Publications by authors named "Josh F Peterson"

82 Publications

Infobuttons for Genomic Medicine: Requirements and Barriers.

Appl Clin Inform 2021 Mar 12;12(2):383-390. Epub 2021 May 12.

Genomic Medicine Institute, Geisinger, Danville, Pennsylvania, United Sates.

Objectives:  The study aimed to understand potential barriers to the adoption of health information technology projects that are released as free and open source software (FOSS).

Methods:  We conducted a survey of research consortia participants engaged in genomic medicine implementation to assess perceived institutional barriers to the adoption of three systems: ClinGen electronic health record (EHR) Toolkit, DocUBuild, and MyResults.org. The survey included eight barriers from the Consolidated Framework for Implementation Research (CFIR), with additional barriers identified from a qualitative analysis of open-ended responses.

Results:  We analyzed responses from 24 research consortia participants from 18 institutions. In total, 14 categories of perceived barriers were evaluated, which were consistent with other observed barriers to FOSS adoption. The most frequent perceived barriers included lack of adaptability of the system, lack of institutional priority to implement, lack of trialability, lack of advantage of alternative systems, and complexity.

Conclusion:  In addition to understanding potential barriers, we recommend some strategies to address them (where possible), including considerations for genomic medicine. Overall, FOSS developers need to ensure systems are easy to trial and implement and need to clearly articulate benefits of their systems, especially when alternatives exist. Institutional champions will remain a critical component to prioritizing genomic medicine projects.
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http://dx.doi.org/10.1055/s-0041-1729164DOI Listing
March 2021

ConceptWAS: A high-throughput method for early identification of COVID-19 presenting symptoms and characteristics from clinical notes.

J Biomed Inform 2021 Mar 25;117:103748. Epub 2021 Mar 25.

Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, USA. Electronic address:

Objective: Identifying symptoms and characteristics highly specific to coronavirus disease 2019 (COVID-19) would improve the clinical and public health response to this pandemic challenge. Here, we describe a high-throughput approach - Concept-Wide Association Study (ConceptWAS) - that systematically scans a disease's clinical manifestations from clinical notes. We used this method to identify symptoms specific to COVID-19 early in the course of the pandemic.

Methods: We created a natural language processing pipeline to extract concepts from clinical notes in a local ER corresponding to the PCR testing date for patients who had a COVID-19 test and evaluated these concepts as predictors for developing COVID-19. We identified predictors from Firth's logistic regression adjusted by age, gender, and race. We also performed ConceptWAS using cumulative data every two weeks to identify the timeline for recognition of early COVID-19-specific symptoms.

Results: We processed 87,753 notes from 19,692 patients subjected to COVID-19 PCR testing between March 8, 2020, and May 27, 2020 (1,483 COVID-19-positive). We found 68 concepts significantly associated with a positive COVID-19 test. We identified symptoms associated with increasing risk of COVID-19, including "anosmia" (odds ratio [OR] = 4.97, 95% confidence interval [CI] = 3.21-7.50), "fever" (OR = 1.43, 95% CI = 1.28-1.59), "cough with fever" (OR = 2.29, 95% CI = 1.75-2.96), and "ageusia" (OR = 5.18, 95% CI = 3.02-8.58). Using ConceptWAS, we were able to detect loss of smell and loss of taste three weeks prior to their inclusion as symptoms of the disease by the Centers for Disease Control and Prevention (CDC).

Conclusion: ConceptWAS, a high-throughput approach for exploring specific symptoms and characteristics of a disease like COVID-19, offers a promise for enabling EHR-powered early disease manifestations identification.
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http://dx.doi.org/10.1016/j.jbi.2021.103748DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7992296PMC
March 2021

The Case for Expanding the FDA Box Warning on Clopidogrel to CYP2C19 Intermediate Metabolizers.

Clin Pharmacol Ther 2021 Mar 10. Epub 2021 Mar 10.

Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

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http://dx.doi.org/10.1002/cpt.2215DOI Listing
March 2021

CYP2C19 Loss-of-Function Associated with First-Time Ischemic Stroke in Non-surgical Asymptomatic Carotid Artery Stenosis During Clopidogrel Therapy.

Transl Stroke Res 2021 Feb 21. Epub 2021 Feb 21.

Surgical Outcomes Center for Kids, Monroe Carell Jr. Children's Hospital at Vanderbilt, Nashville, TN, USA.

This study measures effect of CYP2C19 genotype on ischemic stroke risk during clopidogrel therapy for asymptomatic, extracranial carotid stenosis patients. Using deidentified electronic health records, patients were selected for retrospective cohort using administrative code for carotid stenosis, availability of CYP2C19 genotype result, clopidogrel exposure, and established patient care. Patients with intracranial atherosclerosis, aneurysm, arteriovenous malformation, prior ischemic stroke, or observation time <1 month were excluded. Dual antiplatelet therapy patients were included. Patients with carotid endarterectomy or stenting were analyzed in a separate subgroup. Time-to-event analysis using Cox regression was conducted to model ischemic stroke events based on CYP2C19 loss-of-function allele and adjusted with the most predictive covariates from univariate analysis. Covariates included age, gender, race, length of aspirin, length of concurrent antiplatelet/anticoagulant treatment, diabetes, coagulopathy, hypertension, heart disease, atrial fibrillation, and lipid disorder. A total of 1110 patients met selection criteria for medical therapy cohort (median age 68 [interquartile range (IQR) 60-75] years, 64.9% male, 91.9% Caucasian). Median study period was 2.8 [0.8-5.3] years. A total of 47 patients (4.2%) had an ischemic stroke event during study period. CYP2C19 loss-of-function allele was strongly associated with ischemic stroke events (one allele: HR 2.3, 95% CI 1.1-4.7, p=0.020; two alleles: HR 10.2, 95% CI 2.8-36.8, p<0.001) after adjustment. For asymptomatic carotid stenosis patients receiving clopidogrel to prevent ischemic stroke, CYP2C19 loss-of-function allele is associated with 2- to 10-fold increased risk of ischemic stroke. CYP2C19 genotype may be considered when selecting antiplatelet therapy for stroke prophylaxis in non-procedural, asymptomatic carotid stenosis.
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http://dx.doi.org/10.1007/s12975-021-00896-3DOI Listing
February 2021

DrugWAS: Leveraging drug-wide association studies to facilitate drug repurposing for COVID-19.

medRxiv 2021 Feb 8. Epub 2021 Feb 8.

