Publications by authors named "Deepak Voora"

68 Publications

United States Emergency Department Use of Medications with Pharmacogenetic Recommendations.

West J Emerg Med 2021 Sep 23;22(6):1347-1354. Epub 2021 Sep 23.

Duke University School of Medicine, Division of Cardiology, Durham, North Carolina.

Introduction: Emergency departments (ED) use many medications with a range of therapeutic efficacy and potential significant side effects, and many medications have dosage adjustment recommendations based on the patient's specific genotype. How frequently medications with such pharmaco-genetic recommendations are used in United States (US) EDs has not been studied.

Methods: We conducted a cross-sectional analysis of the 2010-2015 National Hospital Ambulatory Medical Care Survey (NHAMCS). We reported the proportion of ED visits in which at least one medication with Clinical Pharmacogenetics Implementation Consortium (CPIC) recommendation of Level A or B evidence was ordered. Secondary comparisons included distributions and 95% confidence intervals of age, gender, race/ethnicity, ED disposition, geographical region, immediacy, and insurance status between all ED visits and those involving a CPIC medication.

Results: From 165,155 entries representing 805,726,000 US ED visits in the 2010-2015 NHAMCS, 148,243,000 ED visits (18.4%) led to orders of CPIC medications. The most common CPIC medication was tramadol (6.3%). Visits involving CPIC medications had higher proportions of patients who were female, had private insurance and self-pay, and were discharged from the ED. They also involved lower proportions of patients with Medicare and Medicaid.

Conclusion: Almost one fifth of US ED visits involve a medication with a pharmacogenetic recommendation that may impact the efficacy and toxicity for individual patients. While direct application of genotyping is still in development, it is important for emergency care providers to understand and support this technology given its potential to improve individualized, patient-centered care.
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http://dx.doi.org/10.5811/westjem.2021.5.51248DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8597689PMC
September 2021

Aspirin effects on platelet gene expression are associated with a paradoxical, increase in platelet function.

Br J Clin Pharmacol 2021 Oct 27. Epub 2021 Oct 27.

Center for Applied Genomics & Precision Medicine, Duke University School of Medicine, Durham, NC, United States.

Aspirin has known effects beyond inhibiting platelet cyclooxygenase-1 (COX-1) that have been incompletely characterized. Transcriptomics can comprehensively characterize the on- and off-target effects of medications. We used a systems pharmacogenomics approach of aspirin exposure in volunteers coupled with serial platelet function and purified platelet mRNA sequencing to test the hypothesis that aspirin's effects on the platelet transcriptome are associated with platelet function. We prospectively recruited 74 adult volunteers for a randomized crossover study of 81- vs. 325 mg/day, each for 4 weeks. Using mRNA sequencing of purified platelets collected before and after each 4-week exposure, we identified 208 aspirin-responsive genes with no evidence for dosage effects. In independent cohorts of healthy volunteers and patients with diabetes, we validated aspirin's effects on five genes: EIF2S3, CHRNB1, EPAS1, SLC9A3R2 and HLA-DRA. Functional characterization of the effects of aspirin on mRNA as well as platelet ribosomal RNA demonstrated that aspirin may act as an inhibitor of protein synthesis. Database searches for small molecules that mimicked the effects of aspirin on platelet gene expression in vitro identified aspirin but no other molecules that share aspirin's known mechanisms of action. The effects of aspirin on platelet mRNA were correlated with higher levels of platelet function both at baseline and after aspirin exposure-an effect that counteracts aspirin's known antiplatelet effect. In summary, this work collectively demonstrates a dose-independent effect of aspirin on the platelet transcriptome that counteracts the well-known antiplatelet effects of aspirin.
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http://dx.doi.org/10.1111/bcp.15127DOI Listing
October 2021

Evaluation of the Veterans Affairs Pharmacogenomic Testing for Veterans (PHASER) clinical program at initial test sites.

Pharmacogenomics 2021 Nov 27;22(17):1121-1133. Epub 2021 Oct 27.

Durham VA Health Care System, Durham, NC 27705, USA.

The first Plan-Do-Study-Act cycle for the Veterans Affairs Pharmacogenomic Testing for Veterans pharmacogenomic clinical testing program is described. Surveys evaluating implementation resources and processes were distributed to implementation teams, providers, laboratory and health informatics staff. Survey responses were mapped to the Consolidated Framework for Implementation Research constructs to identify implementation barriers. The Expert Recommendation for Implementing Change strategies were used to address implementation barriers. Survey response rate was 23-73% across personnel groups at six Veterans Affairs sites. Nine Consolidated Framework for Implementation Research constructs were most salient implementation barriers. Program revisions addressed these barriers using the Expert Recommendation for Implementing Change strategies related to three domains. Beyond providing free pharmacogenomic testing, additional implementation barriers need to be addressed for improved program uptake.
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http://dx.doi.org/10.2217/pgs-2021-0089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8592066PMC
November 2021

Independent Community Pharmacists' Experience in Offering Pharmacogenetic Testing.

Pharmgenomics Pers Med 2021 15;14:877-886. Epub 2021 Jul 15.

Center for Applied Genomics & Precision Medicine, Durham, NC, 27708, USA.

Objective: This study assessed pharmacist experiences with delivering pharmacogenetic (PGx) testing in independent community pharmacies.

Methods: We conducted a cluster randomized trial of independent community pharmacies in North Carolina randomized to provide either PGx testing as a standalone service or integrated into medication therapy management (MTM) services. Surveys and pharmacist data about the delivery of PGx testing were collected. Semi-structured interviews were also conducted.

