The generalization performance of a risk prediction model can be evaluated by its calibration, which measures the agreement between predicted and observed outcomes on external validation data. Here, methods for assessing the calibration of discrete time-to-event models in the presence of competing risks are proposed. The methods are designed for the class of discrete subdistribution hazard models, which directly relate the cumulative incidence function of one event of interest to a set of covariates. Simulation studies show that the methods are strong tools for calibration assessment even in scenarios with a high censoring rate and/or a large number of discrete time points. The proposed approaches are illustrated by an analysis of nosocomial pneumonia.
An individualized risk prediction model that dynamically updates the probability of a clinical event from a specific cause is valuable for physicians to be able to optimize personalized treatment strategies in real-time by incorporating all available information collected over the follow-up. However, this is more complex and challenging when competing risks are present, because it requires simultaneously updating the overall survival and the cumulative incidence functions (CIFs) while adjusting for the time-dependent covariates and time-varying covariate effects. In this study, we developed a …
In this paper we introduce the subdistribution beta-Stacy process, a novel Bayesian nonparametric process prior for subdistribution functions useful for the analysis of competing risks data. In particular, we i) characterize this process from a predictive perspective by means of an urn model with reinforcement, ii) show that it is conjugate with respect to right-censored data, and iii) highlight its relations with other prior processes for competing risks data. Additionally, we consider the subdistribution beta-Stacy process prior in a nonparametric regression model for competing risks data wh…
Many research questions involve time-to-event outcomes that can be prevented from occurring due to competing events. In these settings, we must be careful about the causal interpretation of classical statistical estimands. In particular, estimands on the hazard scale, such as ratios of cause specific or subdistribution hazards, are fundamentally hard to be interpret causally. Estimands on the risk scale, such as contrasts of cumulative incidence functions, do have a causal interpretation, but they only capture the total effect of the treatment on the event of interest; that is, effects both th…
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 (cHRs) and subdistribution hazard ratios (sHRs). However, they both have some limitations related to model assumptions and clinical interpretation. Therefore, we recommend restricted mean time lost (RMTL) as an alternative that is easy to interpret in a competing risks framework. Based on the difference in restricted mean time lost (RMTLd), we propose a new …
Survival models incorporating random effects to account for unmeasured heterogeneity are being increasingly used in biostatistical and applied research. Specifically, unmeasured covariates whose lack of inclusion in the model would lead to biased, inefficient results are commonly modelled by including a subject-specific (or cluster-specific) frailty term that follows a given distribution (e.g. Gamma or log-Normal). Despite that, in the context of parametric frailty models little is known about the impact of misspecifying the baseline hazard, the frailty distribution, or both. Therefore, our ai…
This paper provides guidance for researchers with some mathematical background on the conduct of time-to-event analysis in observational studies based on intensity (hazard) models. Discussions of basic concepts like time axis, event definition and censoring are given. Hazard models are introduced, with special emphasis on the Cox proportional hazards regression model. We provide check lists that may be useful both when fitting the model and assessing its goodness of fit and when interpreting the results. Special attention is paid to how to avoid problems with immortal time bias by introducing …
Time-to-event analysis often relies on prior parametric assumptions, or, if a non-parametric approach is chosen, Cox's model. This is inherently tied to the assumption of proportional hazards, with the analysis potentially invalidated if this assumption is not fulfilled. In addition, most interpretations focus on the hazard ratio, that is often misinterpreted as the relative risk. In this paper, we introduce an alternative to current methodology for assessing a treatment effect in a two-group situation, not relying on the proportional hazards assumption but assuming proportional risks. Precise…
Many time-to-event studies are complicated by the presence of competing risks. Such data are often analyzed using Cox models for the cause specific hazard function or Fine-Gray models for the subdistribution hazard. In practice regression relationships in competing risks data with either strategy are often complex and may include nonlinear functions of covariates, interactions, high-dimensional parameter spaces and nonproportional cause specific or subdistribution hazards. Model misspecification can lead to poor predictive performance. To address these issues, we propose a novel approach to fl…
This paper develops two orthogonal contributions to scalable sparse regression for competing risks time-to-event data. First, we study and accelerate the broken adaptive ridge method (BAR), an $\ell_0$-based iteratively reweighted $\ell_2$-penalization algorithm that achieves sparsity in its limit, in the context of the Fine-Gray (1999) proportional subdistributional hazards (PSH) model. In particular, we derive a new algorithm for BAR regression, named cycBAR, that performs cyclic update of each coordinate using an explicit thresholding formula. The new cycBAR algorithm effectively avoids fit…
Multi-state survival analysis considers several potential events of interest along a disease pathway. Such analyses are crucial to model complex patient trajectories and are increasingly being used in epidemiological and health economic settings. Multi-state models often make the Markov assumption, whereby an individual's future trajectory is dependent only upon their present state, not their past. In reality, there may be transitional dependence upon either previous events and/or more than one timescale, for example time since entry to the current or previous state(s). The aim of this study w…
Assessing immune responses to study vaccines as surrogates of protection plays a central role in vaccine clinical trials. Motivated by three ongoing or pending HIV vaccine efficacy trials, we consider such surrogate endpoint assessment in a randomized placebo-controlled trial with case-cohort sampling of immune responses and a time to event endpoint. Based on the principal surrogate definition under the principal stratification framework proposed by Frangakis and Rubin [Biometrics 58 (2002) 21--29] and adapted by Gilbert and Hudgens (2006), we introduce estimands that measure the value of an i…
Competing risks data arise frequently in clinical trials. When the proportional subdistribution hazard assumption is violated or two cumulative incidence function (CIF) curves cross, rather than comparing the overall treatment effects, researchers may be interested in focusing on a comparison of clinical utility at some fixed time points. This paper extend a series of tests that are constructed based on a pseudo-value regression technique or different transformation functions for CIFs and their variances based on Gaynor's or Aalen's work, and the differences among CIFs at a given time point ar…
A parametric framework for assessing and estimating sufficient follow-up time in cure models
Federal University of São Carlos（圣卡洛斯联邦大学）；Institute of Mathematics and Computer Sciences（数学与计算机科学学院）；University of São Paulo（圣保罗大学）；MRC Biostatistics Unit（医学研究委员会生物统计单元）；University of Cambridge（剑桥大学）
We compare two multi-state modelling frameworks that can be used to represent dates of events following hospital admission for people infected during an epidemic. The methods are applied to data from people admitted to hospital with COVID-19, to estimate the probability of admission to ICU, the probability of death in hospital for patients before and after ICU admission, the lengths of stay in hospital, and how all these vary with age and gender. One modelling framework is based on defining transition-specific hazard functions for competing risks. A less commonly used framework defines partial…
