Integrative polygenic risk score improves the prediction accuracy of complex traits and diseases.

Polygenic risk scores (PRSs) are an emerging tool to predict the clinical phenotypes and outcomes of individuals. We propose PRSmix, a framework that leverages the PRS corpus of a target trait to improve prediction accuracy, and PRSmix+, which incorporates genetically correlated traits to better capture the human genetic architecture for 47 and 32 diseases/traits in European and South Asian ancestries, respectively. PRSmix demonstrated a mean prediction accuracy improvement of 1.20-fold (95% confidence interval [CI], [1.10; 1.3]; p = 9.17 × 10-5) and 1.19-fold (95% CI, [1.11; 1.27]; p = 1.92 × 10-6), and PRSmix+ improved the prediction accuracy by 1.72-fold (95% CI, [1.40; 2.04]; p = 7.58 × 10-6) and 1.42-fold (95% CI, [1.25; 1.59]; p = 8.01 × 10-7) in European and South Asian ancestries, respectively. Compared to the previously cross-trait-combination methods with scores from pre-defined correlated traits, we demonstrated that our method improved prediction accuracy for coronary artery disease up to 3.27-fold (95% CI, [2.1; 4.44]; p value after false discovery rate (FDR) correction = 2.6 × 10-4). Our method provides a comprehensive framework to benchmark and leverage the combined power of PRS for maximal performance in a desired target population.

Association Between a First-Degree Family History and Self-Reported Personal History of Obesity, Diabetes, and Heart and Blood Conditions: Results From the All of Us Research Program.

Background Family history reflects the complex interplay of genetic susceptibility and shared environmental exposures and is an important risk factor for obesity, diabetes, and heart and blood conditions (ODHB). However, the overlap in family history associations between various ODHBs has not been quantified. Methods and Results We assessed the association between a self-reported family history of ODHBs and their risk in the adult population (age ≥20 years) of the AoU (All of Us) Research Program, a longitudinal cohort study of diverse participants across the United States. We conducted a family history-wide association study to systematically assess the association of a first-degree family history of 15 ODHBs in AoU. We performed stratified analyses based on racial and ethnic categories, education, household income and gender minority status, and quantified associations by type of affected relatives. Of 125 430 participants, 76.8% reported a first-degree family history of any ODHB, most commonly hypertension (n=64 982, 51.8%), high cholesterol (49 753, 39.7%), and heart attack (29 618, 23.6%). We use the FamWAS method to estimate 225 familial associations among 15 ODHBs. The results include overlapping associations between family history of different types of cardiometabolic conditions (such as type 2 diabetes and coronary artery disease), and their risk factors (obesity, hypertension), where adults with a family history of 1 ODHB exhibited 1.1 to 5.6 times (1.5, on average) the odds of having a different ODHB. Conclusions Our findings inform the utility of family history data as a risk assessment and screening tool for the prevention of ODHBs and to provide additional insights into shared risk factors and pathogenic mechanisms.

An Environmental Scan of Consumer-Initiated Germline Genetic Testing for Health Risks.

As patient access to laboratory testing outside the clinic grows, health care providers can expect to confront increasing questions about the utility and interpretation of consumer-initiated genetic testing for health risks. We sought to characterize the marketplace diversity of consumer-initiated germline genetic testing options. An environmental scan was conducted to identify germline genetic testing companies that offer testing for at least one diagnosable health condition and are available for purchase by consumers in the US market without a visit to one's health care provider. We limited our scope to tests available between October 1, 2019, and September 30, 2021. We characterized variability in the content and processes used by 21 companies offering 74 distinct test products that met our inclusion and exclusion criteria. A minority (8 of 21 companies) offered tests that assessed the presence of at least 1 US Centers for Disease Control and Prevention Tier 1 condition for which detection can impact an individual's clinical care and for which evidence-based guidelines for detection and management exist.

Multilevel barriers and facilitators to widespread use of preconception carrier screening in the United States.

