Abstract
BACKGROUND: As large-scale observational data become more available, caution regarding causal assumptions remains critically important. This may be especially true for Mendelian randomisation (MR), an increasingly popular approach. Point estimation in MR usually requires strong, often implausible homogeneity assumptions beyond the core instrumental conditions. Bounding, which does not require homogeneity assumptions, is infrequently applied in MR.
OBJECTIVES: We aimed to demonstrate computing nonparametric bounds for the causal risk difference derived from multiple proposed instruments in an MR study where effect heterogeneity is expected.
METHODS: Using data from the Norwegian Mother, Father and Child Cohort Study (n = 2056) and Avon Longitudinal Study of Parents and Children (n = 6216) to study the average causal effect of maternal pregnancy alcohol use on offspring attention deficit hyperactivity disorder symptoms, we proposed 11 maternal SNPs as instruments. We computed bounds assuming subsets of SNPs were jointly valid instruments, for all combinations of SNPs where the MR model was not falsified.
RESULTS: The MR assumptions were violated for all sets with more than 4 SNPs in one cohort and for all sets with more than 2 SNPs in the other. Bounds assuming one SNP was an individually valid instrument barely improved on assumption-free bounds. Bounds tightened as more SNPs were assumed to be jointly valid instruments, and occasionally identified directions of effect, though bounds from different sets varied.
CONCLUSIONS: Our results suggest that, when proposing multiple instruments, bounds can contextualise plausible magnitudes and directions of effects. Computing bounds over multiple assumption sets, particularly in large, high-dimensional data, offers a means of triangulating results across different potential sources of bias within a study and may help researchers to better evaluate and emphasise which estimates are compatible with the most plausible assumptions for their specific setting.
| Original language | English |
|---|---|
| Article number | 326-337 |
| Pages (from-to) | 326-337 |
| Number of pages | 12 |
| Journal | Paediatric and Perinatal Epidemiology |
| Volume | 37 |
| Issue number | 4 |
| Early online date | 1 Feb 2023 |
| DOIs | |
| Publication status | Published - 8 May 2023 |
Bibliographical note
Funding Information:We thank Hannah Sallis and Laurie Hannigan for their data analytic support. We thank Miguel Hernán for his helpful feedback on earlier drafts of this work. We thank the Norwegian Institute of Public Health (NIPH) for generating high‐quality genomic data. This research is part of the HARVEST collaboration, supported by the Research Council of Norway (NRC) (#229624). We also thank the NORMENT Centre for providing genotype data, funded by NRC (#223273), South East Norway Health Authority and KG Jebsen Stiftelsen. Further we thank the Center for Diabetes Research, the University of Bergen for providing genotype data and performing quality control and imputation of the data funded by the ERC AdG project SELECTionPREDISPOSED, Stiftelsen Kristian Gerhard Jebsen, Trond Mohn Foundation, NRC, the Novo Nordisk Foundation, the University of Bergen and the Western Norway health Authorities (Helse Vest). The Norwegian Mother and Child Cohort Study is supported by the Norwegian Ministry of Health and Care Services and the Ministry of Education and Research. We are grateful to all the participating families in Norway who take part in this on‐going cohort study. This work was performed on the TSD (Tjeneste for Sensitive Data) facilities, owned by the University of Oslo, operated and developed by the TSD service group at the University of Oslo, IT‐Department (USIT). ( [email protected] ). We are extremely grateful to all the families who took part in the ALSPAC study, the midwives for their help in recruiting them, and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists and nurses.
Funding Information:
We thank Hannah Sallis and Laurie Hannigan for their data analytic support. We thank Miguel Hernán for his helpful feedback on earlier drafts of this work. We thank the Norwegian Institute of Public Health (NIPH) for generating high-quality genomic data. This research is part of the HARVEST collaboration, supported by the Research Council of Norway (NRC) (#229624). We also thank the NORMENT Centre for providing genotype data, funded by NRC (#223273), South East Norway Health Authority and KG Jebsen Stiftelsen. Further we thank the Center for Diabetes Research, the University of Bergen for providing genotype data and performing quality control and imputation of the data funded by the ERC AdG project SELECTionPREDISPOSED, Stiftelsen Kristian Gerhard Jebsen, Trond Mohn Foundation, NRC, the Novo Nordisk Foundation, the University of Bergen and the Western Norway health Authorities (Helse Vest). The Norwegian Mother and Child Cohort Study is supported by the Norwegian Ministry of Health and Care Services and the Ministry of Education and Research. We are grateful to all the participating families in Norway who take part in this on-going cohort study. This work was performed on the TSD (Tjeneste for Sensitive Data) facilities, owned by the University of Oslo, operated and developed by the TSD service group at the University of Oslo, IT-Department (USIT). ([email protected]). We are extremely grateful to all the families who took part in the ALSPAC study, the midwives for their help in recruiting them, and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists and nurses.
Funding Information:
This work was partly supported by the South‐Eastern Norway Regional Health Authority (2018059) and the Norwegian Research Council (274611). This project is supported by an innovation programme under the Marie Sklodowska‐Curie grant agreement no. 721567. Dr Swanson is further supported by a NWO/ZonMW Veni Grant (91617066). H. Tiemeier is supported by a grant of the Dutch Ministry of Education, Culture, and Science and the Netherlands Organisation for Scientific Research (NWO grant No. 024.001.003, Consortium on Individual Development). MR Munafò and L Zuccolo are part of the MRC Integrative Epidemiology Unit at the University of Bristol (MC_UU_00011/7, MC_UU_00011/1). The UK Medical Research Council and Wellcome (Grant ref: 217065/Z/19/Z) and the University of Bristol provide core support for ALSPAC. This publication is the work of the authors, and all authors will serve as guarantors for the contents of this paper. A comprehensive list of grants funding is available on the ALSPAC website. Maternal ADH SNP genotyping was funded by MRC grant number G0902144. ALSPAC GWAS data was generated by Sample Logistics and Genotype Facilities at Wellcome Sanger Institute and LabCorp (Laboratory Corporation of America) using support from 23andMe. The design of questions on parental alcohol consumption was funded by a grant from the National Institute of Alcohol Abuse and Alcoholism to Dr. Ruth Little. This research was also supported by the NIHR Bristol Biomedical Research Centre at University Hospitals Bristol NHS Foundation Trust and the University of Bristol. The views expressed in this publication are those of the authors and not necessarily those of the NHS, the National Institute for Health Research, or the Department of Health and Social Care.
Publisher Copyright:
© 2023 The Authors. Paediatric and Perinatal Epidemiology published by John Wiley & Sons Ltd.
