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Primary open-angle glaucoma (POAG) is a degenerative eye disease for which early treatment is critical to mitigate visual impairment and irreversible blindness. POAG-associated loci individually confer incremental risk. Genetic risk score(s) (GRS) could enable POAG risk stratification. Despite significantly higher POAG burden among individuals of African ancestry (AFR), GRS are limited in this population. A recent large-scale, multi-ancestry meta-analysis identified 127 POAG-associated loci and calculated cross-ancestry and ancestry-specific effect estimates, including in European ancestry (EUR) and AFR individuals. We assessed the utility of the 127-variant GRS for POAG risk stratification in EUR and AFR Veterans in the Million Veteran Program (MVP). We also explored the association between GRS and documented invasive glaucoma surgery (IGS).Cross-sectional study.MVP Veterans with imputed genetic data, including 5830 POAG cases (445 with IGS documented in the electronic health record) and 64 476 controls.We tested unweighted and weighted GRS of 127 published risk variants in EUR (3382 cases and 58 811 controls) and AFR (2448 cases and 5665 controls) Veterans in the MVP. Weighted GRS were calculated using effect estimates from the most recently published report of cross-ancestry and ancestry-specific meta-analyses. We also evaluated GRS in POAG cases with documented IGS.Performance of 127-variant GRS in EUR and AFR Veterans for POAG risk stratification and association with documented IGS.GRS were significantly associated with POAG (Plt; 5 × 10sup-5/sup) in both groups; a higher proportion of EUR compared with AFR were consistently categorized in the top GRS decile (21.9%-23.6% and 12.9%-14.5%, respectively). Only GRS weighted by ancestry-specific effect estimates were associated with IGS documentation in AFR cases; all GRS types were associated with IGS in EUR cases.Varied performance of the GRS for POAG risk stratification and documented IGS association in EUR and AFR Veterans highlights (1) the complex risk architecture of POAG, (2) the importance of diverse representation in genomics studies that inform GRS construction and evaluation, and (3) the necessity of expanding diverse POAG-related genomic data so that GRS can equitably aid in screening individuals at high risk of POAG and who may require more aggressive treatment.

Purpose The course of posttraumatic stress disorder (PTSD) symptoms varies among veterans of warzones, but sources of variation in long-term course remain poorly understood. Modeling of symptom growth trajectories facilitates understanding predictors of individual outcomes over time. Although growth mixture modeling (GMM) has been applied to military populations, few studies have incorporated both pre-deployment and follow-up measurements over an extended time. Methods In this prospective study, 1087 US Army soldiers with varying military occupational specialties and geographic locations were assessed before and after deployment to the Iraq War, with long-term follow-up assessment occurring at least five years after return from deployment. The primary outcome variable was the PTSD Checklist, civilian version, summary score. Results GMM yielded four latent profiles: (1) primarily asymptomatic (n = 194; 17·8%), (2) post-deployment worsening symptoms (n = 84; 7·7%), (3) mild symptoms (n = 320; 29·4%), and (4) pre-existing, with chronic post-deployment elevation of symptoms (n = 489; 45·0%). Regression models comparing the primarily asymptomatic class to symptomatic classes revealed that chronic symptom classes were associated with greater stress exposure, less pre-deployment social support, identifying as a racial/ethnic minority, military reservist or veteran status at most recent assessment, and poorer pre-deployment visual memory. Conclusions PTSD symptom course varies considerably over time after military deployment and is associated with potentially modifiable biopsychosocial factors occurring early in its course, in addition to exposures and military status. Trial Registration : This study reported in this article was formally preregistered September 9, 2008 with ClinicalTrials.gov (https://clinicaltrials.gov/ct2/show/NCT00748995).

Serious mental illnesses, including schizophrenia, bipolar disorder, and depression, are heritable, highly multifactorial disorders and major causes of disability worldwide.To benchmark the penetrance of current neuropsychiatric polygenic risk scores (PRSs) in the Veterans Health Administration health care system and to explore associations between PRS and broad categories of human disease via phenome-wide association studies.Extensive Veterans Health Administration's electronic health records were assessed from October 1999 to January 2021, and an embedded cohort of 9378 individuals with confirmed diagnoses of schizophrenia or bipolar 1 disorder were found. The performance of schizophrenia, bipolar disorder, and major depression PRSs were compared in participants of African or European ancestry in the Million Veteran Program (approximately 400 000 individuals), and associations between PRSs and 1650 disease categories based on ICD-9/10 billing codes were explored. Last, genomic structural equation modeling was applied to derive novel PRSs indexing common and disorder-specific genetic factors. Analysis took place from January 2021 to January 2022.Diagnoses based on in-person structured clinical interviews were compared with ICD-9/10 billing codes. PRSs were constructed using summary statistics from genome-wide association studies of schizophrenia, bipolar disorder, and major depression.Of 707 299 enrolled study participants, 459 667 were genotyped at the time of writing; 84 806 were of broadly African ancestry (mean [SD] age, 58 [12.1] years) and 314 909 were of broadly European ancestry (mean [SD] age, 66.4 [13.5] years). Among 9378 individuals with confirmed diagnoses of schizophrenia or bipolar 1 disorder, 8962 (95.6%) were correctly identified using ICD-9/10 codes (2 or more). Among those of European ancestry, PRSs were robustly associated with having received a diagnosis of schizophrenia (odds ratio [OR], 1.81 [95% CI, 1.76-1.87]; P 10-257) or bipolar disorder (OR, 1.42 [95% CI, 1.39-1.44]; P 10-295). Corresponding effect sizes in participants of African ancestry were considerably smaller for schizophrenia (OR, 1.35 [95% CI, 1.29-1.42]; P 10-38) and bipolar disorder (OR, 1.16 [95% CI, 1.11-1.12]; P 10-10). Neuropsychiatric PRSs were associated with increased risk for a range of psychiatric and physical health problems.Using diagnoses confirmed by in-person structured clinical interviews and current neuropsychiatric PRSs, the validity of an electronic health records-based phenotyping approach in US veterans was demonstrated, highlighting the potential of PRSs for disentangling biological and mediated pleiotropy.

