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Fig. 1 | BMC Medical Research Methodology

Fig. 1

From: Trial Sequential Analysis in systematic reviews with meta-analysis

Fig. 1

a Showing Trial Sequential Analysis of meta-analysis before the Target Temperature Management Trial. The Z-value is the test statistic and |Z| = 1.96 corresponds to a P = 0.05; the higher the Z-value, the lower the P-value. Trial Sequential Analysis (TSA) of mortality after out of hospital cardiac arrest patients, randomised to cooling to 33°–34 °C versus 36 °C or no temperature control in four trials performed before the Target Temperature Management (TTM) trial [16, 20]. The required information size to detect or reject the 17% relative risk reduction found in the random-effects model meta-analysis is calculated to 977 participants using the diversity found in the meta-analysis of 23%, mortality in the control groups of 60%, with a double sided α of 0.05 and a β of 0.20 (power of 80.0%). The cumulative Z-curve (black full line with quadratic indicatons of each trial) surpasses the traditional boundary for statistical significance during the third trial and touches the traditional boundary after the fourth trial (95% confidence interval: 0.70 to 1.00; P = 0.05). However, none of the trial sequential monitoring boundaries (etched curves above and below the traditional horizontal lines for statistical significance) have been surpassed in the TSA. Therefore, the result is inconclusive when adjusted for sequential testing on an accumulating number of participants and the fact that the required information size has not yet been achieved. The TSA-adjusted confidence interval is 0.63 to 1.12 after inclusion of the fourth trial [10, 12]. b showing Trial Sequential Analysis of meta-analysis after the Target Temperature Management Trial. The Z-value is the test statistic and |Z| = 1.96 corresponds to a P = 0.05; the higher the Z-value, the lower the P-value. Trial Sequential Analysis (TSA) of mortality after out of hospital cardiac arrest patients, randomised to cooling to 33°–34 °C versus 36 °C or no temperature control in five trials after inclusion of the Target Temperature Management (TTM) Trial [17]. The required information size to detect or reject the 17% relative risk reduction found in the random-effects model meta-analysis prior to the TTM Trial is calculated to 2040 participants using the diversity found in the meta-analysis of 65%, mortality in the control groups of 60%, with a double sided α of 0.05 and a β of 0.20 (power of 80.0%). The cumulative Z-curve (black full line with quadratic indicatons of each trial) touches the boundary for futility indicating that it will be unlikely to reach a statistical significant P < 0.05, even if we proceed to include trials randomising patients until the required information size of 2040 is reached. The result indicates that a 17% relative risk reduction (or more) may be excluded, even though the required information size has not been achieved, adjusting for sparse data and sequential testing on an accumulating number of patients [10, 12]

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