The impact of covariate adjustment at randomization and analysis for binary outcomes: Understanding differences between superiority and noninferioritytrials

Katherine Nicholas*, Sharon D. Yeatts, Wenle Zhao, Jody Ciolino, Keith Borg, Valerie Durkalski

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

The question of when to adjust for important prognostic covariates often arises in the design of clinical trials, and there remain various opinions on whether to adjust during both randomization and analysis, at randomization alone, or at analysis alone. Furthermore, little is known about the impact of covariate adjustment in the context of noninferiority (NI) designs. The current simulation-based research explores this issue in the NI setting, as compared with the typical superiority setting, by assessing the differential impact on power, type I error, and bias in the treatment estimate as well as its standard error, in the context of logistic regression under both simple and covariate adjusted permuted block randomization algorithms.In both the superiority and NI settings, failure to adjust for covariates that influence outcome in the analysis phase, regardless of prior adjustment at randomization, results in treatment estimates that are biased toward zero, with standard errors that are deflated. However, as no treatment difference is approached under the null hypothesis in superiority and under the alternative in NI, this results in decreased power and nominal or conservative (deflated) type I error in the context of superiority but inflated power and type I error under NI. Results from the simulation study suggest that, regardless of the use of the covariate in randomization, it is appropriate to adjust for important prognostic covariates in analysis, as this yields nearly unbiased estimates of treatment as well as nominal type I error.

Original languageEnglish (US)
Pages (from-to)1834-1840
Number of pages7
JournalStatistics in Medicine
Volume34
Issue number11
DOIs
StatePublished - May 20 2015

Keywords

  • Clinical trials
  • Covariates
  • Noninferiority
  • Randomization

ASJC Scopus subject areas

  • Epidemiology
  • Statistics and Probability

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