European Journal of Epidemiology

Estimates from conventional Mendelian randomization (MR) analyses can be biased when the genetic variants proposed as instruments vary over age in their relationship with the exposure. For four exposures commonly studied using MR, we assessed the degree to which their relationship with genetic variants commonly used as instruments varies by age using flexible, spline-based models in UK Biobank data. Using these models, we then estimated how biased MR estimates would be due to age-varying relatio...

PurposeVitamin D has been proposed as a potential causal factor in COVID-19 risk. We aimed to establish whether blood 25-hydroxyvitamin D (25(OH)D) concentration was associated with COVID-19 mortality, and inpatient confirmed COVID-19 infection, in UK Biobank participants. MethodsUK Biobank recruited 502,624 participants aged 37-73 years between 2006 and 2010. Baseline exposure data, including 25(OH)D concentration, were linked to COVID-19 mortality. Univariable and multivariable Cox proportion...

BackgroundMendelian randomisation (MR) is a method of causal inference that uses genetic variation as an instrumental variable (IV) to account for confounding. While the number of MR articles published each year is rapidly rising (partly due to large cohort studies such as the UK Biobank making it easier to conduct MR), it is not currently known whether these studies are appropriately conducted and reported in enough detail for other researchers to accurately replicate and interpret them. Metho...

BackgroundThe interaction between physical activity and sleep with cardiovascular disease remains poorly understood, despite both being key risk factors. This study investigated the independent and joint associations of device-measured physical activity and sleep duration with incident major adverse cardiovascular events (MACE). MethodsProspective analysis of UK Biobank participants who wore a wrist-based accelerometer for seven days. Open-source machine learning algorithms derived daily step c...

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...

Mendelian randomization (MR) is an established epidemiological technique which uses genetic variants to strengthen causal inference regarding modifiable exposures. Non-linear MR is an extension to MR which aims to estimate whether the effect differs across the level of the exposure. Many applications of non-linear MR have focused on Vitamin D as an exposure. Using this technique, the study sample is divided into strata, and separate estimates are calculated in each stratum to estimate causal eff...

ObjectivesTo estimate the causal effect of health conditions and risk factors on social and socioeconomic outcomes in UK Biobank. Evidence on socioeconomic impacts is important to understand because it can help governments, policy-makers and decision-makers allocate resources efficiently and effectively. DesignWe used Mendelian randomization to estimate the causal effects of eight health conditions (asthma, breast cancer, coronary heart disease, depression, eczema, migraine, osteoarthritis, typ...

In this short report we present a preliminary assessment of the serum 25-hydroxyvitamin D status (25(OH)D), body mass index (BMI), ethnicity and other lifestyle factors in the first-reported UK Biobank COVID-19 positive cases (n 580) compared with negative controls (n 723). The COVID-19 cases include those who have been treated as a hospital inpatient as well as those who have not, and are from England only. Mean (SD) for age was 57.5 (8.7) in positive cases and 57.9 (8.7) in negative controls.

Background: Sex-disaggregated data suggest that men with coronavirus disease 2019 (COVID-19) are more likely to die than women. Whether circulating testosterone or sex hormone-binding globulin (SHBG) contributes to such sex differences remains unknown. Objective: To evaluate the associations of circulating total testosterone (TT), free testosterone (FT), and SHBG with COVID-19 mortality. Design: Prospective analysis. Setting: UK Biobank. Participants: We included 1306 COVID-19 patients (678 men ...

Mendelian randomisation (MR) is an established technique in epidemiological investigation, using the principle of random allocation of genetic variants at conception to estimate the causal linear effect of an exposure on an outcome. Extensions to this technique include non-linear approaches that allow for differential effects of the exposure on the outcome depending on the level of the exposure. A widely used non-linear method is the residual approach, which estimates the causal effect within di...

BackgroundVitamin D supplements are widely prescribed to help reduce disease risk. However, this strategy is based on findings using conventional epidemiological methods which are prone to confounding and reverse causation. MethodsIn this short report, we leveraged genetic variants which differentially influence body size during childhood and adulthood within a multivariable Mendelian randomization (MR) framework, allowing us to separate the genetically predicted effects of adiposity at these t...

