Bivariate pseudo-observations for recurrent event analysis with terminal events

Furberg, Julie Kjærulff; Andersen, Per Kragh; Korn, Sofie; Overgaard, Morten; Ravn, Henrik

doi:10.1007/s10985-021-09533-5

Cited by 5 publications

(2 citation statements)

References 19 publications

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“…While the frequently presented crude proportion is not a function of time and does not properly account for censoring [ 5 , 14 ], the Aalen-Johansen estimator of the crude incidence of AEs, commonly used for competing risks analysis [ 15 ], gives a proper estimate of the probability of treatment failure due to AEs over the course of time, where relapse acts as competing event (since AEs are counted only if observed as first events). The description of the observed occurrence of AE through the crude incidence together with the crude incidence of the efficacy endpoint enables to quantify the risks and benefits from the patient perspective [ 16 ]. Of note, the methods described in the previous citation can be useful to perform hypothesis testing on the two types of competing risks.…”

Section: Discussionmentioning

confidence: 99%

Adverse events in single-arm clinical trials with non-fatal time-to-event efficacy endpoint: from clinical questions to methods for statistical analysis

Tassistro,

Bernasconi,

Valsecchi

et al. 2024

BMC Med Res Methodol

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Background In any single-arm trial on novel treatments, assessment of toxicity plays an important role as occurrence of adverse events (AEs) is relevant for application in clinical practice. In the presence of a non-fatal time-to-event(s) efficacy endpoint, the analysis should be broadened to consider AEs occurrence in time. The AEs analysis could be tackled with two approaches, depending on the clinical question of interest. Approach 1 focuses on the occurrence of AE as first event. Treatment ability to protect from the efficacy endpoint event(s) has an impact on the chance of observing AEs due to competing risks action. Approach 2 considers how treatment affects the occurrence of AEs in the potential framework where the efficacy endpoint event(s) could not occur. Methods In the first part of the work we review the strategy of analysis for these two approaches. We identify theoretical quantities and estimators consistent with the following features: (a) estimators should address for the presence of right censoring; (b) theoretical quantities and estimators should be functions of time. In the second part of the work we propose the use of alternative methods (regression models, stratified Kaplan-Meier curves, inverse probability of censoring weighting) to relax the assumption of independence between the potential times to AE and to event(s) in the efficacy endpoint for addressing Approach 2. Results We show through simulations that the proposed methods overcome the bias due to the dependence between the two potential times and related to the use of standard estimators. Conclusions We demonstrated through simulations that one can handle patients selection in the risk sets due to the competing event, and thus obtain conditional independence between the two potential times, adjusting for all the observed covariates that induce dependence.

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Section: Discussionmentioning

confidence: 99%

Adverse events in single-arm clinical trials with non-fatal time-to-event efficacy endpoint: from clinical questions to methods for statistical analysis

Tassistro,

Bernasconi,

Valsecchi

et al. 2024

BMC Med Res Methodol

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“…The assumption that the recurrent events are bounded by a constant,

K

, was made to simplify the proof of the asymptotic distribution of the win and loss parameters. The assumption can be relaxed to a moment condition along the lines of Furberg et al 13 .…”

Section: Discussionmentioning

confidence: 99%

Win‐loss parameters for right‐censored event data, with application to recurrent events

Parner,

Overgaard

2023

Statistics in Medicine

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The win ratio has become a popular method for comparing multiple event data between two groups in clinical cohort studies. The win ratio compares the event data in prioritized order, where the first prioritized event is death and a typical example for the second prioritized event is hospitalization. Literature is sparse on inference for win and loss parameters, including the win ratio, for censored event data. Inference for two prioritized censored event times has been developed for independent right‐censoring. Many clinical studies include recurrent event data such as hospitalizations. In this article, we suggest inference for win‐loss parameters for death and a recurrent event outcome under independent right‐censoring. The small sample properties of the proposed method are studied in a simulation study showing that the variance formula is accurate even for small samples. The method is applied on a data set from a randomized clinical trial.

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Simulation‐based sample size calculations of marginal proportional means models for recurrent events with competing risks

Furberg,

Andersen,

Scheike

et al. 2024

Pharmaceutical Statistics

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In randomised controlled trials, the outcome of interest could be recurrent events, such as hospitalisations for heart failure. If mortality rates are non‐negligible, both recurrent events and competing terminal events need to be addressed when formulating the estimand and statistical analysis is no longer trivial. In order to design future trials with primary recurrent event endpoints with competing risks, it is necessary to be able to perform power calculations to determine sample sizes. This paper introduces a simulation‐based approach for power estimation based on a proportional means model for recurrent events and a proportional hazards model for terminal events. The simulation procedure is presented along with a discussion of what the user needs to specify to use the approach. The method is flexible and based on marginal quantities which are easy to specify. However, the method introduces a lack of a certain type of dependence. This is explored in a sensitivity analysis which suggests that the power is robust in spite of that. Data from a randomised controlled trial, LEADER, is used as the basis for generating data for a future trial. Finally, potential power gains of recurrent event methods as opposed to first event methods are discussed.

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Bivariate pseudo-observations for recurrent event analysis with terminal events

Cited by 5 publications

References 19 publications

Adverse events in single-arm clinical trials with non-fatal time-to-event efficacy endpoint: from clinical questions to methods for statistical analysis

Adverse events in single-arm clinical trials with non-fatal time-to-event efficacy endpoint: from clinical questions to methods for statistical analysis

Win‐loss parameters for right‐censored event data, with application to recurrent events

Simulation‐based sample size calculations of marginal proportional means models for recurrent events with competing risks

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