Results: A total of 36 pharmacists participated in the study from 22 pharmacies. Sixteen pharmacists completed the pre-study and post-study surveys, and four pharmacists completed the semi-structured interviews. Thirty-one percent (11/36) of pharmacists had had some education in personalized medicine or PGx prior to the study. The only outcome that differed by study arm was the use of educational resources, with significantly higher utilization in the PGx testing only arm (p=0.007). Overall, compared to the pre-study assessment, pharmacists' knowledge about PGx significantly improved post-study (p=0.018). In the post-study survey, almost all pharmacists indicated that they felt qualified/able to provide PGx testing at their pharmacy. While 75% of pharmacists indicated that they may continue to provide PGx testing at their pharmacy after the study, the major concerns were lack of reimbursement for PGx counseling and consultation given the necessary time required.

Conclusion: Our findings demonstrated a positive experience with delivering PGx testing in the community pharmacy setting with little difference in pharmacists' experiences in providing PGx testing with or without MTM. Pharmacists were confident in their ability to provide PGx testing and were interested in continuing to offer testing, though sustained delivery may be challenged by lack of prescribing provider engagement and reimbursement.
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http://dx.doi.org/10.2147/PGPM.S314972DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8289463PMC
July 2021

Delivery of Pharmacogenetic Testing with or without Medication Therapy Management in a Community Pharmacy Setting.

Pharmgenomics Pers Med 2021 9;14:785-796. Epub 2021 Jul 9.

Center for Applied Genomics & Precision Medicine, Duke University School of Medicine, Durham, NC, 27708, USA.

Objective: The delivery of pharmacogenetic (PGx) testing has primarily been through clinical and hospital settings. We conducted a study to explore the feasibility of delivering PGx testing through community pharmacies, a less-studied setting.

Methods: We conducted a cluster randomized trial of community pharmacies in North Carolina through two approaches: the provision of PGx testing alone or PGx testing with medication therapy management (MTM).

Results: A total of 150 patient participants were enrolled at 17 pharmacies and reported high satisfaction with their testing experience. Participants in the PGx plus MTM arm were more likely to recall a higher number of results (p=0.04) and more likely to clearly understand their choices for prevention or early detection of side effects (p=0.01). A medication or dose change based on the PGx results was made for 8.7% of participants.

Conclusion: Limited differences were observed in the provision of PGx testing as a standalone test or combined with MTM. A limited number of treatment changes were made based on PGx test results. Patient acceptance of PGx testing offered through the community pharmacy was very high, but the addition of MTM did not impact patient-reported perceptions about PGx testing or medication adherence.
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http://dx.doi.org/10.2147/PGPM.S314961DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8277445PMC
July 2021

Establishing the value of genomics in medicine: the IGNITE Pragmatic Trials Network.

Genet Med 2021 07 29;23(7):1185-1191. Epub 2021 Mar 29.

Division of Genomic Medicine, National Human Genome Research Institute, NIH, Bethesda, MD, USA.

Purpose: A critical gap in the adoption of genomic medicine into medical practice is the need for the rigorous evaluation of the utility of genomic medicine interventions.

Methods: The Implementing Genomics in Practice Pragmatic Trials Network (IGNITE PTN) was formed in 2018 to measure the clinical utility and cost-effectiveness of genomic medicine interventions, to assess approaches for real-world application of genomic medicine in diverse clinical settings, and to produce generalizable knowledge on clinical trials using genomic interventions. Five clinical sites and a coordinating center evaluated trial proposals and developed working groups to enable their implementation.

Results: Two pragmatic clinical trials (PCTs) have been initiated, one evaluating genetic risk APOL1 variants in African Americans in the management of their hypertension, and the other to evaluate the use of pharmacogenetic testing for medications to manage acute and chronic pain as well as depression.

Conclusion: IGNITE PTN is a network that carries out PCTs in genomic medicine; it is focused on diversity and inclusion of underrepresented minority trial participants; it uses electronic health records and clinical decision support to deliver the interventions. IGNITE PTN will develop the evidence to support (or oppose) the adoption of genomic medicine interventions by patients, providers, and payers.
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http://dx.doi.org/10.1038/s41436-021-01118-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8263480PMC
July 2021

North Carolina's multi-institutional pharmacogenomics efforts with the North Carolina Precision Health Collaborative.

Pharmacogenomics 2021 01 15;22(2):73-80. Epub 2021 Jan 15.

Division of Pharmacotherapy & Experimental Therapeutics, The University of North Carolina Chapel Hill Eshelman School of Pharmacy & UNC Health, Chapel Hill, NC 27514, USA.

The North Carolina Precision Health Collaborative is an interdisciplinary, public-private consortium of precision health experts who strategically align statewide resources and strengths to elevate precision health in the state and beyond. Pharmacogenomics (PGx) is a key area of focus for the North Carolina Precision Health Collaborative. Experts from Atrium Health's Levine Cancer Institute, Duke University/Duke Health System, Mission Health and the University of North Carolina (UNC) at Chapel Hill/UNC Health System have collaborated since 2017 to implement strategic PGx initiatives, including basic sciences research, translational research and clinical implementation of germline testing into practice and policy. This institutional profile highlights major PGx programs and initiatives across these organizations and how the collaborative is working together to advance PGx science and implementation.
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http://dx.doi.org/10.2217/pgs-2020-0156DOI Listing
January 2021

Veterans Affairs Pharmacogenomic Testing for Veterans (PHASER) clinical program.

Pharmacogenomics 2021 02 6;22(3):137-144. Epub 2021 Jan 6.

Durham VA Health Care System, Durham, NC 27705, USA.

