid constructs into human hepatoma (HepG2) and colon carcinoma (Caco-2) cells showed that apoAI gene transcription is under the control of two separate and distinct cell-specific promoters. The region between nucleotides -192 and -41 is essential for expression in HepG2 cells, whereas the region from -595 to -192 is essential for expression in Caco-2 cells. A third 0.6 kb DNA fragment in the apoCIII gene promoter region, approximately 5 kb down-stream from the human apoAI gene, enhances transcription mediated by either of these two tissue-specific apoAI promoters. In Caco-2 cells, expression of the apoAI gene and activation by the distal enhancer required the presence of a nuclear hormone receptor response element (NHRRE) located in the -214 to -192 apoAI promoter region. Overexpression of the orphan receptor hepatocyte nuclear factor 4 (HNF-4), which binds to the NHRRE, dramatically stimulates apoAI gene expression in Caco-2 cells but not in HepG2 cells. Maximal stimulation of transcription by HNF-4 in Caco-2 cells required the presence of both the intestinal specific promoter, the NHRRE, and distal enhancer elements. Transactivation by HNF-4 thus appears to result from functional synergy between the NHRRE binding HNF-4 and distal DNA elements containing intestinal-specific DNA binding activities. The apoAI gene provides a model system to define the mechanism(s) governing intestinal cell specific gene regulation and the role of nuclear hormone receptors in the establishment and regulation of enterocytic gene transcription.

Authors
Ginsburg, GS; Ozer, J; Karathanasis, SK
MLA Citation
Ginsburg, G. S., et al. “Intestinal apolipoprotein AI gene transcription is regulated by multiple distinct DNA elements and is synergistically activated by the orphan nuclear receptor, hepatocyte nuclear factor 4..” J Clin Invest, vol. 96, no. 1, July 1995, pp. 528–38. Pubmed, doi:10.1172/JCI118065.
PMID
7615825
Source
pubmed
Published In
The Journal of Clinical Investigation
Volume
96
Issue
1
Publish Date
1995
Start Page
528
End Page
538
DOI
10.1172/JCI118065

Effects of heparin and cardiac catheterization on serum lipoprotein and triglyceride levels.

This study determined whether heparin administration and procedures involving heparin significantly affect lipid measurement. Serum lipid and lipoprotein analyses (total cholesterol, triglycerides, high-density lipoprotein [HDL] cholesterol, low-density lipoprotein [LDL] cholesterol, apolipoprotein B, and apolipoprotein A-I) were performed at baseline and at several time points after (1) intravenous heparin or placebo in 6 healthy volunteers (group 1), (2) cardiac catheterization with heparin in 26 patients (group 2), and (3) peripheral angiography without heparin in 11 patients (group 3). In group 1, after heparinization, triglycerides decreased 50 +/- 12 mg/dl (-57%, p < 0.001 vs baseline and placebo) at 60 minutes. No changes were observed in other lipid or lipoprotein fractions. After cardiac catheterization (group 2), however, decreases were observed not only in triglycerides (58 +/- 26 mg/dl [-40%]), but also in total cholesterol (28 +/- 12 mg/dl [-14%]), LDL cholesterol (19 +/- 22 mg/dl [-15%]), apolipoprotein B (13 +/- 9 mg/dl [-14%]), and apolipoprotein A-I (21 +/- 14 mg/dl [-17%]) (p < 0.001 vs baseline for all), and HDL cholesterol (4 +/- 7 mg/dl [-3%], p = 0.07). With the exception of triglycerides, these values remained significantly decreased for > or = 24 hours. The change in HDL was variable: Whereas most patients had a decrease (n = 24), 2 patients had a dramatic increase (> 100%) after administration of heparin. Similar decreases in total cholesterol, LDL cholesterol, and apolipoproteins B and A-I were observed in group 3 undergoing peripheral angiography without heparin.(ABSTRACT TRUNCATED AT 250 WORDS)

Authors
Leidig, GA; Pasternak, RC; Horowitz, G; Ginsburg, GS
MLA Citation
Leidig, G. A., et al. “Effects of heparin and cardiac catheterization on serum lipoprotein and triglyceride levels..” Am J Cardiol, vol. 74, no. 1, July 1994, pp. 47–52. Pubmed, doi:10.1016/0002-9149(94)90490-1.
PMID
8017305
Source
pubmed
Published In
The American Journal of Cardiology
Volume
74
Issue
1
Publish Date
1994
Start Page
47
End Page
52
DOI
10.1016/0002-9149(94)90490-1

Frequency of hypothyroidism in adults with serum total cholesterol levels > 200 mg/dl.

