Independent and Joint Associations of Circadian Rhythm Patterns and Physical Activity Levels With Venous Thromboembolism: A Large-Scale Cohort Study Using Accelerometry Measurements

BACKGROUND: Venous thromboembolism (VTE) constitutes a significant global health burden, yet the contribution of circadian rhythm disruptions to VTE risk remains insufficiently characterized. This study investigated the independent and joint associations of rest-activity circadian rhythm and physical activity (PA) with VTE incidence in a large cohort. METHODS: A total of 89,473 UK Biobank participants were analyzed (median follow-up: 12.7 y). Rest-activity rhythm was assessed using accelerometer-derived relative amplitude (RA), and PA was measured by average daily acceleration. VTE events were ascertained via International Classification of Diseases, 10th Revision codes. Cox regression models were used to evaluate linear, nonlinear, and joint associations, adjusting for sociodemographic and clinical covariates. Sensitivity analyses, subgroup analyses, and E-value calculations further supported the robustness of the findings. RESULTS: Each SD increase in RA was associated with a 12% lower VTE risk (hazard ratio, 0.88; 95% CI, 0.85-0.91). Nonlinear analysis of PA identified an inflection point at 30.4mg (milligravity); PA below this level was associated with a 37% higher risk (hazard ratio, 1.37; 95% CI, 1.21-1.54). Participants with both low RA and low PA had a 54% higher VTE risk compared with those with high RA and high PA (hazard ratio, 1.54; 95% CI, 1.34-1.76). Chronotype showed no significant association with VTE. CONCLUSIONS: This large-scale cohort study demonstrates that disrupted circadian rhythms and low PA are independently and jointly associated with elevated VTE risk. These findings suggest that circadian and activity monitoring, for example, via wearable devices, may have potential utility in future VTE risk assessment particularly among high-risk populations.