PURPOSE: Although preconception reproductive genetic carrier screening (RGCS) is preferred to screening during pregnancy, population-wide preconception screening is not routinely performed in the United States. We explored the multilevel barriers to the widespread adoption of preconception RGCS in the United States via key informant interviews. METHODS: Semi-structured virtual video interviews were conducted with 29 informants with a breadth of professional expertise between May and October 2022. Data collection and qualitative analyses were guided by the Consolidated Framework for Implementation Research and socioecological model. Analysis focused on identifying barriers to delivering preconception RGCS at and across different levels of health care and exploring potential facilitators of preconception RGCS delivery. RESULTS: Barriers to preconception RGCS were identified at the levels of test characteristics, patients and couples, clinicians and care teams, and the external health care and policy environments. Across the different levels of care delivery, 3 themes of barriers emerged: (1) fragmentation and inconsistencies hinder care delivery, (2) gaps in knowledge, misconceptions, and uncertainties about RGCS are pervasive, and (3) expanding preconception RGCS in the diverse US population presents unique implementation challenges. Potential solutions were detailed by informants. CONCLUSION: Identifying individual and thematic barriers to preconception RGCS delivery may help to define strategies to alleviate obstacles.

Effectiveness of Medical Student Counseling for Hospitalized Patients Addicted to Tobacco (MS-CHAT): a Randomized Controlled Trial.

BACKGROUND: Low-middle-income countries face an enormous burden of tobacco-related illnesses. Counseling for tobacco cessation increases the chance of achieving quit outcomes, yet it remains underutilized in healthcare settings. OBJECTIVE: We tested the hypothesis that utilizing trained medical students to counsel hospitalized patients who use tobacco will lead to an increase in patient quit rates, while also improving medical student knowledge regarding smoking cessation counseling. DESIGN: Investigator-initiated, two-armed, multicenter randomized controlled trial conducted in three medical schools in India. PARTICIPANTS: Eligibility criteria included age 18-70 years, active admission to the hospital, and current smoking. INTERVENTION: A medical student-guided smoking cessation program, initiated in hospitalized patients and continued for 2 months after discharge. MAIN MEASURES: The primary outcome was self-reported 7-day point prevalence of smoking cessation at 6 months. Changes in medical student knowledge were assessed using a pre- and post-questionnaire delivered prior to and 12 months after training. KEY RESULTS: Among 688 patients randomized across three medical schools, 343 were assigned to the intervention group and 345 to the control group. After 6 months of follow up, the primary outcome occurred in 188 patients (54.8%) in the intervention group, and 145 patients (42.0%) in the control group (absolute difference, 12.8%; relative risk, 1.67; 95% confidence interval, 1.24-2.26; p < 0.001). Among 70 medical students for whom data was available, knowledge increased from a mean score of 14.8 (± 0.8) (out of a maximum score of 25) at baseline to a score of 18.1 (± 0.8) at 12 months, an absolute mean difference of 3.3 (95% CI, 2.3-4.3; p < 0.001). CONCLUSIONS: Medical students can be trained to effectively provide smoking cessation counseling to hospitalized patients. Incorporating this program into the medical curriculum can provide experiential training to medical students while improving patient quit rates. TRIAL REGISTRATION: URL: http://www. CLINICALTRIALS: gov . Unique identifier: NCT03521466.

Integrative polygenic risk score improves the prediction accuracy of complex traits and diseases.

Polygenic risk scores (PRS) are an emerging tool to predict the clinical phenotypes and outcomes of individuals. Validation and transferability of existing PRS across independent datasets and diverse ancestries are limited, which hinders the practical utility and exacerbates health disparities. We propose PRSmix, a framework that evaluates and leverages the PRS corpus of a target trait to improve prediction accuracy, and PRSmix+, which incorporates genetically correlated traits to better capture the human genetic architecture. We applied PRSmix to 47 and 32 diseases/traits in European and South Asian ancestries, respectively. PRSmix demonstrated a mean prediction accuracy improvement of 1.20-fold (95% CI: [1.10; 1.3]; P-value = 9.17 × 10-5) and 1.19-fold (95% CI: [1.11; 1.27]; P-value = 1.92 × 10-6), and PRSmix+ improved the prediction accuracy by 1.72-fold (95% CI: [1.40; 2.04]; P-value = 7.58 × 10-6) and 1.42-fold (95% CI: [1.25; 1.59]; P-value = 8.01 × 10-7) in European and South Asian ancestries, respectively. Compared to the previously established cross-trait-combination method with scores from pre-defined correlated traits, we demonstrated that our method can improve prediction accuracy for coronary artery disease up to 3.27-fold (95% CI: [2.1; 4.44]; P-value after FDR correction = 2.6 × 10-4). Our method provides a comprehensive framework to benchmark and leverage the combined power of PRS for maximal performance in a desired target population.

A Pooled Electronic Consultation Program to Improve Access to Genetics Specialists.

