Mendel\u2019s laws, Mendelian randomization and causal inference in observational data: substantive and nomenclatural issues

George Davey Smith,Michael V Holmes,Shah Ebrahim,Neil M Davies

doi:10.1007/s10654-020-00622-7

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.

Highlights

Reading what Mukamal, Stampfer and Rimm ( MSR) consider to be a “review” [1] of Mendelian randomization (MR) we felt we had been transported back many years
Instead we address the substantive issues we can extract from their essay. These are (1) MR is receiving more attention than the general concept of causality, and has been too eagerly adopted; (2) the name “Mendelian randomization” contributes to its inappropriate popularity and should be changed; (3) MSR provide critical commentary on MR of alcohol and cardiovascular disease (CVD), an issue in which their conventional observational studies have produced widely promoted findings; (4) MSR suggest that MR “should be treated with the circumspection that should accompany all forms of observational epidemiology”; with the latter we largely agree
MSR suggest that MR studies showing “lower risk of cardiovascular disease associated with variants linked to lower alcohol consumption may well be proving the harm of binge drinking” [1]

Summary

Introduction

Reading what Mukamal, Stampfer and Rimm ( MSR) consider to be a “review” [1] of Mendelian randomization (MR) we felt we had been transported back many years. These are (1) MR is receiving more attention than the general concept of causality, and has been too eagerly adopted; (2) the name “Mendelian randomization” contributes to its inappropriate popularity and should be changed; (3) MSR provide critical commentary on MR of alcohol and cardiovascular disease (CVD), an issue in which their conventional observational studies have produced widely promoted findings; (4) MSR suggest that MR “should be treated with the circumspection that should accompany all forms of observational epidemiology”; with the latter we largely agree.

Results

Conclusion