Cardiovascular Disease Risk Assessment Using Traditional Risk Factors and Polygenic Risk Scores in the Million Veteran Program.

Importance: Primary prevention of atherosclerotic cardiovascular disease (ASCVD) relies on risk stratification. Genome-wide polygenic risk scores (PRSs) are proposed to improve ASCVD risk estimation. Objective: To determine whether genome-wide PRSs for coronary artery disease (CAD) and acute ischemic stroke improve ASCVD risk estimation with traditional clinical risk factors in an ancestrally diverse midlife population. Design, Setting, and Participants: This was a prognostic analysis of incident events in a retrospectively defined longitudinal cohort conducted from January 1, 2011, to December 31, 2018. Included in the study were adults free of ASCVD and statin naive at baseline from the Million Veteran Program (MVP), a mega biobank with genetic, survey, and electronic health record data from a large US health care system. Data were analyzed from March 15, 2021, to January 5, 2023. Exposures: PRSs for CAD and ischemic stroke derived from cohorts of largely European descent and risk factors, including age, sex, systolic blood pressure, total cholesterol, high-density lipoprotein (HDL) cholesterol, smoking, and diabetes status. Main Outcomes and Measures: Incident nonfatal myocardial infarction (MI), ischemic stroke, ASCVD death, and composite ASCVD events. Results: A total of 79 151 participants (mean [SD] age, 57.8 [13.7] years; 68 503 male [86.5%]) were included in the study. The cohort included participants from the following harmonized genetic ancestry and race and ethnicity categories: 18 505 non-Hispanic Black (23.4%), 6785 Hispanic (8.6%), and 53 861 non-Hispanic White (68.0%) with a median (5th-95th percentile) follow-up of 4.3 (0.7-6.9) years. From 2011 to 2018, 3186 MIs (4.0%), 1933 ischemic strokes (2.4%), 867 ASCVD deaths (1.1%), and 5485 composite ASCVD events (6.9%) were observed. CAD PRS was associated with incident MI in non-Hispanic Black (hazard ratio [HR], 1.10; 95% CI, 1.02-1.19), Hispanic (HR, 1.26; 95% CI, 1.09-1.46), and non-Hispanic White (HR, 1.23; 95% CI, 1.18-1.29) participants. Stroke PRS was associated with incident stroke in non-Hispanic White participants (HR, 1.15; 95% CI, 1.08-1.21). A combined CAD plus stroke PRS was associated with ASCVD deaths among non-Hispanic Black (HR, 1.19; 95% CI, 1.03-1.17) and non-Hispanic (HR, 1.11; 95% CI, 1.03-1.21) participants. The combined PRS was also associated with composite ASCVD across all ancestry groups but greater among non-Hispanic White (HR, 1.20; 95% CI, 1.16-1.24) than non-Hispanic Black (HR, 1.11; 95% CI, 1.05-1.17) and Hispanic (HR, 1.12; 95% CI, 1.00-1.25) participants. Net reclassification improvement from adding PRS to a traditional risk model was modest for the intermediate risk group for composite CVD among men (5-year risk >3.75%, 0.38%; 95% CI, 0.07%-0.68%), among women, (6.79%; 95% CI, 3.01%-10.58%), for age older than 55 years (0.25%; 95% CI, 0.03%-0.47%), and for ages 40 to 55 years (1.61%; 95% CI, -0.07% to 3.30%). Conclusions and Relevance: Study results suggest that PRSs derived predominantly in European samples were statistically significantly associated with ASCVD in the multiancestry midlife and older-age MVP cohort. Overall, modest improvement in discrimination metrics were observed with addition of PRSs to traditional risk factors with greater magnitude in women and younger age groups.

Atrial fibrillation epidemiology, disparity and healthcare contacts: a population-wide study of 5.6 million individuals.

Background: We aimed to evaluate atrial fibrillation occurrence, reasons for healthcare visits, mortality, causes of death and examined patterns by relative deprivation in the UK. Methods: To study the atrial fibrillation (AF) incidence, mortality and case-fatality, we implemented a prospective cohort study with the linked electronic health records of 5.6 million population in the United Kingdom Clinical Practice Research Datalink from 1998 to 2016. A matched case-control study was used to investigate causes of hospitalisation and death comparing individuals with and without incident AF. Results: During a median follow-up of 10.3 years, 199,433(3.6%) patients developed incident AF. Increased risk of hospitalisation for heart failure, cardiovascular conditions and infection was present among patients who later developed AF. Following an AF diagnosis, patients were frequently admitted to the hospital for heart failure, lower respiratory tract infection, chronic obstructive pulmonary disease and ischemic heart disease. One in 5 AF patients died during the first year after diagnosis, and the mortality increased to 42.7% at the fifth year. The excess deaths in AF cases compared to controls may result from cardiovascular diseases, infection and metabolic disorders. Individuals from areas with higher deprivation in socioeconomic and living status had both higher AF incidence and fatality. Interpretation: We observed an elevated risk of hospitalisation for cardiovascular or respiratory diseases among incident AF patients, and the considerable disparity in AF burden by socioeconomic deprivation informs priorities for prevention and provision of patient care. Funding: The study was supported by the GlaxoSmithKline, University College London Hospital and National Institute for Health Research. The funders did not have any role in study design, data collection, data analysis, interpretation, and writing of the report.

