scholarly journals Dynamic borrowing in the presence of treatment effect heterogeneity

Biostatistics ◽  
2020 ◽  
Author(s):  
Ales Kotalik ◽  
David M Vock ◽  
Eric C Donny ◽  
Dorothy K Hatsukami ◽  
Joseph S Koopmeiners
Keyword(s):  
Clinical Trials ◽  
Treatment Effect ◽  
Treatment Effects ◽  
Randomized Clinical Trials ◽  
Potential Outcomes ◽  
Operating Characteristics ◽  
Treatment Effect Heterogeneity ◽  
Using Data ◽  
Effect Heterogeneity ◽  
Potential Outcomes Framework

Summary A number of statistical approaches have been proposed for incorporating supplemental information in randomized clinical trials. Existing methods often compare the marginal treatment effects to evaluate the degree of consistency between sources. Dissimilar marginal treatment effects would either lead to increased bias or down-weighting of the supplemental data. This represents a limitation in the presence of treatment effect heterogeneity, in which case the marginal treatment effect may differ between the sources solely due to differences between the study populations. We introduce the concept of covariate-adjusted exchangeability, in which differences in the marginal treatment effect can be explained by differences in the distributions of the effect modifiers. The potential outcomes framework is used to conceptualize covariate-adjusted and marginal exchangeability. We utilize a linear model and the existing multisource exchangeability models framework to facilitate borrowing when marginal treatment effects are dissimilar but covariate-adjusted exchangeability holds. We investigate the operating characteristics of our method using simulations. We also illustrate our method using data from two clinical trials of very low nicotine content cigarettes. Our method has the ability to incorporate supplemental information in a wider variety of situations than when only marginal exchangeability is considered.

scholarly journals Estimating and reporting treatment effects in clinical trials for weight management: using estimands to interpret effects of intercurrent events and missing data

2021 ◽  
Author(s):  
Sean Wharton ◽  
Arne Astrup ◽  
Lars Endahl ◽  
Michael E. J. Lean ◽  
Altynai Satylganova ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Missing Data ◽  
Weight Management ◽  
Treatment Effect ◽  
Repeated Measures ◽  
Treatment Effects ◽  
Randomized Clinical Trials ◽  
Weight Losses ◽  
The Difference ◽  
Treatment Of Obesity

AbstractIn the approval process for new weight management therapies, regulators typically require estimates of effect size. Usually, as with other drug evaluations, the placebo-adjusted treatment effect (i.e., the difference between weight losses with pharmacotherapy and placebo, when given as an adjunct to lifestyle intervention) is provided from data in randomized clinical trials (RCTs). At first glance, this may seem appropriate and straightforward. However, weight loss is not a simple direct drug effect, but is also mediated by other factors such as changes in diet and physical activity. Interpreting observed differences between treatment arms in weight management RCTs can be challenging; intercurrent events that occur after treatment initiation may affect the interpretation of results at the end of treatment. Utilizing estimands helps to address these uncertainties and improve transparency in clinical trial reporting by better matching the treatment-effect estimates to the scientific and/or clinical questions of interest. Estimands aim to provide an indication of trial outcomes that might be expected in the same patients under different conditions. This article reviews how intercurrent events during weight management trials can influence placebo-adjusted treatment effects, depending on how they are accounted for and how missing data are handled. The most appropriate method for statistical analysis is also discussed, including assessment of the last observation carried forward approach, and more recent methods, such as multiple imputation and mixed models for repeated measures. The use of each of these approaches, and that of estimands, is discussed in the context of the SCALE phase 3a and 3b RCTs evaluating the effect of liraglutide 3.0 mg for the treatment of obesity.

