European Journal of Epidemiology

The doubly-ranked non-linear Mendelian randomization method can yield biased estimates when instrument strength varies across individuals due to gene-environment (GxE) interactions. We propose a simple strategy to mitigate this bias by modelling GxE interactions and removing the fitted GxE component from the exposure before stratification by the doubly-ranked method. In simulations, the proposed GxE correction strategy eliminated GxE-induced bias with null, linear and non-linear exposure-outcome...

BackgroundHigher childhood (pre-morbid) cognitive function (IQ) appears to confer a lower risk of cardiovascular disease (CVD) episodes in adulthood, however, the underpinning mechanisms are uncertain. We tested the association between childhood cognitive ability and later CVD risk factors that may underpin this gradient. MethodsWe used data from two well-characterized prospective birth cohort studies initiated in the United Kingdom in 1958 (N=10870) and 1970 (N=9278). Cognitive function was qu...

BackgroundPrevious research on diet and hip fracture risk focused on selected foods and nutrients. ObjectiveTo conduct a diet-wide association study of hip fracture risk. MethodsThe study population comprised 541,887 postmenopausal women in the Million Women Study. Dietary information was assessed using a validated food frequency questionnaire in 2000-2004, and calibrated using a 24-hour dietary recall from a subset 10 years later. Cox regression was used to estimate hazard ratios (HR) and 95%...

BackgroundThe long preclinical phase of dementia can bias estimated effects of baseline exposures on dementia incidence. We demonstrate simulations informed by reverse Mendelian randomization (MR) findings to quantify the age-specific magnitude of reverse causation bias in analyses in observational studies of the effects of body mass index (BMI) on dementia. MethodsWe simulated longitudinal trajectories of BMI and dementia risk from ages 45 to 90 years, calibrating to published evidence on age-...

Mendelian randomization is currently mainly implemented through the use of genetic variants as instrumental variables to investigate the causal effect of an exposure on an outcome of interest. Mendelian randomization studies are robust to confounding bias and reverse causation, but they remain susceptible to selection bias; for example, this can happen if the exposure or outcome are associated with selection into the study sample. Negative controls are sometimes used to detect biases (typically ...

The ageing society and worldwide rise of chronic disease make adequate early identification of at-risk individuals and preventive intervention highly relevant to public health. Molecular indicators of global health have been developed, such as metabolomics-based MetaboHealth. A shortcoming of molecular biomarkers may be their lack of integration of lifestyle and environmental factors relevant for health span. Hence, we explored the MetaboHealth biomarker and a range of health- and lifestyle fact...

BackgroundEvidence on how leisure-time physical activity (LTPA) improves lifetime body mass index (BMI) remains fragmented and prone to confounding. MethodsWe pooled 14,993 adults (30-90 y; 52.7% women; cohorts: REGICOR-ACRISC, ILERVAS, ARTPER) with baseline estimated LTPA (moderate-to-vigorous LTPA [MVLTPA] in REGICOR-ACRISC), genotype, and repeated BMI values from electronic health records (1990-2024, 36,157 measures). LTPA was categorized into cohort-specific quartiles; MVLTPA in 0, <100, <2...

IntroductionCircadian misalignment is an emerging risk factor for poor cardiovascular health, and chronotype may reflect underlying circadian processes. While previous conventional observational studies have reported adverse associations between evening chronotype and individual cardiovascular risk factors, Mendelian randomization (MR) may provide further insights into the role of chronotype in overall cardiovascular health, as measured by the American Heart Associations Lifes Essential 8 (LE8; ...

Medication use is common in large-scale population cohorts, and can modify phenotypic traits of interest. This can potentially bias effect estimates in genome-wide association studies (GWAS) and impact downstream analyses such as mendelian randomization (MR). The best approach to account for medication use in GWAS is unclear. In this study, we compared seven different methods of adjusting for antihypertensive use in a systolic blood pressure (SBP) GWAS of 407,960 White British individuals in the...

BackgroundThe selection of accelerometer processing methods may influence the shape of the dose-response association between wearable-measured physical activity and health outcomes. We compared the association of stroke and myocardial infarction with Moderate-Vigorous Physical Activity (MVPA) assessed by three accelerometer-generated metrics: modified Euclidean Norm Minus One (ENMO), Machine learning (ML), and activity counts. MethodsWe computed MVPA durations in the UK Biobank accelerometer su...