Authors
Oettgen, P; Ginsburg, GS; Horowitz, GL; Pasternak, RC
MLA Citation
Oettgen, P., et al. “Frequency of hypothyroidism in adults with serum total cholesterol levels > 200 mg/dl..” Am J Cardiol, vol. 73, no. 13, May 1994, pp. 955–57. Pubmed, doi:10.1016/0002-9149(94)90138-4.
PMID
8184852
Source
pubmed
Published In
The American Journal of Cardiology
Volume
73
Issue
13
Publish Date
1994
Start Page
955
End Page
957
DOI
10.1016/0002-9149(94)90138-4

High-density lipoprotein subfractions.

High-density lipoprotein (HDL) consists of a heterogeneous group of particles defined either by size or by apolipoprotein content. Subfractions of HDL appear to have distinct but interrelated metabolic functions, including facilitation of cholesteryl ester transfer to low- and very-low-density lipoproteins, modulation of triglyceride-rich particle catabolism, and, possibly, removal of cholesterol from peripheral tissues. Like HDL cholesterol, HDL subfractions are widely affected by a variety of factors. Subfractions also are markers for epidemiologic risk for coronary artery disease. Because they provide information about the physiologic processes of cholesterol metabolism, HDL subfractions are emerging as an increasingly important tool in the study of the relationship between lipids and cardiovascular disease.

Authors
Silverman, DI; Ginsburg, GS; Pasternak, RC
MLA Citation
Silverman, D. I., et al. “High-density lipoprotein subfractions..” Am J Med, vol. 94, no. 6, June 1993, pp. 636–45. Pubmed, doi:10.1016/0002-9343(93)90217-d.
PMID
8506891
Source
pubmed
Published In
The American Journal of Medicine
Volume
94
Issue
6
Publish Date
1993
Start Page
636
End Page
645
DOI
10.1016/0002-9343(93)90217-d

Antagonism between apolipoprotein AI regulatory protein 1, Ear3/COUP-TF, and hepatocyte nuclear factor 4 modulates apolipoprotein CIII gene expression in liver and intestinal cells.

Apolipoprotein CIII (apoCIII), a lipid-binding protein involved in the transport of triglycerides and cholesterol in the plasma, is synthesized primarily in the liver and the intestine. A cis-acting regulatory element, C3P, located at -90 to -66 upstream from the apoCIII gene transcriptional start site (+1), is necessary for maximal expression of the apoCIII gene in human hepatoma (HepG2) and intestinal carcinoma (Caco2) cells. This report shows that three members of the steroid receptor superfamily of transcription factors, hepatocyte nuclear factor 4 (HNF-4), apolipoprotein AI regulatory protein 1 (ARP-1), and Ear3/COUP-TF, act at the C3P site. HNF-4 activates apoCIII gene expression in HepG2 and Caco2 cells, while ARP-1 and Ear3/COUP-TF repress its expression in the same cells. HNF-4 activation is abolished by increasing amounts of ARP-1 or Ear3/COUP-TF, and repression by ARP-1 or Ear3/COUP-TF is alleviated by increasing amounts of HNF-4. HNF-4 and ARP-1 bind with similar affinities to the C3P site, suggesting that their opposing transcriptional effects may be mediated by direct competition for DNA binding. HNF-4 and ARP-1 mRNAs are present within the same cells in the liver and intestine, and protein extracts from hepatic tissue, HepG2, and Caco2 cells contain significantly more HNF-4 than ARP-1 or Ear3/COUP-TF binding activities. These findings suggest that the transcription of the apoCIII gene in vivo is dependent, at least in part, upon the intracellular balance of these positive and negative regulatory factors.

