Adjustment for index event bias in genome-wide association studies of subsequent events.
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Abstract
Following numerous genome-wide association studies of disease susceptibility, there is increasing interest in genetic associations with prognosis, survival or other subsequent events. Such associations are vulnerable to index event bias, by which selection of subjects according to disease status creates biased associations if common causes of incidence and prognosis are not accounted for. We propose an adjustment for index event bias using the residuals from the regression of genetic effects on prognosis on genetic effects on incidence. Our approach eliminates this bias when direct genetic effects on incidence and prognosis are independent, and otherwise reduces bias in realistic situations. In a study of idiopathic pulmonary fibrosis, we reverse a paradoxical association of the strong susceptibility gene MUC5B with increased survival, suggesting instead a significant association with decreased survival. In re-analysis of a study of Crohn's disease prognosis, four regions remain associated at genome-wide significance but with increased standard errors.
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- Authors
- Dudbridge, F., Allen, R. J., Sheehan, N. A., Schmidt, A. F., Lee, J. C., Jenkins, R. G., Wain, L. V., Hingorani, A. D., & Patel, R. S.
- Affiliations
- University of Leicester (GB)
- University of Groningen (NL)
- University of Cambridge (GB)
- University College London (GB)
- Corresponding author
- Dudbridge, Frank
- ORCID
- Venue
- Nature Communications
- Published
- 2019-04-05
- Volume
- 10
- Issue
- 1
- Pages
- 1561-1561
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC6450903
- OpenAlex
- W2897633068
- Cited by
- 115
- References
- 43
- Citations by year
- 2026: 10 · 2025: 12 · 2024: 16 · 2023: 19 · 2022: 25 · 2021: 15 · 2020: 13 · 2019: 5
- FWCI
- 8.74
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Repository@Nottingham (University of Nottingham) (publishedVersion, cc-by)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (publishedVersion, cc-by)
- LSHTM Research Online (London School of Hygiene and Tropical Medicine) (acceptedVersion)
- Repository@Nottingham (University of Nottingham) (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- UCL Discovery (University College London) (submittedVersion)
- Figshare (submittedVersion, cc-by)
- Leicester Research Archive (University of Leicester) (submittedVersion, cc-by)
- Apollo (University of Cambridge) (submittedVersion, cc-by)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, cc-by)
- Apollo (cc-by)
- Funders
- National Institute for Health and Care Research (NF-SI-0515-10091, CL-2011-11-003)
- British Heart Foundation (RG/10/12/28456, FS/14/76/30933)
- British Lung Foundation
- Rosetrees Trust (M202-F2)
- Medical Research Council (MR/N005953/1)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and phenotypic traits in livestock
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Mapping and Diversity in Plants and Animals
- Keywords
- genome-wide association study, prognosis, survival, incidence, MUC5B, idiopathic pulmonary fibrosis, Crohn's disease
- MeSH terms
- Computer Simulation, Crohn Disease, Humans, Models, Genetic, Regression Analysis, Incidence, Odds Ratio, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Idiopathic Pulmonary Fibrosis, Genome-Wide Association Study, Mucin-5B
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