PURPOSEOver 6.9 million Americans above the age of 65 are living with Alzheimers Disease (AD) or related dementias (ADRDs), which are diseases characterized by cognitive decline and structural brain changes associated with accelerated brain aging. Cardiovascular risk factors, in particular hypertension, are well-studied risk factors for AD/ARD. Evidence suggests that the effects of hypertension on cognitive aging may vary by life stage, yet prior studies have focused on the effects of mid- or la...

ObjectiveSevere infections have been implicated in dementia risk, but their associations with detailed patterns of cognitive performance, and whether poorer cognition in turn increases risk for certain infections, remain unclear. We examined bidirectional associations between hospital-treated infections and domain-specific cognitive function in a cohort of older adults. MethodsWe analysed data from the English Longitudinal Study of Ageing Harmonised Cognitive Assessment Protocol (ELSA-HCAP), co...

Background. Early identification of risk for hospitalisation is crucial to reducing public health burden. Immune and endocrine-related markers are robust indicators of disease in epidemiological studies, but their value has not been consistently established with severe disorders requiring hospitalisation. Patterning of biomarker expression through latent profile analysis (LPA), may improve predictive accuracy for clinical outcomes above individual biomarkers alone. Method. Four biomarkers (C-rea...

1.Disease-specific Polygenic Risk Scores (PRS) are usually evaluated against the incidence of diseases they were derived for. Individuals may be more interested in how these PRS influence their probable cause of death. Using UK Biobank data, we examined the top 10 causes of death among individuals in the highest quintile of disease-specific PRS for Alzheimers disease, bowel cancer, cardiovascular disease, coronary artery disease, ischaemic stroke, breast cancer, epithelial ovarian cancer, and pr...

BackgroundSmoking, unhealthy nutrition, alcohol consumption, and physical inactivity (SNAP behaviours) are major risk factors for multimorbidity but are often studied in isolation. Using longitudinal data, Suhag et al. identified clusters of older adults (aged [&ge;]50) with common SNAP behaviour patterns and distinct sociodemographic profiles and multimorbidity prevalence; whether and how these patterns generalise across adulthood remains unclear. AimTo conceptually replicate Suhag et al. acro...

SHARE, the "Survey of Health, Ageing and Retirement in Europe", is the largest population-based panel survey among people aged 50+ in 28 European countries and Israel. It investigates health, economic and social circumstances over the life-course to shed light on the challenges of population ageing. From 2004 until 2023, more than 615,000 in-depth interviews with 160,000 respondents have been conducted in nine survey waves. Health is crucial to understand ageing. Gold-standard measures are base...

BackgroundFinancial strain has been linked to adverse cardiovascular outcomes, yet whether this association persists beyond objective socioeconomic resources remains unclear. We examined associations of financial strain with incident heart disease and all-cause mortality among US adults aged 50 years or older. MethodsProspective cohort study using the Health and Retirement Study (2006-2022). Among 7219 participants completing the Psychosocial Leave-Behind Questionnaire, the exposure was ongoing...

BackgroundConcern about long-term health effects of repetitive head impacts in football has increased, but it remains unclear whether position-specific exposure patterns were associated with differential long-term all-cause mortality among elite players across the 20th century. MethodsWe conducted two retrospective cohort studies of elite male professional football players. The World Cup cohort included all players on the team rosters from FIFA World Cup tournaments (1930-1990), and the UEFA Eu...

COVID-19 has been shown to cause a range of harmful long-term effects on nearly every organ system1-3. These findings are based on retrospective studies comparing COVID-19 patients to patients with similar medical histories and demographics but no COVID-19 diagnosis4-16. However, concerns have emerged that these comparisons may be biased if COVID-19 patients had unrelated health conditions or other factors not recorded in their medical records17-21. Here, using a massive dataset of 14.4 billion ...

BackgroundSynthetic cohorts created by combining two cohorts can be useful when no single data set includes both the exposure and outcome data of interest. We estimate the effects of depression in early adulthood on later-life memory outcome using two nationally representative cohorts separately and in a synthetic sample. MethodsWe used the National Longitudinal Study of Youth 1979 (NLSY; N=5,747) and the Health and Retirement Study (HRS; N=6,846) and a synthetic cohort combining exposure data ...