External anchors reveal target-population effects hidden by published clinical-trial evidence

Abstract

Meta-analyses guide clinical and policy decisions, but they estimate the effect among published trials, not the effect in the population a decision concerns. We introduce reference-anchored meta-analysis, which uses an external untreated-outcome distribution for two purposes: to define the target population, and, through each trial's control-arm mean as an externally anchored instrument, to correct publication selection. In an antidepressant literature with recovered unpublished trials, a strict holdout -- removing the hidden trials from both fitting and anchoring -- recovers a held-out all-trials benchmark. Applied to insomnia total sleep time and the placebo-controlled HbA1c literature in type-2 diabetes, it returns target-population effects materially smaller than the published averages, while a first-stage diagnostic flags, in advance, where the correction should not be attempted. Evidence synthesis becomes a target-explicit estimate with auditable selection assumptions.