Linking multivariable Mendelian randomization with lifecourse epidemiology: developing the methodology and application to a contemporary exemplar

Rationale

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 lifecourse (2) the degree to which it is possible to separate the causal effect of the same exposure at different stages of the lifecourse. Understanding the effect of an exposure across the lifecourse would identify windows for prevention or treatment, and shed light on the aetiology of disease.

Aims & 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.

Methods

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.

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.

If you have secured your own sponsorship or can self-fund this PhD please visit our information page here for further information on the department of Population Health Science and how to apply.