Cross-sectional research suggests that posttraumatic stress symptoms (PTSS) among war zone veterans are associated with functional impairment and poor quality of life. Less is known about the long-term functional repercussions of PTSS. This study of Iraq War veterans examined the associations between increases in PTSS and long-term functional outcomes, including the potential contributions of neurocognitive decrements. Service members and veterans (N = 594) completed self-report measures of functioning and PTSS severity before Iraq War deployment and again after their return (M = 9.3 years postdeployment). Some participants (n = 278) also completed neurocognitive testing at both times. Multiple regression analyses with the full sample-adjusted for TBI, demographic characteristics, military variables, and predeployment PTSS and functioning-revealed that increased PTSS severity over time was significantly associated with unemployment, aOR = 1.04, 95% CI [1.03, 1.06]; poorer work performance; and poorer physical, emotional, and cognitive health-related functioning at long-term follow-up, f2 s = 0.37-1.79. Among participants who completed neurocognitive testing, a decline in select neurocognitive measures was associated with poorer functioning; however, neurocognitive decrements did not account for associations between increased PTSS and unemployment, aOR = 1.04, 95% CI [1.02, 1.07], with the size and direction upheld after adding neurocognitive variables, or poorer functional outcomes, with small increases after adding neurocognitive measures to the models, f2 s = 0.03-0.10. War zone veterans experiencing long-term increased PTSS and/or neurocognitive decrements may be at elevated risk for higher-level functional impairment over time, suggesting that early PTSS management may enhance long-term functioning.

We conducted genome-wide association analyses of over 250,000 participants of European (EUR) and African (AFR) ancestry from the Million Veteran Program using electronic health record-validated post-traumatic stress disorder (PTSD) diagnosis and quantitative symptom phenotypes. Applying genome-wide multiple testing correction, we identified three significant loci in European case-control analyses and 15 loci in quantitative symptom analyses. Genomic structural equation modeling indicated tight coherence of a PTSD symptom factor that shares genetic variance with a distinct internalizing (mood–anxiety–neuroticism) factor. Partitioned heritability indicated enrichment in several cortical and subcortical regions, and imputed genetically regulated gene expression in these regions was used to identify potential drug repositioning candidates. These results validate the biological coherence of the PTSD syndrome, inform its relationship to comorbid anxiety and depressive disorders and provide new considerations for treatment. Genome-wide association analyses of post-traumatic stress disorder and its symptom subdomains in individuals of European and African ancestry provide insights into its relationship with anxiety and depressive disorders and identify potential candidates for drug repositioning.

Patient-reported outcome measures (PROMs) are self-rated scales and indices developed to improve the detection of the patients’ subjective experience. Given that a considerable number of PROMs are available, it is important to evaluate their validity and usefulness in a specific research or clinical setting. Published guidelines, based on psychometric criteria, do not fit in with the complexity of clinical challenges, because of their quest for homogeneity of components and inadequate attention to sensitivity. Psychometric theory has stifled the field and led to the routine use of scales widely accepted yet with a history of poor performance. Clinimetrics, the science of clinical measurements, may provide a more suitable conceptual and methodological framework. The aims of this paper are to outline the major limitations of the psychometric model and to provide criteria for clinimetric patient-reported outcome measures (CLIPROMs). The characteristics related to reliability, sensitivity, validity, and clinical utility of instruments are critically reviewed, with particular reference to the differences between clinimetric and psychometric approaches. Of note is the fact that PROMs, rating scales, and indices developed according to psychometric criteria may display relevant clinimetric properties. The present paper underpins the importance of the clini­metric methodology in choosing the appropriate PROMs. CLIPROM criteria may also guide the development of new indices and the validation of existing PROMs to be employed in clinical settings.

Background Medical and regulatory communities are increasingly interested in the utility of real-world evidence (RWE) for answering questions pertaining to drug safety and effectiveness, but concerns about validity remain. A principled approach to conducting RWE studies may alleviate concerns and increase confidence in findings. This study sought to predict the findings from the PRONOUNCE trial using a principled approach to generating RWE. Methods This propensity score–matched observational cohort study used 3 claims databases to compare the occurrence of major adverse cardiovascular events among initiators of degarelix vs leuprolide. Patients were included if they had a history of prostate cancer and atherosclerotic cardiovascular disease. Patients were excluded if they did not have continuous database enrollment in the year before treatment initiation, were exposed to androgen deprivation therapy or experienced an acute cardiovascular event within 30 days before treatment initiation, or had a history or risk factors of QT prolongation. Results There were 12 448 leuprolide and 1969 degarelix study-eligible patients before matching, with 1887 in each arm after propensity score matching. The results for major adverse cardiovascular events comparing degarelix with leuprolide in the observational analysis (hazard ratio = 1.35, 95% confidence interval = 0.94 to 1.93) was consistent with the subsequently released PRONOUNCE result (hazard ratio = 1.28, 95% confidence interval = 0.59 to 2.79). Conclusions This study successfully predicted the result of a comparative cardiovascular safety trial in the oncology setting. Although the findings are encouraging, limitations of measuring cancer stage and tumor progression are representative of challenges in attempting to generalize whether claims-based RWE can be used as actionable evidence.