There is an unprecedented need to rapidly identify safe and effective treatments for the novel coronavirus disease 2019 (COVID-19). To systematically investigate if any of the available drugs in Electronic Health Record (EHR), including prescription drugs and dietary supplements, can be repurposed as potential treatment for COVID-19. Based on a retrospective cohort analysis of EHR data, drug-wide association studies (DrugWAS) were performed on COVID-19 patients at Vanderbilt University Medical Center (VUMC). For each drug study, multivariable logistic regression with overlap weighting using propensity score was applied to estimate the effect of drug exposure on COVID-19 disease outcomes. Patient exposure to a drug during 1-year prior to the pandemic and COVID-19 diagnosis was chosen as exposure of interest. Natural language processing was employed to extract drug information from clinical notes, in addition to the prescription drug data available in structured format. All-cause of death was selected as primary outcome. Hospitalization, admission to the intensive care unit (ICU), and need for mechanical ventilation were identified as secondary outcomes. The study included 7,768 COVID-19 patients, of which 509 (6.55%) were hospitalized, 82 (1.06%) were admitted to ICU, 64 (0.82%) received mechanical ventilation, and 90 (1.16%) died. Overall, 15 drugs were significantly associated with decreased COVID-19 severity. Previous exposure to either Streptococcus pneumoniae vaccines (adjusted odds ratio [OR], 0.38; 95% CI, 0.14-0.98), diphtheria toxoid vaccine (OR, 0.39; 95% CI, 0.15-0.98), and tetanus toxoid vaccine (OR, 0.39; 95% CI, 0.15-0.98) were significantly associated with a decreased risk of death (primary outcome). Secondary analyses identified several other significant associations showing lower risk for COVID-19 outcomes: 2 vaccines (acellular pertussis, Streptococcus pneumoniae), 3 dietary supplements (turmeric extract, flaxseed extract, omega-3 fatty acids), methylprednisolone acetate, pseudoephedrine, ethinyl estradiol, estradiol, ibuprofen, and fluticasone. This cohort study leveraged EHR data to identify a list of drugs that could be repurposed to improve COVID-19 outcomes. Further randomized clinical trials are needed to investigate the efficacy of the proposed drugs.
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http://dx.doi.org/10.1101/2021.02.04.21251169DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7872383PMC
February 2021

Opportunity for Genotype-Guided Prescribing Among Adult Patients in 11 US Health Systems.

Clin Pharmacol Ther 2021 Jan 11. Epub 2021 Jan 11.

Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

The value of utilizing a multigene pharmacogenetic panel to tailor pharmacotherapy is contingent on the prevalence of prescribed medications with an actionable pharmacogenetic association. The Clinical Pharmacogenetics Implementation Consortium (CPIC) has categorized over 35 gene-drug pairs as "level A," for which there is sufficiently strong evidence to recommend that genetic information be used to guide drug prescribing. The opportunity to use genetic information to tailor pharmacotherapy among adult patients was determined by elucidating the exposure to CPIC level A drugs among 11 Implementing Genomics In Practice Network (IGNITE)-affiliated health systems across the US. Inpatient and/or outpatient electronic-prescribing data were collected between January 1, 2011 and December 31, 2016 for patients ≥ 18 years of age who had at least one medical encounter that was eligible for drug prescribing in a calendar year. A median of ~ 7.2 million adult patients was available for assessment of drug prescribing per year. From 2011 to 2016, the annual estimated prevalence of exposure to at least one CPIC level A drug prescribed to unique patients ranged between 15,719 (95% confidence interval (CI): 15,658-15,781) in 2011 to 17,335 (CI: 17,283-17,386) in 2016 per 100,000 patients. The estimated annual exposure to at least 2 drugs was above 7,200 per 100,000 patients in most years of the study, reaching an apex of 7,660 (CI: 7,632-7,687) per 100,000 patients in 2014. An estimated 4,748 per 100,000 prescribing events were potentially eligible for a genotype-guided intervention. Results from this study show that a significant portion of adults treated at medical institutions across the United States is exposed to medications for which genetic information, if available, should be used to guide prescribing.
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http://dx.doi.org/10.1002/cpt.2161DOI Listing
January 2021

Prescribing Prevalence of Medications With Potential Genotype-Guided Dosing in Pediatric Patients.

JAMA Netw Open 2020 12 1;3(12):e2029411. Epub 2020 Dec 1.

Personalized Medicine Initiative, Nicklaus Children's Health System, Miami, Florida.

Importance: Genotype-guided prescribing in pediatrics could prevent adverse drug reactions and improve therapeutic response. Clinical pharmacogenetic implementation guidelines are available for many medications commonly prescribed to children. Frequencies of medication prescription and actionable genotypes (genotypes where a prescribing change may be indicated) inform the potential value of pharmacogenetic implementation.

