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Physician-Confirmed and Administrative Definitions of Stroke in UK Biobank Reflect the Same Underlying Genetic Trait
Kristiina Rannikmäe1, Konrad Rawlik2, Amy C Ferguson1
1Centre for Medical Informatics, Usher Institute, University of Edinburgh, Edinburgh, United Kingdom.
Insights
Stroke ascertainment in UK Biobank (UKB) varies by code source and type, impacting case numbers. However, all UKB stroke definitions show significant genetic correlation with large stroke genome-wide association studies (GWASs).
Area of Science:
- Genetics
- Epidemiology
- Bioinformatics
Background:
- Stroke in UK Biobank (UKB) is identified through administrative data linkages and self-reports.
- The accuracy of these stroke ascertainment codes requires validation.
Purpose of the Study:
- To assess the accuracy of different stroke ascertainment codes in UK Biobank using genetic validation.
- To compare various UK Biobank stroke definitions against large-scale genetic association studies.
Main Methods:
- Compiled stroke and cerebrovascular disease (CVD) code lists from multiple sources (Read, ICD-9/-10) and settings.
- Created 12 stroke definitions based on code type and source for 408,210 UK Biobank participants.
- Performed genome-wide association studies (GWASs) for each definition and compared results with the MEGASTROKE GWAS, assessing genetic correlations and locus replication.
Main Results:
- Stroke case numbers varied five-fold across the 12 UKB definitions, from 3,976 to 19,449.
- All 12 UKB stroke definitions demonstrated significant genetic correlations with the MEGASTROKE GWAS results (rg .81–1) and with each other (rg .4–1).
- Six known stroke-associated genetic loci were successfully replicated using at least one UKB stroke definition.
Conclusions:
- The number of stroke cases identified in UK Biobank is highly dependent on the specific codes and sources utilized.
- Despite variations in case ascertainment, all UK Biobank stroke definitions exhibit significant genetic correlation with established large-scale stroke GWAS data.
Background:
Stroke in UK Biobank (UKB) is ascertained via linkages to coded administrative datasets and self-report. We studied the accuracy of these codes using genetic validation.
Methods:
We compiled stroke-specific and broad cerebrovascular disease (CVD) code lists (Read V2/V3, ICD-9/-10) for medical settings (hospital, death record, primary care) and self-report. Among 408,210 UKB participants, we identified all with a relevant code, creating 12 stroke definitions based on the code type and source. We performed genome-wide association studies (GWASs) for each definition, comparing summary results against the largest published stroke GWAS (MEGASTROKE), assessing genetic correlations, and replicating 32 stroke-associated loci.
Results:
The stroke case numbers identified varied widely from 3,976 (primary care stroke-specific codes) to 19,449 (all codes, all sources). All 12 UKB stroke definitions were significantly correlated with the MEGASTROKE summary GWAS results (rg.81-1) and each other (rg.4-1). However, Bonferroni-corrected confidence intervals were wide, suggesting limited precision of some results. Six previously reported stroke-associated loci were replicated using ≥1 UKB stroke definition.
Conclusions:
Stroke case numbers in UKB depend on the code source and type used, with a 5-fold difference in the maximum case-sample size. All stroke definitions are significantly genetically correlated with the largest stroke GWAS to date.
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