Supplemental Digital Content is available in the text., Background: Abdominal aortic aneurysm (AAA) is an important cause of cardiovascular mortality; however, its genetic determinants remain incompletely defined. In total, 10 previously identified risk loci explain a small fraction of AAA heritability. Methods: We performed a genome-wide association study in the Million Veteran Program testing ≈18 million DNA sequence variants with AAA (7642 cases and 172 172 controls) in veterans of European ancestry with independent replication in up to 4972 cases and 99 858 controls. We then used mendelian randomization to examine the causal effects of blood pressure on AAA. We examined the association of AAA risk variants with aneurysms in the lower extremity, cerebral, and iliac arterial beds, and derived a genome-wide polygenic risk score (PRS) to identify a subset of the population at greater risk for disease. Results: Through a genome-wide association study, we identified 14 novel loci, bringing the total number of known significant AAA loci to 24. In our mendelian randomization analysis, we demonstrate that a genetic increase of 10 mm Hg in diastolic blood pressure (odds ratio, 1.43 [95% CI, 1.24–1.66]; P=1.6×10−6), as opposed to systolic blood pressure (odds ratio, 1.06 [95% CI, 0.97–1.15]; P=0.2), likely has a causal relationship with AAA development. We observed that 19 of 24 AAA risk variants associate with aneurysms in at least 1 other vascular territory. A 29-variant PRS was strongly associated with AAA (odds ratioPRS, 1.26 [95% CI, 1.18–1.36]; PPRS=2.7×10−11 per SD increase in PRS), independent of family history and smoking risk factors (odds ratioPRS+family history+smoking, 1.24 [95% CI, 1.14–1.35]; PPRS=1.27×10−6). Using this PRS, we identified a subset of the population with AAA prevalence greater than that observed in screening trials informing current guidelines. Conclusions: We identify novel AAA genetic associations with therapeutic implications and identify a subset of the population at significantly increased genetic risk of AAA independent of family history. Our data suggest that extending current screening guidelines to include testing to identify those with high polygenic AAA risk, once the cost of genotyping becomes comparable with that of screening ultrasound, would significantly increase the yield of current screening at reasonable cost.

The Million Veteran Program (MVP), initiated by the Department of Veterans Affairs (VA), aims to collect biosamples with consent from at least one million veterans. Presently, blood samples have been collected from over 800,000 enrolled participants. The size and diversity of the MVP cohort, as well as the availability of extensive VA electronic health records, make it a promising resource for precision medicine. MVP is conducting array-based genotyping to provide a genome-wide scan of the entire cohort, in parallel with whole-genome sequencing, methylation, and other ‘omics assays. Here, we present the design and performance of the MVP 1.0 custom Axiom array, which was designed and developed as a single assay to be used across the multi-ethnic MVP cohort. A unified genetic quality-control analysis was developed and conducted on an initial tranche of 485,856 individuals, leading to a high-quality dataset of 459,777 unique individuals. 668,418 genetic markers passed quality control and showed high-quality genotypes not only on common variants but also on rare variants. We confirmed that, with non-European individuals making up nearly 30%, MVP’s substantial ancestral diversity surpasses that of other large biobanks. We also demonstrated the quality of the MVP dataset by replicating established genetic associations with height in European Americans and African Americans ancestries. This current dataset has been made available to approved MVP researchers for genome-wide association studies and other downstream analyses. Further data releases will be available for analysis as recruitment at the VA continues and the cohort expands both in size and diversity.

Cognitive impairment is a frequent and serious problem in patients with various forms of severe mental illnesses (SMI), including schizophrenia (SZ) and bipolar disorder (BP). Recent research suggests genetic links to several cognitive phenotypes in both SMI and in the general population. Our goal in this study was to identify potential genomic signatures of cognitive functioning in veterans with severe mental illness and compare them to previous findings for cognition across different populations. Veterans Affairs (VA) Cooperative Studies Program (CSP) Study #572 evaluated cognitive and functional capacity measures among SZ and BP patients. In conjunction with the VA Million Veteran Program, 3,959 European American (1,095 SZ, 2,864 BP) and 2,601 African American (1,095 SZ, 2,864 BP) patients were genotyped using a custom Affymetrix Axiom Biobank array. We performed a genome-wide association study of global cognitive functioning, constructed polygenic scores for SZ and cognition in the general population, and examined genetic correlations with 2,626 UK Biobank traits. Although no single locus attained genome-wide significance, observed allelic effects were strongly consistent with previous studies. We observed robust associations between global cognitive functioning and polygenic scores for cognitive performance, intelligence, and SZ risk. We also identified significant genetic correlations with several cognition-related traits in UK Biobank. In a diverse cohort of U.S. veterans with SZ or BP, we demonstrate broad overlap of common genetic effects on cognition in the general population, and find that greater polygenic loading for SZ risk is associated with poorer cognitive performance.

Gulf War Illness (GWI), a chronic multisymptom illness with a complex and uncertain etiology and pathophysiology, is highly prevalent among veterans deployed to the 1990–1991 GW. We examined how GWI phenotypes varied by demographic and military characteristics among GW-era veterans. Data were from the VA’s Cooperative Studies Program 2006/Million Veteran Program (MVP) 029 cohort, Genomics of GWI. From June 2018 to March 2019, 109,976 MVP enrollees (out of a total of over 676,000) were contacted to participate in the 1990–1991 GW-era Survey. Of 109,976 eligible participants, 45,169 (41.1%) responded to the 2018–2019 survey, 35,902 respondents met study inclusion criteria, 13,107 deployed to the GW theater. GWI phenotypes were derived from Kansas (KS) and Centers for Disease Control and Prevention (CDC) GWI definitions: (a) KS Symptoms (KS Sym+), (b) KS GWI (met symptom criteria and without exclusionary health conditions) [KS GWI: Sym+/Dx−], (c) CDC GWI and (d) CDC GWI Severe. The prevalence of each phenotype was 67.1% KS Sym+, 21.5% KS Sym+/Dx−, 81.1% CDC GWI, and 18.6% CDC GWI severe. These findings affirm the persistent presence of GWI among GW veterans providing a foundation for further exploration of biological and environmental underpinnings of this condition.

Background: Approximately 697,000 members of the U.S. Armed Forces were deployed to the Persian Gulf in support of the 1990–1991 Persian Gulf War (GW). Subsequently, many deployed and some non-deployed veterans developed a chronic multi-symptom illness, now named Gulf War Illness (GWI). This manuscript outlines the methods and rationale for studying the genomics of GWI within the Million Veteran Program (MVP), a VA-based national research program that has linked medical records, surveys, and genomic data, enabling genome-wide association studies (GWASs). Methods: MVP participants who served in the military during the GW era were contacted by mail and invited to participate in the GWI study. A structured health questionnaire, based on a previously tested instrument, was also included in the mailing. Data on deployment locations and exposures, symptoms associated with GWI, clinical diagnoses, personal habits, and health care utilization were collected. Self-reported data will be augmented with chart reviews and structured international classification of disease codes, to classify participants by GWI case status. We will develop a phenotyping algorithm, based on two commonly used case definitions, to determine GWI status, and then conduct a nested case-control GWAS. Genetic variants associated with GWI will be investigated, and gene–gene and gene–environment interactions studied. The genetic overlap of GWI with, and causative mechanisms linking this illness to, other health conditions and the effects of genomic regulatory mechanisms on GWI risk will also be explored. Conclusions: The proposed initial GWAS described in this report will investigate the genomic underpinnings of GWI with a large sample size and state-of-the-art genomic analyses and phenotyping. The data generated will provide a rich and expansive foundation on which to build additional analyses.