Objective: To assess potential opportunities for genotype-guided prescribing in pediatric populations among multiple health systems by examining the prevalence of prescriptions for each drug with the highest level of evidence (Clinical Pharmacogenetics Implementation Consortium level A) and estimating the prevalence of potential actionable prescribing decisions.

Design, Setting, And Participants: This serial cross-sectional study of prescribing prevalences in 16 health systems included electronic health records data from pediatric inpatient and outpatient encounters from January 1, 2011, to December 31, 2017. The health systems included academic medical centers with free-standing children's hospitals and community hospitals that were part of an adult health care system. Participants included approximately 2.9 million patients younger than 21 years observed per year. Data were analyzed from June 5, 2018, to April 14, 2020.

Exposures: Prescription of 38 level A medications based on electronic health records.

Main Outcomes And Measures: Annual prevalence of level A medication prescribing and estimated actionable exposures, calculated by combining estimated site-year prevalences across sites with each site weighted equally.

Results: Data from approximately 2.9 million pediatric patients (median age, 8 [interquartile range, 2-16] years; 50.7% female, 62.3% White) were analyzed for a typical calendar year. The annual prescribing prevalence of at least 1 level A drug ranged from 7987 to 10 629 per 100 000 patients with increasing trends from 2011 to 2014. The most prescribed level A drug was the antiemetic ondansetron (annual prevalence of exposure, 8107 [95% CI, 8077-8137] per 100 000 children). Among commonly prescribed opioids, annual prevalence per 100 000 patients was 295 (95% CI, 273-317) for tramadol, 571 (95% CI, 557-586) for codeine, and 2116 (95% CI, 2097-2135) for oxycodone. The antidepressants citalopram, escitalopram, and amitriptyline were also commonly prescribed (annual prevalence, approximately 250 per 100 000 patients for each). Estimated prevalences of actionable exposures were highest for oxycodone and ondansetron (>300 per 100 000 patients annually). CYP2D6 and CYP2C19 substrates were more frequently prescribed than medications influenced by other genes.

Conclusions And Relevance: These findings suggest that opportunities for pharmacogenetic implementation among pediatric patients in the US are abundant. As expected, the greatest opportunity exists with implementing CYP2D6 and CYP2C19 pharmacogenetic guidance for commonly prescribed antiemetics, analgesics, and antidepressants.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.29411DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7737091PMC
December 2020

A retrospective approach to evaluating potential adverse outcomes associated with delay of procedures for cardiovascular and cancer-related diagnoses in the context of COVID-19.

J Biomed Inform 2021 01 10;113:103657. Epub 2020 Dec 10.

Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, USA. Electronic address:

Objective: During the COVID-19 pandemic, health systems postponed non-essential medical procedures to accommodate surge of critically-ill patients. The long-term consequences of delaying procedures in response to COVID-19 remains unknown. We developed a high-throughput approach to understand the impact of delaying procedures on patient health outcomes using electronic health record (EHR) data.

Materials And Methods: We used EHR data from Vanderbilt University Medical Center's (VUMC) Research and Synthetic Derivatives. Elective procedures and non-urgent visits were suspended at VUMC between March 18, 2020 and April 24, 2020. Surgical procedure data from this period were compared to a similar timeframe in 2019. Potential adverse impact of delay in cardiovascular and cancer-related procedures was evaluated using EHR data collected from January 1, 1993 to March 17, 2020. For surgical procedure delay, outcomes included length of hospitalization (days), mortality during hospitalization, and readmission within six months. For screening procedure delay, outcomes included 5-year survival and cancer stage at diagnosis.

Results: We identified 416 surgical procedures that were negatively impacted during the COVID-19 pandemic compared to the same timeframe in 2019. Using retrospective data, we found 27 significant associations between procedure delay and adverse patient outcomes. Clinician review indicated that 88.9% of the significant associations were plausible and potentially clinically significant. Analytic pipelines for this study are available online.

Conclusion: Our approach enables health systems to identify medical procedures affected by the COVID-19 pandemic and evaluate the effect of delay, enabling them to communicate effectively with patients and prioritize rescheduling to minimize adverse patient outcomes.
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http://dx.doi.org/10.1016/j.jbi.2020.103657DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7728428PMC
January 2021

CYP2C19 Loss-of-Function is Associated with Increased Risk of Ischemic Stroke after Transient Ischemic Attack in Intracranial Atherosclerotic Disease.

J Stroke Cerebrovasc Dis 2021 Feb 24;30(2):105464. Epub 2020 Nov 24.

Department of Neurosurgery, Vanderbilt University Medical Center, Nashville, TN, United States.

Objectives: Intracranial atherosclerotic disease (ICAD) is responsible for 8-10% of acute ischemic strokes, and resistance to antiplatelet therapy is prevalent. CYP2C19 gene loss-of-function (up to 45% of patients) causes clopidogrel resistance. For patients with asymptomatic ICAD and ICAD characterized by transient ischemic attack (TIA), this study measures the effect of CYP2C19 loss-of-function on ischemic stroke risk during clopidogrel therapy.

Materials And Methods: From a deidentified database of medical records, patients were selected with ICD-9/10 code for ICAD, availability of CYP2C19 genotype, clopidogrel exposure, and established patient care. Dual-antiplatelet therapy patients were included. Patients with prior ischemic stroke, other neurovascular condition, intracranial angioplasty/stenting, or observation time <1 month were excluded. Time-to-event analysis using Cox regression was conducted to model first-time ischemic stroke events based on CYP2C19 loss-of-function allele and adjusted for age, gender, race, length of aspirin, length of concurrent antiplatelet/anticoagulant treatment, diabetes, coagulopathy, hypertension, heart disease, atrial fibrillation, and lipid disorder. Subset analyses were performed for asymptomatic and post-TIA subtypes of ICAD.

