Genome-wide association study of post-traumatic stress disorder reexperiencing symptoms in >165,000 US veterans.

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.

Genome-wide Association Study of Maximum Habitual Alcohol Intake in >140,000 U.S. European and African American Veterans Yields Novel Risk Loci.

Background: Habitual alcohol use can be an indicator of alcohol dependence, which is associated with a wide range of serious health problems.

Methods: We completed a genome-wide association study in 126,936 European American and 17,029 African American subjects in the Veterans Affairs Million Veteran Program for a quantitative phenotype based on maximum habitual alcohol consumption.

Results: ADH1B, on chromosome 4, was the lead locus for both populations: for the European American sample, rs1229984 (p = 4.

Validation of an Electronic Medical Record-Based Algorithm for Identifying Posttraumatic Stress Disorder in U.S. Veterans.

We developed an algorithm for identifying U.S. veterans with a history of posttraumatic stress disorder (PTSD), using the Department of Veterans Affairs (VA) electronic medical record (EMR) system.

Genomics of posttraumatic stress disorder in veterans: Methods and rationale for Veterans Affairs Cooperative Study #575B.

Objectives: Heritability in the risk for developing posttraumatic stress disorder (PTSD) has been established, but most genome-wide association studies (GWASs) of PTSD involve relatively small sample sizes and limited identification of associated genetic loci. This report describes the methodology of a Veterans Affairs (VA) Cooperative Studies Program GWAS of PTSD among combat-exposed U.S.

Trans-ethnic association study of blood pressure determinants in over 750,000 individuals.

In this trans-ethnic multi-omic study, we reinterpret the genetic architecture of blood pressure to identify genes, tissues, phenomes and medication contexts of blood pressure homeostasis. We discovered 208 novel common blood pressure SNPs and 53 rare variants in genome-wide association studies of systolic, diastolic and pulse pressure in up to 776,078 participants from the Million Veteran Program (MVP) and collaborating studies, with analysis of the blood pressure clinical phenome in MVP. Our transcriptome-wide association study detected 4,043 blood pressure associations with genetically predicted gene expression of 840 genes in 45 tissues, and mouse renal single-cell RNA sequencing identified upregulated blood pressure genes in kidney tubule cells.

Association between admission haematocrit and mortality among men with acute ischaemic stroke.

Objective: Anaemia is associated with higher mortality among patients with non-stroke cardiovascular conditions; less is known regarding the relationship between anaemia and mortality among patients with acute ischaemic stroke.

Methods: Medical records were abstracted for n=3965 veterans from 131 Veterans Health Administration facilities who were admitted with ischaemic stroke in fiscal year 2007. Haematocrit values within 24 hours of admission were classified as ≤27%, 28%-32%, 33%-37%, 38%-42%, 43%-47% or ≥48%.

Survey Analysis of the Use, Effectiveness, and Patient-Reported Tolerability of Inhaled Oxygen Compared With Injectable Sumatriptan for the Acute Treatment of Cluster Headache.

Objective: In this secondary analysis of the Clusterbusters Medication Use survey, the use, effectiveness, and tolerability of inhaled oxygen were investigated and compared with injectable sumatriptan. We also sought to understand the predictors of medication response.

Background: Inhaled oxygen is a mainstay abortive intervention in cluster headache but is not approved by the Food and Drug Administration (FDA).

Receipt of cardiac screening does not influence 1-year post-cerebrovascular event mortality.

Background: American 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.

Methods: Study participants were Veterans with stroke/TIA (n = 11,306) during fiscal year 2011 who presented to a VA Emergency Department or who were admitted.

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.

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.

Post-stroke hypertension control and receipt of health care services among veterans.

Many ischemic stroke patients do not achieve goal blood pressure (BP < 140/90 mm Hg). To identify barriers to post-stroke hypertension management, we examined healthcare utilization and BP control in the year after index ischemic stroke admission. This retrospective cohort study included patients admitted for acute ischemic stroke to a VA hospital in fiscal year 2011 and who were discharged with a BP ≥ 140/90 mm Hg.

Joint modeling of genetically correlated diseases and functional annotations increases accuracy of polygenic risk prediction.

Accurate prediction of disease risk based on genetic factors is an important goal in human genetics research and precision medicine. Advanced prediction models will lead to more effective disease prevention and treatment strategies. Despite the identification of thousands of disease-associated genetic variants through genome-wide association studies (GWAS) in the past decade, accuracy of genetic risk prediction remains moderate for most diseases, which is largely due to the challenges in both identifying all the functionally relevant variants and accurately estimating their effect sizes.

Leveraging functional annotations in genetic risk prediction for human complex diseases.

Genetic risk prediction is an important goal in human genetics research and precision medicine. Accurate prediction models will have great impacts on both disease prevention and early treatment strategies. Despite the identification of thousands of disease-associated genetic variants through genome wide association studies (GWAS), genetic risk prediction accuracy remains moderate for most diseases, which is largely due to the challenges in both identifying all the functionally relevant variants and accurately estimating their effect sizes in the presence of linkage disequilibrium.

