Interpretation and Potential Biases of Mendelian Randomization Estimates With Time-Varying Exposures
- PMID: 30239571
- DOI: 10.1093/aje/kwy204
Interpretation and Potential Biases of Mendelian Randomization Estimates With Time-Varying Exposures
Abstract
Mendelian randomization (MR) is used to answer a variety of epidemiologic questions. One stated advantage of MR is that it estimates a "lifetime effect" of exposure, though this term remains vaguely defined. Instrumental variable analysis, on which MR is based, has focused on estimating the effects of point or time-fixed exposures rather than "lifetime effects." Here we use an empirical example with data from the Rotterdam Study (Rotterdam, the Netherlands, 2009-2013) to demonstrate how confusion can arise when estimating "lifetime effects." We provide one possible definition of a lifetime effect: the average change in outcome measured at time t when the entire exposure trajectory from conception to time t is shifted by 1 unit. We show that MR only estimates this type of lifetime effect under specific conditions-for example, when the effect of the genetic variants used on exposure does not change over time. Lastly, we simulate the magnitude of bias that would result in realistic scenarios that use genetic variants with effects that change over time. We recommend that investigators in future MR studies carefully consider the effect of interest and how genetic variants whose effects change with time may impact the interpretability and validity of their results.
Similar articles
-
Mendelian Randomization With Repeated Measures of a Time-varying Exposure: An Application of Structural Mean Models.Epidemiology. 2022 Jan 1;33(1):84-94. doi: 10.1097/EDE.0000000000001417. Epidemiology. 2022. PMID: 34847085 Free PMC article.
-
Mendelian randomisation approaches to the study of prenatal exposures: A systematic review.Paediatr Perinat Epidemiol. 2021 Jan;35(1):130-142. doi: 10.1111/ppe.12691. Epub 2020 Aug 11. Paediatr Perinat Epidemiol. 2021. PMID: 32779786 Free PMC article. Review.
-
Genetic instrumental variable analysis: time to call mendelian randomization what it is. The example of alcohol and cardiovascular disease.Eur J Epidemiol. 2020 Feb;35(2):93-97. doi: 10.1007/s10654-019-00578-3. Epub 2019 Nov 24. Eur J Epidemiol. 2020. PMID: 31761964 Review.
-
Mendelian randomization in health research: using appropriate genetic variants and avoiding biased estimates.Econ Hum Biol. 2014 Mar;13(100):99-106. doi: 10.1016/j.ehb.2013.12.002. Epub 2013 Dec 13. Econ Hum Biol. 2014. PMID: 24388127 Free PMC article.
-
The effect of non-differential measurement error on bias, precision and power in Mendelian randomization studies.Int J Epidemiol. 2012 Oct;41(5):1383-93. doi: 10.1093/ije/dys141. Int J Epidemiol. 2012. PMID: 23045203
Cited by
-
Use of the instrumental inequalities in simulated mendelian randomization analyses with coarsened exposures.Eur J Epidemiol. 2024 May;39(5):491-499. doi: 10.1007/s10654-024-01130-8. Epub 2024 May 31. Eur J Epidemiol. 2024. PMID: 38819552
-
A burden of proof study on alcohol consumption and ischemic heart disease.Nat Commun. 2024 May 14;15(1):4082. doi: 10.1038/s41467-024-47632-7. Nat Commun. 2024. PMID: 38744810 Free PMC article.
-
Association Between Neuroinflammation and Parkinson's Disease: A Comprehensive Mendelian Randomization Study.Mol Neurobiol. 2024 May 6. doi: 10.1007/s12035-024-04197-2. Online ahead of print. Mol Neurobiol. 2024. PMID: 38709392
-
Genome-wide association and Mendelian randomisation analysis among 30,699 Chinese pregnant women identifies novel genetic and molecular risk factors for gestational diabetes and glycaemic traits.Diabetologia. 2024 Apr;67(4):703-713. doi: 10.1007/s00125-023-06065-5. Epub 2024 Feb 19. Diabetologia. 2024. PMID: 38372780 Free PMC article.
-
Estimating the health impact of nicotine exposure by dissecting the effects of nicotine versus non-nicotine constituents of tobacco smoke: A multivariable Mendelian randomisation study.PLoS Genet. 2024 Feb 9;20(2):e1011157. doi: 10.1371/journal.pgen.1011157. eCollection 2024 Feb. PLoS Genet. 2024. PMID: 38335242 Free PMC article.
Publication types
MeSH terms
LinkOut - more resources
Full Text Sources
Other Literature Sources