Examining associations between physical activity and cardiovascular mortality using negative control outcomes

Background: The purpose of a negative control is to reproduce a condition that cannot involve the hypothesized causal mechanism, but does involve the same sources of bias and confounding that may distort the primary association of interest. Observational studies suggest physical inactivity is a major risk factor for cardiovascular disease (CVD) although potential sources of bias, including reverse causation and residual confounding, make it difficult to infer causality. The aim was to employ a negative control outcome to explore the extent to which the association between physical activity and CVD mortality is explained by confounding. Methods: The sample comprised 104,851 participants (aged 47 ± 17 yrs; 45.4% male) followed up over mean [SD] 9.4±4.5 years, recruited from The Health Survey for England and the Scottish Health Surveys. Results: There were 10,309 deaths, of which 3,109 were attributed to CVD, and 157 to accidents (negative control outcome). Accidental death was related to age, male sex, smoking, longstanding illness and psychological distress, with some evidence of social patterning. This confounding structure was similar to that seen with CVD mortality, suggesting that our negative control outcome was appropriate. Physical activity (per SD unit increase in MET-hr-wk) was inversely associated with CVD (HR=0.75; 95% CI, 0.70, 0.80); the point estimate between physical activity and accidental death was in the same direction but of lesser magnitude (HR=0.86; 0.69, 1.07). A linear dose-response pattern was observed for physical activity and CVD but not with the negative control. Conclusions: Inverse associations between physical activity and risk of CVD mortality are likely causal but of a smaller magnitude than commonly observed. Negative control studies have potential to improve causal inference within the physical activity field.