Target trial emulation of physical activity and cardiovascular disease risk: What is impact of the exposure assessment method?

Background: Target trial emulation (TTE) designs provide a framework for strengthening causal inference in observational research, but it is unknown how vulnerable they are to substantial error when the emulated intervention (exposure) measurement is imprecise. In physical activity epidemiology specifically, correcting for confounding via TTE designs but not addressing the large measurement errors arising from self-reports (e.g. questionnaires, which typically capture partial behavioural accounts with very low precision) creates uncertainty about possible dominance of type 2 error biases arising from such novel designs. High-resolution wearables-based methods capture most movement, providing an assessment of physical activity behaviour with substantially less, empirically verified, measurement error. No study has examined how physical activity measurement method influences causal inference in TTE studies. Objectives: We applied TTE methodology to sub-samples of the UK Biobank cohort with repeat exposure measurements, to compare the effects of an emulated physical activity intervention on incident CVD risk, when the physical activity exposure was quantified using self-report vs. wearable devices. Methods: The emulated randomized controlled trial identified physically inactive adults (<150 moderate-to-vigorous physical activity (MVPA) mins/week) who had repeat assessments for wearable and self-reported physical activity. At re-examination, participants were categorised into intervention (adopted the current recommendation of ≥150 MVPA mins/week) or control (remained physically inactive) groups. Participants in each group were propensity score-matched to balance lifestyle behaviours, demographic, and health factors. Cumulative risk for CVD incidence was assessed through cumulative risk curves, hazard ratios, risk ratios, using Fine-Gray subdistribution and Poisson regression models. Results: The wearables analytic sample included 490 participants (245 per arm; mean incident CVD follow-up 4.4 years), and the self-report sample included 11,302 participants (5,651 per arm; mean follow-up 6.3 years). In wearables assessments, guideline-adherent participants had markedly lower cumulative CVD risk (cumulative risk = 8.0% vs. 17.0%; hazard ratio [95%CI] = 0.59 [0.36, 0.98]; relative risk = 0.45 [0.28, 0.72]). In contrast, self-report assessments showed near-identical risk trajectories for intervention and control groups (cumulative risk = 21.6% vs. 21.2%; hazard ratio = 0.98 [0.89, 1.08]; relative risk = 0.92 [0.84, 1.00]). Matching the self-report sample to the wearables sample for lifestyle, demographic, and health factors confirmed these findings. Conclusion: Reliance on self-reported measures of physical activity in TTE studies may obscure emulated intervention effects due to non-differential misclassification, increasing considerably risk of Type II error. Exposure assessment using wearable devices may be essential for valid causal inference in TTE studies of physical activity and CVD risk. Future TTE studies of physical activity exposures should prioritise objective measurements to avoid biased inferences that could affect public health policy and guidelines.

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