Results: A total of 337 patients were included (median age 68, 58% male, 88% Caucasian, 26% CYP2C19 loss-of-function). A total of 161 (47.8%) patients had TIA at time of ICAD diagnosis, while 176 (52.2%) were asymptomatic. First-time ischemic stroke was observed among 20 (12.4%) post-TIA ICAD patients and 17 (9.7%) asymptomatic ICAD patients. Median observation time was 2.82 [IQR 1.13-5.17] years. CYP2C19 loss-of-function allele was associated with ischemic stroke event (HR 2.2, 95% CI 1.1-4.3, p=0.020) after adjustment. Post-TIA ICAD patients had a higher risk of ischemic stroke from CYP2C19 loss-of-function (HR 3.4, 95% CI 1.4-8.2, p=0.006).

Conclusions: CYP2C19 loss-of-function was associated with 3-fold increased risk of first-time ischemic stroke for ICAD patients treated with clopidogrel after TIA. This effect was not observed for asymptomatic ICAD. CYP2C19-guided antiplatelet selection may improve stroke prevention in ICAD after TIA.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2020.105464DOI Listing
February 2021

ConceptWAS: a high-throughput method for early identification of COVID-19 presenting symptoms.

medRxiv 2020 Nov 10. Epub 2020 Nov 10.

Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN.

Objective: Identifying symptoms highly specific to COVID-19 would improve the clinical and public health response to infectious outbreaks. Here, we describe a high-throughput approach - Concept-Wide Association Study (ConceptWAS) that systematically scans a disease's clinical manifestations from clinical notes. We used this method to identify symptoms specific to COVID-19 early in the course of the pandemic.

Methods: Using the Vanderbilt University Medical Center (VUMC) EHR, we parsed clinical notes through a natural language processing pipeline to extract clinical concepts. We examined the difference in concepts derived from the notes of COVID-19-positive and COVID-19-negative patients on the PCR testing date. We performed ConceptWAS using the cumulative data every two weeks for early identifying specific COVID-19 symptoms.

Results: We processed 87,753 notes 19,692 patients (1,483 COVID-19-positive) subjected to COVID-19 PCR testing between March 8, 2020, and May 27, 2020. We found 68 clinical concepts significantly associated with COVID-19. We identified symptoms associated with increasing risk of COVID-19, including "absent sense of smell" (odds ratio [OR] = 4.97, 95% confidence interval [CI] = 3.21-7.50), "fever" (OR = 1.43, 95% CI = 1.28-1.59), "with cough fever" (OR = 2.29, 95% CI = 1.75-2.96), and "ageusia" (OR = 5.18, 95% CI = 3.02-8.58). Using ConceptWAS, we were able to detect loss sense of smell or taste three weeks prior to their inclusion as symptoms of the disease by the Centers for Disease Control and Prevention (CDC).

Conclusion: ConceptWAS is a high-throughput approach for exploring specific symptoms of a disease like COVID-19, with a promise for enabling EHR-powered early disease manifestations identification.
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http://dx.doi.org/10.1101/2020.11.06.20227165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7668764PMC
November 2020

Cost-effectiveness of Population-Wide Genomic Screening for Hereditary Breast and Ovarian Cancer in the United States.

JAMA Netw Open 2020 10 1;3(10):e2022874. Epub 2020 Oct 1.

The Comparative Health Outcomes, Policy & Economics (CHOICE) Institute, Department of Pharmacy, University of Washington, Seattle.

Importance: Genomic screening for hereditary breast and ovarian cancer (HBOC) in unselected women offers an opportunity to prevent cancer morbidity and mortality, but the potential clinical impact and cost-effectiveness of such screening have not been well studied.

Objective: To estimate the lifetime incremental incidence of HBOC and the quality-adjusted life-years (QALYs), costs, and cost-effectiveness of HBOC genomic screening in an unselected population vs family history-based testing.

Design, Setting, And Participants: In this study conducted from October 27, 2017, to May 3, 2020, a decision analytic Markov model was developed that included health states for precancer, for risk-reducing mastectomy (RRM) and risk-reducing salpingo-oophorectomy (RRSO), for earlier- and later-stage HBOC, after cancer, and for death. A complimentary cascade testing module was also developed to estimate outcomes in first-degree relatives. Age-specific RRM and RRSO uptake probabilities were estimated from the Geisinger MyCode Community Health Initiative and published sources. Parameters including RRM and RRSO effectiveness, variant-specific cancer risk, costs, and utilities were derived from published sources. Sensitivity and scenario analyses were conducted to evaluate model assumptions and uncertainty.

Main Outcomes And Measures: Lifetime cancer incidence, QALYs, life-years, and direct medical costs for genomic screening in an unselected population vs family history-based testing only were calculated. The incremental cost-effectiveness ratio (ICER) was calculated as the difference in cost between strategies divided by the difference in QALYs between strategies. Earlier-stage and later-stage cancer cases prevented and total cancer cases prevented were also calculated.

Results: The model found that population screening of 30-year-old women was associated with 75 (95% credible range [CR], 60-90) fewer overall cancer cases and 288 QALYs (95% CR, 212-373 QALYs) gained per 100 000 women screened, at an incremental cost of $25 million (95% CR, $21 millon to $30 million) vs family history-based testing; the ICER was $87 700 (78% probability of being cost-effective at a threshold of $100 000 per QALY). In contrast, population screening of 45-year-old women was associated with 24 (95% CR, 18-29) fewer cancer cases and 97 QALYs (95% CR, 66-130 QALYs) gained per 100 000 women screened, at an incremental cost of $26 million (95% CR, $22 million to $30 million); the ICER was $268 200 (0% probability of being cost-effective at a threshold of $100 000 per QALY). A scenario analysis without cascade testing increased the ICER to $92 600 for 30-year-old women and $354 500 for 45-year-old women. A scenario analysis assuming a 5% absolute decrease in mammography screening in women without a variant was associated with the potential for net harm (-90 QALYs per 100 000 women screened; 95% CR, -180 to 10 QALYs).

