From association to causation: interpreting propensity score-based analyses in real-world evidence

Propensity score (PS) methods are widely used in real-world evidence studies to reduce confounders and to approximate randomized comparisons. However, statistical adjustment is often misinterpreted as evidence of causality, leading to overgeneralization and inappropriate clinical conclusions. In this statistical round, we present a clinically oriented framework for interpreting PS-based analyses, focusing on key principles of causal inference, including the definition of the estimand (average treatment effect [ATE] vs. average treatment effect on the treated [ATT]), covariate selection based on causal structure, assessment of positivity and overlap, and evaluation of robustness to unmeasured confounders. Using recent anesthesiology studies, we demonstrate that discrepancies between the analytical methods and interpretations are common. PS matching typically estimates the ATT and may not be generalizable to the entire population, whereas inverse probability of treatment weighting aims to estimate the ATE but may yield unstable estimates in the presence of limited overlap. Even with well-balanced covariates, unmeasured confounders remain a critical limitation. Failure to account for these issues may lead to biased estimates and overinterpretation of observational associations as causal effects. Causal interpretations of PS-based analyses require an alignment among the target estimand, underlying assumptions, and analytical methods. Rather than relying solely on statistical adjustment, researchers and clinicians should critically evaluate overlap, confounders, and generalizability. Transitioning from association to causation requires both advanced statistical methods and rigorous and transparent interpretations grounded in causal reasoning.