Abstract
BackgroundIntermediate outcomes are common and typically on the causal pathway to the final outcome. Some examples include noncompliance, missing data, and truncation by death like pregnancy (e.g. when the trial intervention is given to non-pregnant women and the final outcome is preeclampsia, defined only on pregnant women). The intention-to-treat approach does not account properly for them, and more appropriate alternative approaches like principal stratification are not yet widely known. The purposes of this study are to inform researchers that the intention-to-treat approach unfortunately does not fit all problems we face in experimental research, to introduce the principal stratification approach for dealing with intermediate outcomes, and to illustrate its application to a trial of long term calcium supplementation in women at high risk of preeclampsia.MethodsPrincipal stratification and related concepts are introduced. Two ways for estimating causal effects are discussed and their application is illustrated using the calcium trial, where noncompliance and pregnancy are considered as intermediate outcomes, and preeclampsia is the main final outcome.ResultsThe limitations of traditional approaches and methods for dealing with intermediate outcomes are demonstrated. The steps, assumptions and required calculations involved in the application of the principal stratification approach are discussed in detail in the case of our calcium trial.ConclusionsThe intention-to-treat approach is a very sound one but unfortunately it does not fit all problems we find in randomized clinical trials; this is particularly the case for intermediate outcomes, where alternative approaches like principal stratification should be considered.
Highlights
Intermediate outcomes are common and typically on the causal pathway to the final outcome
The World Health Organization (WHO) randomized trial of calcium supplementation before pregnancy to reduce recurrent preeclampsia [6] aims at assessing if calcium supplementation before and in the first half of pregnancy reduces the incidence of recurrent preeclampsia more effectively than supplementation starting at 20 weeks
Application to the calcium trial Section “Noncompliance as intermediate outcome” will present the application of the methods described in Sections “Compliance as intermediate outcome”, “Assumptions underlying compliers average causal effect (CACE) analyses” and “Simple description of estimation” to the particular scenario of our calcium trial, where noncompliance is considered as an intermediate outcomes (IO) between calcium assignment and pregnancy as the outcome
Summary
Intermediate outcomes are common and typically on the causal pathway to the final outcome. The intention-to-treat approach does not account properly for them, and more appropriate alternative approaches like principal stratification are not yet widely known. The purposes of this study are to inform researchers that the intention-to-treat approach does not fit all problems we face in experimental research, to introduce the principal stratification approach for dealing with intermediate outcomes, and to illustrate its application to a trial of long term calcium supplementation in women at high risk of preeclampsia. The presence of intermediate outcomes (IO), both in experimental and observational research, complicates the assessment of causal effects between exposures and (final) outcomes [1]. The purpose of this article is to present an intuitive introduction to a framework for studying causal effects when IOs are present, principal stratification (PS), and a related statistical technique, instrumental variables (IV). We expect that this paper will help researchers conducting randomized clinical trials (RCT) to become more familiar with these techniques, and that their proper application will be further promoted
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
