Table 1

Methods for strengthening causal inference in physical activity epidemiology studies

Lifecourse approachUse of prospective studies to investigate PA levels at different ages and how they might differently affect lifespanUseful for assessing temporal associations; ability to adjust for the respective outcome measures at baseline (where possible) makes it possible to disentangle prospective associations from tracking effectsLogistically demanding as it requires repeat assessments; residual confounding; measurement error in exposure, outcome and covariables; selection bias
Cross-context comparisonComparison of associations between voluntary leisure-time PA and compulsory occupational PA; PA across different cultures or dissimilar countriesExploring residual confounding; reliable findings if estimates are similar across different contexts (where the confounding structure in these settings is likely to differ)Assumptions about different confounding structures may not be correct; variables in different studies might be measured with varying accuracy and generalisability
Sibling comparisonMZ or DZ twin comparisons among siblings discordant for PAUsing MZ  best controls for familial background and genetic confounding, compared with DZ (or siblings), where 50% of genetic information is sharedAssumes a stable family environment; confounding by factors not perfectly shared by siblings; reverse causation still possible
Mendelian randomisationThe use of genetic variants associated with exercise and fitness, incorporated into a Mendelian randomisation analysis, whereby genotype serves as an instrumental variable for PAGenetic instruments are not subject to confounding from environmental or lifestyle factors, are not influenced by the outcome, do not change over time and are measured with high accuracyLow power; lack of instruments; pleiotropy and linkage disequlibrium; population stratification; canalisation
Objective measures of the exposure and biomarkersThe use of objective measures of PA (eg, accelerometry data), fitness (eg, VO2 max) or the incorporation of other biomarkers (eg, DNA methylation)More precise measurement of underlying risk factor reduces measurement error in documented PA and problems with regression dilution bias; biomarkers may serve as surrogate endpoints in PA trials and longitudinal studies without long-term follow-upDoes not evade problems of confounding or reverse causation
  • DZ, dizygotic; MZ, monozygotic; PA, physical activity.