Innovative service delivery models are needed to increase access to genetics specialists. Electronic consultation (e-Consult) programs can connect clinicians with specialists. At Massachusetts General Hospital, an e-Consult service was created to address genomics-related questions. In its first year, the e-Consult service triaged 153 requests and completed 122 in an average of 3.2 days. Of the 95 e-Consults with actionable recommendations, there was documentation that most ordering clinicians followed through (82%). A variety of providers used the service, although the majority (77%) were generalists. E-Consult models should be considered as one way to increase access to genetics care.

Association of Patient and Site-of-Care Characteristics With Reproductive Carrier Screening Timing in a Large Integrated Health System.

Importance: Reproductive genetic carrier screening can be performed prior to or during pregnancy to assess a reproductive couple's risk of having a child with a recessively inherited disorder. Although professional societies endorse preconception screening as preferable to prenatal screening to allow for greater reproductive choice, implementation of preconception screening is challenging. Objective: To determine how carrier screening timing varies by multilevel factors associated with health care delivery including patient, clinician, and location across a large integrated health care system. Design, Setting, and Participants: This cross-sectional study used a mixed-methods approach including (1) quantitative analysis of multilevel factors associated with the timing of reproductive carrier screening and (2) qualitative analyses of data from interviews conducted with clinicians ordering carrier screenings. The setting was the Mass General Brigham, a large integrated health care system in the greater Boston, Massachusetts area. Participants included adult female patients who completed reproductive carrier screening performed by Myriad Women's Health between October 1, 2018, to September 30, 2019. Exposures: Site of care (ordering clinical location and hospital affiliate), ordering clinician specialty, and patient characteristics, including age at date of test collection, self-reported race and ethnicity, primary insurance payor, and number of comorbidities. Main Outcomes and Measures: The primary outcome was the timing of carrier screening (preconception vs prenatal). A series of 4 multilevel logistic regression models were fitted to measure the relative contribution of site, clinician, and patient-level factors on the timing of screening. Interviews with ordering clinicians (N = 9) were analyzed using a framework approach to explore barriers to preconception screening. Results: Among 6509 adult female patients who completed carrier screenings, 770 (12%) were Asian, 352 (5%) were Hispanic, 640 (10%) were non-Hispanic Black, 3844 (59%) were non-Hispanic White, 858 (13%) were other or multiple races and ethnicities, and 2611 (40%) were aged 31 to 35 years; 4701 (63%) had prenatal screening and 2438 (37%) had preconception screening; screenings were ordered by 161 distinct clinicians across 32 clinical locations affiliated with 4 hospitals. In model 1, adjusted for hospital (fixed effect), clinic and clinician (random effects), 49% of the variability in timing was associated with clinician-level effects (intraclass correlation coefficient [ICC], 0.49) and 28% was associated with clinic-level effects (ICC, 0.28). Clinician specialty explained the greatest amount of variation in screening timing. Interviewed clinicians (N = 9) supported preconception screening but cited several barriers to offering population-based preconception screening. Conclusions and Relevance: In this cross-sectional study, multilevel factors were associated with carrier screening timing. These findings suggest that increasing access to preconception screening may involve engaging specific medical specialties.

Clinical Implementation of Combined Monogenic and Polygenic Risk Disclosure for Coronary Artery Disease.

BACKGROUND: State-of-the-art genetic risk interpretation for a common complex disease such as coronary artery disease (CAD) requires assessment for both monogenic variants-such as those related to familial hypercholesterolemia-as well as the cumulative impact of many common variants, as quantified by a polygenic score. OBJECTIVES: The objective of the study was to describe a combined monogenic and polygenic CAD risk assessment program and examine its impact on patient understanding and changes to clinical management. METHODS: Study participants attended an initial visit in a preventive genomics clinic and a disclosure visit to discuss results and recommendations, primarily via telemedicine. Digital postdisclosure surveys and chart review evaluated the impact of disclosure. RESULTS: There were 60 participants (mean age 51 years, 37% women, 72% with no known CAD), including 30 (50%) referred by their cardiologists and 30 (50%) self-referred. Two (3%) participants had a monogenic variant pathogenic for familial hypercholesterolemia, and 19 (32%) had a high polygenic score in the top quintile of the population distribution. In a postdisclosure survey, both the genetic test report (in 80% of participants) and the discussion with the clinician (in 89% of participants) were ranked as very or extremely helpful in understanding the result. Of the 42 participants without CAD, 17 or 40% had a change in management, including statin initiation, statin intensification, or coronary imaging. CONCLUSIONS: Combined monogenic and polygenic assessments for CAD risk provided by preventive genomics clinics are beneficial for patients and result in changes in management in a significant portion of patients.

