Systematic Analysis of Adverse Event Reports for Sex Differences in Adverse Drug Events

Abstract

Increasing evidence has shown that sex differences exist in Adverse Drug Events (ADEs). Identifying those sex differences in ADEs could reduce the experience of ADEs for patients and could be conducive to the development of personalized medicine. In this study, we analyzed a normalized US Food and Drug Administration Adverse Event Reporting System (FAERS). Chi-squared test was conducted to discover which treatment regimens or drugs had sex differences in adverse events. Moreover, reporting odds ratio (ROR) and P value were calculated to quantify the signals of sex differences for specific drug-event combinations. Logistic regression was applied to remove the confounding effect from the baseline sex difference of the events. We detected among 668 drugs of the most frequent 20 treatment regimens in the United States, 307 drugs have sex differences in ADEs. In addition, we identified 736 unique drug-event combinations with significant sex differences. After removing the confounding effect from the baseline sex difference of the events, there are 266 combinations remained. Drug labels or previous studies verified some of them while others warrant further investigation.

Figure 1. Heat Map of Sex Differences in drug-event combinations of 20 Treatment Regimens at the System Organ Class Category Level.

Heat map shows positive signals of sex differences. The color of each cell is based on the logarithmic reporting odds ratio (ROR) for occurrence of drug-event combinations in the sex; blue cell represents the log₂ ROR > 0, red cell represents the log₂ ROR < 0; the darker the color, the greater the absolute value of ROR. P values were calculated using a proportion test and were adjusted by Bonferroni correction. Only drug-event combinations with sex differences significant at P ≤ .05 were selected. ADHD indicates attention-deficit/hypersensitivity disorder; incl, including.

Figure 2. Volcano Plot of Significant Adverse Drug Event (ADE) Signals.

In the volcano plot of ADE signals, the signal detection result shows the magnitude (log₂ reporting odds ratio [ROR], x-axis) and significance (−log₁₀ adjusted P value, y-axis) for sex- drug-event combinations associations of specific drugs. Each spot represents a specific drug- drug-event combination interaction. The dashed horizontal green line signals statistical significance threshold (P ≤ 0.05 after adjustment with Bonferroni correction). Two vertical green lines show the threshold of ROR (log₂ ROR > 1 or < −1). The blue spots represent the drug-event combinations more frequently associated with female patients; the red spots, drug-event combinations more frequently associated with male patients.