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J Am Med Inform Assoc. 2019 Oct 16. pii: ocz180. doi: 10.1093/jamia/ocz180. [Epub ahead of print]

An augmented estimation procedure for EHR-based association studies accounting for differential misclassification.

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Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, The University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Department of Epidemiology, Kaiser Permanente Washington Health Research Institute, Seattle, Washington, USA.
Department of Statistics, School of Mathematical Sciences, Zhejiang University, Hangzhou, Zhejiang, China.



The ability to identify novel risk factors for health outcomes is a key strength of electronic health record (EHR)-based research. However, the validity of such studies is limited by error in EHR-derived phenotypes. The objective of this study was to develop a novel procedure for reducing bias in estimated associations between risk factors and phenotypes in EHR data.


The proposed method combines the strengths of a gold-standard phenotype obtained through manual chart review for a small validation set of patients and an automatically-derived phenotype that is available for all patients but is potentially error-prone (hereafter referred to as the algorithm-derived phenotype). An augmented estimator of associations is obtained by optimally combining these 2 phenotypes. We conducted simulation studies to evaluate the performance of the augmented estimator and conducted an analysis of risk factors for second breast cancer events using data on a cohort from Kaiser Permanente Washington.


The proposed method was shown to reduce bias relative to an estimator using only the algorithm-derived phenotype and reduce variance compared to an estimator using only the validation data.


Our simulation studies and real data application demonstrate that, compared to the estimator using validation data only, the augmented estimator has lower variance (ie, higher statistical efficiency). Compared to the estimator using error-prone EHR-derived phenotypes, the augmented estimator has smaller bias.


The proposed estimator can effectively combine an error-prone phenotype with gold-standard data from a limited chart review in order to improve analyses of risk factors using EHR data.


association study; bias reduction; differential misclassification; electronic health records; error in phenotype


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