Development, Validation, and Assessment of an Ischemic Stroke or Transient Ischemic Attack-Specific Prediction Tool for Obstructive Sleep Apnea.

Background: Screening instruments for obstructive sleep apnea (OSA), as used routinely to guide clinicians regarding patient referral for polysomnography (PSG), rely heavily on symptomatology. We sought to develop and validate a cerebrovascular disease-specific OSA prediction model less reliant on symptomatology, and to compare its performance with commonly used screening instruments within a population with ischemic stroke or transient ischemic attack (TIA).

Methods: Using data on demographic factors, anthropometric measurements, medical history, stroke severity, sleep questionnaires, and PSG from 2 independently derived, multisite, randomized trials that enrolled patients with stroke or TIA, we developed and validated a model to predict the presence of OSA (i.

Impact of genotyping errors on statistical power of association tests in genomic analyses: A case study.

A key step in genomic studies is to assess high throughput measurements across millions of markers for each participant's DNA, either using microarrays or sequencing techniques. Accurate genotype calling is essential for downstream statistical analysis of genotype-phenotype associations, and next generation sequencing (NGS) has recently become a more common approach in genomic studies. How the accuracy of variant calling in NGS-based studies affects downstream association analysis has not, however, been studied using empirical data in which both microarrays and NGS were available.

Phenotypes in obstructive sleep apnea: A definition, examples and evolution of approaches.

Obstructive sleep apnea (OSA) is a complex and heterogeneous disorder and the apnea hypopnea index alone can not capture the diverse spectrum of the condition. Enhanced phenotyping can improve prognostication, patient selection for clinical trials, understanding of mechanisms, and personalized treatments. In OSA, multiple condition characteristics have been termed "phenotypes.

The Association between Nocturnal Cardiac Arrhythmias and Sleep-Disordered Breathing: The DREAM Study.

Study Objectives: To determine whether sleep-disordered breathing (SDB) is associated with cardiac arrhythmia in a clinic-based population with multiple cardiovascular comorbidities and severe SDB.

Methods: This was a cross-sectional analysis of 697 veterans who underwent polysomnography for suspected SDB. SDB was categorized according to the apnea-hypopnea index (AHI): none (AHI < 5), mild (5 ≥ AHI < 15), and moderate-severe (AHI ≥ 15).

Using Radiological Data to Estimate Ischemic Stroke Severity.

Background: Risk-adjusted poststroke mortality has been proposed for use as a measure of stroke care quality. Although valid measures of stroke severity (e.g.

The Determining Risk of Vascular Events by Apnea Monitoring (DREAM) study: design, rationale, and methods.

Purpose: The goal of the Determining Risk of Vascular Events by Apnea Monitoring (DREAM) study is to develop a prognostic model for cardiovascular outcomes, based on physiologic variables-related to breathing, sleep architecture, and oxygenation-measured during polysomnography in US veterans.

Methods: The DREAM study is a multi-site, retrospective observational cohort study conducted at three Veterans Affairs (VA) centers (West Haven, CT; Indianapolis, IN; Cleveland, OH). Veterans undergoing polysomnography between January 1, 2000 and December 31, 2004 were included based on referral for evaluation of sleep-disordered breathing, documented history and physical prior to sleep testing, and ≥2-h sleep monitoring.

Million Veteran Program: A mega-biobank to study genetic influences on health and disease.

Objective: To describe the design and ongoing conduct of the Million Veteran Program (MVP), as an observational cohort study and mega-biobank in the Department of Veterans Affairs (VA) health care system.

Study Design And Setting: Data are being collected from participants using questionnaires, the VA electronic health record, and a blood sample for genomic and other testing. Several ongoing projects are linked to MVP, both as peer-reviewed research studies and as activities to help develop an infrastructure for future, broad-based research uses.

What will the emperor say? Screening for prostate cancer as of 2008.

Screening for prostate cancer with prostate-specific antigen remains controversial approximately 20 years after its introduction into routine clinical care. Although numerous research studies have generated evidence to support or refute a benefit of screening, very few reports focus on the most relevant outcome of reducing mortality, and even fewer use rigorous methods of patient-oriented research. In addition, the tendency for personal beliefs (among investigators) to influence the interpretation of data introduces further complexity.

Association between impaired insulin sensitivity and stroke.

Background: Prior research has indicated an association between insulin resistance and stroke; we sought to determine if this association persists after adjusting for stroke risk factors, including glycemic control.

Methods: We used data from the Third National Health and Nutrition Survey (1988-1994), including participants aged > or =40 years. We assessed insulin sensitivity using the homeostasis model assessment (HOMA): HOMA = (FPGSI x FPI)/22.

Intravenous thrombolysis in acute ischaemic stroke: optimising its use in routine clinical practice.

Stroke is a common and important medical problem. Intravenous thrombolysis with alteplase (recombinant tissue plasminogen activator; rtPA) is the only available direct treatment that reduces neurological injury following ischaemic stroke. Strong efficacy data from randomised, controlled trials support the use of intravenous thrombolysis to improve outcomes for patients with acute ischaemic stroke.