Venous thromboembolism (VTE) is a significant cause of mortality1, yet its genetic determinants remain incompletely defined. We performed a discovery genome-wide association study in the Million Veteran Program and UK Biobank testing ~13 million DNA sequence variants for association with VTE (26,066 cases; 624,053 controls) and meta-analyzed both studies, followed by independent replication with up to 17,672 VTE cases and 167,295 controls. We identified 22 novel loci, bringing the total number of VTE-associated loci to 33 and subsequently fine-mapped these associations. We developed a genome-wide polygenic risk score for VTE that identifies 5% of the population at equivalent incident VTE risk to carriers of the established F5 Leiden (p.R506Q) and prothrombin G20210A mutations. Our data provide new mechanistic insights into the genetic epidemiology of VTE and suggest a greater overlap among venous and arterial cardiovascular disease than previously suggested., Editorial summary Genome-wide analysis of venous thromboembolism identifies 22 new risk loci and facilitates construction of a polygenic risk score. Comparison to arterial vascular disease highlights shared pathophysiology and potential therapeutic strategies.

Large-scale multi-ethnic cohorts offer unprecedented opportunities to elucidate the genetic factors influencing complex traits related to health and disease among minority populations. At the same time, the genetic diversity in these cohorts presents new challenges for analysis and interpretation. We consider the utility of race and/or ethnicity categories in genome-wide association studies (GWASs) of multi-ethnic cohorts. We demonstrate that race/ethnicity information enhances the ability to understand population-specific genetic architecture. To address the practical issue that self-identified racial/ethnic information may be incomplete, we propose a machine learning algorithm that produces a surrogate variable, termed HARE. We use height as a model trait to demonstrate the utility of HARE and ethnicity-specific GWASs.

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.

OBJECTIVES: In order to maximize the therapeutic benefits of cognitive behavioral therapy (CBT) for chronic pain, individuals need to be motivated to adopt a self-management approach. The Pain Stages of Change Questionnaire (PSOCQ) was developed to measure patients’ readiness to adopt a self-management approach to chronic pain. The present study examined whether pre- and post-treatment PSOCQ change scores among chronic low back pain patients could predict six and twelve-month follow-up outcomes, and the stability of post-treatment PSOCQ scores during follow-up. METHODS: Participants were recruited from a VA primary care clinic. Data from 60 participants assigned to either regular CBT or a modified CBT (i.e., PRIME CBT) condition were analyzed in the present study. Self-report measures including PSOCQ, pain severity, disability, and depressive symptom severity were administered at pre-treatment, 10 weeks post-treatment, 6-month follow-up, and 12-month follow-up assessments. RESULTS: Multiple regression analyses showed that pre- and post-treatment changes in the Action/Maintenance scores significantly predicted pain severity at 6 months, and changes in the Precontemplation scores significantly predicted disability at 6 months. None of the PSOCQ change scores significantly predicted depressive symptom severity. Post-treatment Pre-contemplation and Action/Maintenance scores were quite stable, even at 12-month follow up. CONCLUSIONS: Changes in patients’ attitudes toward adopting a pain self-management approach may serve as one of the therapeutic mechanisms and predict long-term function. This study also revealed that changed attitudes toward chronic pain self-management remain quite stable over time. Adoption of beliefs consistent with chronic pain self-management during treatment may promote sustained benefits.

Post-traumatic stress disorder (PTSD) is a major problem among military veterans and civilians alike, yet its pathophysiology remains poorly understood. We performed a genome-wide association study and bioinformatic analyses, which included 146,660 European Americans and 19,983 African Americans in the US Million Veteran Program, to identify genetic risk factors relevant to intrusive reexperiencing of trauma, which is the most characteristic symptom cluster of PTSD. In European Americans, eight distinct significant regions were identified. Three regions had values of P

Peripheral artery disease (PAD) is a leading cause of cardiovascular morbidity and mortality; however, the extent to which genetic factors increase risk for PAD is largely unknown. Using electronic health record data, we performed a genome-wide association study in the Million Veteran Program testing ~32 million DNA sequence variants with PAD (31,307 cases and 211,753 controls) across veterans of European, African and Hispanic ancestry. The results were replicated in an independent sample of 5,117 PAD cases and 389,291 controls from the UK Biobank. We identified 19 PAD loci, 18 of which have not been previously reported. Eleven of the 19 loci were associated with disease in three vascular beds (coronary, cerebral, peripheral), including LDLR, LPL and LPA, suggesting that therapeutic modulation of low-density lipoprotein cholesterol, the lipoprotein lipase pathway or circulating lipoprotein(a) may be efficacious for multiple atherosclerotic disease phenotypes. Conversely, four of the variants appeared to be specific for PAD, including F5 p.R506Q, highlighting the pathogenic role of thrombosis in the peripheral vascular bed and providing genetic support for Factor Xa inhibition as a therapeutic strategy for PAD. Our results highlight mechanistic similarities and differences among coronary, cerebral and peripheral atherosclerosis and provide therapeutic insights.

