1. Trial sequential boundary (TSB) Cumulated Z-curve Traditional P=0.05 criteria Z-value ( II) Antibiotics for Necrotizing EnteroColitis in newborns (5 trials with 456 patients) Spurious TSB (and P<0.05) value (n=3) Cross line of P=0.05 Number of patients included in meta-analyses OIS Number of patients included in meta-analyses Z-value (I) High vs. low umbilical catheters in newborns (5 trials with 1569 patients) Cross line of P = 0.05 Cross line of TSB Potential spurious P<0.05 value (n=1) OIS Z-value ( III) Immunglobulin for infection in preterm infants (6 trials with 318 patients) Number of patients included in meta-analyses Spurious P<0.05 values (n=4 & 5) Cross line of P=0.05 OIS = 634 Number of patients included in meta-analyses ( VI) Nitric oxide for newborn infants (6 trials with 753 patients) Z-value OIS reached within one trial OIS Number of patients included in meta-analyses Z-value (V) Surfactant for preterm infants (8 trials with 988 patients) Cross line of P=0.05 OIS reached within three trials OIS Z-value Number of patients included in meta-analyses Z-curve does not cross either TSB or P=0.05 OIS>2.000.000 (IV) Vitamin E supplementation for preterm infants (10 trials with 1732 patients) TRIAL SEQUENTIAL ANALYSES OF SIX COCHRANE NEONATAL GROUP META-ANALYSES CONSIDERING ADEQUACY OF ALLOCATION CONCEALMENT Jesper Brok, Kristian Thorlund, Jørn Wetterslev, and Christian Gluud Copenhagen Trial Unit, Centre for Clinical Research, H:S Rigshospitalet, Denmark. E-mail: jbrok@ctu.rh.dk 1. Background Meta-analyses are rarely analysed with trial sequential boundaries (TSB). TSB require calculation of optimal information size (OIS) to determine when strong evidence is reached. 1 Allocation concealment of randomized clinical trials (RCT) are categorised as adequate or inadequate when included in meta-analyses in Cochrane reviews. RCTs with inadequate allocation concealment may overestimate intervention effects. 2 Two Z-curves crossed Z=1.96 temporarily but returned to non-significant values (II, III). One of these Z-curves also crossed TSB (II). One Z-curve never crossed Z=1.96 or TSB (IV). 6. Conclusions Three meta-analyses with P<0.05 were supported by Z- curves crossing the TSB. However, one meta-analysis showing temporary P<0.05 never crossed the TSB. Accordingly, trials sequential analyses based on trials with adequate allocation concealment may reduce the risk of type I error without increasing the risk of type 2 error. 2. Objectives To examine meta-analyses for spurious (unreliable) P<0.05 values with Lan-DeMets discrete sequential boundaries based on OIS, calculated from empirical intervention effect of trials with adequate allocation concealment. 3. Material We randomly selected six meta-analyses with at least five trials reporting a binary primary outcome from the 170 systematic Cochrane Neonatal reviews. 4. Methods Relations between the cumulated Z-curve, each cumulative Z-value determined by fixed or random effects model, the traditional criterion Z=1.96, and the TSB were analyzed using OIS. OIS was calculated based on intervention effect from trials with adequate allocation concealment. 5. Results Three meta-analyses presented firm evidence for a beneficial intervention effect as the cumulated Z-curve crossed both Z=1.96 and TSB during the first trials (I,V,VI). 1 : Pogue JM. CCT 1997;18:580-93. 2: Kjeargaard LL. Ann Intern Med. 2001;135(11):982-9.