Authors
Mietus-Snyder, M; Sladek, FM; Ginsburg, GS; Kuo, CF; Ladias, JA; Darnell, JE; Karathanasis, SK
MLA Citation
Mietus-Snyder, M., et al. “Antagonism between apolipoprotein AI regulatory protein 1, Ear3/COUP-TF, and hepatocyte nuclear factor 4 modulates apolipoprotein CIII gene expression in liver and intestinal cells..” Mol Cell Biol, vol. 12, no. 4, Apr. 1992, pp. 1708–18. Pubmed, doi:10.1128/mcb.12.4.1708.
PMID
1312668
Source
pubmed
Published In
Molecular and Cellular Biology
Volume
12
Issue
4
Publish Date
1992
Start Page
1708
End Page
1718
DOI
10.1128/mcb.12.4.1708

Coronary artery disease risk when total cholesterol levels are desirable

Authors
Ginsburg, GS; Pasternak, RC
MLA Citation
Ginsburg, G. S., and R. C. Pasternak. “Coronary artery disease risk when total cholesterol levels are desirable.” Cardiology Board Review, vol. 9, no. 5, Jan. 1992, pp. 83-84+89.
Source
scopus
Published In
Cardiology Board Review
Volume
9
Issue
5
Publish Date
1992
Start Page
83
End Page
84+89

Frequency of low serum high-density lipoprotein cholesterol levels in hospitalized patients with "desirable" total cholesterol levels.

Because the National Cholesterol Education Program guidelines suggest that levels of total serum cholesterol less than 5.17 mmol/liter (200 mg/dl) are "desirable," we performed a retrospective observational analysis to determine the prevalence of coronary artery disease (CAD) in patients with total cholesterol less than 5.17 mmol/liter (200 mg/dl) and the prevalence of total cholesterol less than 5.17 mmol/liter (200 mg/dl) in patients with CAD by angiography. Cholesterol levels less than 5.17 mmol/liter (200 mg/dl) were found in 1,084 of 2,535 patients (42%) having cholesterol measured on hospital admission; 690 of these 1,084 (64%) had CAD. These patients were mostly men, had a family history of premature CAD, and 60% (414 of 690) had high-density lipoprotein (HDL) cholesterol less than 0.90 mmol/liter (35 mg/dl). In a separate group of patients defined from the same admission population but having angiographically established CAD, 32% (424 of 1,197) had a total cholesterol less than 5.17 mmol/liter (200 mg/dl), 59% of whom (252 of 424) had HDL less than 0.90 mmol/liter (35 mg/dl). An analysis of persons admitted electively for angiography (to exclude any effects of hospitalization per se on serum lipids) revealed a similar proportion of persons with total cholesterol less than 5.17 mmol/liter (200 mg/dl) (35%), CAD (82%), and HDL less than 0.90 mmol/liter (35 mg/dl).(ABSTRACT TRUNCATED AT 250 WORDS)

Authors
Ginsburg, GS; Safran, C; Pasternak, RC
MLA Citation
Ginsburg, G. S., et al. “Frequency of low serum high-density lipoprotein cholesterol levels in hospitalized patients with "desirable" total cholesterol levels..” Am J Cardiol, vol. 68, no. 2, July 1991, pp. 187–92. Pubmed, doi:10.1016/0002-9149(91)90742-4.
PMID
2063780
Source
pubmed
Published In
The American Journal of Cardiology
Volume
68
Issue
2
Publish Date
1991
Start Page
187
End Page
192
DOI
10.1016/0002-9149(91)90742-4

Reassembled plasma low density lipoproteins. Phospholipid-cholesterol ester-apoprotein B complexes.