Estimating Treatment Effects in the Presence of Noncompliance and Nonresponse: The Generalized Endogenous Treatment Model

2011 ◽  
Vol 19 (2) ◽  
pp. 205-226 ◽  
Author(s):  
Kevin M. Esterling ◽  
Michael A. Neblo ◽  
David M. J. Lazer
Keyword(s):  
Treatment Effect ◽  
Instrumental Variable ◽  
Treatment Effects ◽  
Mean Squared Error ◽  
Principal Stratification ◽  
Squared Error ◽  
Treatment Effect Heterogeneity ◽  
Causal Treatment ◽  
Effect Heterogeneity ◽  
And Control

If ignored, noncompliance with a treatment or nonresponse on outcome measures can bias estimates of treatment effects in a randomized experiment. To identify and estimate causal treatment effects in the case where compliance and response depend on unobservables, we propose the parametric generalized endogenous treatment (GET) model. GET incorporates behavioral responses within an experiment to measure each subject's latent compliance type and identifies causal effects via principal stratification. Using simulation methods and an application to field experimental data, we show GET has a dramatically lower mean squared error for treatment effect estimates than existing approaches to principal stratification that impute, rather than measure, compliance type. In addition, we show that GET allows one to relax and test the instrumental variable exclusion restriction assumption, to test for the presence of treatment effect heterogeneity across a range of compliance types, and to test for treatment ignorability when treatment and control samples are balanced on observable covariates.

scholarly journals Extending the I-squared statistic to describe treatment effect heterogeneity in cluster, multi-centre randomized trials and individual patient data meta-analysis

2020 ◽  
pp. 096228022094855
Author(s):  
Karla Hemming ◽  
James P Hughes ◽  
Joanne E McKenzie ◽  
Andrew B Forbes
Keyword(s):  
Randomized Trial ◽  
Treatment Effect ◽  
Treatment Effects ◽  
Randomized Trials ◽  
Individual Patient Data ◽  
Meta Analysis ◽  
Cluster Randomized Trial ◽  
Patient Data ◽  
Treatment Effect Heterogeneity ◽  
Effect Heterogeneity

Treatment effect heterogeneity is commonly investigated in meta-analyses to identify if treatment effects vary across studies. When conducting an aggregate level data meta-analysis it is common to describe the magnitude of any treatment effect heterogeneity using the I-squared statistic, which is an intuitive and easily understood concept. The effect of a treatment might also vary across clusters in a cluster randomized trial, or across centres in multi-centre randomized trial, and it can be of interest to explore this at the analysis stage. In cross-over trials and other randomized designs, in which clusters or centres are exposed to both treatment and control conditions, this treatment effect heterogeneity can be identified. Here we derive and evaluate a comparable I-squared measure to describe the magnitude of heterogeneity in treatment effects across clusters or centres in randomized trials. We further show how this methodology can be used to estimate treatment effect heterogeneity in an individual patient data meta-analysis.

scholarly journals A Unified Survey of Treatment Effect Heterogeneity Modelling and Uplift Modelling

2022 ◽  
Vol 54 (8) ◽  
pp. 1-36
Author(s):  
Weijia Zhang ◽  
Jiuyong Li ◽  
Lin Liu
Keyword(s):  
Treatment Effect ◽  
Treatment Effects ◽  
Causal Effect ◽  
Personalised Medicine ◽  
Online Marketing ◽  
Heterogeneous Treatment Effects ◽  
Source Codes ◽  
Outcome Framework ◽  
Treatment Effect Heterogeneity ◽  
Effect Heterogeneity

A central question in many fields of scientific research is to determine how an outcome is affected by an action, i.e., to estimate the causal effect or treatment effect of an action. In recent years, in areas such as personalised healthcare, sociology, and online marketing, a need has emerged to estimate heterogeneous treatment effects with respect to individuals of different characteristics. To meet this need, two major approaches have been taken: treatment effect heterogeneity modelling and uplifting modelling. Researchers and practitioners in different communities have developed algorithms based on these approaches to estimate the heterogeneous treatment effects. In this article, we present a unified view of these two seemingly disconnected yet closely related approaches under the potential outcome framework. We provide a structured survey of existing methods following either of the two approaches, emphasising their inherent connections and using unified notation to facilitate comparisons. We also review the main applications of the surveyed methods in personalised marketing, personalised medicine, and sociology. Finally, we summarise and discuss the available software packages and source codes in terms of their coverage of different methods and applicability to different datasets, and we provide general guidelines for method selection.

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