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Robust methods in Mendelian randomization via penalization of heterogeneous causal estimates.

Accepted version
Peer-reviewed

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Type

Article

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Authors

Rees, Jessica MB 
Wood, Angela M 
Dudbridge, Frank 

Abstract

Methods have been developed for Mendelian randomization that can obtain consistent causal estimates under weaker assumptions than the standard instrumental variable assumptions. The median-based estimator and MR-Egger are examples of such methods. However, these methods can be sensitive to genetic variants with heterogeneous causal estimates. Such heterogeneity may arise from over-dispersion in the causal estimates, or specific variants with outlying causal estimates. In this paper, we develop three extensions to robust methods for Mendelian randomization with summarized data: 1) robust regression (MM-estimation); 2) penalized weights; and 3) Lasso penalization. Methods using these approaches are considered in two applied examples: one where there is evidence of over-dispersion in the causal estimates (the causal effect of body mass index on schizophrenia risk), and the other containing outliers (the causal effect of low-density lipoprotein cholesterol on Alzheimer's disease risk). Through an extensive simulation study, we demonstrate that robust regression applied to the inverse-variance weighted method with penalized weights is a worthwhile additional sensitivity analysis for Mendelian randomization to provide robustness to variants with outlying causal estimates. The results from the applied examples and simulation study highlight the importance of using methods that make different assumptions to assess the robustness of findings from Mendelian randomization investigations with multiple genetic variants.

Description

Keywords

Alzheimer Disease, Body Mass Index, Causality, Cholesterol, LDL, Genetic Predisposition to Disease, Humans, Mendelian Randomization Analysis, Models, Statistical, Regression Analysis, Risk Factors, Schizophrenia

Journal Title

PLoS One

Conference Name

Journal ISSN

1932-6203
1932-6203

Volume Title

14

Publisher

Public Library of Science (PLoS)

Rights

All rights reserved
Sponsorship
Wellcome Trust (204623/Z/16/Z)
British Heart Foundation (None)
Medical Research Council (MC_UU_00002/7)
British Heart Foundation (RG/18/13/33946)