Is Cohort Study Representativeness Passé ? Matching the UK Biobank Sample to Target Population Characteristics and Recalculating the Associations between Lifestyle Risk Factors and Mortality

Background: The UK Biobank (UKB) has been used widely to examine the associations between lifestyle risk factors (LRF) and mortality outcomes. It is unknown if the extremely low UKB response rate (5·5%) and lack of representativeness materially affects the magnitude and direction of observed associations. Methods: We used post-stratification to match the UKB sample to the target population in terms of age, sex, education, and prevalence of LRFs (physical inactivity, alcohol intake, smoking, fruit and vegetable intake, and obesity). We compared unweighted and post-stratified associations between each LRF and tertiles of a lifestyle index score with all-cause, CVD, and cancer mortality.  We also calculated the unweighted/post-stratified ratio of hazard ratios and 95%CI (RHR) as a marker of statistically significant effect sizes difference. Findings: Out of 371,974 UKB participants with no missing data, 302,009 had no history of CVD or cancer, corresponding to 2,345142 person years of follow-up.  The protective associations between alcohol use and CVD mortality observed in the unweighted UKB were attenuated to the null after post-stratification, e.g. from an HR of 0·63 (0·45 to 0·87) unweighted to 0·99 (0·65 to 1·50) post-stratified  for drinking ≥5 times/week compared to never drinker. The post-stratified all-cause mortality HRs were consistently lower than the unweighted estimates across obesity groups. The magnitude of the post-stratified all-cause mortality HR comparing the least healthy with the healthiest tertiles of the lifestyle risk factor index was 9% higher (95%CI: 2% to 18%) than the unweighted estimates. Interpretation: Lack of representativeness may lead to spurious cardio-protective associations of alcohol; may under-estimate health hazards among those with the least healthy lifestyles; and may exaggerate the risks of BMI-defined obesity.  Funding Statement: This study did not receive specific funding. Declaration of Interests: None of the authors reported a conflict of interest related to this study. Ethics Approval Statement: All participants consented to the use of their de-identified data, including access to their health-related records, for research.