Drug-drug-gene interaction risk among opioid users in the U.S. Department of Veterans Affairs.

ABSTRACT: Response to analgesic therapy is influenced by several factors including genetics and drug-drug interactions. Pharmacogenetic (PGx) variants in the CYP2D6 gene modify response to opioids by altering drug metabolism. We sought to determine the potential impact of PGx testing on the care of Veterans with noncancer pain prescribed opioids metabolized by CYP2D6 (codeine, hydrocodone, or tramadol). A retrospective analysis was performed within the Veterans Health Administration evaluating prescription records for pain medications metabolized by CYP2D6 and interacting drugs from 2012 to 2017. Among 2,436,654 Veterans Health Administration pharmacy users with at least 1 opioid prescription, 34% met the definition of chronic use (longer than 90 days with more than 10 prescriptions or 120 days-supply). Opioids were commonly coprescribed with antidepressants interacting with CYP2D6 (28%). An estimated 21.6% (n = 526,905) of these patients are at an elevated risk of an undesirable response to their opioid medication based on predicted phenotypes and drug-drug interactions: 3.5% are predicted CYP2D6 ultrarapid metabolizers and at increased risk for toxicity, 5.4% are poor metabolizers at higher risk for nonresponse, and 12.8% are normal or intermediate metabolizers coprescribed a CYP2D6 inhibitor leading to phenoconversion into poor metabolizer. Despite the high rate of coprescription of opioids and interacting drugs, CYP2D6 testing was infrequent in the sample (0.02%), and chart review suggests that test results were used to optimize antidepressant treatments rather than pain medications. Using PGx testing combined with consideration of phenoconversion may allow for an enhanced precision medicine approach to pain management in Veterans.

Self-rated family health history knowledge among All of Us program participants.

PURPOSE: Disparities in access to genetics services are well-documented. Family health history is routinely used to determine whether patients should be screened for heritable conditions. We sought to explore variation in levels of self-rated family health history knowledge as a possible contributer to this disparity. METHODS: We performed a cross-sectional analysis of survey data from the All of Us Research Program. We compared the characteristics of participants who reported "None," "Some", and "A lot" of family health history knowledge using multinomial logistic regression. RESULTS: Self-rated family health history data were available for 116,799 participants. A minority of survey participants (37%) endorsed "A lot" of knowledge about their family health history (n = 43,661). Most participants (60%) endorsed "Some" family health history knowledge (n = 69,914) and 3% (n = 3224) endorsed "None." In adjusted analyses, those who indicated "Some" family health history knowledge or "None" were more likely to be assigned male sex at birth, identify as possible gender and sexual minorities, have a self-reported race other than White, have a lower household annual income (<$25,000), or report lower educational attainment (

Rationale and Design of a Randomized Controlled Trial to Evaluate the Effectiveness of Medical Student Counseling for Hospitalized Patients Addicted to Tobacco (the MS-CHAT Trial).

Globally, India is the second largest consumer of tobacco. However, Indian medical students do not receive adequate training in smoking cessation counseling. Each patient hospitalization is an opportunity to counsel smokers. Medical Student Counseling for Hospitalized patients Addicted to Tobacco (MS-CHAT) is a 2-arm multicenter randomized controlled trial (RCT) that compares the effectiveness of a medical student-guided smoking cessation program initiated in inpatients and continued for two months after discharge versus standard hospital practice. Current smokers admitted to the hospital are randomized to receive either usual care or the intervention. The intervention group receives inpatient counseling and longitudinal postdischarge telephone follow-up by medical students. The control group receives counseling at the discretion of the treating physician. The primary outcome is biochemically verified 7-day point prevalence of smoking cessation at 6 months after enrollment. Changes in medical student knowledge and attitude will also be studied using a pre- and postquestionnaire delivered prior to and 12 months after training. This trial tests a unique model that seeks to provide hands-on experience in smoking cessation counseling to medical students while simultaneously improving cessation outcomes among hospitalized smokers in India.

Association of the transthyretin variant V122I with polyneuropathy among individuals of African ancestry.

