title: Continuous covariate imbalance and conditional power for clinical trial interim analyses.
abstract: Oftentimes valid statistical analyses for clinical trials involve adjustment for known influential covariates, regardless of imbalance observed in these covariates at baseline across treatment groups. Thus, it must be the case that valid interim analyses also properly adjust for these covariates. There are situations, however, in which covariate adjustment is not possible, not planned, or simply carries less merit as it makes inferences less generalizable and less intuitive. In this case, covariate imbalance between treatment groups can have a substantial effect on both interim and final primary outcome analyses. This paper illustrates the effect of influential continuous baseline covariate imbalance on unadjusted conditional power (CP), and thus, on trial decisions based on futility stopping bounds. The robustness of the relationship is illustrated for normal, skewed, and bimodal continuous baseline covariates that are related to a normally distributed primary outcome. Results suggest that unadjusted CP calculations in the presence of influential covariate imbalance require careful interpretation and evaluation.
authors.affiliation: Department of Preventive Medicine, Northwestern University, Chicago, IL, USA. Electronic address: jody.ciolino@northwestern.edu.
authors.forename: Jody D
authors.initials: JD
authors.lastname: Ciolino
authors.affiliation: Medical University of South Carolina, Charleston, SC, USA.
authors.forename: Renee' H
authors.initials: RH
authors.lastname: Martin
authors.affiliation: Medical University of South Carolina, Charleston, SC, USA.
authors.forename: Wenle
authors.initials: W
authors.lastname: Zhao
authors.affiliation: Medical University of South Carolina, Charleston, SC, USA.
authors.forename: Edward C
authors.initials: EC
authors.lastname: Jauch
authors.affiliation: University of Calgary, AB, Canada.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Hill
authors.affiliation: Medical University of South Carolina, Charleston, SC, USA.
authors.forename: Yuko Y
authors.initials: YY
authors.lastname: Palesch
mesh_terms: D002986:Clinical Trials as Topic / Q000379:methods*; D003198:Computer Simulation; D003627:Data Interpretation, Statistical; D006801:Humans; D012107:Research Design
keywords: Conditional power; Covariate adjusted analysis; Covariate imbalance