Racial and Ethnic Disparities in U.S. Veteran Health Characteristics.

Racial/ethnic health disparities persist among veterans despite comparable access and quality of care. We describe racial/ethnic differences in self-reported health characteristics among 437,413 men and women (mean age (SD) = 64.5 (12.6), 91% men, 79% White) within the Million Veteran Program. The Cochran-Mantel-Haenszel test and linear mixed models were used to compare age-standardized frequencies and means across race/ethnicity groups, stratified by gender. Black, Hispanic, and Other race men and women reported worse self-rated health, greater VA healthcare utilization, and more combat exposure than Whites. Compared to White men, Black and Other men reported more circulatory, musculoskeletal, mental health, and infectious disease conditions while Hispanic men reported fewer circulatory and more mental health, infectious disease, kidney, and neurological conditions. Compared to White women, Black women reported more circulatory and infectious disease conditions and Other women reported more infectious disease conditions. Smoking rates were higher among Black men, but lower for other minority groups compared to Whites. Minority groups were less likely to drink alcohol and had lower physical fitness than Whites. By identifying differences in burden of various health conditions and risk factors across different racial/ethnic groups, our findings can inform future studies and ultimately interventions addressing disparities.

Data-driven identification of ageing-related diseases from electronic health records.

Reducing the burden of late-life morbidity requires an understanding of the mechanisms of ageing-related diseases (ARDs), defined as diseases that accumulate with increasing age. This has been hampered by the lack of formal criteria to identify ARDs. Here, we present a framework to identify ARDs using two complementary methods consisting of unsupervised machine learning and actuarial techniques, which we applied to electronic health records (EHRs) from 3,009,048 individuals in England using primary care data from the Clinical Practice Research Datalink (CPRD) linked to the Hospital Episode Statistics admitted patient care dataset between 1 April 2010 and 31 March 2015 (mean age 49.7 years (s.d. 18.6), 51% female, 70% white ethnicity). We grouped 278 high-burden diseases into nine main clusters according to their patterns of disease onset, using a hierarchical agglomerative clustering algorithm. Four of these clusters, encompassing 207 diseases spanning diverse organ systems and clinical specialties, had rates of disease onset that clearly increased with chronological age. However, the ages of onset for these four clusters were strikingly different, with median age of onset 82 years (IQR 82-83) for Cluster 1, 77 years (IQR 75-77) for Cluster 2, 69 years (IQR 66-71) for Cluster 3 and 57 years (IQR 54-59) for Cluster 4. Fitting to ageing-related actuarial models confirmed that the vast majority of these 207 diseases had a high probability of being ageing-related. Cardiovascular diseases and cancers were highly represented, while benign neoplastic, skin and psychiatric conditions were largely absent from the four ageing-related clusters. Our framework identifies and clusters ARDs and can form the basis for fundamental and translational research into ageing pathways.

Metabolic profiles of socio-economic position: a multi-cohort analysis.

BACKGROUND: Low socio-economic position (SEP) is a risk factor for multiple health outcomes, but its molecular imprints in the body remain unclear. METHODS: We examined SEP as a determinant of serum nuclear magnetic resonance metabolic profiles in ∼30 000 adults and 4000 children across 10 UK and Finnish cohort studies. RESULTS: In risk-factor-adjusted analysis of 233 metabolic measures, low educational attainment was associated with 37 measures including higher levels of triglycerides in small high-density lipoproteins (HDL) and lower levels of docosahexaenoic acid (DHA), omega-3 fatty acids, apolipoprotein A1, large and very large HDL particles (including levels of their respective lipid constituents) and cholesterol measures across different density lipoproteins. Among adults whose father worked in manual occupations, associations with apolipoprotein A1, large and very large HDL particles and HDL-2 cholesterol remained after adjustment for SEP in later life. Among manual workers, levels of glutamine were higher compared with non-manual workers. All three indicators of low SEP were associated with lower DHA, omega-3 fatty acids and HDL diameter. At all ages, children of manual workers had lower levels of DHA as a proportion of total fatty acids. CONCLUSIONS: Our work indicates that social and economic factors have a measurable impact on human physiology. Lower SEP was independently associated with a generally unfavourable metabolic profile, consistent across ages and cohorts. The metabolites we found to be associated with SEP, including DHA, are known to predict cardiovascular disease and cognitive decline in later life and may contribute to health inequalities.

The Consortium of Metabolomics Studies (COMETS): Metabolomics in 47 Prospective Cohort Studies.