Alcohol consumption level and alcohol use disorder (AUD) diagnosis are moderately heritable traits. We conduct genome-wide association studies of these traits using longitudinal Alcohol Use Disorder Identification Test-Consumption (AUDIT-C) scores and AUD diagnoses in a multi-ancestry Million Veteran Program sample (N = 274,424). We identify 18 genome-wide significant loci: 5 associated with both traits, 8 associated with AUDIT-C only, and 5 associated with AUD diagnosis only. Polygenic Risk Scores (PRS) for both traits are associated with alcohol-related disorders in two independent samples. Although a significant genetic correlation reflects the overlap between the traits, genetic correlations for 188 non-alcohol-related traits differ significantly for the two traits, as do the phenotypes associated with the traits’ PRS. Cell type group partitioning heritability enrichment analyses also differentiate the two traits. We conclude that, although heavy drinking is a key risk factor for AUD, it is not a sufficient cause of the disorder., The genetic underpinnings of alcohol use disorder and consumption are incompletely understood. Here, the authors perform GWAS for Alcohol Use Disorder (AUD) Identification Test-Consumption scores and AUD diagnosis from electronic health records of 274,424 individuals and identify a total of 18 associated loci.

Construction of a patient narrative (case history) is a core strategy in the care of patients. Recent advances in biomarker identification and digital sensors to monitor physiological and behavioral features have made constructing a case history more complex. Notably, however, although a biological profile is increasingly a part of the patient’s profile, an analogous patient-based biographical (life experience) profile is typically overlooked. Evolving concepts such as allostasis and allostatic load refer to processes promoting stability of physiological systems in the presence of diverse life experiences. Integrating details of both biology and biography is a goal of “precision medicine.” In this review, we describe how complex interactions between biology and biography affect disease risk and treatment response and highlight a strategy to develop narratives that establish the integration of biology and biography as the scientific basis for precision medicine.

Older men are more likely to have advanced prostate cancer at time of their diagnosis, but whether prostate tumors are inherently (biologically) more aggressive with advancing age is uncertain. To address this gap in knowledge, we analyzed data from veterans (n=971) diagnosed with prostate cancer during 1991–1995. Factors included age, detection of prostate cancer by screening, prostate-specific antigen (PSA) level, anatomic stage, and Gleason score. Information on molecular markers obtained from immunohistochemical staining of prostate tissue, included B cell lymphoma-2 (bcl-2), p53, and microvessel density (MVD), each having a previously documented association with disease progression and increased risk of prostate cancer death. We first examined the bivariate association of demographic, clinical, and molecular factors with age, and found evidence that race, screening status, Gleason score, PSA, bcl-2, p53, and MVD varied across categories of age in this study population. After further characterizing the association between age and Gleason score, we used logistic regression to examine the association between age and molecular markers—accounting for race, screening status, PSA, and Gleason score. Comparing men older than 80 years to those younger than 70 years, adjusted ORs and 95% CIs were 1.89 (0.73 to 4.92), 1.91 (1.05 to 3.46), and 2.00 (1.06 to 3.78), for positive bcl-2, p53, and MVD markers, respectively; no statistically significant associations were found for men 70–79 years old, compared with men younger than 70 years. These novel findings suggest that very elderly men often present with biologically aggressive prostate cancer; the results also have potential implications for therapeutic decision-making.

Background and Purpose: Practice guidelines recommend that most patients receive moderate- or high-potency statins after ischemic stroke or transient ischemic attack (TIA) of atherosclerotic origin. We tested the association of different patterns of potency for prescribed statin therapy—assessed before admission and at hospital discharge for ischemic stroke or TIA—on mortality in a large, nationwide sample of US Veterans. Methods: The study population included patients with an ischemic stroke or TIA occurring during 2011 at any of the 134 Veterans Health Administration facilities. We used electronic outpatient pharmacy files to identify statin dose at hospital admission and within 7 days after hospital discharge. We categorized statin dosing as low, moderate, or high potency; moderate or high potency was considered at goal. We created 6 mutually exclusive groups to reflect patterns of statin potency from hospital admission to discharge: goal to goal, low to goal, goal to low or goal to none (deintensification), none to none, none to low, and low to low. We used logistic regression to compare 30-day and 1-year mortality across statin potency groups. Results: The population included 9380 predominately White (71.1%) men (96.3%) who were hospitalized for stroke or TIA. In this sample, 34.1% of patients (n=3194) were discharged off a statin medication. Deintensification occurred in 14.0% of patients (n=1312) and none to none in 20.5% (n=1924). Deintensification and none to none were associated with a higher odds of mortality as compared with goal to goal (adjusted odds ratio 1-year mortality: deintensification versus goal to goal, 1.26 [95% CI, 1.02–1.57]; none to none versus goal to goal, 1.59 [95% CI, 1.30–1.93]). Adjustments for differences in baseline characteristics using propensity weighted scores demonstrated similar results. Conclusions: Underutilization of statins, including no treatment or underdosing after stroke (deintensification), was observed in approximately one-third of veterans with ischemic stroke or TIA and was associated with higher mortality when compared with patients who were at goal for statin prescription dosing.

Background Schizophrenia (SCZ) and bipolar disorder (BIP) are debilitating neuropsychiatric disorders, collectively affecting 2% of the world’s population. Recognizing the major impact of these psychiatric disorders on the psychosocial function of more than 200 000 US Veterans, the Department of Veterans Affairs (VA) recently completed genotyping of more than 8000 veterans with SCZ and BIP in the Cooperative Studies Program (CSP) #572. Methods We performed genome-wide association studies (GWAS) in CSP #572 and benchmarked the predictive value of polygenic risk scores (PRS) constructed from published findings. We combined our results with available summary statistics from several recent GWAS, realizing the largest and most diverse studies of these disorders to date. Results Our primary GWAS uncovered new associations between CHD7 variants and SCZ, and novel BIP associations with variants in Sortilin Related VPS10 Domain Containing Receptor 3 (SORCS3) and downstream of PCDH11X. Combining our results with published summary statistics for SCZ yielded 39 novel susceptibility loci including CRHR1, and we identified 10 additional findings for BIP (28 326 cases and 90 570 controls). PRS trained on published GWAS were significantly associated with case-control status among European American (P < 10–30) and African American (P < .0005) participants in CSP #572. Conclusions We have demonstrated that published findings for SCZ and BIP are robustly generalizable to a diverse cohort of US veterans. Leveraging available summary statistics from GWAS of global populations, we report 52 new susceptibility loci and improved fine-mapping resolution for dozens of previously reported associations.

