4-year PhD Studentship: Linking multivariable Mendelian randomization with lifecourse epidemiology: developing the methodology and application to a contemporary exemplar

Mendelian randomization (MR) uses genetic variants as instrumental variables to estimate the causal effect of an exposure on an outcome, free from bias due to unobserved confounding. E.g. the effect of BMI on cancer incidence.

Multivariable MR (MVMR) is an extension of MR that jointly estimates the causal effect of multiple exposures on an outcome. MVMR can be used to adjust for pleiotropic effects, where genetic variants are associated with multiple traits biasing MR estimates.

Many exposures, such as BMI, vary across an individual’s lifetime, however genetic variants are fixed. Recent research has focused on (1) how MR estimates should be interpreted when the exposure varies across the life course (2) the degree to which it is possible to separate the causal effect of the same exposure at different stages of the life course. Understanding the effect of an exposure across the life course would identify windows for prevention or treatment, and shed light on the aetiology of disease.

Aims and objectives

The aim of this project is to conduct research on the estimation and interpretation of different MR methods with time varying exposures. There will be a particular focus on the estimation of the causal effects of multiple exposures that vary over time through MVMR. MVMR can be used to estimate the proportion of an effect that is mediated through other exposures and this project will also consider how MVMR for mediation can be interpreted when both the exposure and mediators vary over time.

Methodology

The focus of this project is on developing and applying methods for MVMR. The project will use simulation analysis to understand the methods and interpretation considered. This project will also involve the analysis of individual and summary level data for MR and MVMR estimation to illustrate the results obtained.

The project is methodological in focus, and the student will have the opportunity to develop an application of the methods considered. This could be on a topic that is relevant to their own applied research interests, or can be developed in consultation with the supervisors.

The student will develop skills in MR methodology, life course methodology and simulation analysis. The student will also develop skills in applied data analysis and working with large scale and genetic data.

How to apply for this project

This project will be based in Bristol Medical School - Population Health Sciences in the Faculty of Health Sciences at the University of Bristol.

Please visit the Faculty of Health Sciences website for details of how to apply