title: Between-centre differences and treatment effects in randomized controlled trials: a case study in traumatic brain injury.
abstract: BACKGROUND
  In Traumatic Brain Injury (TBI), large between-centre differences in outcome exist and many clinicians believe that such differences influence estimation of the treatment effect in randomized controlled trial (RCTs). The aim of this study was to assess the influence of between-centre differences in outcome on the estimated treatment effect in a large RCT in TBI.
  
  
  METHODS
  We used data from the MRC CRASH trial on the efficacy of corticosteroid infusion in patients with TBI. We analyzed the effect of the treatment on 14 day mortality with fixed effect logistic regression. Next we used random effects logistic regression with a random intercept to estimate the treatment effect taking into account between-centre differences in outcome. Between-centre differences in outcome were expressed with a 95% range of odds ratios (OR) for centres compared to the average, based on the variance of the random effects (tau2). A random effects logistic regression model with random slopes was used to allow the treatment effect to vary by centre. The variation in treatment effect between the centres was expressed in a 95% range of the estimated treatment ORs.
  
  
  RESULTS
  In 9978 patients from 237 centres, 14-day mortality was 19.5%. Mortality was higher in the treatment group (OR = 1.22, p = 0.00010). Using a random effects model showed large between-centre differences in outcome (95% range of centre effects: 0.27- 3.71), but did not substantially change the estimated treatment effect (OR = 1.24, p = 0.00003). There was limited, although statistically significant, between-centre variation in the treatment effect (OR = 1.22, 95% treatment OR range: 1.17-1.26).
  
  
  CONCLUSIONS
  Large between-centre differences in outcome do not necessarily affect the estimated treatment effect in RCTs, in contrast to current beliefs in the clinical area of TBI.
authors.affiliation: Department of Public Health, Erasmus MC, P,O, Box 2040, 3000 CA Rotterdam, the Netherlands. h.lingsma@erasmusmc.nl
authors.forename: Hester F
authors.initials: HF
authors.lastname: Lingsma
authors.forename: Bob
authors.initials: B
authors.lastname: Roozenbeek
authors.forename: Pablo
authors.initials: P
authors.lastname: Perel
authors.forename: Ian
authors.initials: I
authors.lastname: Roberts
authors.forename: Andrew I R
authors.initials: AI
authors.lastname: Maas
authors.forename: Ewout W
authors.initials: EW
authors.lastname: Steyerberg
mesh_terms: D000305:Adrenal Cortex Hormones / Q000008:administration & dosage* / Q000009:adverse effects; D000328:Adult; D001930:Brain Injuries / Q000175:diagnosis / Q000188:drug therapy* / Q000401:mortality; D019317:Evidence-Based Medicine; D005260:Female; D017052:Hospital Mortality; D006801:Humans; D016015:Logistic Models; D008297:Male; D008775:Methylprednisolone / Q000008:administration & dosage* / Q000009:adverse effects; D008875:Middle Aged; D016017:Odds Ratio; D015203:Reproducibility of Results; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000305:Adrenal Cortex Hormones; D008775:Methylprednisolone