Mendelian Randomisation: A Tool for Assessing Causality in Observational Epidemiology

Abstract

Detection and assessment of the effect of a modifiable risk factor on a disease with view to informing public health intervention policies are of fundamental concern in aetiological epidemiology. In order to have solid evidence that such a public health intervention has the desired effect, it is necessary to ascertain that an observed association or correlation between a risk factor and a disease means that the risk factor is causal for the disease. Inferring causality from observational data is difficult, typically due to confounding by social, behavioural, or physiological factors which are difficult to control for and particularly difficult to measure accurately. A possible approach to inferring causality when confounding is believed to be present but unobservable, as it may not even be fully understood, is based on the method of instrumental variables and is known under the name of Mendelian randomisation if the instrument is a genetic variant. While testing for the presence of a causal effect using this method is generally straightforward, point estimates of such an effect are only obtainable under additional parametric assumptions. This chapter introduces the concept and illustrates the method and its assumptions with simple real-life examples. It concludes with a brief discussion on pitfalls and limitations.