Aim Million Veteran Program (MVP) is the largest ongoing mega-cohort biobank program in the US with 570,131 enrollees as of May 2017. The primary aim is to describe demographics, military service, and major diseases and comorbidities of the MVP cohort. Our secondary aim is to examine body mass index (BMI), a proxy for general health, among enrollees. Materials and Method The study population consists of Veterans who actively use the Veterans Health Administration in the US. Data evaluated in this paper combine health information from multiple sources to provide the most comprehensive demographic profile and information on height and weight of MVP enrollees. A standardized cleaning algorithm was used to curate the demographic variables for each participant in MVP. For height and weight, we derived a final data point for each participant to evaluate BMI. Statistical Analysis Used Multivariable logistic regression was used to compare the differences in BMI categories across enrollment years adjusting for gender, race, and age. P < 0.05 was considered statistically significant. All analyses were conducted using Statistical Analysis System 9.2. Results The MVP cohort consists of 90.4% of males with an average age of 61.9 years (standard deviation [SD] = 13.9). MVP is the largest multiethnic biobank cohort within the Veteran population with 73.9% White, 19.0% Black, and 6.5% Hispanic. The most common self-reported disease was hypertension (62.6%) for males and depression (47.5%) for females. Mean BMI was 29.7 kg/m2 (SD = 5.8) with 38.2% obese and 42.3% overweight. Conclusions Our findings suggest that demographic representation in MVP is similar to the Veterans Health Administration population and contrasts with the overall National Health and Nutrition Examination Survey US population. The prevalence of overweight and obese is high among US Veterans, and future studies will examine the role of BMI and disease risk in the Veteran population.

We report a large meta-analysis of depression using data from the Million Veteran Program (MVP), 23andMe Inc., UK Biobank, and FinnGen; including individuals of European ancestry (n=1,154,267; 340,591 cases) and African ancestry (n=59,600; 25,843 cases). We identified 223 and 233 independent SNPs associated with depression in European ancestry and transancestral analysis, respectively. Genetic correlations within the MVP cohort across electronic health records diagnosis, survey self-report of diagnosis, and a 2-item depression screen exceeded 0.81. Using transcriptome-wide association study (TWAS) we found significant associations for gene expression in several brain regions, including hypothalamus (NEGR1, p=3.19×10−25) and nucleus accumbens (DRD2, p=1.87×10−20). 178 genomic risk loci were fine-mapped to find likely causal variants. We identified likely pathogenicity in these variants and overlapping gene expression for 17 genes from our TWAS, including TRAF3. This study sheds light on the genetic architecture of depression and provides new insight into the interrelatedness of complex psychiatric traits.

Major depressive disorder is the most common neuropsychiatric disorder, affecting 11% of veterans. Here we report results of a large meta-analysis of depression using data from the Million Veteran Program, 23andMe, UK Biobank and FinnGen, including individuals of European ancestry (n = 1,154,267; 340,591 cases) and African ancestry (n = 59,600; 25,843 cases). Transcriptome-wide association study analyses revealed significant associations with expression of NEGR1 in the hypothalamus and DRD2 in the nucleus accumbens, among others. We fine-mapped 178 genomic risk loci, and we identified likely pathogenicity in these variants and overlapping gene expression for 17 genes from our transcriptome-wide association study, including TRAF3. Finally, we were able to show substantial replications of our findings in a large independent cohort (n = 1,342,778) provided by 23andMe. This study sheds light on the genetic architecture of depression and provides new insight into the interrelatedness of complex psychiatric traits. This bi-ancestral genome-wide association study of major depressive disorder (MDD) identified 178 risk variants. The results advance understanding of the biology of MDD and hint at new treatment possibilities.

Many veterans of the Iraq and Afghanistan Wars have experienced traumatic brain injury (TBI). Although prior work has examined associations between TBI and development of psychiatric syndromes, less is known about associations between TBI and component emotions constituting these syndromes, especially in the long term. The purpose of this study was to examine the long-term emotional consequences of deployment-related TBI.As part of VA Cooperative Studies Program #566, we assessed a sample ofWarzone TBI events, particularly when greater than mild in severity, were independently associated with depression, anxiety, and stress severity at long-term follow-up, even after taking into account variance attributable to pre-deployment emotional distress and war-zone stress. Post-hoc analyses did not detect independent associations of either number of events or injury mechanism with outcomes.These findings highlight the potentially enduring and multi-faceted emotional effects of deployment TBI, underscoring the need for early assessment of negative affectivity in warzone veterans reporting TBI.

BACKGROUND To help reduce expenses, shorten timelines, and improve the quality of final deliverables, the Veterans Health Administration (VA) and other health care systems promote sharing of expertise among informatics user groups. Traditional barriers to time-efficient sharing of expertise include difficulties in finding potential collaborators and availability of a mechanism to share expertise. OBJECTIVE We aim to describe how the VA shares expertise among its informatics groups by describing a custom-built tool, the Data Object Exchange (DOEx), along with statistics on its usage. METHODS A centrally managed web application was developed in the VA to share informatics expertise using database objects. Visitors to the site can view a catalog of objects published by other informatics user groups. Requests for subscription and publication made through the site are routed to database administrators, who then actualize the resource requests through modifications of database object permissions. RESULTS As of April 2019, the DOEx enabled the publication of 707 database objects to 1202 VA subscribers from 758 workgroups. Overall, over 10,000 requests are made each year regarding permissions on these shared database objects, involving diverse information. Common “flavors” of shared data include disease-specific study populations (eg, patients with asthma), common data definitions (eg, hemoglobin laboratory results), and results of complex analyses (eg, models of anticipated resource utilization). Shared database objects also enable construction of community-built data pipelines. CONCLUSIONS To increase the efficiency of informatics user groups, a method was developed to facilitate intraorganizational collaboration by managed data sharing. The advantages of this system include (1) reduced duplication of work (thereby reducing expenses and shortening timelines) and (2) higher quality of work based on simplifying the adoption of specialized knowledge among groups.

