title: Accounting for center in the Early External Cephalic Version trials: an empirical comparison of statistical methods to adjust for center in a multicenter trial with binary outcomes.
abstract: BACKGROUND
  Clustering of outcomes at centers involved in multicenter trials is a type of center effect. The Consolidated Standards of Reporting Trials Statement recommends that multicenter randomized controlled trials (RCTs) should account for center effects in their analysis, however most do not. The Early External Cephalic Version (EECV) trials published in 2003 and 2011 stratified by center at randomization, but did not account for center in the analyses, and due to the nature of the intervention and number of centers, may have been prone to center effects. Using data from the EECV trials, we undertook an empirical study to compare various statistical approaches to account for center effect while estimating the impact of external cephalic version timing (early or delayed) on the outcomes of cesarean section, preterm birth, and non-cephalic presentation at the time of birth.
  
  
  METHODS
  The data from the EECV pilot trial and the EECV2 trial were merged into one dataset. Fisher's exact method was used to test the overall effect of external cephalic version timing unadjusted for center effects. Seven statistical models that accounted for center effects were applied to the data. The models included: i) the Mantel-Haenszel test, ii) logistic regression with fixed center effect and fixed treatment effect, iii) center-size weighted and iv) un-weighted logistic regression with fixed center effect and fixed treatment-by-center interaction, iv) logistic regression with random center effect and fixed treatment effect, v) logistic regression with random center effect and random treatment-by-center interaction, and vi) generalized estimating equations.
  
  
  RESULTS
  For each of the three outcomes of interest approaches to account for center effect did not alter the overall findings of the trial. The results were similar for the majority of the methods used to adjust for center, illustrating the robustness of the findings.
  
  
  CONCLUSIONS
  Despite literature that suggests center effect can change the estimate of effect in multicenter trials, this empirical study does not show a difference in the outcomes of the EECV trials when accounting for center effect.
  
  
  BACKGROUND
  The EECV2 trial was registered on 30 July 30 2005 with Current Controlled Trials: ISRCTN 56498577.
authors.affiliation: Midwifery Education Program, McMaster University, 1280 Main St, W,, MDCL 2210, Hamilton, ON L8S 4 K1, Canada. reitsmah@mcmaster.ca.
authors.forename: Angela
authors.initials: A
authors.lastname: Reitsma
authors.forename: Rong
authors.initials: R
authors.lastname: Chu
authors.forename: Julia
authors.initials: J
authors.lastname: Thorpe
authors.forename: Sarah
authors.initials: S
authors.lastname: McDonald
authors.forename: Lehana
authors.initials: L
authors.lastname: Thabane
authors.forename: Eileen
authors.initials: E
authors.lastname: Hutton
mesh_terms: D001946:Breech Presentation / Q000175:diagnosis / Q000628:therapy*; D002170:Canada; D002585:Cesarean Section / Q000706:statistics & numerical data; D016000:Cluster Analysis; D003627:Data Interpretation, Statistical; D005260:Female; D006801:Humans; D016015:Logistic Models; D010865:Pilot Projects; D011247:Pregnancy; D047928:Premature Birth / Q000209:etiology; D015203:Reproducibility of Results; D012107:Research Design / Q000706:statistics & numerical data*; D016896:Treatment Outcome; D014710:Version, Fetal / Q000009:adverse effects / Q000706:statistics & numerical data*