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In clinical follow-up studies with a time-to-event end point, the difference in the restricted mean survival time (RMST) is a suitable substitute for the hazard ratio (HR). However, the RMST only measures the survival of patients over a…

Methodology · Statistics 2023-06-27 Zijing Yang , Chengfeng Zhang , Yawen Hou , Zheng Chen

Survival time is the primary endpoint of many randomized controlled trials, and a treatment effect is typically quantified by the hazard ratio under the assumption of proportional hazards. Awareness is increasing that in many settings this…

Methodology · Statistics 2023-10-04 Robin Ristl , Heiko Götte , Armin Schüler , Martin Posch , Franz König

The log-rank test is most powerful under proportional hazards (PH). In practice, non-PH patterns are often observed in clinical trials, such as in immuno-oncology; therefore, alternative methods are needed to restore the efficiency of…

Desirability Of Outcome Ranking (DOOR) methodology accounts for problems that conventional benefit:risk analyses in clinical trials ignore, such as competing risks and the trade-off relationship between efficacy and toxicity. DOOR levels…

Methodology · Statistics 2025-05-19 Shiyu Shu , Guoqing Diao , Toshimitsu Hamasaki , Scott Evans

A common feature of many recent trials evaluating the effects of immunotherapy on survival is that non-proportional hazards can be anticipated at the design stage. This raises the possibility to use a statistical method tailored towards…

Applications · Statistics 2021-08-27 Dominic Magirr , José L. Jiménez

The conventional nonparametric tests in survival analysis, such as the log-rank test, assess the null hypothesis that the hazards are equal at all times. However, hazards are hard to interpret causally, and other null hypotheses are more…

Methodology · Statistics 2019-01-29 Mats Julius Stensrud , Kjetil Røysland , Pål Christie Ryalen

One of the most common ways researchers compare survival outcomes across treatments when confounding is present is using Cox regression. This model is limited by its underlying assumption of proportional hazards; in some cases, substantial…

Applications · Statistics 2021-02-02 Elizabeth A. Handorf , Marc Smaldone , Sujana Movva , Nandita Mitra

In oncology, conduct well-powered time-to-event randomized clinical trials may be challenging due to limited patietns number. Many designs for single-arm trials (SATs) have recently emerged as an alternative to overcome this issue. They…

Applications · Statistics 2026-04-10 Chloé Szurewsky , Guosheng Yin , Gwénaël Le Teuff

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

Several methods in survival analysis are based on the proportional hazards assumption. However, this assumption is very restrictive and often not justifiable in practice. Therefore, effect estimands that do not rely on the proportional…

Methodology · Statistics 2024-03-20 Merle Munko , Marc Ditzhaus , Dennis Dobler , Jon Genuneit

In clinical and epidemiological studies, hazard ratios are often applied to compare treatment effects between two groups for survival data. For competing risks data, the corresponding quantities of interest are cause-specific hazard ratios…

Applications · Statistics 2021-12-21 Hongji Wu , Hao Yuan , Zijing Yang , Yawen Hou , Zheng Chen

The restricted mean survival time (RMST) is the mean survival time in the study population followed up to a specific time point, and is simply the area under the survival curve up to the specific time point. The difference between two RMSTs…

Methodology · Statistics 2025-09-18 Peter Zhang , Brent Logan , Michael Martens

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

We propose a new class of weighted logrank tests (WLRT) that control the risk of concluding that a new drug is more efficacious than standard of care, when, in fact, it is uniformly inferior. Perhaps surprisingly, this risk is not…

Applications · Statistics 2018-07-31 Dominic Magirr , Carl-Fredrik Burman

A fundamental concept in two-arm non-parametric survival analysis is the comparison of observed versus expected numbers of events on one of the treatment arms (the choice of which arm is arbitrary), where the expectation is taken assuming…

Applications · Statistics 2020-07-10 Dominic Magirr

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

Investigating the causal relationship between exposure and the time-to-event outcome is an important topic in biomedical research. Previous literature has discussed the potential issues of using the hazard ratio as a marginal causal effect…

Methodology · Statistics 2022-05-05 Zihan Lin , Ai Ni , Bo Lu

Recent observations, especially in cancer immunotherapy clinical trials with time-to-event outcomes, show that the commonly used proportial hazard assumption is often not justifiable, hampering an appropriate analyse of the data by hazard…

Methodology · Statistics 2021-02-23 Marc Ditzhaus , Menggang Yu , Jin Xu

The difference in restricted mean survival time (RMST) is a clinically meaningful measure to quantify treatment effect in randomized controlled trials, especially when the proportional hazards assumption does not hold. Several frequentist…

Covariate adjustment is desired by both practitioners and regulators of randomized clinical trials because it improves precision for estimating treatment effects. However, covariate adjustment presents a particular challenge in…

Methodology · Statistics 2023-07-20 Yunfan Li , Jessica L. Ross , Aaron M. Smith , David P. Miller