{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,26]],"date-time":"2026-03-26T05:53:28Z","timestamp":1774504408019,"version":"3.50.1"},"reference-count":37,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2025,1,9]],"date-time":"2025-01-09T00:00:00Z","timestamp":1736380800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100008335","name":"Arizona Biomedical Research Commission","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008335","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Evaluation Clinical Practice"],"published-print":{"date-parts":[[2025,2]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:sec><jats:title>Rationale<\/jats:title><jats:p>Zero\u2010event counts are common in clinical studies, particularly when assessing rare adverse events. These occurrences can result from low event rates, short follow\u2010up periods, and small sample sizes. When both intervention and control groups report zero events in a clinical trial, the study is referred to as a double\u2010zero\u2010event study, which presents methodological challenges for evidence synthesis. There has been ongoing debate about whether these studies should be excluded from evidence synthesis, as traditional two\u2010stage meta\u2010analysis methods may not estimate an effect size for them. Recent research suggests that these studies may still contain valuable clinical and statistical information.<\/jats:p><\/jats:sec><jats:sec><jats:title>Aims and Objectives<\/jats:title><jats:p>This study examines the role of double\u2010zero\u2010event studies from the perspective of the fragility index (FI), a popular metric for assessing the robustness of clinical results. We aim to determine how including or excluding double\u2010zero\u2010event studies affects FI derivations in meta\u2010analyses.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We conducted an illustrative case study to demonstrate how double\u2010zero\u2010event studies can impact FI derivations. Additionally, we performed a large\u2010scale analysis of 12,184 Cochrane meta\u2010analyses involving zero\u2010event studies to assess the prevalence and effect of double\u2010zero\u2010event studies on FI calculations.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Our analysis revealed that FI derivations in 6608 (54.2%) of these meta\u2010analyses involved double\u2010zero\u2010event studies. Excluding double\u2010zero\u2010event studies could lead to artificially inflated FI values, potentially misrepresenting the results as more robust than they are.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>We advocate for retaining double\u2010zero\u2010event studies in meta\u2010analyses and emphasise the importance of carefully considering their role in FI assessments. Including these studies ensures a more accurate evaluation of the robustness of clinical results in evidence synthesis.<\/jats:p><\/jats:sec>","DOI":"10.1111\/jep.14301","type":"journal-article","created":{"date-parts":[[2025,1,9]],"date-time":"2025-01-09T03:07:37Z","timestamp":1736392057000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["The Role of Double\u2010Zero\u2010Event Studies in Evidence Synthesis: Evaluating Robustness Using the Fragility Index"],"prefix":"10.1111","volume":"31","author":[{"given":"Zelin","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Epidemiology and Biostatistics University of Arizona Tucson Arizona USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xing","family":"Xing","sequence":"additional","affiliation":[{"name":"Department of Biostatistics Johns Hopkins Bloomberg School of Public Health Baltimore Maryland 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