Misspecification of at-risk periods and distributional assumptions in estimating COPD exacerbation rates: The resultant bias in treatment effect estimation

M. Law*, M. J. Sweeting, G. C. Donaldson, J. A. Wedzicha

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

Abstract

In trials comparing the rate of chronic obstructive pulmonary disease exacerbation between treatment arms, the rate is typically calculated on the basis of the whole of each patient's follow-up period. However, the true time a patient is at risk should exclude periods in which an exacerbation episode is occurring, because a patient cannot be at risk of another exacerbation episode until recovered. We used data from two chronic obstructive pulmonary disease randomized controlled trials and compared treatment effect estimates and confidence intervals when using two different definitions of the at-risk period. Using a simulation study we examined the bias in the estimated treatment effect and the coverage of the confidence interval, using these two definitions of the at-risk period. We investigated how the sample size required for a given power changes on the basis of the definition of at-risk period used. Our results showed that treatment efficacy is underestimated when the at-risk period does not take account of exacerbation duration, and the power to detect a statistically significant result is slightly diminished. Correspondingly, using the correct at-risk period, some modest savings in required sample size can be achieved. Using the proposed at-risk period that excludes recovery times requires formal definitions of the beginning and end of an exacerbation episode, and we recommend these be always predefined in a trial protocol.

Original languageEnglish
Pages (from-to)201-209
Number of pages9
JournalPharmaceutical Statistics
Volume16
Issue number3
DOIs
Publication statusPublished - 1 May 2017
Externally publishedYes

Bibliographical note

Funding Information:
We would like to thank the staff and patients who participated and provide data from the randomized trials. Martin Law is used by the UK Medical Research Council (Funding, NIHR grant RP-PG-0109-10056).

Publisher Copyright:
Copyright © 2016 The Authors. Pharmaceutical Statistics Published by John Wiley & Sons Ltd.

Keywords

  • chronic obstructive pulmonary disease
  • exacerbation rate
  • negative binomial
  • recurrent events

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