Interpreting findings from Mendelian randomization using the MR-Egger method
Publication Date
2017-05-19Journal Title
European Journal of Epidemiology
ISSN
0393-2990
Publisher
Springer
Volume
32
Issue
5
Pages
377-389
Language
English
Type
Article
This Version
VoR
Metadata
Show full item recordCitation
Burgess, S., & Thompson, S. (2017). Interpreting findings from Mendelian randomization using the MR-Egger method. European Journal of Epidemiology, 32 (5), 377-389. https://doi.org/10.1007/s10654-017-0255-x
Abstract
Mendelian randomization-Egger (MR-Egger) is an analysis method for Mendelian randomization using summarized genetic data. MR-Egger consists of three parts: (1) a test for directional pleiotropy, (2) a test for a causal effect, and (3) an estimate of the causal effect. While conventional analysis methods for Mendelian randomization assume that all genetic variants satisfy the instrumental variable assumptions, the MR-Egger method is able to assess whether genetic variants have pleiotropic effects on the outcome that differ on average from zero (directional pleiotropy), as well as to provide a consistent estimate of the causal effect, under a weaker assumption-the InSIDE (INstrument Strength Independent of Direct Effect) assumption. In this paper, we provide a critical assessment of the MR-Egger method with regard to its implementation and interpretation. While the MR-Egger method is a worthwhile sensitivity analysis for detecting violations of the instrumental variable assumptions, there are several reasons why causal estimates from the MR-Egger method may be biased and have inflated Type 1 error rates in practice, including violations of the InSIDE assumption and the influence of outlying variants. The issues raised in this paper have potentially serious consequences for causal inferences from the MR-Egger approach. We give examples of scenarios in which the estimates from conventional Mendelian randomization methods and MR-Egger differ, and discuss how to interpret findings in such cases.
Keywords
instrumental variable, MR-Egger, Mendelian randomization, robust methods, summarized data
Sponsorship
Stephen Burgess is supported by Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (Grant Number 204623/Z/16/Z). Simon G. Thompson is supported by the British Heart Foundation (Grant Number CH/12/2/ 29428).
Funder references
Wellcome Trust (100114/Z/12/Z)
MRC (G0700463)
MRC (MR/L003120/1)
Wellcome Trust (204623/Z/16/Z)
British Heart Foundation (CH/12/2/29428)
British Heart Foundation (RG/08/014/24067)
Medical Research Council (MC_UU_00002/7)
Embargo Lift Date
2100-01-01
Identifiers
External DOI: https://doi.org/10.1007/s10654-017-0255-x
This record's URL: https://www.repository.cam.ac.uk/handle/1810/265871
Rights
Attribution 4.0 International, Attribution 4.0 International