An emerging challenge for time-to-event data is studying semi-competing risks, namely when two event times are of interest: a non-terminal event time (e.g. age at disease diagnosis), and a terminal event time (e.g. age at death). The non-terminal event is observed only if it precedes the terminal event, which may occur before or after the non-terminal event. Studying treatment or intervention effects on the dual event times is complicated because for some units, the non-terminal event may occur under one treatment value but not under the other. Until recently, existing approaches (e.g., the survivor average causal effect) generally disregarded the time-to-event nature of both outcomes. More recent research focused on principal strata effects within time-varying populations under Bayesian approaches. In this paper, we propose alternative non time-varying estimands, based on a single stratification of the population. We present a novel assumption utilizing the time-to-event nature of the data, which is weaker than the often-invoked monotonicity assumption. We derive results on partial identifiability, suggest a sensitivity analysis approach, and give conditions under which full identification is possible. Finally, we present non-parametric and semi-parametric estimation methods for right-censored data.
In time-to-event settings, the presence of competing events complicates the definition of causal effects. Here we propose the new separable effects to study the causal effect of a treatment on an event of interest. The separable direct effect is the treatment effect on the event of interest not mediated by its effect on the competing event. The separable indirect effect is the treatment effect on the event of interest only through its effect on the competing event. Similar to Robins and Richardson's extended graphical approach for mediation analysis, the separable effects can only be identifie…
We develop a Bayesian nonparametric (BNP) approach to evaluate the causal effect of treatment in a randomized trial where a nonterminal event may be censored by a terminal event, but not vice versa (i.e., semi-competing risks). Based on the idea of principal stratification, we define a novel estimand for the causal effect of treatment on the nonterminal event. We introduce identification assumptions, indexed by a sensitivity parameter, and show how to draw inference using our BNP approach. We conduct simulation studies and illustrate our methodology using data from a brain cancer trial.
This paper discusses endogenous treatment models with duration outcomes, competing risks and random right censoring. The endogeneity issue is solved using a discrete instrumental variable. We show that the competing risks model generates a non-parametric quantile instrumental regression problem. The cause-specific cumulative incidence, the cause-specific hazard and the subdistribution hazard can be recovered from the regression function. A distinguishing feature of the model is that censoring and competing risks prevent identification at some quantiles. We characterize the set of quantiles for…
When interested in a time-to-event outcome, competing events that prevent the occurrence of the event of interest may be present. In the presence of competing events, various statistical estimands have been suggested for defining the causal effect of treatment on the event of interest. Depending on the estimand, the competing events are either accommodated or eliminated, resulting in causal effects with different interpretation. The former approach captures the total effect of treatment on the event of interest while the latter approach captures the direct effect of treatment on the event of i…
In failure-time settings, a competing risk event is any event that makes it impossible for the event of interest to occur. For example, cardiovascular disease death is a competing event for prostate cancer death because an individual cannot die of prostate cancer once he has died of cardiovascular disease. Various statistical estimands have been defined as possible targets of inference in the classical competing risks literature. Many reviews have described these statistical estimands and their estimating procedures with recommendations about their use. However, this previous work has not used…
Time-to-event analyses are often plagued by both -- possibly unmeasured -- confounding and competing risks. To deal with the former, the use of instrumental variables for effect estimation is rapidly gaining ground. We show how to make use of such variables in competing risk analyses. In particular, we show how to infer the effect of an arbitrary exposure on cause-specific hazard functions under a semi-parametric model that imposes relatively weak restrictions on the observed data distribution. The proposed approach is flexible accommodating exposures and instrumental variables of arbitrary ty…
Illustrating implications of misaligned causal questions and statistics in settings with competing events and interest in treatment mechanisms
