Algorithms Outperform Metabolite Tests in Predicting Response of Patients With Inflammatory Bowel Disease to Thiopurines

Abstract

Levels of the thiopurine metabolites 6-thioguanine nucleotide (6-TGN) and 6-methylmercaptopurine commonly are monitored during thiopurine therapy for inflammatory bowel disease despite this test's high cost and poor prediction of clinical response (sensitivity, 62%; specificity, 72%). We investigated whether patterns in common laboratory parameters might be used to identify appropriate immunologic responses to thiopurine and whether they are more accurate than measurements of thiopurine metabolites in identifying patients who respond to therapy. We identified 774 patients with inflammatory bowel disease on thiopurine therapy using metabolite and standard laboratory tests over a 24-hour time period. Machine learning algorithms were developed using laboratory values and age in a random training set of 70% of the cases; these algorithms were tested in the remaining 30% of the cases. A random forest algorithm was developed based on laboratory and age data; it differentiated clinical responders from nonresponders in the test set with an area under the receiver operating characteristic (AUROC) curve of 0.856. In contrast, 6-TGN levels differentiated clinical responders from nonresponders with an AUROC of 0.594 (P < .001). Algorithms developed to identify thiopurine nonadherence (AUROC, 0.813) and thiopurine shunters (AUROC, 0.797) were accurate. Algorithms that use age and laboratory values can differentiate clinical response, nonadherence, and shunting of thiopurine metabolism among patients who take thiopurines. This approach was less costly and more accurate than 6-TGN metabolite measurements in predicting clinical response. If validated, this approach would provide a low-cost, rapid alternative to metabolite measurements for monitoring thiopurine use.