The Consortium of Metabolomics Studies (COMETS) was established in 2014 to facilitate large-scale collaborative research on the human metabolome and its relationship with disease etiology, diagnosis, and prognosis. COMETS comprises 47 cohorts from Asia, Europe, North America, and South America that together include more than 136,000 participants with blood metabolomics data on samples collected from 1985 to 2017. Metabolomics data were provided by 17 different platforms, with the most frequently used labs being Metabolon, Inc. (14 cohorts), the Broad Institute (15 cohorts), and Nightingale Health (11 cohorts). Participants have been followed for a median of 23 years for health outcomes including death, cancer, cardiovascular disease, diabetes, and others; many of the studies are ongoing. Available exposure-related data include common clinical measurements and behavioral factors, as well as genome-wide genotype data. Two feasibility studies were conducted to evaluate the comparability of metabolomics platforms used by COMETS cohorts. The first study showed that the overlap between any 2 different laboratories ranged from 6 to 121 metabolites at 5 leading laboratories. The second study showed that the median Spearman correlation comparing 111 overlapping metabolites captured by Metabolon and the Broad Institute was 0.79 (interquartile range, 0.56-0.89).

Predictors of patterns of change in health-related quality of life in older women over 7 years: evidence from a prospective cohort study.

BACKGROUND: the evaluation of the determinants of change over time in health-related quality of life (HR-QoL) in older people is limited. This study aims to identify patterns of change in HR-QoL over 7 years and their determinants using data from the British Women's Heart and Health Study, a representative sample of older women (n = 4286). METHODS: longitudinal latent class analysis was used to identify subpopulations of women with similar HR-QoL trajectories from 1999-2000 to 2007. HR-QoL was measured using the EQ-5D. Multivariate multinomial logistic regression was used to model the association of identified trajectories with baseline predictors after multiple imputation of missing data. RESULTS: four distinct EQ-5D trajectories were suggested: high (19% of women), high decline (22%), intermediate (42%) and low decline (16%). Prevalent arthritis (OR = 13.4; 95% CI: 8.8, 20.5), diabetes (OR = 4.6; 95% CI: 1.5, 14.2) and obesity (OR = 3.9; 95% CI: 2.5, 6.0) were the strongest predicting health conditions of adverse changes in HR-QoL and physical activity the strongest predicting lifestyle factor (OR = 2.8; 95% CI: 2.0, 3.9). CONCLUSIONS: findings suggest that older women without obesity or pre-existing health conditions who undertake more physical activity are more likely to experience high HR-QoL, reinforcing the importance of these factors for healthy ageing.

A 'polypill' aimed at preventing cardiovascular disease could prove highly cost-effective for use in Latin America.

We evaluated the cost-effectiveness of administering a daily "polypill" consisting of three antihypertensive drugs, a statin, and aspirin to prevent cardiovascular disease among high-risk patients in Latin America. We found that the lifetime risk of cardiovascular disease could be reduced by 15 percent in women and by 21 percent in men if the polypill were used by people with a risk of cardiovascular disease equal to or greater than 15 percent over ten years. Attaining this goal would require treating 26 percent of the population at a cost of $34-$36 per quality-adjusted life-year. Offering the polypill to women at high risk and to men age fifty-five or older would be the best approach and would yield acceptable incremental cost-effectiveness ratios. The polypill would be very cost-effective even in the country with the lowest gross national income in our study. However, policy makers must weigh the value of intervention with the polypill against other interventions, as well as their country's willingness and ability to pay for the intervention.

Effect of changes in moderate or vigorous physical activity on changes in health-related quality of life of elderly British women over seven years.

PURPOSE: This study investigates the effect of changes in moderate or vigorous physical activity (MVPA) on trajectories in health-related quality of life (HR-QoL) over 7 years in British elderly women. METHODS: A total of 1,926 women from the British Women's Heart and Health Study with information on MVPA and HR-QoL [measured using Euro quality of life 5 dimension (EQ-5D)] at baseline and at 7 years of follow-up were included in the analysis. Baseline and 7-year follow-up MVPA values were categorised into 3 groups, generating 9 categories of change in MVPA. Logistic regression was used to obtain odds ratios (ORs) of maintaining or improving HR-QoL according to different patterns of change in MVPA level. RESULTS: Women who remained inactive over the 7 years of follow-up had the largest reduction in their EQ-5D scores. Compared to these women, women that increased their MPVA level from "inactive" to "low" or to "moderate-high" were more likely to maintain or improve their HR-QoL over 7 years (ORs 1.65 or 2.70, respectively, p value for trend <0.001). After adjustment for baseline EQ-5D score and a wide range of potential confounders, results remained largely unchanged, though precision of the estimates generally decreased. CONCLUSIONS: Our findings suggest that relatively regular MVPA, even taken up later in life, can help older women prevent a decline in HR-QoL and even improve their enjoyment of life.