In 2019, the Veterans Affairs (VA), the largest integrated US healthcare system, started the Pharmacogenomic Testing for Veterans (PHASER) clinical program that provides multi-gene pharmacogenomic (PGx) testing for up to 250,000 veterans at approximately 50 sites. PHASER is staggering program initiation at sites over a 5-year period from 2019 to 2023, as opposed to simultaneous initiation at all sites, to facilitate iterative program quality improvements through Plan-Do-Study-Act cycles. Current resources in the PGx field have not focused on multisite, remote implementation of panel-based PGx testing. In addition to bringing large scale PGx testing to veterans, the PHASER program is developing a roadmap to maximize uptake and optimize the use of PGx to improve drug response outcomes.
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http://dx.doi.org/10.2217/pgs-2020-0173DOI Listing
February 2021

Modeling statin myopathy in a human skeletal muscle microphysiological system.

PLoS One 2020 25;15(11):e0242422. Epub 2020 Nov 25.

Duke Center for Applied Genomics & Precision Medicine, Durham, NC, United States of America.

Statins are used to lower cholesterol and prevent cardiovascular disease. Musculoskeletal side effects known as statin associated musculoskeletal symptoms (SAMS), are reported in up to 10% of statin users, necessitating statin therapy interruption and increasing cardiovascular disease risk. We tested the hypothesis that, when exposed to statins ex vivo, engineered human skeletal myobundles derived from individuals with (n = 10) or without (n = 14) SAMS and elevated creatine-kinase levels exhibit statin-dependent muscle defects. Myoblasts were derived from muscle biopsies of individuals (median age range of 62-64) with hyperlipidemia with (n = 10) or without (n = 14) SAMS. Myobundles formed from myoblasts were cultured with growth media for 4 days, low amino acid differentiation media for 4 days, then dosed with 0 and 5μM of statins for 5 days. Tetanus forces were subsequently measured. To model the change of tetanus forces among clinical covariates, a mixed effect model with fixed effects being donor type, statin concentration, statin type and their two way interactions (donor type*statin concentration and donor type* statin type) and the random effect being subject ID was applied. The results indicate that statin exposure significantly contributed to decrease in force (P<0.001) and the variability in data (R2C [R square conditional] = 0.62). We found no significant differences in force between myobundles from patients with/without SAMS, many of whom had chronic diseases. Immunofluorescence quantification revealed a positive correlation between the number of straited muscle fibers and tetanus force (R2 = 0.81,P = 0.015) and negative correlation between number of fragmented muscle fibers and tetanus force (R2 = 0.482,P = 0.051) with no differences between donors with or without SAMS. There is also a correlation between statin exposure and presence of striated fibers (R2 = 0.833, P = 0.047). In patient-derived myobundles, statin exposure results in myotoxicity disrupting SAA organization and reducing force. We were unable to identify differences in ex vivo statin myotoxicity in this system. The results suggest that it is unlikely that there is inherent susceptibility to or persistent effects of statin myopathy using patient-derived myobundles.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0242422PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7688150PMC
January 2021

Platelet reactivity in response to aspirin and ticagrelor in African-Americans and European-Americans.

J Thromb Thrombolysis 2021 Feb 6;51(2):249-259. Epub 2020 Nov 6.

Center for Applied Genomics & Precision Medicine, Duke University, 2187 CIEMAS, Campus Box 3382, Durham, NC, 27708, USA.

Platelet gene polymorphisms are associated with variable on-treatment platelet reactivity and vary by race. Whether differences in platelet reactivity and aspirin or ticagrelor exist between African-American and European-Americans remains poorly understood. Biological samples from three prior prospective antiplatelet challenge studies at the Duke Clinical Research Unit were used to compare platelet reactivity between African-American and European-American subjects. Platelet reactivity at baseline, on-aspirin, on-ticagrelor, and the treatment effect of aspirin or ticagrelor were compared between groups using an adjusted mixed effects model. Compared with European-Americans (n = 282; 50% female; mean ± standard deviation age, 50 ± 16), African-Americans (n = 209; 67% female; age 48 ± 12) had lower baseline platelet reactivity with platelet function analyzer-100 (PFA-100) (p < 0.01) and with light transmission aggregometry (LTA) in response to arachidonic acid (AA), adenosine diphosphate (ADP), and epinephrine agonists (p < 0.05). African-Americans had lower platelet reactivity on aspirin in response to ADP, epinephrine, and collagen (p < 0.05) and on ticagrelor in response to AA, ADP, and collagen (p < 0.05). The treatment effect of aspirin was greater in European-Americans with an AA agonist (p = 0.002). Between-race differences with in vitro aspirin mirrored those seen in vivo. The treatment effect of ticagrelor was greater in European-Americans in response to ADP (p < 0.05) but with collagen, the treatment effect was greater for African-Americans (p < 0.05). Platelet reactivity was overall lower in African-Americans off-treatment, on aspirin, and on ticagrelor. European-Americans experienced greater platelet suppression on aspirin and on ticagrelor. The aspirin response difference in vivo and in vitro suggests a mechanism intrinsic to the platelet. Whether the absolute level of platelet reactivity or the degree of platelet suppression after treatment is more important for clinical outcomes is uncertain.
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http://dx.doi.org/10.1007/s11239-020-02327-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7889728PMC
February 2021

Identifying End Users' Preferences about Structuring Pharmacogenetic Test Orders in an Electronic Health Record System.

J Mol Diagn 2020 10;22(10):1264-1271

San Francisco VA Health Care System, San Francisco, California; Division of Hematology-Oncology, Department of Pediatrics University of California, San Francisco School of Medicine, San Francisco, California; Department of Medicine, and the Division of Medical Genetics, Department of Pediatrics, University of California, San Francisco School of Medicine, San Francisco, California.

