Credible Mendelian Randomization Studies in the Presence of Selection Bias Using Control Exposures

Selection bias is increasingly acknowledged as a limitation of Mendelian randomization (MR). However, few methods exist to assess this issue. We focus on two plausible causal structures relevant to MR studies and illustrate the data-generating process underlying selection bias via simulation studies...

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Autores principales:	Zhao Yang, C. Mary Schooling, Man Ki Kwok
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	causal estimates control exposures Mendelian randomization reproducible selection bias Genetics QH426-470
Acceso en línea:	https://doaj.org/article/8adafa097ae04f409d5b2b2c4ca3dde3
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spelling	oai:doaj.org-article:8adafa097ae04f409d5b2b2c4ca3dde32021-11-30T19:05:23ZCredible Mendelian Randomization Studies in the Presence of Selection Bias Using Control Exposures1664-802110.3389/fgene.2021.729326https://doaj.org/article/8adafa097ae04f409d5b2b2c4ca3dde32021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fgene.2021.729326/fullhttps://doaj.org/toc/1664-8021Selection bias is increasingly acknowledged as a limitation of Mendelian randomization (MR). However, few methods exist to assess this issue. We focus on two plausible causal structures relevant to MR studies and illustrate the data-generating process underlying selection bias via simulation studies. We conceptualize the use of control exposures to validate MR estimates derived from selected samples by detecting potential selection bias and reproducing the exposure–outcome association of primary interest based on subject matter knowledge. We discuss the criteria for choosing the control exposures. We apply the proposal in an MR study investigating the potential effect of higher transferrin with stroke (including ischemic and cardioembolic stroke) using transferrin saturation and iron status as control exposures. Theoretically, selection bias affects associations of genetic instruments with the outcome in selected samples, violating the exclusion-restriction assumption and distorting MR estimates. Our applied example showing inconsistent effects of genetically predicted higher transferrin and higher transferrin saturation on stroke suggests the potential selection bias. Furthermore, the expected associations of genetically predicted higher iron status on stroke and longevity indicate no systematic selection bias. The routine use of control exposures in MR studies provides a valuable tool to validate estimated causal effects. Like the applied example, an antagonist, decoy, or exposure with similar biological activity as the exposure of primary interest, which has the same potential selection bias sources as the exposure–outcome association, is suggested as the control exposure. An additional or a validated control exposure with a well-established association with the outcome is also recommended to explore possible systematic selection bias.Zhao YangC. Mary SchoolingC. Mary SchoolingMan Ki KwokFrontiers Media S.A.articlecausal estimatescontrol exposuresMendelian randomizationreproducibleselection biasGeneticsQH426-470ENFrontiers in Genetics, Vol 12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	causal estimates control exposures Mendelian randomization reproducible selection bias Genetics QH426-470
spellingShingle	causal estimates control exposures Mendelian randomization reproducible selection bias Genetics QH426-470 Zhao Yang C. Mary Schooling C. Mary Schooling Man Ki Kwok Credible Mendelian Randomization Studies in the Presence of Selection Bias Using Control Exposures
description	Selection bias is increasingly acknowledged as a limitation of Mendelian randomization (MR). However, few methods exist to assess this issue. We focus on two plausible causal structures relevant to MR studies and illustrate the data-generating process underlying selection bias via simulation studies. We conceptualize the use of control exposures to validate MR estimates derived from selected samples by detecting potential selection bias and reproducing the exposure–outcome association of primary interest based on subject matter knowledge. We discuss the criteria for choosing the control exposures. We apply the proposal in an MR study investigating the potential effect of higher transferrin with stroke (including ischemic and cardioembolic stroke) using transferrin saturation and iron status as control exposures. Theoretically, selection bias affects associations of genetic instruments with the outcome in selected samples, violating the exclusion-restriction assumption and distorting MR estimates. Our applied example showing inconsistent effects of genetically predicted higher transferrin and higher transferrin saturation on stroke suggests the potential selection bias. Furthermore, the expected associations of genetically predicted higher iron status on stroke and longevity indicate no systematic selection bias. The routine use of control exposures in MR studies provides a valuable tool to validate estimated causal effects. Like the applied example, an antagonist, decoy, or exposure with similar biological activity as the exposure of primary interest, which has the same potential selection bias sources as the exposure–outcome association, is suggested as the control exposure. An additional or a validated control exposure with a well-established association with the outcome is also recommended to explore possible systematic selection bias.
format	article
author	Zhao Yang C. Mary Schooling C. Mary Schooling Man Ki Kwok
author_facet	Zhao Yang C. Mary Schooling C. Mary Schooling Man Ki Kwok
author_sort	Zhao Yang
title	Credible Mendelian Randomization Studies in the Presence of Selection Bias Using Control Exposures
title_short	Credible Mendelian Randomization Studies in the Presence of Selection Bias Using Control Exposures
title_full	Credible Mendelian Randomization Studies in the Presence of Selection Bias Using Control Exposures
title_fullStr	Credible Mendelian Randomization Studies in the Presence of Selection Bias Using Control Exposures
title_full_unstemmed	Credible Mendelian Randomization Studies in the Presence of Selection Bias Using Control Exposures
title_sort	credible mendelian randomization studies in the presence of selection bias using control exposures
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/8adafa097ae04f409d5b2b2c4ca3dde3
work_keys_str_mv	AT zhaoyang crediblemendelianrandomizationstudiesinthepresenceofselectionbiasusingcontrolexposures AT cmaryschooling crediblemendelianrandomizationstudiesinthepresenceofselectionbiasusingcontrolexposures AT cmaryschooling crediblemendelianrandomizationstudiesinthepresenceofselectionbiasusingcontrolexposures AT mankikwok crediblemendelianrandomizationstudiesinthepresenceofselectionbiasusingcontrolexposures
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Credible Mendelian Randomization Studies in the Presence of Selection Bias Using Control Exposures

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