title: Adjustment for strong predictors of outcome in traumatic brain injury trials: 25% reduction in sample size requirements in the IMPACT study.
abstract: The aim of this study was to quantify the potential reduction in sample size that can be achieved by adjustment for predictors of outcome in traumatic brain injury (TBI) trials. We used individual patient data from seven therapeutic phase III randomized clinical trials (RCTs; n = 6166) in moderate or severe TBI, and three TBI surveys (n = 2238). The primary outcome was the dichotomized Glasgow Outcome Scale at 6 months (favorable/unfavorable). Baseline predictors of outcome considered were age, motor score, pupillary reactivity, computed tomography (CT) classification, traumatic subarachnoid hemorrhage, hypoxia, hypotension, glycemia, and hemoglobin. We calculated the potential sample size reduction obtained by adjustment of a hypothetical treatment effect for one to seven predictors with logistic regression models. The distribution of predictors was more heterogeneous in surveys than in trials. Adjustment of the treatment effect for the strongest predictors (age, motor score, and pupillary reactivity) yielded a reduction in sample size of 16-23% in RCTs and 28-35% in surveys. Adjustment for seven predictors yielded a reduction of about 25% in most studies: 20-28% in RCTs and 32-39% in surveys. A major reduction in sample size can be obtained with covariate adjustment in TBI trials. Covariate adjustment for strong predictors should be incorporated in the analysis of future TBI trials.
authors.affiliation: Department of Public Health, Erasmus MC-University Medical Center Rotterdam, Rotterdam, The Netherlands.
authors.forename: Adrián V
authors.initials: AV
authors.lastname: Hernández
authors.forename: Ewout W
authors.initials: EW
authors.lastname: Steyerberg
authors.forename: Isabella
authors.initials: I
authors.lastname: Butcher
authors.forename: Nino
authors.initials: N
authors.lastname: Mushkudiani
authors.forename: Gillian S
authors.initials: GS
authors.lastname: Taylor
authors.forename: Gordon D
authors.initials: GD
authors.lastname: Murray
authors.forename: Anthony
authors.initials: A
authors.lastname: Marmarou
authors.forename: Sung C
authors.initials: SC
authors.lastname: Choi
authors.forename: Juan
authors.initials: J
authors.lastname: Lu
authors.forename: J Dik F
authors.initials: JD
authors.lastname: Habbema
authors.forename: Andrew I R
authors.initials: AI
authors.lastname: Maas
mesh_terms: D000367:Age Factors; D001930:Brain Injuries / Q000628:therapy*; D023261:Glasgow Outcome Scale; D006306:Health Surveys; D006801:Humans; D009043:Motor Activity; D017063:Outcome Assessment, Health Care; D016032:Randomized Controlled Trials as Topic; D012025:Reflex, Pupillary; D018401:Sample Size