Pharmacogenetics (PGx) testing can be used for detecting genetic variations that may affect an individual's anticipated metabolism of, or response to, medications. Although several studies have focused on developing tools for delivering results from PGx testing, there is a relative dearth of information about how to design provider-friendly electronic order-entry systems for PGx. The U.S. Department of Veterans Affairs (VA) is preparing to implement a new electronic health records system. In this study, VA PGx test end users were surveyed about their preferences for how electronic test orders for PGx should be structured, including the nomenclature that should be used to search for and identify PGx-test orders, whether to offer single- versus multigene tests, and whether information about test methodology should be included in the order name. Responses were analyzed systematically to identify areas of agreement and disagreement with the survey options, and areas where respondents' opinions diverged. End users endorsed preferences for flexible ways to identify and order PGx tests and multigene panel tests; opinions on whether test methodology should be included in the test name were divergent. The results could be used for both informing the VA's new electronic health records implementation (including how PGx tests are searched for and ordered) and for providing insights for other health systems implementing PGx-testing programs.
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http://dx.doi.org/10.1016/j.jmoldx.2020.06.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7527867PMC
October 2020

Association of Hepatic Steatosis With Major Adverse Cardiovascular Events, Independent of Coronary Artery Disease.

Clin Gastroenterol Hepatol 2021 07 21;19(7):1480-1488.e14. Epub 2020 Jul 21.

Cardiovascular Imaging Research Center, Massachusetts General Hospital, Boston, Massachusetts; Knight Cardiovascular Institute, Oregon Health and Science University, Portland, Oregon.

Background & Aims: Hepatic steatosis has been associated with increased risk of major adverse cardiovascular events (MACE) but it is not clear whether steatosis is independently associated with risk of MACE. We investigated whether steatosis is associated with risk of MACE independently of the presence and extent of baseline coronary artery disease, assessed by comprehensive contrast-enhanced computed tomography angiography (CTA).

Methods: We conducted a nested cohort study of 3756 subjects (mean age, 60.6 years; 48.4% men) who underwent coronary CTA at 193 sites in North America, from July 2010 through September 2013, as part of the PROMISE study, which included noninvasive cardiovascular analyses of symptomatic outpatients without coronary artery disease. Independent core laboratory readers measured hepatic and splenic attenuation, using non-contrast computed tomography images to identify steatosis, and evaluated coronary plaques and stenosis in coronary CTA images. We collected data on participants' cardiovascular risk factors, presence of metabolic syndrome, and body mass index. The primary endpoint was an adjudicated composite of MACE (death, myocardial infarction, or unstable angina) during a median follow-up time of 25 months.

Results: Among the 959 subjects who had steatosis (25.5% of the cohort), 42 had MACE (4.4%), whereas among the 2797 subjects without steatosis, 73 had MACE (2.6%) (hazard ratio [HR] for MACE in subjects with steatosis, 1.69; 95% CI, 1.16-2.48; P = .006 for MACE in subjects with vs without steatosis). This association remained after adjustment for atherosclerotic cardiovascular disease risk scores, significant stenosis, and metabolic syndrome (adjusted HR, 1.72; 95% CI, 1.16-2.54; P = .007) or obesity (adjusted HR, 1.75; 95% CI, 1.19-2.59; P = .005). Steatosis remained independently associated with MACE after adjustment for all CTA measures of plaques and stenosis.

Conclusions: Hepatic steatosis is associated with MACE independently of other cardiovascular risk factors or extent of coronary artery disease. Strategies to reduce steatosis might reduce risk of MACE. ClinicalTrials.gov no: NCT01174550.
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http://dx.doi.org/10.1016/j.cgh.2020.07.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855524PMC
July 2021

Influence of Sex on Platelet Reactivity in Response to Aspirin.

J Am Heart Assoc 2020 07 11;9(14):e014726. Epub 2020 Jul 11.

Division of Cardiology Duke University Durham NC.

Background There are sex differences in the efficacy and safety of aspirin for the prevention of myocardial infarction and stroke. Whether this is explained by underlying differences in platelet reactivity and aspirin response remains poorly understood. Methods and Results Healthy volunteers (n=378 208 women) and patients with coronary artery disease or coronary artery disease risk factors (n=217 112 women) took aspirin for 4 weeks. Light transmittance aggregometry using platelet-rich plasma was used to measure platelet reactivity in response to epinephrine, collagen, and ADP at baseline, 3 hours after the first aspirin dose, and after 4 weeks of daily aspirin therapy. A subset of patients underwent pharmacokinetic and pharmacodynamic assessment with levels of salicylate and cyclooxygenase-1-derived prostaglandin metabolites and light transmittance aggregometry in response to arachidonic acid and after ex vivo exposure to aspirin. At baseline, women had increased platelet aggregation in response to ADP and collagen. Innate platelet response to aspirin, assessed with ex vivo aspirin exposure of baseline platelets, did not differ by sex. Three hours after the first oral aspirin dose, platelet aggregation was inhibited in women to a greater degree in response to epinephrine and to a lesser degree with collagen. After 4 weeks of daily therapy, despite higher salicylate concentrations and greater cyclooxygenase-1 inhibition, women exhibited an attenuation of platelet inhibition in response to epinephrine and ADP. Conclusions We observed agonist-dependent sex differences in platelet responses to aspirin. Despite higher cyclooxygenase-1 inhibition, daily aspirin exposure resulted in a paradoxical attenuation of platelet inhibition in response to epinephrine and ADP over time in women but not in men.
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http://dx.doi.org/10.1161/JAHA.119.014726DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7660714PMC
July 2020

Understanding the state of pharmacogenomic testing for thiopurine methyltransferase within a large health system.

Pharmacogenomics 2020 04 20;21(6):411-418. Epub 2020 Apr 20.

Duke Center for Applied Genomics & Precision Medicine, Duke University School of Medicine, Durham, NC 27708, USA.