Hereditary transthyretin-mediated (hATTR) amyloidosis is an underdiagnosed, progressively debilitating disease caused by mutations in the transthyretin (TTR) gene. V122I, a common pathogenic TTR mutation, is found in 3-4% of individuals of African ancestry in the United States and has been associated with cardiomyopathy and heart failure. To better understand the phenotypic consequences of carrying V122I, we conducted a phenome-wide association study scanning 427 ICD diagnosis codes in UK Biobank participants of African ancestry (n = 6062). Significant associations were tested for replication in the Penn Medicine Biobank (n = 5737) and the Million Veteran Program (n = 82,382). V122I was significantly associated with polyneuropathy in the UK Biobank (odds ratio [OR] = 6.4, 95% confidence interval [CI] 2.6-15.6, p = 4.2 × 10-5), which was replicated in the Penn Medicine Biobank (OR = 1.6, 95% CI 1.2-2.4, p = 6.0 × 10-3) and Million Veteran Program (OR = 1.5, 95% CI 1.2-1.8, p = 1.8 × 10-4). Polyneuropathy prevalence among V122I carriers was 2.1%, 9.0%, and 4.8% in the UK Biobank, Penn Medicine Biobank, and Million Veteran Program, respectively. The cumulative incidence of common hATTR amyloidosis manifestations (carpal tunnel syndrome, polyneuropathy, cardiomyopathy, heart failure) was significantly enriched in V122I carriers compared with non-carriers (HR = 2.8, 95% CI 1.7-4.5, p = 2.6 × 10-5) in the UK Biobank, with 37.4% of V122I carriers having at least one of these manifestations by age 75. Our findings show that V122I carriers are at increased risk of polyneuropathy. These results also emphasize the underdiagnosis of disease in V122I carriers with a significant proportion of subjects showing phenotypic changes consistent with hATTR amyloidosis. Greater understanding of the manifestations associated with V122I is critical for earlier diagnosis and treatment.

Primary care and mental health providers' perceptions of implementation of pharmacogenetics testing for depression prescribing.

BACKGROUND: Pharmacogenetic testing (PGx) has the potential to improve the quality of psychiatric prescribing by considering patients' genetic profile. However, there is limited scientific evidence supporting its efficacy or guiding its implementation. The Precision Medicine in Mental Health (PRIME) Care study is a pragmatic randomized controlled trial evaluating the effectiveness of a specific commercially-available pharmacogenetic (PGx) test to inform antidepressant prescribing at 22 sites across the U.S. Simultaneous implementation science methods using the Consolidated Framework for Implementation Research (CFIR) are integrated throughout the trial to identify contextual factors likely to be important in future implementation of PGx. The goal of this study was to understand providers' perceptions of PGx for antidepressant prescribing and implications for future implementation. METHODS: Qualitative focus groups (n = 10) were conducted at the beginning of the trial with Primary Care and Mental Health providers (n = 31) from six PRIME Care sites. Focus groups were audio-recorded and transcribed and data were analyzed using rapid analytic procedures organized by CFIR domains. RESULTS: Analysis revealed themes in the CFIR Intervention Characteristics domain constructs of Evidence, Relative Advantage, Adaptability, Trialability, Complexity, and Design that are important for understanding providers' perceptions of PGx testing. Results indicate: 1) providers had limited experience and knowledge of PGx testing and its evidence base, particularly for psychiatric medications; 2) providers were hopeful that PGx could increase their precision in depression prescribing and improve patient engagement, but were uncertain about how results would influence treatment; 3) providers were concerned about potential misinterpretation of PGx results and how to incorporate testing into their workflow; 4) primary care providers were less familiar and comfortable with application of PGx testing to antidepressant prescribing than psychiatric providers. CONCLUSIONS: Provider perceptions may serve as facilitators or barriers to implementation of PGx for psychiatric prescribing. Incorporating implementation science into the conduct of the RCT adds value by uncovering factors to be addressed in preparing for future implementation, should the practice prove effective. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT03170362 ; Registered 31 May 2017.

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

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.

Early adoption of pharmacogenetic testing for veterans prescribed psychotropic medications.

Aim: Describe the characteristics of providers ordering, patients receiving, and clinical impact of a psychotropic pharmacogenetic test on veteran care. Patients & methods: Observational cohort study linking veterans' laboratory results to electronic health record data. Changes in psychotropic medication prescribing were measured as a function of test results. Results: A total of 38 providers tested 181 veterans between 10/6/2014 and 2/1/2018. Prescriptions for medications with severe gene-drug interactions decreased; however, 11 such medications were used after testing. For 43 patients, documentation of the results was missing. Conclusion: Most prescribing decisions were congruent with test results, but in a nontrivial number of cases, prescribers appeared not to act on the results. Poor result documentation impeded the potential of results to inform clinical care.

Association of APOL1 Risk Alleles With Cardiovascular Disease in Blacks in the Million Veteran Program.

