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http://conacyt.repositorioinstitucional.mx/jspui/handle/1000/345| Exploring and mitigating potential bias when genetic instrumental variables are associated with multiple non-exposure traits in Mendelian randomization | |
| Eleanor Sanderson Maria Carolina Borges Qian Yang Kate Tilling Debbie A Lawlor | |
| Novel Coronavirus | |
| Acceso Abierto | |
| Atribución | |
| 10.1101/19009605 | |
| Background: Our aim is to produce guidance on exploring and mitigating possible bias when genetic instrumental variables (IVs) associate with traits other than the exposure of interest in Mendelian randomization (MR) studies. Methods: We use causal diagrams to illustrate scenarios that could result in IVs being related to (non-exposure) traits. We recommend that MR studies explore possible IV-non-exposure associations across a much wider range of traits than is usually the case. Where associations are found, confounding by population stratification should be assessed through adjusting for relevant population structure variables. To distinguish vertical from horizontal pleiotropy we suggest using bidirectional MR between the exposure and non-exposure traits and MR of the effect of the non-exposure traits on the outcome of interest. If vertical pleiotropy is plausible, standard MR methods should be unbiased. If horizontal pleiotropy is plausible, we recommend using multivariable MR to control for observed pleiotropic traits and conducting sensitivity analyses which do not require prior knowledge of specific invalid IVs or pleiotropic paths. Results: We applied our recommendations to an illustrative example of the effect of maternal insomnia on offspring birthweight in the UK Biobank. We found little evidence that unexpected IV-non-exposure associations were driven by population stratification. Three out of six observed non-exposure traits plausibly reflected horizontal pleiotropy. Multivariable MR and sensitivity analyses suggested an inverse association of insomnia with birthweight, but effects were imprecisely estimated in some of these analyses. Conclusions: We provide guidance for MR studies where genetic IVs associate with non-exposure traits. ### Competing Interest Statement D.A.L. reports receiving research support from Medtronic and Roche Diagnostics for research outside the submitted work. All other authors declare no competing interests. ### Funding Statement This work was supported by the University of Bristol and UK Medical Research Council [grant numbers, MM_UU_00011/1, MM_UU_00011/2, MM_UU_00011/3 and MM_UU_00011/6], the US National Institute for Health (R01 DK10324),the European Research Council via Advanced Grant 669545, the British Heart Foundation (AA/18/7/34219) and the NIHR Biomedical Research Centre at University Hospitals Bristol NHS Foundation Trust and the University of Bristol. Q.Y. is funded by a China Scholarship Council PhD Scholarship (CSC201808060273). M.C.B. is funded by a UK Medical Research Council Skills Development Fellowship (MR/P014054/1). D.A.L. is an NIHR Senior Investigator (NF-0616-10102). The funders had no influence on the study design, data collection and analysis, decision to publish, or preparation of the manuscript. ### Author Declarations All relevant ethical guidelines have been followed and any necessary IRB and/or ethics committee approvals have been obtained. Not Applicable All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. Not Applicable Any clinical trials involved have been registered with an ICMJE-approved registry such as ClinicalTrials.gov and the trial ID is included in the manuscript. Not Applicable I have followed all appropriate research reporting guidelines and uploaded the relevant Equator, ICMJE or other checklist(s) as supplementary files, if applicable. Not Applicable The data reported in this paper are available by applying directly to the UK Biobank. <https://www.ukbiobank.ac.uk> | |
| Cold Spring Harbor Laboratory Press | |
| 2019 | |
| Preimpreso | |
| https://www.medrxiv.org/content/10.1101/19009605v1 | |
| Inglés | |
| VIRUS RESPIRATORIOS | |
| Aparece en las colecciones: | Artículos científicos |
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