Medication-wide association studies

Abstract

Undiscovered side effects of drugs can have a profound effect on the health of the nation, and electronic health-care databases offer opportunities to speed up the discovery of these side effects. We applied a "medication-wide association study" approach that combined multivariate analysis with exploratory visualization to study four health outcomes of interest in an administrative claims database of 46 million patients and a clinical database of 11 million patients. The technique had good predictive value, but there was no threshold high enough to eliminate false-positive findings. The visualization not only highlighted the class effects that strengthened the review of specific products but also underscored the challenges in confounding. These findings suggest that observational databases are useful for identifying potential associations that warrant further consideration but are unlikely to provide definitive evidence of causal effects.

Figure 1

Medication-wide association study (MWAS) analyses in Commercial Claims and Encounters (CCAE) database for (a) acute myocardial infarction, (b) acute liver injury, (c) acute kidney injury, and (d) upper gastrointestinal bleeding. Y-axis displays P values on the negative log scale. X-axis displays all the drugs studied for a given outcome, grouped by the Anatomical Therapeutic Chemical classification system. OMOP, Observational Medical Outcomes Partnership.

Figure 2

P-value plots for negative controls, trellised by outcome. Y-axis lists the P value for each drug–outcome pair and X-axis shows the percentile of the negative control drugs which have a P value at or below that P value. The black dashed line indicates the 45° line, which should approximate the P-value curves if the statistical tests were independent and unbiased. CCAE, Commercial Claims and Encounters; OMOP, Observational Medical Outcomes Partnership.

Figure 3

Comparison between Commercial Claims and Encounters (CCAE) and GE databases of medication-wide association study (MWAS) analyses for acute myocardial infarction. Y-axis displays P values on the negative log scale. X-axis displays all the drugs studied for a given outcome, grouped by the Anatomical Therapeutic Chemical classification system. OMOP, Observational Medical Outcomes Partnership.