Reassembled low density lipoprotein (LDL) complexes have been prepared by the interaction of lipid-free sodium deoxycholate-solubilized apoprotein B (apoB) of native human LDL with preformed, 200 A in diameter, microemulsions of cholesteryl oleate (CO), surface-stabilized by either egg yolk phosphatidylcholine ( EYPC ) or dimyristoyl phosphatidylcholine (DMPC). Gel chromatography of PC/CO/apoB complexes shows co-elution of the complex at 43% PC, 43% CO, and 14% apoB. Negative stain electron microscopy shows the particles to be circular, homogeneous, and approximately 200 A in diameter. PC/CO/apoB complexes exhibit beta-migration on agarose gels and show one high molecular weight protein band on 3.0% sodium dodecyl sulfate-polyacrylamide gels. Differential scanning calorimetry and x-ray scattering show the lipids in the complexes to undergo at least two specific thermal transitions depending on lipid composition, one associated with the core-located cholesterol esters similar to LDL and the protein-free microemulsions and the other from the phospholipid forming the surface monolayer. In addition, particle disruption-protein unfolding/denaturation occur irreversibly at 80-85 degrees C. At 4 degrees C, the secondary structure of apoB on complexes of EYPC /CO/apoB is similar to that of native LDL. For complexes of DMPC/CO/apoB, the secondary structure shows less alpha-helix which correlates with the difference in surface lipid environment. The reassembled complexes of PC/CO/apoB provide a defined system in which the components may be varied systematically in order to study the molecular organization, molecular interactions, and metabolism of LDL.

Authors
Ginsburg, GS; Walsh, MT; Small, DM; Atkinson, D
MLA Citation
Ginsburg, G. S., et al. “Reassembled plasma low density lipoproteins. Phospholipid-cholesterol ester-apoprotein B complexes..” J Biol Chem, vol. 259, no. 10, May 1984, pp. 6667–73.
PMID
6725265
Source
pubmed
Published In
The Journal of Biological Chemistry
Volume
259
Issue
10
Publish Date
1984
Start Page
6667
End Page
6673

Physical properties of cholesteryl esters.

Cholesteryl esters, the intracellular storage form and intravascular transport form of cholesterol, can exist in crystal, liquid crystal and liquid states. The physical state of cholesteryl esters at physiologic temperatures may be a determinant of their pathogenicity. This review has surveyed saturated aliphatic cholesteryl esters of chain length 1 to 24 carbons and a series of medium-chained unsaturated cholesteryl esters from chain lengths 14 to 24 carbons. A systematic study of transition temperatures by polarizing microscopy and enthalpies by differential scanning calorimetry has provided unifying concepts concerning the phase behavior as a function of chain length and unsaturation. Neat cholesteryl esters show chain-length dependence of transition temperature and enthalpy of both the crystal and liquid crystal transitions. Double bond position along the fatty acyl chain affected stability of the liquid crystal phases; a smectic phase was not observed for any cholesteryl ester with a double bond more proximal than delta 9. 13C NMR spectroscopy in the isotropic liquid phase has provided evidence suggesting a balance of ring-ring vs. chain-chain interactions as a determinant for isotropic liquid----cholesteric vs. isotropic liquid----smectic transitions. Specifically, anisotropic molecular motions of the steroid ring are greater for cholesteryl esters forming a cholesteric phase than a smectic phase from the melt. Chain-chain interactions apparently predominate in smectic phase formation. The X-ray diffraction patterns of cholesteryl esters as a function of chain length reveal several isostructural series and known single crystal data are presented. A chain length depending on the periodicity of the smectic phase is observed which may be different for saturated vs. unsaturated esters. In summary, the phase behavior of cholesteryl ester molecules is complex and cannot be determined a priori from the phase behavior of component cholesterol and fatty acid. The data presented here should provide insight into the biological behavior of this lipid class.

Authors
Ginsburg, GS; Atkinson, D; Small, DM
MLA Citation
Ginsburg, G. S., et al. “Physical properties of cholesteryl esters..” Prog Lipid Res, vol. 23, no. 3, 1984, pp. 135–67.
PMID
6399750
Source
pubmed
Published In
Progress in Lipid Research
Volume
23
Issue
3
Publish Date
1984
Start Page
135
End Page
167

Temperature-dependent molecular motions of cholesterol esters: a carbon-13 nuclear magnetic resonance study.