To investigate the current state of TPMT testing at a single-academic medical center. Single-center, retrospective chart review for patients newly prescribed a thiopurine. Data collection and evaluation included the prevalence and timing of TPMT testing, correct dosage adjustment if applicable, and incidence of myelosuppression. 121 patients (71%) received TPMT testing. Out of the tested patients, 110 (90.9%) were designated as wild-type with normal metabolism. Dosing modification was appropriate in applicable patients. In unadjusted analysis, there was a lower incidence of myelosuppression among patients who were tested versus those who were not (16.5 vs 36.7%). Based on the study results, TPMT testing opportunities exist for nearly 30% of patients. Testing may reduce the incidence of myelosuppression.
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http://dx.doi.org/10.2217/pgs-2019-0148DOI Listing
April 2020

Cost-Effectiveness of Multigene Pharmacogenetic Testing in Patients With Acute Coronary Syndrome After Percutaneous Coronary Intervention.

Value Health 2020 01 25;23(1):61-73. Epub 2019 Sep 25.

Division of Pharmacotherapy and Experimental Therapeutics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Center for Pharmacogenomics and Individualized Therapy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

Objective: To evaluate the cost-effectiveness of multigene testing (CYP2C19, SLCO1B1, CYP2C9, VKORC1) compared with single-gene testing (CYP2C19) and standard of care (no genotyping) in acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI) from Medicare's perspective.

Methods: A hybrid decision tree/Markov model was developed to simulate patients post-PCI for ACS requiring antiplatelet therapy (CYP2C19 to guide antiplatelet selection), statin therapy (SLCO1B1 to guide statin selection), and anticoagulant therapy in those that develop atrial fibrillation (CYP2C9/VKORC1 to guide warfarin dose) over 12 months, 24 months, and lifetime. The primary outcome was cost (2016 US dollar) per quality-adjusted life years (QALYs) gained. Costs and QALYs were discounted at 3% per year. Probabilistic sensitivity analysis (PSA) varied input parameters (event probabilities, prescription costs, event costs, health-state utilities) to estimate changes in the cost per QALY gained.

Results: Base-case-discounted results indicated that the cost per QALY gained was $59 876, $33 512, and $3780 at 12 months, 24 months, and lifetime, respectively, for multigene testing compared with standard of care. Single-gene testing was dominated by multigene testing at all time horizons. PSA-discounted results indicated that, at the $50 000/QALY gained willingness-to-pay threshold, multigene testing had the highest probability of cost-effectiveness in the majority of simulations at 24 months (61%) and over the lifetime (81%).

Conclusions: On the basis of projected simulations, multigene testing for Medicare patients post-PCI for ACS has a higher probability of being cost-effective over 24 months and the lifetime compared with single-gene testing and standard of care and could help optimize medication prescribing to improve patient outcomes.
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http://dx.doi.org/10.1016/j.jval.2019.08.002DOI Listing
January 2020

Longitudinal RNA-Seq Analysis of the Repeatability of Gene Expression and Splicing in Human Platelets Identifies a Platelet Splice QTL.

Circ Res 2020 02 19;126(4):501-516. Epub 2019 Dec 19.

From the Molecular Medicine Program (M.T.R., H.S., J.F.H., O.L., S.C.B., A.S.E., E.M., R.A.C., N.D.T., Y.K., A.S.W., P.F.B., J.W.R.).

Rationale: Longitudinal studies are required to distinguish within versus between-individual variation and repeatability of gene expression. They are uniquely positioned to decipher genetic signal from environmental noise, with potential application to gene variant and expression studies. However, longitudinal analyses of gene expression in healthy individuals-especially with regards to alternative splicing-are lacking for most primary cell types, including platelets.

Objective: To assess repeatability of gene expression and splicing in platelets and use repeatability to identify novel platelet expression quantitative trait loci (QTLs) and splice QTLs.

Methods And Results: We sequenced the transcriptome of platelets isolated repeatedly up to 4 years from healthy individuals. We examined within and between individual variation and repeatability of platelet RNA expression and exon skipping, a readily measured alternative splicing event. We find that platelet gene expression is generally stable between and within-individuals over time-with the exception of a subset of genes enriched for the inflammation gene ontology. We show an enrichment among repeatable genes for associations with heritable traits, including known and novel platelet expression QTLs. Several exon skipping events were also highly repeatable, suggesting heritable patterns of splicing in platelets. One of the most repeatable was exon 14 skipping of . Accordingly, we identify rs6128 as a platelet splice QTL and define an rs6128-dependent association between exon 14 skipping and race. In vitro experiments demonstrate that this single nucleotide variant directly affects exon 14 skipping and changes the ratio of transmembrane versus soluble P-selectin protein production.

Conclusions: We conclude that the platelet transcriptome is generally stable over 4 years. We demonstrate the use of repeatability of gene expression and splicing to identify novel platelet expression QTLs and splice QTLs. rs6128 is a platelet splice QTL that alters exon 14 skipping and soluble versus transmembrane P-selectin protein production.
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http://dx.doi.org/10.1161/CIRCRESAHA.119.315215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7323475PMC
February 2020

Genetic influences on aspirin response in patients undergoing percutaneous coronary intervention.

Cardiovasc Res 2019 08;115(10):1452-1453

Division of Cardiology, Duke University, Duke University Medical Center, 2301 Erwin Road, Durham, NC, USA.

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http://dx.doi.org/10.1093/cvr/cvz110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6933505PMC
August 2019

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

PLoS One 2019 1;14(2):e0211762. Epub 2019 Feb 1.

Center for Applied Genomics & Precision Medicine, Duke University, Durham, North Carolina, United States of America.

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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0211762PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6358091PMC
November 2019

Effects of Delivering SLCO1B1 Pharmacogenetic Information in Randomized Trial and Observational Settings.

