Michele Fusaroli, Daniele Sartori, Eugène P van Puijenbroek, G Niklas Norén
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Using VigiBase, the WHO global database of adverse event reports, and the Information Component disproportionality metric, we provide selected examples to highlight common sources of error that can introduce spurious disproportionalities or lead to missing important signals: confounding (by age, sex, indication, comedication), effect modification (by age), notoriety bias, masking, misclassification (by miscoding, incomplete or imprecise event retrieval), neglecting report utility, and violated independence assumption. Additionally, we present how sophisticated analyses may introduce new biases or amplify existing ones, such as collider bias or masking amplification. Due to its pitfalls, disproportionality analysis plays a supportive rather than decisive role in signal detection and assessment. Careful design and interpretation of disproportionality analysis, with appropriate subgrouping and clinical assessment, are essential. While subgrouping can mitigate some pitfalls, it reduces sample size and may introduce or amplify existing biases and needs to be used with care. Further development of tools to detect and mitigate biases in disproportionality analyses, and to assess their risk of bias, is needed.</p>","PeriodicalId":11382,"journal":{"name":"Drug Safety","volume":" ","pages":""},"PeriodicalIF":3.8000,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Charting and Sidestepping the Pitfalls of Disproportionality Analysis.\",\"authors\":\"Michele Fusaroli, Daniele Sartori, Eugène P van Puijenbroek, G Niklas Norén\",\"doi\":\"10.1007/s40264-025-01604-y\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Disproportionality analysis is used by many pharmacovigilance organizations for detecting and assessing signals of potential adverse drug reactions. 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Due to its pitfalls, disproportionality analysis plays a supportive rather than decisive role in signal detection and assessment. Careful design and interpretation of disproportionality analysis, with appropriate subgrouping and clinical assessment, are essential. While subgrouping can mitigate some pitfalls, it reduces sample size and may introduce or amplify existing biases and needs to be used with care. 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Charting and Sidestepping the Pitfalls of Disproportionality Analysis.
Disproportionality analysis is used by many pharmacovigilance organizations for detecting and assessing signals of potential adverse drug reactions. However, its goal is often misunderstood and the approach misapplied, leading to erroneous conclusions due to neglected violated assumptions. In this paper we illustrate how simplistic use and interpretation of disproportionality analysis can lead to incorrect conclusions. Using VigiBase, the WHO global database of adverse event reports, and the Information Component disproportionality metric, we provide selected examples to highlight common sources of error that can introduce spurious disproportionalities or lead to missing important signals: confounding (by age, sex, indication, comedication), effect modification (by age), notoriety bias, masking, misclassification (by miscoding, incomplete or imprecise event retrieval), neglecting report utility, and violated independence assumption. Additionally, we present how sophisticated analyses may introduce new biases or amplify existing ones, such as collider bias or masking amplification. Due to its pitfalls, disproportionality analysis plays a supportive rather than decisive role in signal detection and assessment. Careful design and interpretation of disproportionality analysis, with appropriate subgrouping and clinical assessment, are essential. While subgrouping can mitigate some pitfalls, it reduces sample size and may introduce or amplify existing biases and needs to be used with care. Further development of tools to detect and mitigate biases in disproportionality analyses, and to assess their risk of bias, is needed.
期刊介绍:
Drug Safety is the official journal of the International Society of Pharmacovigilance. The journal includes:
Overviews of contentious or emerging issues.
Comprehensive narrative reviews that provide an authoritative source of information on epidemiology, clinical features, prevention and management of adverse effects of individual drugs and drug classes.
In-depth benefit-risk assessment of adverse effect and efficacy data for a drug in a defined therapeutic area.
Systematic reviews (with or without meta-analyses) that collate empirical evidence to answer a specific research question, using explicit, systematic methods as outlined by the PRISMA statement.
Original research articles reporting the results of well-designed studies in disciplines such as pharmacoepidemiology, pharmacovigilance, pharmacology and toxicology, and pharmacogenomics.
Editorials and commentaries on topical issues.
Additional digital features (including animated abstracts, video abstracts, slide decks, audio slides, instructional videos, infographics, podcasts and animations) can be published with articles; these are designed to increase the visibility, readership and educational value of the journal’s content. In addition, articles published in Drug Safety Drugs may be accompanied by plain language summaries to assist readers who have some knowledge of, but not in-depth expertise in, the area to understand important medical advances.