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Survival bias in Mendelian randomization studies

a threat to causal inference

Smit, Roelof AJ1,2; Trompet, Stella1,2; Dekkers, Olaf M3,4,5; Jukema, J Wouter1,6; le Cessie, Saskia4,7

doi: 10.1097/EDE.0000000000001072
Brief Report: PDF Only

It has been argued that survival bias may distort results in Mendelian randomization studies in older populations. Through simulations of a simple causal structure we investigate the degree to which instrumental variable (IV)-estimators may become biased in the context of exposures that affect survival. We observed that selecting on survival decreased instrument strength and, for exposures with directionally concordant effects on survival (and outcome), introduced downward bias of the IV-estimator when the exposures reduced the probability of survival till study inclusion. Higher ages at study inclusion generally increased this bias, particularly when the true causal effect was not equal to null. Moreover, the bias in the estimated exposure–outcome relation depended on whether the estimation was conducted in the one- or two-sample setting. Finally, we briefly discuss which statistical approaches might help to alleviate this and other types of selection bias.

1Department of Cardiology, Leiden University Medical Center (LUMC), Leiden, The Netherlands

2Section of Gerontology and Geriatrics, Department of Internal Medicine, LUMC, Leiden, the Netherlands

3Section of Endocrinology, Department of Internal Medicine, LUMC, Leiden, the Netherlands

4Department of Clinical Epidemiology, LUMC, Leiden, The Netherlands

5Department of Clinical Epidemiology, Aarhus University, Aarhus, Denmark

6Einthoven Laboratory for Experimental Vascular Medicine, LUMC, Leiden, the Netherlands

7Section of Medical Statistics, Department of Biomedical Data Sciences, LUMC, Leiden, The Netherlands.

Conflicts of interest: None declared.

Source of funding: None.

Computing code availability: Annotated code uploaded as supplemental material.

Address for Correspondence (current address): Roelof AJ Smit, Charles Bronfman Institute for Personalized Medicine, room A18-80, Icahn School of Medicine at Mount Sinai, 1468 Madison Ave, New York, NY 10029, Tel: +1 (212) 241 2537, E-mail:

This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

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