Abstract
BackgroundWe wished to compare the nuisance parameters of pediatric vs. adult randomized-trials (RCTs) and determine if the latter can be used in sample size computations of the former.MethodsIn this meta-epidemiologic empirical evaluation we examined meta-analyses from the Cochrane Database of Systematic-Reviews, with at least one pediatric-RCT and at least one adult-RCT. Within each meta-analysis of binary efficacy-outcomes, we calculated the pooled-control-group event-rate (CER) across separately all pediatric and adult-trials, using random-effect models and subsequently calculated the control-group event-rate risk-ratio (CER-RR) of the pooled-pediatric-CERs vs. adult-CERs. Within each meta-analysis with continuous outcomes we calculated the pooled-control-group effect standard deviation (CE-SD) across separately all pediatric and adult-trials and subsequently calculated the CE-SD-ratio of the pooled-pediatric-CE-SDs vs. adult-CE-SDs. We then calculated across all meta-analyses the pooled-CER-RRs and pooled-CE-SD-ratios (primary endpoints) and the pooled-magnitude of effect-sizes of CER-RRs and CE-SD-ratios using REMs. A ratio < 1 indicates that pediatric trials have smaller nuisance parameters than adult trials.ResultsWe analyzed 208 meta-analyses (135 for binary-outcomes, 73 for continuous-outcomes). For binary outcomes, pediatric-RCTs had on average 10% smaller CERs than adult-RCTs (summary-CE-RR: 0.90; 95% CI: 0.83, 0.98). For mortality outcomes the summary-CE-RR was 0.48 (95% CIs: 0.31, 0.74). For continuous outcomes, pediatric-RCTs had on average 26% smaller CE-SDs than adult-RCTs (summary-CE-SD-ratio: 0.74).ConclusionsClinically relevant differences in nuisance parameters between pediatric and adult trials were detected. These differences have implications for design of future studies. Extrapolation of nuisance parameters for sample-sizes calculations from adult-trials to pediatric-trials should be cautiously done.
Highlights
We wished to compare the nuisance parameters of pediatric vs. adult randomized-trials (RCTs) and determine if the latter can be used in sample size computations of the former
Selection of meta-analyses We addressed the above questions by examining 106 systematic reviews from the Cochrane Database of Systematic Reviews (CDSR) (Issue 1, 2007), that have been previously analyzed [9] in an empirical evaluation of the comparative effectiveness of medical interventions in children versus adults
All meta-analyses comprised a total of 2110 Randomized control trial (RCT); 1515 adult RCTs (1126 with binary and 389 with continuous outcomes) and 595 pediatric RCTs (355 with binary and 240 with continuous outcomes)
Summary
We wished to compare the nuisance parameters of pediatric vs. adult randomized-trials (RCTs) and determine if the latter can be used in sample size computations of the former. The investigators have to estimate parameters that are not of direct interest, but Determining an appropriate sample size for an RCT has always been a challenge due to these nuisance parameters being unknown and needing to be estimated [1, 2]. They can only be estimated from previous studies on the same topic, but there is always a problem when the new study is the first trial on the topic. A systematic empirical evaluation of nuisance parameters in pediatric RCTs, as compared to adult RCTs has not been previously performed
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