Impact of follow-up time and analytical approaches to account for reverse causality on the association between physical activity and health outcomes in UK Biobank

Abstract Background The advent of very large cohort studies (n > 500 000) has given rise to prospective analyses of health outcomes being undertaken after short (<4 years) follow-up periods. However, these studies are potentially at risk of reverse causality bias. We investigated differences in the associations between self-reported physical activity and all-cause and cardiovascular disease (CVD) mortality, and incident CVD, using different follow-up time cut-offs and methods to account for reverse causality bias. Methods Data were from n = 452 933 UK Biobank participants, aged 38–73 years at baseline. Median available follow-up time was 7 years (for all-cause and CVD mortality) and 6.1 years (for incident CVD). We additionally analysed associations at 1-, 2- and 4-year cut-offs after baseline. We fit up to four models: (1) adjusting for prevalent CVD and cancer, (2) excluding prevalent disease, (3) and (4) Model 2 excluding incident cases in the first 12 and 24 months, respectively. Results The strength of associations decreased as follow-up time cut-off increased. For all-cause mortality, Model 1 hazard ratios were 0.73 (0.69–0.78) after 1 year and 0.86 (0.84–0.87) after 7 years. Associations were weaker with increasing control for possible reverse causality. After 7-years follow-up, the hazard ratios were 0.86 (0.84–0.87) and 0.88 (0.86–0.90) for Models 1 and 4, respectively. Associations with CVD outcomes followed similar trends. Conclusions As analyses with longer follow-up times and increased control for reverse causality showed weaker associations, there are implications for the decision about when to analyse a cohort study with ongoing data collection, the interpretation of study results and their contribution to meta-analyses.