2F-04 - Tree-based Scan Statistics to Evaluate Drug Safety in Pediatric Populations: Sulfamethoxazole/trimethoprim as a Positive Test Case

Background: Clinicians treating pediatric patients commonly rely on evidence generated in adults. However, the safety profile of medications may differ for children. Tree-based scan statistic (TBSS) approaches can be used to identify safety issues by systematically screening thousands of potential adverse outcomes while controlling type 1 error, but their performance in pediatric populations has not been evaluated.

Objectives: We aimed to assess whether TBSS can identify rare, serious adverse effects, using Stevens-Johnson Syndrome (SJS) as a test case, and to describe the pattern of observed alerts.

Methods: Using U.S.-nationwide cohorts nested in the Medicaid (2008-2018) and MarketScan (2008-2021) databases, we compared children who initiated sulfamethoxazole/trimethoprim (SMX-TMP) to those initiating cephalexin and clindamycin, respectively. The outcome tree was based on hierarchical groupings of diagnostic codes in the International Classification of Disease system. Incident outcomes were identified in the 30 days after treatment initiation, using a 90-day washout. A permutation algorithm was used to approximate the global null distribution of the TBSS statistic, accounting for node-specific washout and controlling for type 1 error. We adjusted for potential confounders using propensity score overlap weights. A p-value threshold of 0.05 was used to define statistical alerts for potential safety signals.

Results: There were 2,939,183 children exposed to SMX-TMP, 3,908,066 to cephalexin, and 755,945 to clindamycin. Comparing SMX-TMP to cephalexin, 278 statistical alerts were detected out of 8,517 outcomes screened. Among these, 91 (33%) alerts were plausible events previously recognized as adverse effects of SMX-TMP (relative risk [RR] ranges: 1.04-62.43); the remainder being unlikely consequences of antibiotic use (e.g., infections or chronic illnesses; RR ranges: 1.03-17.23). Compared to clindamycin, 144 alerts were identified, 60 (42%) of which were known effects (RR ranges: 1.06-35.79) and the rest unlikely events due to exposure (RR ranges: 1.08-5.89). The known alerts for SMX-TMP exposed children were similar for both comparisons and included poisoning by sulfonamides, drug dermatitis, and drug-induced neutropenia. Increased risks for SJS among SMX-TMP users were found in both comparisons (p < 0.05; 194 SMX-TMP exposed cases), with RRs of 3.71 vs cephalexin and of 2.57 vs clindamycin.

Conclusions: TBSS identified the known risk of SJS, a rare but serious condition associated with SMX-TMP, in addition to detecting other known adverse reactions. Our findings support the feasibility of this signal detection approach in pediatric populations.