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Article: Use of Multivariable Mendelian Randomization to Address Biases Due to Competing Risk Before Recruitment

TitleUse of Multivariable Mendelian Randomization to Address Biases Due to Competing Risk Before Recruitment
Authors
Keywordsselection bias
competing risk
Mendelian randomization
shared etiology
instrumental variable analysis
Issue Date2021
PublisherFrontiers Research Foundation. The Journal's web site is located at http://www.frontiersin.org/genetics
Citation
Frontiers in Genetics, 2021, v. 11, p. article no. 610852 How to Cite?
AbstractBackground: Mendelian randomization (MR) provides unconfounded estimates. MR is open to selection bias when the underlying sample is selected on surviving to recruitment on the genetically instrumented exposure and competing risk of the outcome. Few methods to address this bias exist. Methods: We show that this selection bias can sometimes be addressed by adjusting for common causes of survival and outcome. We use multivariable MR to obtain a corrected MR estimate for statins on stroke. Statins affect survival, and stroke typically occurs later in life than ischemic heart disease (IHD), making estimates for stroke open to bias from competing risk. Results: In univariable MR in the UK Biobank, genetically instrumented statins did not protect against stroke [odds ratio (OR) 1.33, 95% confidence interval (CI) 0.80–2.20] but did in multivariable MR (OR 0.81, 95% CI 0.68–0.98) adjusted for major causes of survival and stroke [blood pressure, body mass index (BMI), and smoking initiation] with a multivariable Q-statistic indicating absence of selection bias. However, the MR estimate for statins on stroke using MEGASTROKE remained positive and the Q statistic indicated pleiotropy. Conclusion: MR studies of harmful exposures on late-onset diseases with shared etiology need to be conceptualized within a mechanistic understanding so as to identify any potential bias due to survival to recruitment on both genetically instrumented exposure and competing risk of the outcome, which may then be investigated using multivariable MR or estimated analytically and results interpreted accordingly.
Persistent Identifierhttp://hdl.handle.net/10722/298734
ISSN
2023 Impact Factor: 2.8
2023 SCImago Journal Rankings: 0.853
PubMed Central ID
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorSchooling, CM-
dc.contributor.authorLopez, PM-
dc.contributor.authorYANG, Z-
dc.contributor.authorZhao, JV-
dc.contributor.authorAu Yeung, SL-
dc.contributor.authorHuang, JV-
dc.date.accessioned2021-04-12T03:02:39Z-
dc.date.available2021-04-12T03:02:39Z-
dc.date.issued2021-
dc.identifier.citationFrontiers in Genetics, 2021, v. 11, p. article no. 610852-
dc.identifier.issn1664-8021-
dc.identifier.urihttp://hdl.handle.net/10722/298734-
dc.description.abstractBackground: Mendelian randomization (MR) provides unconfounded estimates. MR is open to selection bias when the underlying sample is selected on surviving to recruitment on the genetically instrumented exposure and competing risk of the outcome. Few methods to address this bias exist. Methods: We show that this selection bias can sometimes be addressed by adjusting for common causes of survival and outcome. We use multivariable MR to obtain a corrected MR estimate for statins on stroke. Statins affect survival, and stroke typically occurs later in life than ischemic heart disease (IHD), making estimates for stroke open to bias from competing risk. Results: In univariable MR in the UK Biobank, genetically instrumented statins did not protect against stroke [odds ratio (OR) 1.33, 95% confidence interval (CI) 0.80–2.20] but did in multivariable MR (OR 0.81, 95% CI 0.68–0.98) adjusted for major causes of survival and stroke [blood pressure, body mass index (BMI), and smoking initiation] with a multivariable Q-statistic indicating absence of selection bias. However, the MR estimate for statins on stroke using MEGASTROKE remained positive and the Q statistic indicated pleiotropy. Conclusion: MR studies of harmful exposures on late-onset diseases with shared etiology need to be conceptualized within a mechanistic understanding so as to identify any potential bias due to survival to recruitment on both genetically instrumented exposure and competing risk of the outcome, which may then be investigated using multivariable MR or estimated analytically and results interpreted accordingly.-
dc.languageeng-
dc.publisherFrontiers Research Foundation. The Journal's web site is located at http://www.frontiersin.org/genetics-
dc.relation.ispartofFrontiers in Genetics-
dc.rightsThis Document is Protected by copyright and was first published by Frontiers. All rights reserved. It is reproduced with permission.-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.subjectselection bias-
dc.subjectcompeting risk-
dc.subjectMendelian randomization-
dc.subjectshared etiology-
dc.subjectinstrumental variable analysis-
dc.titleUse of Multivariable Mendelian Randomization to Address Biases Due to Competing Risk Before Recruitment-
dc.typeArticle-
dc.identifier.emailSchooling, CM: cms1@hkucc.hku.hk-
dc.identifier.emailZhao, JV: janezhao@hku.hk-
dc.identifier.emailAu Yeung, SL: ayslryan@hku.hk-
dc.identifier.authoritySchooling, CM=rp00504-
dc.identifier.authorityZhao, JV=rp02336-
dc.identifier.authorityAu Yeung, SL=rp02224-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.3389/fgene.2020.610852-
dc.identifier.pmid33519914-
dc.identifier.pmcidPMC7845663-
dc.identifier.scopuseid_2-s2.0-85100097893-
dc.identifier.hkuros322140-
dc.identifier.volume11-
dc.identifier.spagearticle no. 610852-
dc.identifier.epagearticle no. 610852-
dc.identifier.isiWOS:000612836600001-
dc.publisher.placeSwitzerland-

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