Carbon-13 NMR spectroscopy at 50.3 MHz has been used to study four long-chain cholesterol esters with a double bond in the omega-9 position: cholesteryl oleate, C18:1, omega-9; cholesteryl linoleate, C18:2, omega-6,9; cholesteryl erucate, C22:1, omega-9; cholesteryl nervonate, C24:1, omega-9. The linoleate and oleate esters exhibit two metastable liquid-crystalline phases (cholesteric and smectic), whereas the longer chain esters form a stable smectic phase but no cholesteric phase [Ginsburg, G. S., & Small, D. M. (1981) Biochim. Biophys. Acta 664, 98-107]. Line widths (nu 1/2), spin--lattice relaxation times (T1), and nuclear Overhauser enhancements (NOE) were measured for all well-resolved resonances from ring and fatty acyl (FA) carbons at different temperatures in the isotropic liquid of each ester. T1 and NOE values of FA resonances were constant between the FA-2 carbon and olefinic region of each acyl chain and increased markedly for carbons near the chain terminus. FA carbon motions are thus restricted and/or highly correlated in the region between the ring and the olefinic carbons, suggesting that strong interactions occur between cholesterol ester molecules in this region of the FA chain. These results also suggest that the FA chains are approximately extended in the isotropic liquid. Steroid ring methine C-6 and C-3 nu 1/2's increased differentially on cooling to the liquid leads to liquid crystal transition temperature (Tm) of each ester, indicative of increasingly anisotropic ring rotations. The rotational anisotropy was quantitated by using a prolate ellipsoid model for the cholesterol ester molecule for which two correlation times (corresponding to rotations about the long and short molecular axes) were calculated from the C-3 and C-6 nu 1/2 values. The C-3/C-6 nu 1/2 ratio was directly proportional to the anisotropy of the ring motions as measured by the ratio of the two correlation times. At any given temperature relative to Tm, the C-3 and C-6 nu 1/2's and the C-3/C-6 nu 1/2 ratios were larger for cholesterol esters which have a cholesteric phase than for esters which have no cholesteric phase, showing that steroid ring motions were more restricted and more anisotropic prior to the formation of a cholesteric phase. Cholesteryl erucate and cholesteryl nervonate have longer regions of FA chain interactions which result in greater chain cooperativity, apparently preventing the preordering of steroid rings to the degree necessary for formation of a cholesteric phase. Thus, these esters form the smectic phase directly from the isotropic liquid. These results are applied to the cholesterol ester transition in plasma low-density lipoproteins.

Authors
Ginsburg, GS; Small, DM; Hamilton, JA
MLA Citation
Ginsburg, G. S., et al. “Temperature-dependent molecular motions of cholesterol esters: a carbon-13 nuclear magnetic resonance study..” Biochemistry, vol. 21, no. 26, Dec. 1982, pp. 6857–67. Pubmed, doi:10.1021/bi00269a036.
PMID
7159569
Source
pubmed
Published In
Biochemistry
Volume
21
Issue
26
Publish Date
1982
Start Page
6857
End Page
6867
DOI
10.1021/bi00269a036

Microemulsions of phospholipids and cholesterol esters. Protein-free models of low density lipoprotein.

Authors
Ginsburg, GS; Small, DM; Atkinson, D
MLA Citation
Ginsburg, G. S., et al. “Microemulsions of phospholipids and cholesterol esters. Protein-free models of low density lipoprotein..” J Biol Chem, vol. 257, no. 14, July 1982, pp. 8216–27.
PMID
7085667
Source
pubmed
Published In
The Journal of Biological Chemistry
Volume
257
Issue
14
Publish Date
1982
Start Page
8216
End Page
8227

Physical properties of cholesteryl esters having 20 carbons or more.