Circ Genom Precis Med 2018 09;11(9):e002228

Department of Medicine (B.P., K.S., G.T., D.V.), Center for Applied Genomics & Precision Medicine, Duke University, Durham, NC. United States (S.B.H., M.D.M., D.V.).

Background: Outcomes of tailoring statin-type based on solute carrier organic anion transporterfamily member 1B1 ( SLCO1B1)pharmacogenetic toxicity information on patient, provider, and pharmacological outcomes are unknown.

Methods: The trial randomized 159 patients not taking statins because of prior statin myalgia 1:1 to receiving SLCO1B1 GIST (Genotype Informed Statin Therapy) versus usual care (UC) and followed for up to 8 months. The UC arm received their SLCO1B1 results post-trial. The primary outcome was statin adherence using the Morisky Medication Adherence Scale, which was assessed in those patients who reinitiated statins. Secondary outcomes assessed in all participants included statin reinitiation and LDLc (low-density lipoprotein cholesterol), within and post-trial. Using commercial laboratory data, serial LDLc were compared between 1907 patients receiving SLCO1B1 testing and propensity-matched, untested controls.

Results: Trial participants were 25% SLCO1B1*5 carriers. Statin adherence was similar between arms (Morisky Medication Adherence Scale in GIST versus UC, 6.8±1.5 versus 6.9±1.6, P=0.96). GIST led to more new statin prescriptions (55.4% versus 38.0%, P=0.04) and lower LDLc at 3 months (131.9±42.0 versus 144.4±43.0 mg/dL; P=0.048) with similar magnitude at 8 months (128.6±37.9 versus 141.0±44.4; P=0.12). SLCO1B1*5 carriers exhibited a greater drop in LDLc with GIST versus UC (interaction P=0.048). Post-trial, LDLc decreased in UC participants who crossed over to GIST compared with those allocated to GIST (-14.9±37.8 versus +9.0±37.3 mg/dL, P=0.03). Patients tested for SLCO1B1 though a commercial laboratory had a greater LDLc decrease ( P=0.04) compared with controls.

Conclusions: Delivery of SLCO1B1 pharmacogenetic testing that addresses statin myalgia improved statin reinitiation and LDLc but did not improve self-reported statin adherence.

Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01894230.
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http://dx.doi.org/10.1161/CIRCGEN.118.002228DOI Listing
September 2018

Equilibrative nucleoside transporter 1 gene polymorphisms and clinical outcomes following acute coronary syndromes: findings from the PLATelet inhibition and patient Outcomes (PLATO) study.

Platelets 2019 31;30(5):579-588. Epub 2018 May 31.

a Department of Infection, Immunity and Cardiovascular Disease , University of Sheffield , Sheffield , United Kingdom.

In the PLATelet inhibition and patient Outcomes (PLATO) study, the P2Y inhibitors ticagrelor and clopidogrel were compared in the treatment of acute coronary syndromes (ACS). Ticagrelor was shown to reduce occurrence of the primary end point - a composite of death from vascular causes, myocardial infarction, or stroke - compared to clopidogrel. Ticagrelor's pleiotropic effects on reuptake of adenosine via inhibition of equilibrative nucleoside transporter 1 (ENT1) have been hypothesized to contribute to this. Several polymorphisms of ENT1 are known to exist. We explored the interaction between ENT1 polymorphisms and clinical outcomes in ACS patients participating in the PLATO genetic substudy. Using genotyping data obtained in a genome-wide association study, the gene region encoding ENT1 was assessed and 94 polymorphisms were identified. After quality control filtering, data from 9943 participants were included. Subjects were divided into discovery (phase 1, n = 3970) and replication (phase 2, n = 5973) cohorts. Cox-regression analysis of the relationship between variants and seven efficacy and safety outcomes was performed in discovery, replication, and combined cohorts. Treatment-marker interactions were also determined. Although 35 variants were found with associations to the investigated outcomes reaching p < 0.05 in the discovery cohort, only one of these was replicated in phase 2 of the analysis and also reached the predetermined level of statistical significance in the combined data, taking into account the number of tests performed: the rare polymorphism rs141034817, with a frequency of 0.2%, was significantly associated with bleeding. Thirty-three treatment-marker interactions were found with a significance level of p < 0.05 in phase 1, but none was replicated in phase 2. We found no significant interaction between ENT1 genotype and clinical outcomes in ACS patients treated with ticagrelor or clopidogrel, apart from the association between a rare polymorphism and bleeding that requires further study. If ticagrelor's pleiotropic effects on adenosine uptake are clinically relevant, these do not appear to be significantly affected by variation in the ENT1 gene.
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http://dx.doi.org/10.1080/09537104.2018.1478404DOI Listing
November 2019

Future directions in pharmacogenomics discovery in cardiovascular disease.

Pharmacogenomics 2018 04 23;19(5):375-377. Epub 2018 Mar 23.

Division of Cardiology, Duke University, Durham, NC 27710, USA.

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http://dx.doi.org/10.2217/pgs-2018-0002DOI Listing
April 2018

Peripheral blood gene expression signatures which reflect smoking and aspirin exposure are associated with cardiovascular events.

BMC Med Genomics 2018 01 12;11(1). Epub 2018 Jan 12.

Center for Applied Genomics & Precision Medicine, Department of Medicine, Duke University, 101 Science Drive, 2187 CIEMAS, Durham, NC, 27708, UK.

Background: Cardiovascular disease and its sequelae are major causes of global mortality, and better methods are needed to identify patients at risk for future cardiovascular events. Gene expression analysis can inform on the molecular underpinnings of risk factors for cardiovascular events. Smoking and aspirin have known opposing effects on platelet reactivity and MACE, however their effects on each other and on MACE are not well described.

