Data Mining for Adverse Events of Tumor Necrosis Factor-Alpha Inhibitors in Pediatric Patients: Tree-Based Scan Statisti
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ORIGINAL RESEARCH ARTICLE
Data Mining for Adverse Events of Tumor Necrosis Factor‑Alpha Inhibitors in Pediatric Patients: Tree‑Based Scan Statistic Analyses of Danish Nationwide Health Data Viktor Wintzell1 · Henrik Svanström1,2 · Mads Melbye2,3,4 · Jonas F. Ludvigsson5,6,7,8 · Björn Pasternak1,2 · Martin Kulldorff9 Accepted: 7 October 2020 © The Author(s) 2020
Abstract Background and Objectives Tumor necrosis factor-alpha (TNF-α) inhibitors are efficacious and considered generally safe in adults. However, pediatric-specific safety evidence is scarce. The aim of this study was to screen for signals of previously unknown adverse events of TNF-α inhibitors in pediatric patients. Methods We conducted a data-mining study based on routinely collected, nationwide Danish healthcare data for 2004–2016. Using tree-based scan statistics to identify events with unexpectedly high incidence during TNF-α inhibitor use among patients with inflammatory bowel disease or juvenile idiopathic arthritis, two analyses were performed: comparison with episodes of no use and with other time periods from the same patient. Based on incident physician-assigned diagnosis codes from outpatient and inpatient visits in specialist care, we screened thousands of potential adverse events while adjusting for multiple testing. Results We identified 1310 episodes of new TNF-α inhibitor use that met the eligibility criteria. Two signals of adverse events of TNF-α inhibitors, as compared with no use, were detected. First, there were excess events of dermatologic complications (ICD-10: L00-L99, 87 vs. 44 events, risk difference [RD] 3.3%), which have been described previously in adults and children. Second, there were excess events of psychiatric diagnosis adjustment disorders (ICD-10: F432, 33 vs. 7 events, RD 2.0%), which was likely associated with the underlying disease and its severity, rather than with the treatment. The selfcontrolled analysis generated no signal. Conclusions No signals of previously unknown adverse events of TNF-α inhibitors in pediatric patients were detected. The study showed that real-world data and newly developed methods for adverse events data mining can play a particularly important role in pediatrics where pre-approval drug safety data are scarce. Key Points Based on screening of thousands of diagnoses from nationwide Danish health registers, we identified no signals of previously unknown adverse events of TNF-α inhibitors in pediatric patients. Surveillance of adverse events from routinely collected real-world data can complement other analyses in generating pediatric-specific drug-safety evidence. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s40261-020-00977-5) contains supplementary material, which is available to authorized users. * Viktor Wintzell [email protected] Extended author information available on the last page of the article
1 Introduction Tumor necrosis factor-alpha (TNF-α) inhibitors have revolutionized the treatment of chronic inflammatory d
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