Conclusions And Relevance: The results of this study suggest that population HBOC screening may be cost-effective among younger women but not among older women. Cascade testing of first-degree relatives added a modest improvement in clinical and economic value. The potential for harm conferred by inappropriate reduction in mammography among noncarriers should be quantified.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.22874DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7596578PMC
October 2020

A Tutorial for Pharmacogenomics Implementation Through End-to-End Clinical Decision Support Based on Ten Years of Experience from PREDICT.

Clin Pharmacol Ther 2021 Jan 15;109(1):101-115. Epub 2020 Nov 15.

Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

Vanderbilt University Medical Center implemented pharmacogenomics (PGx) testing with the Pharmacogenomic Resource for Enhanced Decisions in Care and Treatment (PREDICT) initiative in 2010. This tutorial reviews the laboratory considerations, technical infrastructure, and programmatic support required to deliver panel-based PGx testing across a large health system with examples and experiences from the first decade of the PREDICT initiative. From the time of inception, automated clinical decision support (CDS) has been a critical capability for delivering PGx results to the point-of-care. Key features of the CDS include human-readable interpretations and clinical guidance that is anticipatory, actionable, and adaptable to changes in the scientific literature. Implementing CDS requires that structured results from the laboratory be encoded in standards-based messages that are securely ingested by electronic health records. Translating results to guidance also requires an informatics infrastructure with multiple components: (1) to manage the interpretation of raw genomic data to "star allele" results to expected phenotype, (2) to define the rules that associate a phenotype with recommended changes to clinical care, and (3) to manage and update the knowledge base. Knowledge base management is key to processing new results with the latest guidelines, and to ensure that historical genomic results can be reinterpreted with revised CDS. We recommend that these components be deployed with institutional authorization, programmatic support, and clinician education to govern the CDS content and policies around delivery.
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http://dx.doi.org/10.1002/cpt.2079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7902340PMC
January 2021

Genetic testing and employer-sponsored wellness programs: An overview of current vendors, products, and practices.

Mol Genet Genomic Med 2020 10 26;8(10):e1414. Epub 2020 Jul 26.

Genomic Medicine Institute, Geisinger, Danville, PA, USA.

Background: Employer-sponsored corporate wellness programs have spread despite limited evidence of effectiveness in improving health or reducing costs. Some programs have offered genetic testing as a benefit to employees, but little is known about this practice.

Methods: In December 2019, we conducted a systematic Google search to identify vendors offering corporate wellness programs involving genetics. We performed qualitative content analysis of publicly available information about the vendors' products and practices disclosed on their websites.

Results: Fifteen vendors were identified. Details regarding genetic testing offered within wellness programs were difficult to decipher from vendors' websites, including which specific products were included. No evidence was provided to support vendor claimed improvements in employer costs, employee health, and job performance. Only half offered health and genetic counseling services. Most vendors were ambiguous regarding data sharing. Disclaimer language was included in vendors' stated risks and limitations, ostensibly to avoid oversight and liability.

Conclusion: We found a lack of transparency among corporate wellness program vendors, underscoring challenges that stakeholders encounter when trying to assess (a) how such programs are using genetics, (b) the potential benefits of such applications, and (c) the adequacy of protections to ensure scientific evidence support any health claims and genetic nondiscrimination.
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http://dx.doi.org/10.1002/mgg3.1414DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7549551PMC
October 2020

Returning Results in the Genomic Era: Initial Experiences of the eMERGE Network.

J Pers Med 2020 Apr 27;10(2). Epub 2020 Apr 27.

Genomic Medicine Institute, Geisinger, Danville, PA 17822, USA.

A goal of the 3rd phase of the Electronic Medical Records and Genomics (eMERGE3) Network was to examine the return of results (RoR) of actionable variants in more than 100 genes to consenting participants and their healthcare providers. Each of the 10 eMERGE sites developed plans for three essential elements of the RoR process: Disclosure to the participant, notification of the health care provider, and integration of results into the electronic health record (EHR). Procedures and protocols around these three elements were adapted as appropriate to individual site requirements and limitations. Detailed information about the RoR procedures at each site was obtained through structured telephone interviews and follow-up surveys with the clinical investigator leading or participating in the RoR process at each eMERGE3 institution. Because RoR processes at each of the 10 sites allowed for taking into account differences in population, disease focus and institutional requirements, significant heterogeneity of process was identified, including variability in the order in which patients and clinicians were notified and results were placed in the EHR. This heterogeneity in the process flow for eMERGE3 RoR reflects the "real world" of genomic medicine in which RoR procedures must be shaped by the needs of the patients and institutional environments.
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http://dx.doi.org/10.3390/jpm10020030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7354592PMC
April 2020

Health Economics Tools and Precision Medicine: Opportunities and Challenges.

Forum Health Econ Policy 2020 03 5;23(1). Epub 2020 Mar 5.

Hutchinson Cancer Research Center, Seattle, WA, USA.