Anxiety disorders are common and often disabling. The goal of this study was to examine the genetic architecture of anxiety disorders and anxiety symptoms, which are also frequently comorbid with other mental disorders, such as major depressive disorder.Using one of the world's largest biobanks including genetic, environmental, and medical information, the Million Veteran Program, the authors performed a genome-wide association study (GWAS) of a continuous trait for anxiety (based on score on the Generalized Anxiety Disorder 2-item scale [GAD-2], N=199,611) as the primary analysis and self-report of physician diagnosis of anxiety disorder (N=224,330) as a secondary analysis.The authors identified five genome-wide significant signals for European Americans and one for African Americans on GAD-2 score. The strongest were on chromosome 3 (rs4603973) nearThis is the largest GWAS of anxiety traits to date. The authors identified novel genome-wide significant associations near genes involved with global regulation of gene expression (

The Million Veteran Program (MVP), initiated by the Department of Veterans Affairs (VA), aims to collect consented biosamples from at least one million Veterans. Presently, blood samples have been collected from over 800,000 enrolled participants. The size and diversity of the MVP cohort, as well as the availability of extensive VA electronic health records make it a promising resource for precision medicine. MVP is conducting array-based genotyping to provide genome-wide scan of the entire cohort, in parallel with whole genome sequencing, methylation, and other omics assays. Here, we present the design and performance of MVP 1.0 custom Axiom® array, which was designed and developed as a single assay to be used across the multi-ethnic MVP cohort. A unified genetic quality control analysis was developed and conducted on an initial tranche of 485,856 individuals leading to a high-quality dataset of 459,777 unique individuals. 668,418 genetic markers passed quality control and showed high quality genotypes not only on common variants but also on rare variants. We confirmed the substantial ancestral diversity of MVP with nearly 30% non-European individuals, surpassing other large biobanks. We also demonstrated the quality of the MVP dataset by replicating established genetic associations with height in European Americans and African Americans ancestries. This current data set has been made available to approved MVP researchers for genome-wide association studies and other downstream analyses. Further data releases will be available for analysis as recruitment at the VA continues and the cohort expands both in size and diversity.

A validated, scalable approach to characterizing (phenotyping) smoking status is needed to facilitate genetic discovery. Using established DNA methylation sites from blood samples as a criterion standard for smoking behavior, we compare three candidate electronic medical record (EMR) smoking metrics based on longitudinal EMR text notes. With data from the Veterans Aging Cohort Study (VACS), we employed a validated algorithm to translate each smoking-related text note into current, past or never categories. We compared three alternative summary characterizations of smoking: most recent, modal and trajectories using descriptive statistics and Spearman's correlation coefficients. Logistic regression and area under the curve analyses were used to compare the associations of these phenotypes with the DNA methylation sites, cg05575921 and cg03636183, which are known to have strong associations with current smoking. DNA methylation data were available from the VACS Biomarker Cohort (VACS-BC), a sub-study of VACS. We also considered whether the associations differed by the certainty of trajectory group assignment (

BACKGROUND AND AIMS Longitudinal electronic health record (EHR) data offer a large-scale, untapped source of phenotypical information on harmful alcohol use. Using established, alcohol-associated variants in the gene that encodes the enzyme alcohol dehydrogenase 1B (ADH1B) as criterion standards, we compared the individual and combined validity of three longitudinal EHR-based phenotypes of harmful alcohol use: Alcohol Use Disorders Identification Test-Consumption (AUDIT-C) trajectories; mean age-adjusted AUDIT-C; and diagnoses of alcohol use disorder (AUD). DESIGN With longitudinal EHR data from the Million Veteran Program (MVP) linked to genetic data, we used two population-specific polymorphisms in ADH1B that are associated strongly with AUD in African Americans (AAs) and European Americans (EAs): rs2066702 (Arg369Cys, AAs) and rs1229984 (Arg48His, EAs) as criterion measures. SETTING United States Department of Veterans Affairs Healthcare System. PARTICIPANTS A total of 167 721 veterans (57 677 AAs and 110 044 EAs; 92% male, mean age = 63 years) took part in this study. Data were collected from 1 October 2007 to 1 May 2017. MEASUREMENTS Using all AUDIT-C scores and AUD diagnostic codes recorded in the EHR, we calculated age-adjusted mean AUDIT-C values, longitudinal statistical trajectories of AUDIT-C scores and ICD-9/10 diagnostic groupings for AUD. FINDINGS A total of 19 793 AAs (34.3%) had one or two minor alleles at rs2066702 [minor allele frequency (MAF) = 0.190] and 6933 EAs (6.3%) had one or two minor alleles at rs1229984 (MAF = 0.032). In both populations, trajectories and age-adjusted mean AUDIT-C were correlated (r = 0.90) but, when considered separately, highest score (8+ versus 0) of age-adjusted mean AUDIT-C demonstrated a stronger association with the ADH1B variants [adjusted odds ratio (aOR) 0.54 in AAs and 0.37 in AAs] than did the highest trajectory (aOR 0.71 in AAs and 0.53 in EAs); combining AUDIT-C metrics did not improve discrimination. When age-adjusted mean AUDIT-C score and AUD diagnoses were considered together, age-adjusted mean AUDIT-C (8+ versus 0) was associated with lower odds of having the ADH1B minor allele than were AUD diagnostic codes: aOR = 0.59 versus 0.86 in AAs and 0.48 versus 0.68 in EAs. These independent associations combine to yield an even lower aOR of 0.51 for AAs and 0.33 for EAs. CONCLUSIONS The age-adjusted mean AUDIT-C score is associated more strongly with genetic polymorphisms of known risk for alcohol use disorder than are longitudinal trajectories of AUDIT-C or AUD diagnostic codes. AUD diagnostic codes modestly enhance this association.

