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

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Title: Misspecification of at-risk periods and distributional assumptions in estimating COPD exacerbation rates: the resultant bias in treatment effect estimation
Author(s): Law, M
Sweeting, MJ
Donaldson, GC
Wedzicha, JA
Item Type: Journal Article
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.
Publication Date: 14-Dec-2016
Date of Acceptance: 11-Nov-2016
URI: http://hdl.handle.net/10044/1/44697
DOI: https://dx.doi.org/10.1002/pst.1798
ISSN: 1539-1604
Publisher: Wiley
Start Page: 201
End Page: 209
Journal / Book Title: Pharmaceutical Statistics
Volume: 16
Issue: 3
Copyright Statement: © 2016 The Authors. Pharmaceutical Statistics Published by John Wiley & Sons Ltd. This is an open access article under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Sponsor/Funder: Medical Research Council
Funder's Grant Number: G0800570/1
Keywords: Science & Technology
Life Sciences & Biomedicine
Physical Sciences
Pharmacology & Pharmacy
Statistics & Probability
Mathematics
chronic obstructive pulmonary disease
exacerbation rate
negative binomial
recurrent events
OBSTRUCTIVE PULMONARY-DISEASE
INFLAMMATORY MARKERS
TIOTROPIUM
TRISTAN
EXAMPLE
THERAPY
TRIALS
ISOLDE
chronic obstructive pulmonary disease
exacerbation rate
negative binomial
recurrent events
Statistics & Probability
0104 Statistics
1115 Pharmacology And Pharmaceutical Sciences
Publication Status: Published
Appears in Collections:National Heart and Lung Institute
Airway Disease
Faculty of Medicine



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