Precision medicine - individualizing care for patients and addressing variations in treatment response - is likely to be important in improving the nation's health in a cost-effective manner. Despite this promise, widespread use of precision medicine, specifically genomic markers, in clinical care has been limited in practice to date. Lack of evidence, clear evidence thresholds, and reimbursement have been cited as major barriers. Health economics frameworks and tools can elucidate the effects of legal, regulatory, and reimbursement policies on the use of precision medicine while guiding research investments to enhance the appropriate use of precision medicine. Despite the capacity of economics to enhance the clinical and human impact of precision medicine, application of health economics to precision medicine has been limited - in part because precision medicine is a relatively new field - but also because precision medicine is complex, both in terms of its applications and implications throughout medicine and the healthcare system. The goals of this review are several-fold: (1) provide an overview of precision medicine and key policy challenges for the field; (2) explain the potential utility of economics methods in addressing these challenges; (3) describe recent research activities; and (4) summarize opportunities for cross-disciplinary research.
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http://dx.doi.org/10.1515/fhep-2019-0013DOI Listing
March 2020

Cost-effectiveness of CYP2C19-guided antiplatelet therapy in patients with acute coronary syndrome and percutaneous coronary intervention informed by real-world data.

Pharmacogenomics J 2020 10 11;20(5):724-735. Epub 2020 Feb 11.

Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, USA.

Current guidelines recommend dual antiplatelet therapy (DAPT) consisting of aspirin and a P2Y12 inhibitors following percutaneous coronary intervention (PCI). CYP2C19 genotype can guide DAPT selection, prescribing ticagrelor or prasugrel for loss-of-function (LOF) allele carriers (genotype-guided escalation). Cost-effectiveness analyses (CEA) are traditionally grounded in clinical trial data. We conduct a CEA using real-world data using a 1-year decision-analytic model comparing primary strategies: universal empiric clopidogrel (base case), universal ticagrelor, and genotype-guided escalation. We also explore secondary strategies commonly implemented in practice, wherein all patients are prescribed ticagrelor for 30 days post PCI. After 30 days, all patients are switched to clopidogrel irrespective of genotype (nonguided de-escalation) or to clopidogrel only if patients do not harbor an LOF allele (genotype-guided de-escalation). Compared with universal clopidogrel, both universal ticagrelor and genotype-guided escalation were superior with improvement in quality-adjusted life years (QALY's). Only genotype-guided escalation was cost-effective ($42,365/QALY) and demonstrated the highest probability of being cost-effective across conventional willingness-to-pay thresholds. In the secondary analysis, compared with the nonguided de-escalation strategy, although genotype-guided de-escalation and universal ticagrelor were more effective, with ICER of $188,680/QALY and $678,215/QALY, respectively, they were not cost-effective. CYP2C19 genotype-guided antiplatelet prescribing is cost-effective compared with either universal clopidogrel or universal ticagrelor using real-world implementation data. The secondary analysis suggests genotype-guided and nonguided de-escalation may be viable strategies, needing further evaluation.
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http://dx.doi.org/10.1038/s41397-020-0162-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7417282PMC
October 2020

A Decision-Theoretic Approach to Panel-Based, Preemptive Genotyping.

MDM Policy Pract 2019 Jul-Dec;4(2):2381468319864337. Epub 2019 Aug 17.

Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee.

We discuss a decision-theoretic approach to building a panel-based, preemptive genotyping program. The method is based on findings that a large percentage of patients are prescribed medications that are known to have pharmacogenetic associations, and over time, a substantial proportion are prescribed additional such medication. Preemptive genotyping facilitates genotype-guided therapy at the time medications are prescribed; panel-based testing allows providers to reuse previously collected genetic data when a new indication arises. Because it is cost-prohibitive to conduct panel-based genotyping on all patients, we describe a three-step approach to identify patients with the highest anticipated benefit. First, we construct prediction models to estimate the risk of being prescribed one of the target medications using readily available clinical data. Second, we use literature-based estimates of adverse event rates, variant allele frequencies, secular death rates, and costs to construct a discrete event simulation that estimates the expected benefit of having an individual's genetic data in the electronic health record after an indication has occurred. Finally, we combine medication prescription risk with expected benefit of genotyping once a medication is indicated to calculate the expected benefit of preemptive genotyping. For each patient-clinic visit, we calculate this expected benefit across a range of medications and select patients with the highest expected benefit overall. We build a proof of concept implementation using a cohort of patients from a single academic medical center observed from July 2010 through December 2012. We then apply the results of our modeling strategy to show the extent to which we can improve clinical and economic outcomes in a cohort observed from January 2013 through December 2015.
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http://dx.doi.org/10.1177/2381468319864337DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6699004PMC
August 2019

Building evidence and measuring clinical outcomes for genomic medicine.

Lancet 2019 Aug 5;394(10198):604-610. Epub 2019 Aug 5.

Genomic Medicine Institute, Geisinger, Danville, PA, USA.

Human genomic sequencing has potential diagnostic, prognostic, and therapeutic value across a wide breadth of clinical disciplines. One barrier to widespread adoption is the paucity of evidence for improved outcomes in patients who do not already have an indication for more focused testing. In this Series paper, we review clinical outcome studies in genomic medicine and discuss the important features and key challenges to building evidence for next generation sequencing in the context of routine patient care.
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http://dx.doi.org/10.1016/S0140-6736(19)31278-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6730663PMC
August 2019

Genomic medicine for undiagnosed diseases.

Lancet 2019 Aug 5;394(10197):533-540. Epub 2019 Aug 5.

National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.

One of the primary goals of genomic medicine is to improve diagnosis through identification of genomic conditions, which could improve clinical management, prevent complications, and promote health. We explore how genomic medicine is being used to obtain molecular diagnoses for patients with previously undiagnosed diseases in prenatal, paediatric, and adult clinical settings. We focus on the role of clinical genomic sequencing (exome and genome) in aiding patients with conditions that are undiagnosed even after extensive clinical evaluation and testing. In particular, we explore the impact of combining genomic and phenotypic data and integrating multiple data types to improve diagnoses for patients with undiagnosed diseases, and we discuss how these genomic sequencing diagnoses could change clinical management.
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http://dx.doi.org/10.1016/S0140-6736(19)31274-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6709871PMC
August 2019

Pharmacogenomics.