STUDY OBJECTIVES: Determine the prevalence of, and clinical features associated with, a low respiratory arousal threshold (ArTH) among patients with obstructive sleep apnea (OSA), and to assess whether a low ArTH is associated with reduced long-term CPAP use. METHODS: Cross-sectional and longitudinal analyses were performed in an observational study conducted among 940 male Veterans with OSA. Data for clinical characteristics, polysomnography characteristics, and long-term (5 ± 2 years) CPAP use were obtained from clinical records. Logistic regression was used to assess the associations between low ArTH and clinical features, including regular CPAP use. RESULTS: A low ArTH was observed in 38% of participants overall, and was more common among nonobese (body mass index < 30 kg/m(2)) patients (55%). In adjusted analyses, increasing body mass index (per 5 kg/m(2)) and antihypertensive medication use were negatively associated with low ArTH, with odds ratio (OR) (95% confidence interval [CI]) of 0.77 (0.69, 0.87) and 0.69 (0.49, 0.98), respectively. Conversely, increasing age (per 10 years) and antidepressant use—OR (95% CI) 1.15 (1.01,1.31) and 1.54 (1.14,1.98), respectively—were positively associated with low ArTH. Nonobese patients with low ArTH were less likely to be regular CPAP users—OR (95% CI) 0.38 (0.20, 0.72)—in an adjusted model. CONCLUSIONS: Low ArTH is a common trait among Veterans with OSA and is more frequent among those who are older and nonobese and those taking antidepressants, but is less frequent among patients taking antihypertensive medications. A marked reduction of long-term CPAP use in nonobese patients with low ArTH highlights the importance of understanding a patient's physiologic phenotype for OSA management, and suggests potential targets to improve CPAP adherence. COMMENTARY: A commentary on this article appears in this issue on page 713. CITATION: Zinchuk A, Edwards BA, Jeon S, Koo BB, Concato J, Sands S, Wellman A, Yaggi HK. Prevalence, associated clinical features, and impact on continuous positive airway pressure use of a low respiratory arousal threshold among male United States Veterans with obstructive sleep apnea. J Clin Sleep Med. 2018;14(5):809–817.

Moderate alcohol consumption has been associated with a lower risk of coronary artery disease (CAD) in the general population but has not been well studied in US veterans. We obtained self-reported alcohol consumption from Million Veteran Program participants. Using electronic health records, CAD events were defined as 1 inpatient or 2 outpatient diagnosis codes for CAD, or 1 code for a coronary procedure. We excluded participants with prevalent CAD (n = 69,995) or incomplete alcohol information (n = 8,449). We used a Cox proportional hazards model to estimate hazard ratios and 95% confidence intervals for CAD, adjusting for age, gender, body mass index, race, smoking, education, and exercise. Among 156,728 participants, the mean age was 65.3 years (standard deviation = 12.1) and 91% were men. There were 6,153 CAD events during a mean follow-up of 2.9 years. Adjusted hazard ratios (95% confidence intervals) for CAD were 1.00 (reference), 1.02 (0.92 to 1.13), 0.83 (0.74 to 0.93), 0.77 (0.67 to 0.87), 0.71 (0.62 to 0.81), 0.62 (0.51 to 0.76), 0.58 (0.46 to 0.74), and 0.95 (0.85 to 1.06) for categories of never drinker; former drinker; current drinkers of ≤0.5 drink/day, >0.5 to 1 drink/day, >1 to 2 drinks/day, >2 to 3 drinks/day, and >3 to 4 drinks/day; and heavy drinkers (>4 drinks/day) or alcohol use disorder, respectively. For a fixed amount of ethanol, intake at ≥3 days/week was associated with lower CAD risk compared with ≤1 day/week. Beverage preference (beer, wine, or liquor) did not influence the alcohol-CAD relation. Our data show a lower risk of CAD with light-to-moderate alcohol consumption among US veterans, and drinking frequency may provide a further reduction in risk.

Prostate-specific antigen (PSA) measurements after primary treatment reflect residual tumor burden among men with prostate cancer. Using a mixture model analysis, we identified distinct trajectories of post-treatment PSA measurements and evaluated their associations with prostate cancer mortality. The study sample included 623 US Veterans treated for prostate cancer with curative intent during 1991–1995; 225 men received surgery and 398 men received radiation therapy. Post-treatment PSA measurements over a 2-year period for each patient were evaluated in latent class mixture models using the SAS TRAJ procedure, and groups of men with distinct trajectories of PSA were identified. These groups were then assessed for associations with 10-year prostate cancer mortality using proportional hazards analysis. Analyses identified three distinct groups—representing patterns of both initial values and changes in PSA over time—after surgery (n=172/31/14) and radiation therapy (n=253/103/22). Men in groups with patterns of higher (compared with the group with lowest) PSA values tended to have worse survival experience: HRs for prostate cancer mortality were 3.45 (P=0.18) and 22.7 (P

BackgroundAmerican Heart Association/American Stroke Association expert consensus guidelines recommend consideration of cardiac stress testing to screen for occult coronary heart disease (CHD) among patients with ischemic stroke/TIA who have a high-risk Framingham Cardiac Risk Score (FCRS). Whether this guideline is being implemented in routine clinical practice, and the association of its implementation with mortality, is less clear.MethodsStudy participants were Veterans with stroke/TIA (n = 11,306) during fiscal year 2011 who presented to a VA Emergency Department or who were admitted. Patients were excluded (n = 6,915) based on prior CHD/angina/chest pain history, receipt of cardiac stress testing within 18 months prior to cerebrovascular event, death within 90 days of discharge, discharge to hospice, transfer to a non-VA acute care facility, or missing/unknown race. FCRS ≥20% was classified as high risk for CHD. ICD-9 and Common Procedural Terminology codes were used to identify receipt of any cardiac stress testing.ResultsAmong 4,391 eligible patients, 62.8% (n = 2,759) had FCRS ≥20%. Cardiac stress testing was performed infrequently and in similar proportion among high-risk (4.5% [123/2,759]) vs low/intermediate-risk (4.4% [72/1,632]) patients (adjusted odds ratio [aOR] 0.77, 95% confidence interval [CI] 0.54–1.10). Receipt of stress testing was not associated with reduced 1-year mortality (aOR 0.59, CI 0.26–1.30).ConclusionsIn this observational cohort study of patients with cerebrovascular disease, cardiac screening was relatively uncommon and was not associated with 1-year mortality. Additional work is needed to understand the utility of CHD screening among high-risk patients with cerebrovascular disease.