BackgroundPrevious studies on the reproducibility of 7-day accelerometer measurements have been limited by small sample sizes and short follow-up periods. We aimed to assess the long-term reproducibility of accelerometer-derived physical activity and sleep, and to illustrate the impact of regression dilution bias on the association between daily step count and coronary heart disease (CHD) in UK Biobank (UKB). MethodsWe analysed data from 3138 UKB participants in the main accelerometry sub-study...

Background and aimMendelian Randomization (MR) is a widely used tool to estimate causal effects using genetic variants as instrumental variables. MR is limited to cross-sectional summary statistics of different samples and time points to analyse time-varying effects. We aimed at using longitudinal summary statistics for an exposure in a multivariable MR setting and validating the effect estimates for the mean, slope and within-individual variability. Simulation studyWe tested our approach in tw...

A growing body of evidence shows that poor vitamin D status has been associated with an increased susceptibility to viral and bacterial respiratory infections. In this study, we aimed to examine the association between vitamin D and COVID-19 risk and outcomes, and to explore potential causal effects. We used logistic regression to identify associations between different vitamin D variables (25-hydroxyvitamin D concentration (25-OHD), ambient UVB and genetically-predicted 25-OHD concentrations) a...

BackgroundNumerous observational studies have shown an association between higher circulating 25 hydroxyvitamin D (vitamin D) and lower body mass index (BMI). Whether this represents a causal effect remains unclear. Mendelian randomization (MR) is an approach to causal inference that uses genetic variants as instrumental variables to estimate the effect of exposures on outcomes of interest. MR estimates are not biased by confounding, reverse causation and other biases in the same way as conventi...

BackgroundThe National Child and Development Study (1958 British Birth Cohort) follows the lives of over 17 000 people born in a single week in England, Scotland, and Wales. Since the initial recruitment there have been nine sweeps to gather subsequent life-course data, and a Biomedical Sweep (Age 44) - between Sweeps 6 (Age 42) and 7 (Age 46) - that has found widespread application in genetic studies. Due to its non-selective recruitment, the survey is frequently used as a representative proxy ...

ObjectiveTo evaluate the association of Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diet with risk of dementia in three prospective cohort studies, and to conduct a meta-analysis of cohort studies. Design & SettingThree prospective cohort studies - the Whitehall II study (WII, mean follow-up=13.2 years), the Health and Retirement Study (HRS, mean follow-up=4.3 years) and Framingham Heart Study Offspring cohort (FOS, mean follow-up=10.4 years), and meta-analysis of cohort ...

BackgroundEarly-life growth adversity is important to later-life health, but precision assessment in adulthood is challenging. We evaluated whether the difference between attained and genotype-predicted adult height ("height-GaP") would associate with prospectively ascertained early-life growth adversity and later-life all-cause and cardiovascular mortality. MethodsData were first analyzed from the Avon Longitudinal Study of Parents and Children (ALSPAC) and UKBiobank. Genotype-predicted height...

BackgroundCoronavirus disease 2019 (COVID-19) deteriorates suddenly primarily due to excessive inflammatory injury, and insulin-like growth factor-1 (IGF-1) is implicated in endocrine control of the immune system. However, the effect of IGF-1 levels on COVID-19 prognosis remains unknown. ObjectiveTo investigate the association between circulating IGF-1 concentrations and mortality risk among COVID-19 patients. DesignProspective analysis. SettingUK Biobank. Participants1425 COVID-19 patients ...

BackgroundPhysical activity (PA) is associated with a lower risk of cognitive decline and all-cause dementia in later life. Pathways underpinning this association are unclear but may involve either mediation and/or moderation by cardiorespiratory fitness (CRF). MethodsData on participation in PA (exposure) at 42y, non-exercise testing CRF (NETCRF, mediator/moderator) at 45y and overall cognitive function (outcome) at 50y were obtained from 9,385 participants in the 1958 British birth cohort stu...