Genotypes generated in next generation sequencing studies contain errors which can significantly impact the power to detect signals in common and rare variant association tests. These genotyping errors are not explicitly filtered by the standard GATK Variant Quality Score Recalibration (VQSR) tool and thus remain a source of errors in whole exome sequencing (WES) projects that follow GATK’s recommended best practices. Therefore, additional data filtering methods are required to effectively remove these errors before performing association analyses with complex phenotypes. Here we empirically derive thresholds for genotype and variant filters that, when used in conjunction with the VQSR tool, achieve higher data quality than when using VQSR alone. The detailed filtering strategies improve the concordance of sequenced genotypes with array genotypes from 99.33% to 99.77%; improve the percent of discordant genotypes removed from 10.5% to 69.5%; and improve the Ti/Tv ratio from 2.63 to 2.75. We also demonstrate that managing batch effects by separating samples based on different target capture and sequencing chemistry protocols results in a final data set containing 40.9% more high-quality variants. In addition, imputation is an important component of WES studies and is used to estimate common variant genotypes to generate additional markers for association analyses. As such, we demonstrate filtering methods for imputed data that improve genotype concordance from 79.3% to 99.8% while removing 99.5% of discordant genotypes. The described filtering methods are advantageous for large population-based WES studies designed to identify common and rare variation associated with complex diseases. Compared to data processed through standard practices, these strategies result in substantially higher quality data for common and rare association analyses.

An association between body height and venous thromboembolism (VTE) has been suggested by previous studies including males only. The aim of this prospective cohort study was to investigate the sex-specific impact of body height on risk of VTE in a general population. Risk factors, including body height and weight, were registered for 26,727 subjects aged 25–96 years who participated in the Tromsø Study (Norway) in 1994–1995. Incident VTE events were registered through September 1, 2007. There were 462 VTE events during a median 12.5 years of follow-up. Body height was a risk factor for VTE in men, but not in women. Multivariable hazard ratios per 10 cm, adjusted for age, body mass index, diabetes, smoking, and hormone therapy (women), were 1.34 (95% confidence interval: 1.09, 1.64) for men and 1.13 (95% confidence interval: 0.91, 1.40) for women. Hazard ratios by quartiles of body height revealed that men in the upper quartile (>181 cm) had a 1.99-fold (95% confidence interval: 1.35, 2.92) increased risk of VTE compared with men in the lowest quartile (<173 cm) (P for trend across quartiles = 0.002). There was no significant trend (P = 0.2) across quartiles of body height for women. Study findings revealed that body height is a sex-specific risk factor for VTE in men.

The relationship between chronic obstructive pulmonary disease (COPD) and risk of venous thromboembolism (VTE) has been scarcely studied in the general population. We aimed to investigate the association between COPD and risk of VTE and mortality in a population-based cohort.Spirometry was conducted in 8646 males and females, participating in the fifth (2001–02) and sixth (2007–08) surveys of the Tromsø Study. Incident VTE events during follow-up were registered from the date of inclusion to December 31, 2011. Cox-regression models with COPD stages and confounders as time varying covariates were used to calculate hazard ratios with 95% confidence intervals for VTE and all-cause mortality.During a median follow-up of 6.2 years, 215 subjects developed VTE. Subjects with COPD stage III/IV had a two-fold higher risk of secondary VTE compared to subjects with normal airflow (HR 2.05, 95% CI 1.02–4.10). COPD patients, particularly those with stage III/IV disease, with VTE had a higher mortality rate than COPD patients without VTE (50.2%versus5.6% per year).Our findings suggest that patients with severe COPD may have increased risk of secondary VTE, and that COPD patients with VTE have a higher mortality rate than COPD patients without VTE.

Objective—: To investigate and compare the impact of traditional atherosclerotic risk factors for the risk of arterial and venous thrombosis, taking into account competing risks. Methods and Results—: In 1994–1995, 26,185 subjects were screened in the Tromsø study. Information on traditional atherosclerotic risk factors was obtained by physical examination, blood samples, and questionnaires. Subjects were followed to the first incident event of myocardial infarction (MI) or venous thromboembolism (VTE), or December 31, 2005. During a median of 10.8 years of follow-up, there were 1279 cases of incident MI and 341 VTE events. Advancing age and high body mass index were both associated with MI and VTE. Hazard ratio per decade of age was 2.34 (95% CI: 2.25–2.43) for MI and 1.87 (1.74–2.01) for VTE, and 3 kg/m ² increase in body mass index was associated with 1.16 (1.11–1.21) and 1.20 (1.12–1.29) increased risk of MI and VTE, respectively. Blood pressure, high levels of triglycerides and total cholesterol, low HDL cholesterol, self-reported diabetes, and smoking were all associated with increased risk of MI but not associated with VTE. Conclusion—: Our findings imply that traditional atherosclerotic risk factors, such as smoking, hypertension, dyslipidemia, and diabetes mellitus are not shared by arterial and venous thrombosis.