Inflation of type I error rates due to differential misclassification in EHR‐derived outcomes: Empirical illustration using breast cancer recurrence

PURPOSE: Many outcomes derived from electronic health records (EHR) not only are imperfect but also may suffer from exposure-dependent differential misclassification due to variability in the quality and availability of EHR data across exposure groups. The objective of this study was to quantify the inflation of type I error rates that can result from differential outcome misclassification. METHODS: We used data on gold-standard and EHR-derived second breast cancers in a cohort of women with a prior breast cancer diagnosis from 1993 to 2006 enrolled in Kaiser Permanente Washington. We simulated an exposure that was independent of the true outcome status. A surrogate outcome was then simulated with varying sensitivity and specificity according to exposure status. We estimated the type I error rate for a test of association relating this exposure to the surrogate outcome, while varying outcome sensitivity and specificity in exposed individuals. RESULTS: Type I error rates were substantially inflated above the nominal level (5%) for even modest departures from nondifferential misclassification. Holding sensitivity in exposed and unexposed groups at 85%, a difference in specificity of 10% between the exposed and unexposed (80% vs 90%) resulted in a 36% type I error rate. Type I error was inflated more by differential specificity than sensitivity. CONCLUSIONS: Differential outcome misclassification may induce spurious findings. Researchers using EHR-derived outcomes should use misclassification-adjusted methods whenever possible or conduct sensitivity analyses to investigate the possibility of false-positive findings, especially for exposures that may be related to the accuracy of outcome ascertainment.