• Jørn Wetterslev, Kristian Thorlund, Jesper Brok, and Christian Gluud.
• Copenhagen Trial Unit, Centre for Clinical Intervention Research, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, Copenhagen, Denmark. wetterslev@ctu.rh.dk
• J Clin Epidemiol. 2008 Jan 1; 61 (1): 64-75.

Background And ObjectiveCumulative meta-analyses are prone to produce spurious P<0.05 because of repeated testing of significance as trial data accumulate. Information size in a meta-analysis should at least equal the sample size of an adequately powered trial. Trial sequential analysis (TSA) corresponds to group sequential analysis of a single trial and may be applied to meta-analysis to evaluate the evidence.Study Design And SettingSix randomly selected neonatal meta-analyses with at least five trials reporting a binary outcome were examined. Low-bias heterogeneity-adjusted information size and information size determined from an assumed intervention effect of 15% were calculated. These were used for constructing trial sequential monitoring boundaries. We assessed the cumulative z-curves' crossing of P=0.05 and the boundaries.ResultsFive meta-analyses showed early potentially spurious P<0.05 values. In three significant meta-analyses the cumulative z-curves crossed both boundaries, establishing firm evidence of an intervention effect. In two nonsignificant meta-analyses the cumulative z-curves crossed P=0.05, but never the boundaries, demonstrating early potentially spurious P<0.05 values. In one nonsignificant meta-analysis the cumulative z-curves never crossed P=0.05 or the boundaries.ConclusionTSAs may establish when firm evidence is reached in meta-analysis.

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