By polarizing microscopy and differential scanning calorimetry we observed that the relative stability of the smectic and cholesteric mesophases of cholesteryl esters of acyl chain length of 20 carbons or more depends on the length of the acyl chain and its degree of unsaturation. Significantly, the addition of a single double bond to the acyl chain of a fully saturated cholesteryl ester which exhibits no mesophases (e.g., cholesteryl behenate (C22:0) and cholesteryl lignocerate (C24:0) yields an ester which displays an unusually stable smectic mesophase, bot no cholesteric mesophase. In fact, increasing unsaturation was found to have a destabilizing effect on the cholesteric phase. Similarly, a decrease in thermal stability of the cholesteric mesophase was observed with increasing thermal stability of the smectic mesophase increased in the same series. X-ray scattering data are presented on the smectic mesophase of cholesteryl erucate (C22:1) and cholesteryl nervonate (C24:1). Significant differences in molecular packing of these two monounsaturated omega = 9 cholesteryl esters in the crystalline state are demonstrated by preliminary X-ray scattering experiments.

Authors
Ginsburg, GS; Small, DM
MLA Citation
Ginsburg, G. S., and D. M. Small. “Physical properties of cholesteryl esters having 20 carbons or more..” Biochim Biophys Acta, vol. 664, no. 1, Apr. 1981, pp. 98–107. Pubmed, doi:10.1016/0005-2760(81)90032-1.
PMID
7236700
Source
pubmed
Published In
Biochimica Et Biophysica Acta
Volume
664
Issue
1
Publish Date
1981
Start Page
98
End Page
107
DOI
10.1016/0005-2760(81)90032-1

Stereoelectronic Control in the Electrochemical and Mercury-Promoted Reductive Acetoxylation of α,α’-Dibromobicycloalkanones

Reductions in acetic acid of the stereochemically well-defined α,α'-dibromo ketones cis-2,6-dibromo-3,3,5,5-tetramethylcyclohexanone, cis-2,6-dibromo-4-tert-butylcyclohexanone, 2,4-dibromobicyclo[3.2.1]octan-3-one (and its 2,4-dimethyl derivative), and dibromoisopinocamphone were carried out both electrochemically and by finely dispersed mercury. The results are consistent with a previously proposed mechanism for such reactions involving as its key step the ionization of an enol allylic bromide to a 2-hydroxyallyl cation. © 1979, American Chemical Society. All rights reserved.

Authors
Fry, AJ; Ginsburg, GS
MLA Citation
Fry, A. J., and G. S. Ginsburg. “Stereoelectronic Control in the Electrochemical and Mercury-Promoted Reductive Acetoxylation of α,α’-Dibromobicycloalkanones.” Journal of the American Chemical Society, vol. 101, no. 14, July 1979, pp. 3927–32. Scopus, doi:10.1021/ja00508a034.
Source
scopus
Published In
Journal of the American Chemical Society
Volume
101
Issue
14
Publish Date
1979
Start Page
3927
End Page
3932
DOI
10.1021/ja00508a034

Additions and Corrections: Stereoelectronic Control in the Electrochemical and Mercury-Promoted Reductive Acetoxylation of α,α⎹-Dibromobicycloalkanones (Journal of the American Chemical Society (1979) 101(24) (7439))

Page 3928, column 2: The caption to a drawing is in error. The proper placement of numbers is given below. © 1979, American Chemical Society. All rights reserved.

Authors
Fry, AJ; Ginsburg, GS
MLA Citation
Fry, A. J., and G. S. Ginsburg. “Additions and Corrections: Stereoelectronic Control in the Electrochemical and Mercury-Promoted Reductive Acetoxylation of α,α⎹-Dibromobicycloalkanones (Journal of the American Chemical Society (1979) 101(24) (7439)).” Journal of the American Chemical Society, vol. 101, no. 24, Feb. 1979. Scopus, doi:10.1021/ja00518a610.
Source
scopus
Published In
Journal of the American Chemical Society
Volume
101
Issue
24
Publish Date
1979
Start Page
7439
DOI
10.1021/ja00518a610

Reductive Acetoxylation on α, α's-Dibromocycloalkanones by Ultrasonically Dispersed Mercury

The α, α's-dibromocycloalkanones of ring size 5-12 were reduced by ultrasonically dispersed mercury in acetic acid. Products were the corresponding cycloalkanone and α-acetoxycycloalkanone. The ratio of these two is quite sensitive to ring size, and this fact is used to support the intermediat