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Intercurrent events, such as treatment switching, rescue medication, dropout, or truncation by death, frequently complicate intention-to-treat analyses in randomized clinical trials. Existing causal inference frameworks typically target…

Methodology · Statistics 2026-03-12 Georgi Baklicharov , Kelly Van Lancker , Stijn Vansteelandt

Case-cohort studies are conducted within cohort studies, wherein collection of exposure data is limited to a subset of the cohort, leading to a large proportion of missing data by design. Standard analysis uses inverse probability weighting…

In randomized controlled trials (RCTs) that focus on time-to-event outcomes, intercurrent events can arise in two ways: as semi-competing events, which modify the hazard of the primary outcome events, or as competing events, which make the…

Methodology · Statistics 2026-05-26 Yuhao Deng , Shasha Han , Xiao-Hua Zhou

Recurrent events, including cardiovascular events, are commonly observed in biomedical studies. Researchers must understand the effects of various treatments on recurrent events and investigate the underlying mediation mechanisms by which…

Methodology · Statistics 2025-07-08 Yan-Lin Chen , Yan-Hong Chen , Pei-Fang Su , Huang-Tz Ou , An-Shun Tai

Multiple imputation is a highly recommended technique to deal with missing data, but the application to longitudinal datasets can be done in multiple ways. When a new wave of longitudinal data arrives, we can treat the combined data of…

Methodology · Statistics 2026-05-18 X. M. Kavelaars , S. van Buuren , J. R. van Ginkel

Longitudinal studies are often subject to missing data. The ICH E9(R1) addendum addresses the importance of defining a treatment effect estimand with the consideration of intercurrent events. Jump-to-reference (J2R) is one classically…

Methodology · Statistics 2023-12-06 Siyi Liu , Shu Yang , Yilong Zhang , Guanghan , Liu

Causal inference from observational data requires assumptions. These assumptions range from measuring confounders to identifying instruments. Traditionally, causal inference assumptions have focused on estimation of effects for a single…

Machine Learning · Statistics 2019-03-04 Rajesh Ranganath , Adler Perotte

While recurrent event analyses have been extensively studied, limited attention has been given to causal inference within the framework of recurrent event analysis. We develop a multiply robust estimation framework for causal inference in…

Methodology · Statistics 2025-09-30 Benjamin R. Baer , Trang Bui , Daniel Mork , Robert L. Strawderman , Ashkan Ertefaie

We consider studies where multiple measures on an outcome variable are collected over time, but some subjects drop out before the end of follow up. Analyses of such data often proceed under either a 'last observation carried forward' or…

Methodology · Statistics 2022-07-26 Oliver Dukes , David Richardson , Eric Tchetgen Tchetgen

The estimand framework proposed by ICH in 2017 has brought fundamental changes in the pharmaceutical industry. It clearly describes how a treatment effect in a clinical question should be precisely defined and estimated, through attributes…

Other Statistics · Statistics 2025-12-09 Jinghong Zeng

Recurrent events are common and important clinical trial endpoints in many disease areas, e.g., cardiovascular hospitalizations in heart failure, relapses in multiple sclerosis, or exacerbations in asthma. During a trial, patients may…

Methodology · Statistics 2026-04-08 Jiren Sun , Tobias Mutze , Richard Cook , Tianmeng Lyu

Estimands can help to clarify the research questions being addressed in randomised trials. Because the choice of estimand can affect how relevant trial results are to patients and other stakeholders, such as clinicians or policymakers, it…

Many research questions concern treatment effects on outcomes that can recur several times in the same individual. For example, medical researchers are interested in treatment effects on hospitalizations in heart failure patients and sports…

Methodology · Statistics 2024-12-31 Matias Janvin , Jessica G. Young , Pål C. Ryalen , Mats J. Stensrud

We present a framework for generating multiple imputations for continuous data when the missing data mechanism is unknown. Imputations are generated from more than one imputation model in order to incorporate uncertainty regarding the…

Applications · Statistics 2013-01-14 Juned Siddique , Ofer Harel , Catherine M. Crespi

The ICH E9(R1) guideline presents a framework of estimand for clinical trials, proposes five strategies for handling intercurrent events (ICEs), and provides a comprehensive discussion and many real-life clinical examples for quantitative…

Methodology · Statistics 2025-10-20 Yixin Fang , Man Jin

We propose a novel approach for inferring the individualized causal effects of a treatment (intervention) from observational data. Our approach conceptualizes causal inference as a multitask learning problem; we model a subject's potential…

Machine Learning · Computer Science 2017-06-20 Ahmed M. Alaa , Michael Weisz , Mihaela van der Schaar

Data collected in clinical trials are often composed of multiple types of variables. For example, laboratory measurements and vital signs are longitudinal data of continuous or categorical variables, adverse events may be recurrent events,…

Methodology · Statistics 2023-01-12 Tuo Wang , Rachel Zilinskas , Ying Li , Yongming Qu

Background: Existing guidelines for handling missing data are generally not consistent with the goals of prediction modelling, where missing data can occur at any stage of the model pipeline. Multiple imputation (MI), often heralded as the…

Methodology · Statistics 2022-06-27 Rose Sisk , Matthew Sperrin , Niels Peek , Maarten van Smeden , Glen P. Martin

In studies of recurrent events, joint modeling approaches are often needed to allow for potential dependent censoring by a terminal event such as death. Joint frailty models for recurrent events and death with an additional dependence…

Methodology · Statistics 2023-04-25 Marie Böhnstedt , Jutta Gampe , Monique A. A. Caljouw , Hein Putter

In many areas, practitioners seek to use observational data to learn a treatment assignment policy that satisfies application-specific constraints, such as budget, fairness, simplicity, or other functional form constraints. For example,…

Statistics Theory · Mathematics 2020-09-08 Susan Athey , Stefan Wager