Survivor bias in Mendelian randomization analysis
Abstract
Mendelian randomization studies employ genotypes as experimental handles to infer the effect of genetically modified exposures (e.g. vitamin D exposure) on disease outcomes (e.g. mortality). The statistical analysis of these studies makes use of the standard instrumental variables framework. Many of these studies focus on elderly populations, thereby ignoring the problem of left truncation, which arises due to the selection of study participants being conditional upon surviving up to the time of study onset. Such selection, in general, invalidates the assumptions on which the instrumental variables analysis rests. We show that Mendelian randomization studies of adult or elderly populations will therefore, in general, return biased estimates of the exposure effect when the considered genotype affects mortality; in contrast, standard tests of the causal null hypothesis that the exposure does not affect the mortality rate remain unbiased, even when they ignore this problem of left truncation. To eliminate "survivor bias" or "truncation bias" from the effect of exposure on mortality, we next propose various simple strategies under a semi-parametric additive hazard model. We examine the performance of the proposed methods in simulation studies and use them to infer the effect of vitamin D on all-cause mortality based on the Monica10 study with the genetic variant filaggrin as instrumental variable.
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Study participation is heritable and influenced by a number of different traits, and large studies such as the UK Biobank have high levels of selection in those who participate.
“Study participation has shown to be heritable and is influenced by a number of different traits, and large studies such as the UK Biobank have been shown to have high levels of selection in those who participate.31,170–172”
From Mendelian randomization (2022) · cites this paper as [172]
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- Authors
- Vansteelandt, S., Dukes, O., & Martinussen, T.
- Affiliations
- Ghent University (BE)
- University of Copenhagen (DK)
- Corresponding author
- Vansteelandt, Stijn
- Venue
- Biostatistics
- Publisher
- Oxford University Press (OUP)
- Published
- 2017-09-27
- Volume
- 19
- Issue
- 4
- Pages
- 426-443
- ISSN
- 1465-4644 (ISSN-L)
- 1468-4357
- OpenAlex
- W2765843292
- Cited by
- 46
- References
- 27
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 2 · 2023: 10 · 2022: 4 · 2021: 8 · 2020: 4 · 2019: 6 · 2018: 5
- FWCI
- 2.72
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Biostatistics (publishedVersion)
- PubMed (publishedVersion)
- Ghent University Academic Bibliography (Ghent University) (submittedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- Funders
- Research Foundation - Flanders
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Physical Sciences › Mathematics › Statistics and Probability › Advanced Causal Inference Techniques
- Physical Sciences › Mathematics › Statistics and Probability › Statistical Methods in Epidemiology
- Keywords
- survivorship bias, left truncation, Mendelian randomization, instrumental variables, mortality, vitamin D, filaggrin, causal inference, older adults, exposure effect estimation
- MeSH terms
- Filaggrin Proteins, Adult, Aged, Humans, Intermediate Filament Proteins, Middle Aged, Vitamin D, Models, Statistical, Bias, Biostatistics, Mendelian Randomization Analysis
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