Investigation of the structure and magnitude of time-varying uncontrolled confounding in simulated cohort data analyzed using g-computation.

Abstract

When estimating the effect of time-varying exposures on longer-term outcomes, the assumption of conditional exchangeability or no uncontrolled confounding extends beyond baseline confounding to include time-varying confounding. We illustrate the structures and magnitude of uncontrolled time-varying confounding in exposure effect estimates obtained from g-computation when sequential conditional exchangeability is violated. We used directed acyclic graphs (DAGs) to depict time-varying uncontrolled confounding. We performed simulations and used g-computation to quantify the effects of each time-varying exposure for each DAG type. Models adjusting all time-varying confounders were considered the true (bias-adjusted) estimate. The exclusion of time-varying uncontrolled confounders represented the biased effect estimate and an unmet 'no uncontrolled confounding' assumption. True and biased estimates were compared across DAGs, with different magnitudes of uncontrolled confounding. Time-varying uncontrolled confounding can present in several scenarios, including relationships into subsequently measured exposure(s), outcome, unmeasured confounder(s) and other measured confounder(s). In simulations, effect estimates obtained from g-computation were more biased in DAGs when the uncontrolled confounders were directly related to the outcome. Complex DAGs that included relationships between uncontrolled confounders and other variables and relationships where exposures caused uncontrolled confounders at the next time point resulted in the most biased effect estimates. In these complex DAGs, excluding uncontrolled confounders affected the multiple effect estimates. Time-varying uncontrolled confounding has the potential to substantially impact observed effect estimates. Given the importance of longitudinal studies in advising public health, the impact of time-varying uncontrolled confounding warrants more recognition and evaluation using quantitative bias analysis.