title: Trial sequential analysis reveals insufficient information size and potentially false positive results in many meta-analyses.
abstract: OBJECTIVE
  To evaluate meta-analyses with trial sequential analysis (TSA). TSA adjusts for random error risk and provides the required number of participants (information size) in a meta-analysis. Meta-analyses not reaching information size are analyzed with trial sequential monitoring boundaries analogous to interim monitoring boundaries in a single trial.
  
  
  METHODS
  We applied TSA on meta-analyses performed in Cochrane Neonatal reviews. We calculated information sizes and monitoring boundaries with three different anticipated intervention effects of 30% relative risk reduction (TSA(30%)), 15% (TSA(15%)), or a risk reduction suggested by low-bias risk trials of the meta-analysis corrected for heterogeneity (TSA(LBHIS)).
  
  
  RESULTS
  A total of 174 meta-analyses were eligible; 79 out of 174 (45%) meta-analyses were statistically significant (P<0.05). In the significant meta-analyses, TSA(30%) showed firm evidence in 61%. TSA(15%) and TSA(LBHIS) found firm evidence in 33% and 73%, respectively. The remaining significant meta-analyses had potentially spurious evidence of effect. In the 95 statistically nonsignificant (P>or=0.05) meta-analyses, TSA(30%) showed absence of evidence in 80% (insufficient information size). TSA(15%) and TSA(LBHIS) found that 95% and 91% had absence of evidence. The remaining nonsignificant meta-analyses had evidence of lack of effect.
  
  
  CONCLUSIONS
  TSA reveals insufficient information size and potentially false positive results in many meta-analyses.
authors.affiliation: Copenhagen Trial Unit, Centre for Clinical Intervention Research, The Cochrane Hepato-Biliary Group, Dept. 3344, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, DK-2100 Copenhagen, Denmark. jbrok@ctu.rh.dk
authors.forename: Jesper
authors.initials: J
authors.lastname: Brok
authors.forename: Kristian
authors.initials: K
authors.lastname: Thorlund
authors.forename: Christian
authors.initials: C
authors.lastname: Gluud
authors.forename: Jørn
authors.initials: J
authors.lastname: Wetterslev
mesh_terms: D003627:Data Interpretation, Statistical; D005189:False Positive Reactions; D006801:Humans; D007231:Infant, Newborn; D015201:Meta-Analysis as Topic; D016032:Randomized Controlled Trials as Topic; D012107:Research Design / Q000592:standards*; D012196:Review Literature as Topic; D018401:Sample Size