BACKGROUND: Approximately 13% of black individuals carry 2 copies of the apolipoprotein L1 (APOL1) risk alleles G1 or G2, which are associated with 1.5- to 2.5-fold increased risk of chronic kidney disease. There have been conflicting reports as to whether an association exists between APOL1 risk alleles and cardiovascular disease (CVD) that is independent of the effects of APOL1 on kidney disease. We sought to test the association of APOL1 G1/G2 alleles with coronary artery disease, peripheral artery disease, and stroke among black individuals in the Million Veteran Program. METHODS: We performed a time-to-event analysis of retrospective electronic health record data using Cox proportional hazard and competing-risks Fine and Gray subdistribution hazard models. The primary exposure was APOL1 risk allele status. The primary outcome was incident coronary artery disease among individuals without chronic kidney disease during the 12.5-year follow-up period. We separately analyzed the cross-sectional association of APOL1 risk allele status with lipid traits and 115 cardiovascular diseases using phenome-wide association. RESULTS: Among 30 903 black Million Veteran Program participants, 3941 (13%) carried the 2 APOL1 risk allele high-risk genotype. Individuals with normal kidney function at baseline with 2 risk alleles had slightly higher risk of developing coronary artery disease compared with those with no risk alleles (hazard ratio, 1.11 [95% CI, 1.01-1.21]; P=0.039). Similarly, modest associations were identified with incident stroke (hazard ratio, 1.20 [95% CI, 1.05-1.36; P=0.007) and peripheral artery disease (hazard ratio, 1.15 [95% CI, 1.01-1.29l; P=0.031). When both cardiovascular and renal outcomes were modeled, APOL1 was strongly associated with incident renal disease, whereas no significant association with the CVD end points could be detected. Cardiovascular phenome-wide association analyses did not identify additional significant associations with CVD subsets. CONCLUSIONS: APOL1 risk variants display a modest association with CVD, and this association is likely mediated by the known APOL1 association with chronic kidney disease.

Projected Prevalence of Actionable Pharmacogenetic Variants and Level A Drugs Prescribed Among US Veterans Health Administration Pharmacy Users.

Importance: Implementation of pharmacogenetic testing to guide drug prescribing has potential to improve drug response and prevent adverse events. Robust data exist for more than 30 gene-drug pairs linking genotype to drug response phenotypes; however, it is unclear which pharmacogenetic tests, if implemented, would provide the greatest utility for a given patient population. Objectives: To project the proportion of veterans in the US Veterans Health Administration (VHA) with actionable pharmacogenetic variants and evaluate how testing might be associated with prescribing decisions. Design, Setting, and Participants: This cross-sectional study included veterans who used national VHA pharmacy services from October 1, 2011, to September 30, 2017. Data analyses began April 26, 2018, and were completed February 6, 2019. Exposures: Receipt of level A drugs based on VHA pharmacy dispensing records. Main Outcomes and Measures: Projected prevalence of actionable pharmacogenetic variants among VHA pharmacy users based on variant frequencies from the 1000 Genomes Project and veteran demographic characteristics; incident number of level A prescriptions, and proportion of new level A drug recipients projected to carry an actionable pharmacogenetic variant. Results: During the study, 7 769 359 veterans (mean [SD] age, 58.1 [17.8] years; 7 021 504 [90.4%] men) used VHA pharmacy services. It was projected that 99% of VHA pharmacy users would carry at least 1 actionable pharmacogenetic variant. Among VHA pharmacy users, 4 259 153 (54.8%) received at least 1 level A drug with 1 188 124 (15.3%) receiving 2 drugs, and 912 189 (11.7%) receiving 3 or more drugs. The most common incident prescriptions during the study were tramadol (923 671 new recipients), simvastatin (533 928 new recipients), citalopram (266 952 new recipients), and warfarin (205 177 new recipients). Gene-drug interactions projected to have substantial clinical impacts in the VHA population include the interaction of SLCO1B1 with simvastatin (1 988 956 veterans [25.6%]), CYP2D6 with tramadol (318 544 veterans [4.1%]), and CYP2C9 or VKORC1 with warfarin (7 163 349 veterans [92.2%]). Conclusions and Relevance: Clinically important pharmacogenetic variants are highly prevalent in the VHA population. Almost all veterans would carry an actionable variant, and more than half of the population had been exposed to a drug affected by these variants. These results suggest that pharmacogenetic testing has the potential to affect pharmacotherapy decisions for commonly prescribed outpatient medications for many veterans.