On the uncertainty from the first-stage estimation of prognostic covariate adjustment in randomized controlled trials

TL;DR

This paper investigates the impact of estimating prognostic scores on variance estimation in covariate adjustment for randomized trials, showing that the asymptotic variances are equal and providing guidance on variance estimator choice.

Contribution

The study derives and compares asymptotic variances for covariate adjustment methods, clarifies their equivalence, and offers practical recommendations for variance estimation.

Findings

Asymptotic variances are equal whether the prognostic score is known or estimated.

Variance estimators treating the prognostic score as known are generally valid and simpler.

Explicitly accounting for prognostic score estimation is recommended with small historical data.

Abstract

Prognostic covariate adjustment (PROCOVA) is a two-sample two-stage estimation method used in randomized controlled trials. In the first stage, a prognostic score, defined as the conditional expectation of an outcome given covariates under the control treatment, is estimated using historical data. In the second stage, analysis of covariance with the estimated prognostic score and treatment assignment as explanatory variables is performed, and the average treatment effect is estimated. Although the prognostic score is estimated in this procedure, the variance estimator, which treats the prognostic score as known, has been used. Furthermore, the difference in the asymptotic variance between cases where the prognostic score is known versus where it is estimated has not been previously clarified. In this study, we derived these two asymptotic variances and showed that they are equal. We also constructed two variance estimator: one that treats the prognostic score as known, and another that accounts for its estimation, and compared their performance through simulation studies and data applications. For PROCOVA, since both variance estimators are asymptotically valid, it is generally recommended to use a variance estimator that treats the prognostic score as known, as it is simpler to derive and implement. However, when historical data is small, a variance estimator that explicitly accounts for prognostic score estimation is recommended if conservative inference is preferred.