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A targeted learning (TL) framework is developed to estimate the difference in the restricted mean survival time (RMST) for a clinical trial with time-to-event outcomes. The approach starts by defining the target estimand as the RMST…

Methodology · Statistics 2026-01-21 Man Jin , Yixin Fang

Researchers in genetics and other life sciences commonly use permutation tests to evaluate differences between groups. Permutation tests have desirable properties, including exactness if data are exchangeable, and are applicable even when…

Computation · Statistics 2018-11-01 Brian Segal , Thomas Braun , Michael Elliott , Hui Jiang

What can be considered an appropriate statistical method for the primary analysis of a randomized clinical trial (RCT) with a time-to-event endpoint when we anticipate non-proportional hazards owing to a delayed effect? This question has…

Methodology · Statistics 2023-04-18 José L. Jiménez , Isobel Barrott , Francesca Gasperoni , Dominic Magirr

Meta-analysis is a well-established tool used to combine data from several independent studies, each of which usually compares the effect of an experimental treatment with a control group. While meta-analyses are often performed using…

Methodology · Statistics 2025-06-02 Phuc Thien Tran , Long-Hao Xu , Christian Röver , Tim Friede

Permutation tests are widely recognized as robust alternatives to tests based on normal theory. Random permutation tests have been frequently employed to assess the significance of variables in linear models. Despite their widespread use,…

Methodology · Statistics 2023-12-29 Leying Guan

In the process of clinical diagnosis and treatment, the restricted mean survival time (RMST), which reflects the life expectancy of patients up to a specified time, can be used as an appropriate outcome measure. However, the RMST only…

Applications · Statistics 2021-06-22 Zijing Yang , Hongji Wu , Yawen Hou , Hao Yuan , Zheng Chen

The use of the non-parametric Restricted Mean Survival Time endpoint (RMST) has grown in popularity as trialists look to analyse time-to-event outcomes without the restrictions of the proportional hazards assumption. In this paper, we…

Methodology · Statistics 2023-11-06 Emily Alger , David S. Robertson , Abigail J. Burdon

The restricted mean survival time (RMST) difference offers an interpretable causal contrast to estimate the treatment effect for time-to-event outcomes, yet a wide range of available estimators leaves limited guidance for practice. We…

Methodology · Statistics 2026-03-02 Charlotte Voinot , Clément Berenfeld , Imke Mayer , Bernard Sebastien , Julie Josse

In the context of right-censored data, we study the problem of predicting the restricted time to event based on a set of covariates. Under a quadratic loss, this problem is equivalent to estimating the conditional Restricted Mean Survival…

Statistics Theory · Mathematics 2024-04-29 Ariane Cwiling , Vittorio Perduca , Olivier Bouaziz

Factorial survival designs with right-censored observations are commonly inferred by Cox regression and explained by means of hazard ratios. However, in case of non-proportional hazards, their interpretation can become cumbersome;…

Methodology · Statistics 2020-06-26 Marc Ditzhaus , Dennis Dobler , Markus Pauly

Hazard ratios are ubiquitously used in time to event analysis to quantify treatment effects. Although hazard ratios are invaluable for hypothesis testing, other measures of association, both relative and absolute, may be used to fully…

Methodology · Statistics 2020-11-02 Federico Ambrogi , Simona Iacobelli , Per Kragh Andersen

The 'gold standard' design for three-arm trials refers to trials with an active control and a placebo control in addition to the experimental treatment group. This trial design is recommended when being ethically justifiable and it allows…

Applications · Statistics 2017-03-22 Tobias Mütze , Frank Konietschke , Axel Munk , Tim Friede

Proportional hazards are a common assumption when designing confirmatory clinical trials in oncology. With the emergence of immunotherapy and novel targeted therapies, departure from the proportional hazard assumption is not rare in…

Methodology · Statistics 2020-08-27 José L. Jiménez

Background: For RCTs with time-to-event endpoints, proportional hazard (PH) models are typically used to estimate treatment effects and logrank tests are commonly used for hypothesis testing. There is growing support for replacing this…

Methodology · Statistics 2024-12-10 Dominic Magirr , Craig Wang , Xinlei Deng , Tim Morris , Mark Baillie

Restricted mean survival time (RMST) models have gained popularity when analyzing time-to-event outcomes because RMST models offer more straightforward interpretations of treatment effects with fewer assumptions than hazard ratios commonly…

Methodology · Statistics 2023-10-23 Kaiyuan Hua , Xiaofei Wang , Hwanhee Hong

Epidemiologic studies and clinical trials with a survival outcome are often challenged by immortal time (IMT), a period of follow-up during which the survival outcome cannot occur because of the observed later treatment initiation. It has…

Applications · Statistics 2022-02-08 Jiping Wang , Peter Peduzzi , Michael Wininger , Shuangge Ma

In qualitative statistics, permutation tests are very popular, mainly because of their finite-sample exactness under exchangeability. However, in non-exchangeable settings, the covariance structure of permuted statistics typically differs…

Methodology · Statistics 2026-04-09 Merle Munko , Paavo Sattler

Most statistical tests for treatment effects used in randomized clinical trials with survival outcomes are based on the proportional hazards assumption, which often fails in practice. Data from early exploratory studies may provide evidence…

Statistics Theory · Mathematics 2020-05-28 Andrea Arfé , Brian Alexander , Lorenzo Trippa

We present a new estimator of the restricted mean survival time in randomized trials where there is right censoring that may depend on treatment and baseline variables. The proposed estimator leverages prognostic baseline variables to…

Statistics Theory · Mathematics 2016-08-22 Iván Díaz , Elizabeth Colantuoni , Daniel F. Hanley , Michael Rosenblum

Permutation testing in linear models, where the number of nuisance coefficients is smaller than the sample size, is a well-studied topic. The common approach of such tests is to permute residuals after regressing on the nuisance covariates.…

Methodology · Statistics 2020-10-09 Jesse Hemerik , Magne Thoresen , Livio Finos