Bias in causal estimates from Mendelian randomization studies with weak instruments
Abstract
Mendelian randomization studies using genetic instrumental variables (IVs) are now being commonly used to estimate the causal association of a phenotype on an outcome. Even when the necessary underlying assumptions are valid, estimates from analyses using IVs are biased in finite samples. The source and nature of this bias appear poorly understood in the epidemiological field. We explain why the bias is in the direction of the confounded observational association, with magnitude relating to the statistical strength of association between the instrument and phenotype. We comment on the size of the bias, from simulated data, showing that when multiple instruments are used, although the variance of the IV estimator decreases, the bias increases. We discuss ways to analyse Mendelian randomization studies to alleviate the problem of weak instrument bias. Copyright © 2011 John Wiley & Sons, Ltd.
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When using genetic variants as instruments, the association between the instrumental variable and the exposure is often weak, and using the interaction between this variant and a baseline covariate as an instrumental variable for the mediator would typically result in an even weaker instrumental variable for the mediator, leading to substantial finite sample bias and imprecision, even if all theIV
“When using genetic variants as instruments, the association between the IV and the exposure is often weak, and thus using the interaction between this variant and a baseline covariate as an IV for the mediator would typically result in an even weaker IV for the mediator, leading to substantial finite sample bias and imprecision, even if all the IV assumptions were met.50”
From Network Mendelian randomization: using genetic variants as instrumental variables to investigate mediation in causal pathways. (2015) · cites this paper as [50]
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- Authors
- Burgess, S., & Thompson, S. G.
- Affiliations
- University of Cambridge (GB)
- Corresponding author
- Burgess, Stephen
- Venue
- Statistics in Medicine
- Publisher
- Wiley
- Published
- 2011-03-22
- Volume
- 30
- Issue
- 11
- Pages
- 1312-1323
- ISSN
- 0277-6715 (ISSN-L)
- 1097-0258
- OpenAlex
- W2166082348
- Cited by
- 421
- References
- 37
- Citations by year
- 2026: 34 · 2025: 79 · 2024: 113 · 2023: 64 · 2022: 39 · 2021: 24 · 2020: 10 · 2019: 11 · 2018: 7 · 2017: 7 · 2016: 7 · 2015: 7 · 2014: 6 · 2013: 9 · 2012: 4
- FWCI
- 5.33
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Statistics in Medicine (publishedVersion)
- PubMed (publishedVersion)
- Funders
- British Heart Foundation (RG/08/014/24067)
- Medical Research Council
- Topics
- Physical Sciences › Mathematics › Statistics and Probability › Advanced Causal Inference Techniques
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Physical Sciences › Mathematics › Statistics and Probability › Statistical Methods in Epidemiology
- Keywords
- Mendelian randomization, weak instrument bias, genetic instruments, finite-sample bias, multiple instruments, confounding, causal inference, instrument strength, bias-variance trade-off
- MeSH terms
- Data Interpretation, Statistical, Genotype, Models, Genetic, Phenotype, Random Allocation, Bias
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