Lancet 2019 08 5;394(10197):521-532. Epub 2019 Aug 5.

Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA; Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, USA.

Genomic medicine, which uses DNA variation to individualise and improve human health, is the subject of this Series of papers. The idea that genetic variation can be used to individualise drug therapy-the topic addressed here-is often viewed as within reach for genomic medicine. We have reviewed general mechanisms underlying variability in drug action, the role of genetic variation in mediating beneficial and adverse effects through variable drug concentrations (pharmacokinetics) and drug actions (pharmacodynamics), available data from clinical trials, and ongoing efforts to implement pharmacogenetics in clinical practice.
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http://dx.doi.org/10.1016/S0140-6736(19)31276-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6707519PMC
August 2019

Current practices in the delivery of pharmacogenomics: Impact of the recommendations of the Pharmacy Practice Model Summit.

Am J Health Syst Pharm 2019 Apr;76(8):521-529

Mayo Clinic College of Medicine, Hospital Pharmacy Services, Mayo Clinic, Rochester, MN.

Purpose: This report examines and evaluates pharmacogenomics as an emerging science as it relates to the Practice Advancement Initiative and its predecessor the Pharmacy Practice Model Initiative's consensus statements for optimal pharmacy practice models.

Summary: Pharmacogenomics is one of many emerging sciences to impact medication management and delivery of patient care. Increasingly, biomarkers are included in drug labeling and can assist pharmacists with personalizing medicine to optimize patient therapies and avoid adverse effects. The 2011 ASHP Pharmacy Practice Model Summit generated a list of 147 consensus statements for optimal pharmacy practice. Of these, 1 statement explicitly describes adjustment of drug regimens based on genetic factors as an essential activity of pharmacist-provided drug regimens, and 9 other statements provide additional support for incorporation of this emerging science into all aspects of patient care provided by pharmacists. We describe 4 institutions that have made significant inroads to implementing pharmacogenomics, to provide a framework and serve as resources for other institutions initiating their own pharmacogenomics implementation journeys.

Conclusion: Through prioritized efforts of the pharmacy profession and health care institutions, pharmacogenomics will be disseminated and implemented, and the goal of the Pharmacy Practice Model Initiative's consensus statements of improving health care using patients' genetic characteristics will be realized.
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http://dx.doi.org/10.1093/ajhp/zxz024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6480071PMC
April 2019

Multi-site investigation of strategies for the clinical implementation of CYP2D6 genotyping to guide drug prescribing.

Genet Med 2019 10 21;21(10):2255-2263. Epub 2019 Mar 21.

Department of Medicine, Division of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis, IN, USA.

Purpose: A number of institutions have clinically implemented CYP2D6 genotyping to guide drug prescribing. We compared implementation strategies of early adopters of CYP2D6 testing, barriers faced by both early adopters and institutions in the process of implementing CYP2D6 testing, and approaches taken to overcome these barriers.

Methods: We surveyed eight early adopters of CYP2D6 genotyping and eight institutions in the process of adoption. Data were collected on testing approaches, return of results procedures, applications of genotype results, challenges faced, and lessons learned.

Results: Among early adopters, CYP2D6 testing was most commonly ordered to assist with opioid and antidepressant prescribing. Key differences among programs included test ordering and genotyping approaches, result reporting, and clinical decision support. However, all sites tested for copy-number variation and nine common variants, and reported results in the medical record. Most sites provided automatic consultation and had designated personnel to assist with genotype-informed therapy recommendations. Primary challenges were related to stakeholder support, CYP2D6 gene complexity, phenotype assignment, and sustainability.

Conclusion: There are specific challenges unique to CYP2D6 testing given the complexity of the gene and its relevance to multiple medications. Consensus lessons learned may guide those interested in pursuing similar clinical pharmacogenetic programs.
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http://dx.doi.org/10.1038/s41436-019-0484-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6754805PMC
October 2019

Pharmacogenomic clinical decision support design and multi-site process outcomes analysis in the eMERGE Network.

J Am Med Inform Assoc 2019 02;26(2):143-148

Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.

To better understand the real-world effects of pharmacogenomic (PGx) alerts, this study aimed to characterize alert design within the eMERGE Network, and to establish a method for sharing PGx alert response data for aggregate analysis. Seven eMERGE sites submitted design details and established an alert logging data dictionary. Six sites participated in a pilot study, sharing alert response data from their electronic health record systems. PGx alert design varied, with some consensus around the use of active, post-test alerts to convey Clinical Pharmacogenetics Implementation Consortium recommendations. Sites successfully shared response data, with wide variation in acceptance and follow rates. Results reflect the lack of standardization in PGx alert design. Standards and/or larger studies will be necessary to fully understand PGx impact. This study demonstrated a method for sharing PGx alert response data and established that variation in system design is a significant barrier for multi-site analyses.
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http://dx.doi.org/10.1093/jamia/ocy156DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6339514PMC
February 2019

The eMERGE genotype set of 83,717 subjects imputed to ~40 million variants genome wide and association with the herpes zoster medical record phenotype.

Genet Epidemiol 2019 02 8;43(1):63-81. Epub 2018 Oct 8.

Feinberg School of Medicine, Northwestern University, Chicago, Illinois.

