Extrapolation before imputation reduces bias when imputing censored covariates

TL;DR

This paper introduces a hybrid extrapolation-imputation method that reduces bias in censored covariate imputation, especially under heavy censoring, by extending survival function estimates beyond observed data.

Contribution

It proposes a novel hybrid approach combining semiparametric and parametric models to improve the accuracy of imputing censored covariates in clinical trial data.

Findings

Significantly reduces bias in censored covariate imputation.

Effective even with misspecified parametric extensions.

Enhances patient prioritization for clinical trials.

Abstract

Modeling symptom progression to identify informative subjects for a new Huntington's disease clinical trial is problematic since time to diagnosis, a key covariate, can be heavily censored. Imputation is an appealing strategy where censored covariates are replaced with their conditional means, but existing methods saw over 200% bias under heavy censoring. Calculating these conditional means well requires estimating and then integrating over the survival function of the censored covariate from the censored value to infinity. To estimate the survival function flexibly, existing methods use the semiparametric Cox model with Breslow's estimator, leaving the integrand for the conditional means (the estimated survival function) undefined beyond the observed data. The integral is then estimated up to the largest observed covariate value, and this approximation can cut off the tail of the survival function and lead to severe bias, particularly under heavy censoring. We propose a hybrid approach that splices together the semiparametric survival estimator with a parametric extension, making it possible to approximate the integral up to infinity. In simulation studies, our proposed approach of extrapolation then imputation substantially reduces the bias seen with existing imputation methods, even when the parametric extension was misspecified. We further demonstrate how imputing with corrected conditional means helps to prioritize patients for future clinical trials.