Mendel's laws, Mendelian randomization and causal inference in observational data: substantive and nomenclatural issues

Abstract

We respond to criticisms of Mendelian randomization (MR) by Mukamal, Stampfer and Rimm (MSR). MSR consider that MR is receiving too much attention and should be renamed. We explain how MR links to Mendel's laws, the origin of the name and our lack of concern regarding nomenclature. We address MSR's substantive points regarding MR of alcohol and cardiovascular disease, an issue on which they dispute the MR findings. We demonstrate that their strictures with respect to population stratification, confounding, weak instrument bias, pleiotropy and confounding have been addressed, and summarise how the field has advanced in relation to the issues they raise. We agree with MSR that "the hard problem of conducting high-quality, reproducible epidemiology" should be addressed by epidemiologists. However we see more evidence of confrontation of this issue within MR, as opposed to conventional observational epidemiology, within which the same methods that have demonstrably failed in the past are simply rolled out into new areas, leaving their previous failures unexamined.

Keywords: Alcohol; Causal inference; Genetic epidemiology; Mendelian randomization; Nutritional epidemiology.

Fig. 1

Google Scholar citations to the papers that heralded a marked upturn in use of the terms “causal inference” [8] and “Mendelian randomization” [2] within epidemiology

Fig. 2

Exemplar of misleading epidemiological research, used to illustrate the need to develop alternatives to naïve observational analyses, in an early review of MR (reproduced from [24]). Vitamin E supplement use and risk of CHD in two observational studies [9, 10] and in a meta-analysis of RCTs [111]. RR: relative risk

Fig. 3

Relative risk of coronary heart disease by daily alcohol consumption, compared to non-drinkers. Data from Rimm et al. [25]

Fig. 4

A Relative risk (RR) of stroke according to drinking patterns (left hand panel) and MR analyses (right hand panel) in men. B RR of coronary heart disease according to drinking patterns (left hand panel) and MR analyses (right hand panel) in men [51]

Fig. 5

CHD odds ratio (TT versus CC MTHFR C677T genotype) in each probable folate status category, from a meta-analyses of 19 unpublished datasets. US United States, ANZ Australia, New Zealand) [92]