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In this paper, we systematically evaluated different statistical methods of accounting for center in settings with low outcome event proportions.<\/jats:p>\n<\/jats:sec>\n<jats:sec>\n<jats:title>Methods<\/jats:title>\n<jats:p>We conducted a simulation study and a reanalysis of a completed RCT to compare five popular methods of estimating an odds ratio for multicenter trials with stratified randomization by center: (i) no center adjustment, (ii) random intercept model, (iii) Mantel\u2013Haenszel model, (iv) generalized estimating equation (GEE) with an exchangeable correlation structure, and (v) GEE with small sample correction (GEE-small sample correction). We varied the number of total participants (200, 500, 1000, 5000), number of centers (5, 50, 100), control group outcome percentage (2%, 5%, 10%), true odds ratio (1, &gt;\u20091), intra-class correlation coefficient (ICC) (0.025, 0.075), and distribution of participants across the centers (balanced, skewed).<\/jats:p>\n<\/jats:sec>\n<jats:sec>\n<jats:title>Results<\/jats:title>\n<jats:p>Mantel\u2013Haenszel methods generally performed poorly in terms of power and bias and led to the exclusion of participants from the analysis because some centers had no events. Failure to account for center in the analysis generally led to lower power and type I error rates than other methods, particularly with ICC\u2009=\u20090.075. GEE had an inflated type I error rate except in some settings with a large number of centers. GEE-small sample correction maintained the type I error rate at the nominal level but suffered from reduced power and convergence issues in some settings when the number of centers was small. Random intercept models generally performed well in most scenarios, except with a low event rate (i.e., 2% scenario) and small total sample size (<jats:italic>n<\/jats:italic>\u2009\u2264\u2009500), when all methods had issues.<\/jats:p>\n<\/jats:sec>\n<jats:sec>\n<jats:title>Discussion<\/jats:title>\n<jats:p>Random intercept models generally performed best across most scenarios. GEE-small sample correction performed well when the number of centers was large. We do not recommend the use of Mantel\u2013Haenszel, GEE, or models that do not account for center. When the expected event rate is low, we suggest that the statistical analysis plan specify an alternative method in the case of non-convergence of the primary method.<\/jats:p>\n<\/jats:sec>","DOI":"10.1186\/s13063-020-04801-5","type":"journal-article","created":{"date-parts":[[2020,11,9]],"date-time":"2020-11-09T23:02:36Z","timestamp":1604962956000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Analysis of multicenter clinical trials with very low event rates"],"prefix":"10.1186","volume":"21","author":[{"given":"Jiyu","family":"Kim","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea B.","family":"Troxel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott D.","family":"Halpern","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin G.","family":"Volpp","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brennan C.","family":"Kahan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tim P.","family":"Morris","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0553-674X","authenticated-orcid":false,"given":"Michael O.","family":"Harhay","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,11,9]]},"reference":[{"issue":"4","key":"4801_CR1","doi-asserted-by":"publisher","first-page":"385","DOI":"10.1002\/(SICI)1521-4036(199808)40:4<385::AID-BIMJ385>3.0.CO;2-#","volume":"40","author":"M Parzen","year":"1998","unstructured":"Parzen M, Lipsitz SR, Dear KB. 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