{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T18:04:56Z","timestamp":1792173896435,"version":"4.4.0"},"reference-count":30,"publisher":"National Academy of Sciences","issue":"3","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2001,1,30]]},"abstract":"<jats:p>\n                    Evidence on how much medical interventions work may change\n over time. It is important to determine what fluctuations in the\n treatment effect reported by randomized trials and their metaanalyses\n may be expected and whether extreme fluctuations signal future major\n changes. We applied recursive cumulative metaanalysis of randomized\n controlled trials to evaluate the relative change in the pooled\n treatment effect (odds ratio) over time for 60 interventions in two\n medical fields (pregnancy\/perinatal medicine,\n                    <jats:italic>n<\/jats:italic>\n                    =\n 45 interventions; myocardial infarction,\n                    <jats:italic>n<\/jats:italic>\n                    = 15\n interventions). We evaluated the scatter of relative changes for\n different numbers of total patients in previous trials. Outlier cases\n were noted with changes greater than 2.5 standard deviations of the\n expected. With 500 accumulated patients, the pooled odds ratio may\n change by 0.6- to 1.7-fold in the immediate future. When 2000 patients\n have already been randomized, the respective figures are between 0.74-\n and 1.35-fold for pregnancy\/perinatal medicine and between 0.83- and\n 1.21-fold for myocardial infarction studies. Extreme early fluctuations\n in the treatment effect were observed in three interventions (magnesium\n in myocardial infarction, calcium and antiplatelet agents for\n prevention of preeclampsia), where recent mega-trials have contradicted\n prior metaanalyses, as well as in four other examples where early large\n treatment effects were dissipated when more data appeared. Past\n experience may help quantify the uncertainty surrounding the treatment\n effects reported in early clinical trials and their metaanalyses. Early\n wide oscillations in the evolution of the treatment effect for specific\n interventions may sometimes signal further major changes in the future.\n                  <\/jats:p>","DOI":"10.1073\/pnas.98.3.831","type":"journal-article","created":{"date-parts":[[2012,7,26]],"date-time":"2012-07-26T19:06:14Z","timestamp":1343329574000},"page":"831-836","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":158,"title":["Evolution of treatment effects over time: Empirical insight from recursive cumulative metaanalyses"],"prefix":"10.1073","volume":"98","author":[{"given":"John P. A.","family":"Ioannidis","sequence":"first","affiliation":[{"name":"Division of Clinical Care Research, New England Medical Center,\r Tufts University School of Medicine, Boston, MA 02111; and\r Clinical Trials and Evidence-Based Medicine Unit,\r Department of Hygiene and Epidemiology, University of Ioannina School\r of Medicine, Ioannina, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph","family":"Lau","sequence":"additional","affiliation":[{"name":"Division of Clinical Care Research, New England Medical Center,\r Tufts University School of Medicine, Boston, MA 02111; and\r Clinical Trials and Evidence-Based Medicine Unit,\r Department of Hygiene and Epidemiology, University of Ioannina School\r of Medicine, Ioannina, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2001,1,23]]},"reference":[{"key":"e_1_3_2_1_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.pu.17.050196.000245"},{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1097-0258(19960630)15:12<1263::AID-SIM305>3.0.CO;2-K"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.315.7109.617"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/0895-4356(94)00106-Z"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.1996.03540160054033"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199708213370806"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.7326\/0003-4819-123-11-199512010-00010"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.279.14.1089"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(95)90865-X"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(94)92633-6"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199707103370201"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199207233270406"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0895-4356(98)00159-0"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1097-0258(19980915)17:17<1923::AID-SIM874>3.0.CO;2-6"},{"key":"e_1_3_2_15_2","volume-title":"The Cochrane Collaboration Pregnancy and Childbirth Database","author":"Enkin M W","year":"1994","unstructured":", eds M W Enkin, M J Keirse, M J Renfrew, J P Neilson (Update Software, Oxford The Cochrane Collaboration Pregnancy and Childbirth Database, , Disk issue 2. 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