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

Abstract

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 years; 45.4% male) followed up over mean (SD) 9.4 ± 4.5 years, recruited from the Health Survey for England and the Scottish Health Survey. Results There were 10 309 deaths, of which 3109 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 [hazard ratio (HR) = 0.75; 95% confidence interval (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; 95% CI: 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 the potential to improve causal inference within the physical activity field.

Association of Membership at a Medical Fitness Facility With Adverse Health Outcomes

“…Unadjusted Cox proportional hazards regression was used to compare the confounding structure of the negative control and mortality. 31 Statistical analyses were performed using SAS/STAT, version 9.4, from 2018 to 2020.…”

Reallocation of time between device-measured movement behaviours and risk of incident cardiovascular disease

“…To investigate unmeasured and residual confounding, we used a negative control outcome of accidents without a plausible mechanistic link to movement behaviours (accidents excluding falls, cycling accidents and intentional self-harm; see online supplemental table 3). 34 We also used E-values to assess the minimum strength of association that an unmeasured confounder would need with both exposure and outcome to explain away the observed association (see online supplemental methods). 35 36 Two further sensitivity analyses, addressing the treatment of zero values and comparing with a linear isotemporal substitution approach, are reported in online supplemental methods.…”

Adults with current asthma but not former asthma have higher all-cause and cardiovascular mortality: a population-based prospective cohort study

“…The other cause-specific mortality included heart disease (I00–I09, I11, I13, I20–I51), Stroke (I60–I69), influenza and pneumonia (J09–J18), chronic lower respiratory diseases (CLRD) (J40–J47), diabetes mellitus (E10–E14), Alzheimer’s disease (G30), kidney disease (N00–N07, N17–N19, N25–N27) and accidents (unintentional injuries) (V01–X59, Y85–Y86). Because accidents deaths have no plausible links with asthma but do have similar confounding structure to mortality, and thus accidental deaths were used as a negative control outcome 16 .…”