Methods: We measured peripheral blood gene expression levels of ITGA2B, which is upregulated by aspirin and correlates with platelet reactivity on aspirin, and a 5 gene validated smoking gene expression score (sGES) where higher expression correlates with smoking status, in participants from the previously reported PREDICT trial (NCT 00500617). The primary outcome was a composite of death, myocardial infarction, and stroke/TIA (MACE). We tested whether selected genes were associated with MACE risk using logistic regression.

Results: Gene expression levels were determined in 1581 subjects (50.5% female, mean age 60.66 +/-11.46, 18% self-reported smokers); 3.5% of subjects experienced MACE over 12 months follow-up. Elevated sGES and ITGA2B expression were each associated with MACE (odds ratios [OR] =1.16 [95% CI 1.10-1.31] and 1.42 [95% CI 1.00-1.97], respectively; p < 0.05). ITGA2B expression was inversely associated with self-reported smoking status and the sGES (p < 0.001). A logistic regression model combining sGES and ITGA2B showed better performance (AIC = 474.9) in classifying MACE subjects than either alone (AIC = 479.1, 478.2 respectively).

Conclusion: Gene expression levels associated with smoking and aspirin are independently predictive of an increased risk of cardiovascular events.
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http://dx.doi.org/10.1186/s12920-017-0318-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5767057PMC
January 2018

An electronic health record based model predicts statin adherence, LDL cholesterol, and cardiovascular disease in the United States Military Health System.

PLoS One 2017 20;12(11):e0187809. Epub 2017 Nov 20.

Department of Medicine, Duke University, Durham, NC, United States of America.

HMG-CoA reductase inhibitors (or "statins") are important and commonly used medications to lower cholesterol and prevent cardiovascular disease. Nearly half of patients stop taking statin medications one year after they are prescribed leading to higher cholesterol, increased cardiovascular risk, and costs due to excess hospitalizations. Identifying which patients are at highest risk for not adhering to long-term statin therapy is an important step towards individualizing interventions to improve adherence. Electronic health records (EHR) are an increasingly common source of data that are challenging to analyze but have potential for generating more accurate predictions of disease risk. The aim of this study was to build an EHR based model for statin adherence and link this model to biologic and clinical outcomes in patients receiving statin therapy. We gathered EHR data from the Military Health System which maintains administrative data for active duty, retirees, and dependents of the United States armed forces military that receive health care benefits. Data were gathered from patients prescribed their first statin prescription in 2005 and 2006. Baseline billing, laboratory, and pharmacy claims data were collected from the two years leading up to the first statin prescription and summarized using non-negative matrix factorization. Follow up statin prescription refill data was used to define the adherence outcome (> 80 percent days covered). The subsequent factors to emerge from this model were then used to build cross-validated, predictive models of 1) overall disease risk using coalescent regression and 2) statin adherence (using random forest regression). The predicted statin adherence for each patient was subsequently used to correlate with cholesterol lowering and hospitalizations for cardiovascular disease during the 5 year follow up period using Cox regression. The analytical dataset included 138 731 individuals and 1840 potential baseline predictors that were reduced to 30 independent EHR "factors". A random forest predictive model taking patient, statin prescription, predicted disease risk, and the EHR factors as potential inputs produced a cross-validated c-statistic of 0.736 for classifying statin non-adherence. The addition of the first refill to the model increased the c-statistic to 0.81. The predicted statin adherence was independently associated with greater cholesterol lowering (correlation = 0.14, p < 1e-20) and lower hospitalization for myocardial infarction, coronary artery disease, and stroke (hazard ratio = 0.84, p = 1.87E-06). Electronic health records data can be used to build a predictive model of statin adherence that also correlates with statins' cardiovascular benefits.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0187809PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5695792PMC
December 2017

Multisite Investigation of Outcomes With Implementation of CYP2C19 Genotype-Guided Antiplatelet Therapy After Percutaneous Coronary Intervention.

JACC Cardiovasc Interv 2018 01 1;11(2):181-191. Epub 2017 Nov 1.

Department of Medicine, University of Maryland, Baltimore, Maryland.

Objectives: This multicenter pragmatic investigation assessed outcomes following clinical implementation of CYP2C19 genotype-guided antiplatelet therapy after percutaneous coronary intervention (PCI).

Background: CYP2C19 loss-of-function alleles impair clopidogrel effectiveness after PCI.

Methods: After clinical genotyping, each institution recommended alternative antiplatelet therapy (prasugrel, ticagrelor) in PCI patients with a loss-of-function allele. Major adverse cardiovascular events (defined as myocardial infarction, stroke, or death) within 12 months of PCI were compared between patients with a loss-of-function allele prescribed clopidogrel versus alternative therapy. Risk was also compared between patients without a loss-of-function allele and loss-of-function allele carriers prescribed alternative therapy. Cox regression was performed, adjusting for group differences with inverse probability of treatment weights.

Results: Among 1,815 patients, 572 (31.5%) had a loss-of-function allele. The risk for major adverse cardiovascular events was significantly higher in patients with a loss-of-function allele prescribed clopidogrel versus alternative therapy (23.4 vs. 8.7 per 100 patient-years; adjusted hazard ratio: 2.26; 95% confidence interval: 1.18 to 4.32; p = 0.013). Similar results were observed among 1,210 patients with acute coronary syndromes at the time of PCI (adjusted hazard ratio: 2.87; 95% confidence interval: 1.35 to 6.09; p = 0.013). There was no difference in major adverse cardiovascular events between patients without a loss-of-function allele and loss-of-function allele carriers prescribed alternative therapy (adjusted hazard ratio: 1.14; 95% confidence interval: 0.69 to 1.88; p = 0.60).

