Trial sequential analysis may establish when firm evidence is reached in cumulative meta-analysis.
OBJECTIVE
Cumulative 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.


METHODS
Six 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.


RESULTS
Five 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.


CONCLUSIONS
TSAs may establish when firm evidence is reached in meta-analysis.
Wetterslev
Jørn
J
Copenhagen Trial Unit, Centre for Clinical Intervention Research, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, Copenhagen, Denmark. wetterslev@ctu.rh.dk
Thorlund
Kristian
K
Brok
Jesper
J
Gluud
Christian
C
D003627:Data Interpretation, Statistical; D019317:Evidence-Based Medicine; D006801:Humans; D007224:Infant Care / Q000379:methods; D007231:Infant, Newborn; D007232:Infant, Newborn, Diseases / Q000628:therapy; D015201:Meta-Analysis as Topic; D016032:Randomized Controlled Trials as Topic / Q000379:methods*; D018401:Sample Size