Abstract
OBJECTIVES: It has become increasingly common for multiple computable phenotypes from electronic health records (EHR) to be developed for a given phenotype. However, EHR-based association studies often focus on a single phenotype. In this paper, we develop a method aiming to simultaneously make use of multiple EHR-derived phenotypes for reduction of bias due to phenotyping error and improved efficiency of phenotype/exposure associations. MATERIALS AND METHODS: The proposed method combines multiple algorithm-derived phenotypes with a small set of validated outcomes to reduce bias and improve estimation accuracy and efficiency. The performance of our method was evaluated through simulation studies and real-world application to an analysis of colon cancer recurrence using EHR data from Kaiser Permanente Washington. RESULTS: In settings where there was no single surrogate performing uniformly better than all others in terms of both sensitivity and specificity, our method achieved substantial bias reduction compared to using a single algorithm-derived phenotype. Our method also led to higher estimation efficiency by up to 30% compared to an estimator that used only one algorithm-derived phenotype. DISCUSSION: Simulation studies and application to real-world data demonstrated the effectiveness of our method in integrating multiple phenotypes, thereby enhancing bias reduction, statistical accuracy and efficiency. CONCLUSIONS: Our method combines information across multiple surrogates using a statistically efficient seemingly unrelated regression framework. Our method provides a robust alternative to single-surrogate-based bias correction, especially in contexts lacking information on which surrogate is superior.