Sensitivity analysis for clinical trials with missing continuous outcome data using controlled multiple imputation: a practical guide
File(s)sim.8569.pdf (2.22 MB)
Published version
Author(s)
Cro, Suzie
Morris, Tim P
Kenward, Michael G
Carpenter, James R
Type
Journal Article
Abstract
Missing data due to loss to follow‐up or intercurrent events are unintended, but unfortunately inevitable in clinical trials. Since the true values of missing data are never known, it is necessary to assess the impact of untestable and unavoidable assumptions about any unobserved data in sensitivity analysis. This tutorial provides an overview of controlled multiple imputation (MI) techniques and a practical guide to their use for sensitivity analysis of trials with missing continuous outcome data. These include δ ‐ and reference‐based MI procedures. In δ ‐based imputation, an offset term, δ , is typically added to the expected value of the missing data to assess the impact of unobserved participants having a worse or better response than those observed. Reference‐based imputation draws imputed values with some reference to observed data in other groups of the trial, typically in other treatment arms. We illustrate the accessibility of these methods using data from a pediatric eczema trial and a chronic headache trial and provide Stata code to facilitate adoption. We discuss issues surrounding the choice of δ in δ ‐based sensitivity analysis. We also review the debate on variance estimation within reference‐based analysis and justify the use of Rubin's variance estimator in this setting, since as we further elaborate on within, it provides information anchored inference.
Date Issued
2020-08-06
Date Acceptance
2020-04-18
Citation
Statistics in Medicine, 2020, 39 (21), pp.2815-2842
ISSN
0277-6715
Publisher
Wiley
Start Page
2815
End Page
2842
Journal / Book Title
Statistics in Medicine
Volume
39
Issue
21
Copyright Statement
© 2020 The Authors. Statistics in Medicine published by John Wiley & Sons, Ltd.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
License URL
Identifier
https://onlinelibrary.wiley.com/doi/full/10.1002/sim.8569
Subjects
Science & Technology
Life Sciences & Biomedicine
Physical Sciences
Mathematical & Computational Biology
Public, Environmental & Occupational Health
Medical Informatics
Medicine, Research & Experimental
Statistics & Probability
Research & Experimental Medicine
Mathematics
clinical trials
controlled multiple imputation
missing data
multiple imputation
sensitivity analysis
LONGITUDINAL TRIALS
ACCESSIBLE ASSUMPTIONS
PROTOCOL DEVIATION
EVENT DATA
INFERENCE
FRAMEWORK
RELEVANT
EFFICACY
IMPROVE
PLACEBO
clinical trials
controlled multiple imputation
missing data
multiple imputation
sensitivity analysis
Statistics & Probability
0104 Statistics
1117 Public Health and Health Services
Publication Status
Published
Date Publish Online
2020-05-17