Conclusions: These data from real-world observations demonstrate a higher risk for cardiovascular events in patients with a CYP2C19 loss-of-function allele if clopidogrel versus alternative therapy is prescribed. A future randomized study of genotype-guided antiplatelet therapy may be of value.
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http://dx.doi.org/10.1016/j.jcin.2017.07.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5775044PMC
January 2018

The need for sex-specific precision biomarkers for antiplatelet therapies.

Future Cardiol 2017 Sep 23;13(5):419-422. Epub 2017 Aug 23.

Department of Medicine, Duke University, Durham, NC 27710, USA.

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http://dx.doi.org/10.2217/fca-2017-0043DOI Listing
September 2017

The Expressed Genome in Cardiovascular Diseases and Stroke: Refinement, Diagnosis, and Prediction: A Scientific Statement From the American Heart Association.

Circ Cardiovasc Genet 2017 Aug;10(4)

There have been major advances in our knowledge of the contribution of DNA sequence variations to cardiovascular disease and stroke. However, the inner workings of the body reflect the complex interplay of factors beyond the DNA sequence, including epigenetic modifications, RNA transcripts, proteins, and metabolites, which together can be considered the "expressed genome." The emergence of high-throughput technologies, including epigenomics, transcriptomics, proteomics, and metabolomics, is now making it possible to address the contributions of the expressed genome to cardiovascular disorders. This statement describes how the expressed genome can currently and, in the future, potentially be used to diagnose diseases and to predict who will develop diseases such as coronary artery disease, stroke, heart failure, and arrhythmias.
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http://dx.doi.org/10.1161/HCG.0000000000000037DOI Listing
August 2017

Transcription Factor RUNX1 Regulates Platelet (Phosphatidylcholine Transfer Protein): Implications for Cardiovascular Events: Differential Effects of RUNX1 Variants.

Circulation 2017 Sep 4;136(10):927-939. Epub 2017 Jul 4.

From Sol Sherry Thrombosis Research Center (G.M., N.S., F.E.D.C.-C., L.E.G., A.K.R.), Hematology Section, Department of Medicine (N.S., A.K.R.), and Department of Anatomy and Cell Biology (L.E.G.), Lewis Katz School of Medicine at Temple University, Philadelphia, PA; and Duke Center for Applied Genomics and Precision Medicine, Department of Medicine, Duke University, Durham, NC (D.V., R.A.M.).

Background: PCTP (phosphatidylcholine transfer protein) regulates the intermembrane transfer of phosphatidylcholine. Higher platelet PCTP expression is associated with increased platelet responses on activation of protease-activated receptor 4 thrombin receptors noted in black subjects compared with white subjects. Little is known about the regulation of platelet . Haplodeficiency of RUNX1, a major hematopoietic transcription factor, is associated with thrombocytopenia and impaired platelet responses on activation. Platelet expression profiling of a patient with a loss-of-function mutation revealed a 10-fold downregulation of the gene compared with healthy controls.

Methods: We pursued the hypothesis that is regulated by RUNX1 and that expression is correlated with cardiovascular events. We studied RUNX1 binding to the promoter using DNA-protein binding studies and human erythroleukemia cells and promoter activity using luciferase reporter studies. We assessed the relationship between and in peripheral blood RNA and and death or myocardial infarction in 2 separate patient cohorts (587 total patients) with cardiovascular disease.

Results: Platelet PCTP protein in the patient was reduced by ≈50%. DNA-protein binding studies showed RUNX1 binding to consensus sites in ≈1 kB of promoter. expression was increased with overexpression and reduced with knockdown in human erythroleukemia cells, indicating that is regulated by RUNX1. Studies in 2 cohorts of patients showed that expression in blood correlated with gene expression; expression was higher in black compared with white subjects and was associated with future death/myocardial infarction after adjustment for age, sex, and race (odds ratio, 2.05; 95% confidence interval 1.6-2.7; <0.0001). expression is known to initiate at 2 alternative promoters, a distal P1 and a proximal P2 promoter. In patient cohorts, there were differential effects of isoforms on expression with a negative correlation in blood between expressed from the P1 promoter and expression.

Conclusions: is a direct transcriptional target of RUNX1. expression is associated with death/myocardial infarction in patients with cardiovascular disease. RUNX1 regulation of may play a role in the pathogenesis of platelet-mediated cardiovascular events.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.116.023711DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5591032PMC
September 2017

Assessing feasibility of delivering pharmacogenetic testing in a community pharmacy setting.

Pharmacogenomics 2017 Mar 22;18(4):327-335. Epub 2017 Feb 22.

Center for Applied Genomics & Precision Medicine, Duke University School of Medicine, 304 Research Drive, Box 90141, Durham, NC 27708, USA.

Aim: To describe the rationale and design of a study evaluating the delivery of pharmacogenetic (PGx) testing in community pharmacies. Study rationale: Pharmacists have expressed interest in offering PGx testing; however, their lack of knowledge and experience, patients' acceptance and feasibility are unknown in this setting.

Study Design: Through a cluster randomized trial, we will assess pharmacist and patient experiences with delivery of PGx testing as a standalone service or integrated into medication therapy management services. Anticipated results: We anticipate that PGx testing can be delivered in a community pharmacy setting and accepted and valued by patients.

Conclusion: This study is expected to provide valuable evidence about the real-world feasibility and acceptance of a community pharmacist-delivered approach of PGx testing.
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http://dx.doi.org/10.2217/pgs-2016-0175DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5558549PMC
March 2017

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 2017 Feb 15;184:133-140. Epub 2016 Nov 15.

Department of Medicine, Duke University School of Medicine, Durham, NC; Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC.

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.
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http://dx.doi.org/10.1016/j.ahj.2016.11.004DOI Listing
February 2017
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