Interpreting findings from Mendelian randomization using the MR-Egger method

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.Electronic supplementary materialThe online version of this article (doi:10.1007/s10654-017-0255-x) contains supplementary material, which is available to authorized users.

Life Course Adiposity and Amyotrophic Lateral Sclerosis: A Mendelian Randomization Study

“…Sensitivity analyses, such as the simple median, weighted median, and MR‐Egger regression methods, were additionally conducted. Pleiotropy was evaluated through the intercept obtained from the MR‐Egger method . To assess the robustness of the significant results, we conducted a leave‐one‐SNP‐out analysis to detect heterogeneous outcomes.…”

“…Pleiotropy was evaluated through the intercept obtained from the MR-Egger method. 25 To assess the robustness of the significant results, we conducted a leave-one-SNP-out analysis to detect heterogeneous outcomes.…”

Causal association between body mass index and risk of rheumatoid arthritis: A Mendelian randomization study

“…18 The slope of this regression represents the causal effect estimate, and the intercept can be interpreted as an estimate of the average horizontal pleiotropic effect across the genetic variants. 19 The weighted median estimator provides a consistent estimate of the causal effect, even when up to 50% of the information contributing to the analysis comes from genetic variants that are invalid IVs. 20 Compared to the MR-Egger analysis, the weighted median estimator has the advantage of retaining greater precision in the estimates.…”

Uric acid level, gout and bone mineral density: A Mendelian randomization study

“…MR-Egger regression analysis tests and accounts for the presence of unbalanced pleiotropy by introducing a parameter for this bias, through the incorporation of summary data estimates of the causal effects from multiple individual variants, making it robust to invalid instruments. 19 The weighted median estimator provides a consistent estimate of the causal effect, even when up to 50% of the information contributing to the analysis comes from genetic variants that are invalid IVs. 18 The slope of this regression represents the causal effect estimate, and the intercept can be interpreted as an estimate of the average horizontal pleiotropic effect across the genetic variants.…”