The Electronic Medical Records and Genomics (eMERGE) network is a network of medical centers with electronic medical records linked to existing biorepository samples for genomic discovery and genomic medicine research. The network sought to unify the genetic results from 78 Illumina and Affymetrix genotype array batches from 12 contributing medical centers for joint association analysis of 83,717 human participants. In this report, we describe the imputation of eMERGE results and methods to create the unified imputed merged set of genome-wide variant genotype data. We imputed the data using the Michigan Imputation Server, which provides a missing single-nucleotide variant genotype imputation service using the minimac3 imputation algorithm with the Haplotype Reference Consortium genotype reference set. We describe the quality control and filtering steps used in the generation of this data set and suggest generalizable quality thresholds for imputation and phenotype association studies. To test the merged imputed genotype set, we replicated a previously reported chromosome 6 HLA-B herpes zoster (shingles) association and discovered a novel zoster-associated loci in an epigenetic binding site near the terminus of chromosome 3 (3p29).
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http://dx.doi.org/10.1002/gepi.22167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6375696PMC
February 2019

Harmonizing Outcomes for Genomic Medicine: Comparison of eMERGE Outcomes to ClinGen Outcome/Intervention Pairs.

Healthcare (Basel) 2018 Jul 13;6(3). Epub 2018 Jul 13.

Genomic Medicine Institute, Geisinger, Danville, PA 17822, USA.

Genomic medicine is moving from research to the clinic. There is a lack of evidence about the impact of genomic medicine interventions on health outcomes. This is due in part to a lack of standardized outcome measures that can be used across different programs to evaluate the impact of interventions targeted to specific genetic conditions. The eMERGE Outcomes working group (OWG) developed measures to collect information on outcomes following the return of genomic results to participants for several genetic disorders. These outcomes were compared to outcome intervention pairs for genetic disorders developed independently by the ClinGen Actionability working group (AWG). In general, there was concordance between the defined outcomes between the two groups. The ClinGen outcomes tended to be from a higher level and the AWG scored outcomes represented a subset of outcomes referenced in the accompanying AWG evidence review. eMERGE OWG outcomes were more detailed and discrete, facilitating a collection of relevant information from the health records. This paper demonstrates that common outcomes for genomic medicine interventions can be identified. Further work is needed to standardize outcomes across genomic medicine implementation projects and to make these publicly available to enhance dissemination and assist in making precision public health a reality.
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http://dx.doi.org/10.3390/healthcare6030083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6164315PMC
July 2018

Empowering genomic medicine by establishing critical sequencing result data flows: the eMERGE example.

J Am Med Inform Assoc 2018 10;25(10):1375-1381

Genomic Medicine Institute, Geisinger, Danville, Pennsylvania, USA.

The eMERGE Network is establishing methods for electronic transmittal of patient genetic test results from laboratories to healthcare providers across organizational boundaries. We surveyed the capabilities and needs of different network participants, established a common transfer format, and implemented transfer mechanisms based on this format. The interfaces we created are examples of the connectivity that must be instantiated before electronic genetic and genomic clinical decision support can be effectively built at the point of care. This work serves as a case example for both standards bodies and other organizations working to build the infrastructure required to provide better electronic clinical decision support for clinicians.
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http://dx.doi.org/10.1093/jamia/ocy051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6188517PMC
October 2018

Opportunities and Challenges in Cardiovascular Pharmacogenomics: From Discovery to Implementation.

Circ Res 2018 04;122(9):1176-1190

From the Department of Medicine (D.M.R., S.L.V.D., Q.S.W., J.D.M., J.C.D., J.F.P.).

This review will provide an overview of the principles of pharmacogenomics from basic discovery to implementation, encompassing application of tools of contemporary genome science to the field (including areas of apparent divergence from disease-based genomics), a summary of lessons learned from the extensively studied drugs clopidogrel and warfarin, the current status of implementing pharmacogenetic testing in practice, the role of genomics and related tools in the drug development process, and a summary of future opportunities and challenges.
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http://dx.doi.org/10.1161/CIRCRESAHA.117.310965DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5926807PMC
April 2018

Benefit of Preemptive Pharmacogenetic Information on Clinical Outcome.

Clin Pharmacol Ther 2018 05 13;103(5):787-794. Epub 2018 Mar 13.

Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

The development of new knowledge around the genetic determinants of variable drug action has naturally raised the question of how this new knowledge can be used to improve the outcome of drug therapy. Two broad approaches have been taken: a point-of-care approach in which genotyping for specific variant(s) is undertaken at the time of drug prescription, and a preemptive approach in which multiple genetic variants are typed in an individual patient and the information archived for later use when a drug with a "pharmacogenetic story" is prescribed. This review addresses the current state of implementation, the rationale for these approaches, and barriers that must be overcome. Benefits to pharmacogenetic testing are only now being defined and will be discussed.
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http://dx.doi.org/10.1002/cpt.1035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6134843PMC
May 2018

Multisite Investigation of Strategies for the Implementation of CYP2C19 Genotype-Guided Antiplatelet Therapy.

Clin Pharmacol Ther 2018 10 30;104(4):664-674. Epub 2018 Jan 30.

Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

CYP2C19 genotype-guided antiplatelet therapy following percutaneous coronary intervention is increasingly implemented in clinical practice. However, challenges such as selecting a testing platform, communicating test results, building clinical decision support processes, providing patient and provider education, and integrating methods to support the translation of emerging evidence to clinical practice are barriers to broad adoption. In this report, we compare and contrast implementation strategies of 12 early adopters, describing solutions to common problems and initial performance metrics for each program. Key differences between programs included the test result turnaround time and timing of therapy changes, which are both related to the CYP2C19 testing model and platform used. Sites reported the need for new informatics infrastructure, expert clinicians such as pharmacists to interpret results, physician champions, and ongoing education. Consensus lessons learned are presented to provide a path forward for those seeking to implement similar clinical pharmacogenomics programs within their institutions.
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http://dx.doi.org/10.1002/cpt.1006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6019555PMC
October 2018

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