Harvard Medical School（哈佛医学院）；Harvard Pilgrim Health Care Institute（哈佛皮尔格林健康保健研究所）；The University of Tokyo Hospital（东京大学医院）；Yale School of Public Health（耶鲁大学公共卫生学院）；Harvard T. H. Chan School of Public Health（哈佛陈曾熙公共卫生学院）
Background: Under competing risks, the commonly used sub-distribution hazard ratio (SHR) is not easy to interpret clinically and is valid only under the proportional sub-distribution hazard (SDH) assumption. This paper introduces an alternative statistical measure: the restricted mean time lost (RMTL). Methods: First, the definition and estimation methods of the measures are introduced. Second, based on the differences in RMTLs, a basic difference test (Diff) and a supremum difference test (sDiff) are constructed. Then, the corresponding sample size estimation method is proposed. The statistic…
In this paper, we discuss causal inference on the efficacy of a treatment or medication on a time-to-event outcome with competing risks. Although the treatment group can be randomized, there can be confoundings between the compliance and the outcome. Unmeasured confoundings may exist even after adjustment for measured co- variates. Instrumental variable (IV) methods are commonly used to yield consistent estimations of causal parameters in the presence of unmeasured confoundings. Based on a semi-parametric additive hazard model for the subdistribution hazard, we pro- pose an instrumental variab…
In semicompeting risks problems, nonterminal time-to-event outcomes such as time to hospital readmission are subject to truncation by death. These settings are often modeled with illness-death models for the hazards of the terminal and nonterminal events, but evaluating causal treatment effects with hazard models is problematic due to conditioning on survival (a post-treatment outcome) that is embedded in the definition of a hazard. Extending an existing survivor average causal effect (SACE) estimand, we frame the evaluation of treatment effects in the context of semicompeting risks with princ…
We are interested in the estimation of average treatment effects based on right-censored data of an observational study. We focus on causal inference of differences between t-year absolute event risks in a situation with competing risks. We derive doubly robust estimation equations and implement estimators for the nuisance parameters based on working regression models for the outcome, the censoring and the treatment distribution conditional on auxiliary baseline covariates. We use the functional delta method to show that our estimators are regular asymptotically linear estimators and estimate …
A Guide to Estimating Conditional Average Treatment Effects in Competing Risks Settings
Department of Statistics, TU Dortmund University（图恩-多特蒙德大学统计学系）；Research Center Trustworthy Data Science and Security, University Alliance Ruhr (UA Ruhr)（鲁尔大学联盟可信数据科学与安全研究中心）；Institute for Mathematics, University of Augsburg（艾希施泰特大学数学研究所）
Recent years have seen many advances in methods for causal structure learning from data. The empirical assessment of such methods, however, is much less developed. Motivated by this gap, we pose the following question: how can one assess, in a given problem setting, the practical efficacy of one or more causal structure learning methods? We formalize the problem in a decision-theoretic framework, via a notion of expected loss or risk for the causal setting. We introduce a theoretical notion of causal risk as well as sample quantities that can be computed from data, and study the relationship b…
It is emphasised that for epidemiological studies where disease incidence is rare, results from conventional proportional hazards models can often correctly estimate causal associations. The well-known "backdoor criteria" from causal-inference is applied to the common epidemiological study of rare diseases with a proportional hazards model, providing an example of when and how estimates from conventional proportional hazards studies can be used. A similar study with the "frontdoor criteria", that allows studies with unmeasured confounders, finds similar results to conventional mediation analys…
Background: In epidemiology, causal inference and prediction modeling methodologies have been historically distinct. Directed Acyclic Graphs (DAGs) are used to model a priori causal assumptions and inform variable selection strategies for causal questions. Although tools originally designed for prediction are finding applications in causal inference, the counterpart has remained largely unexplored. The aim of this theoretical and simulation-based study is to assess the potential benefit of using DAGs in clinical risk prediction modeling. Methods and Findings: We explore how incorporating knowl…
No unmeasured confounding is often assumed in estimating treatment effects in observational data when using approaches such as propensity scores and inverse probability weighting. However, in many such studies due to the limitation of the databases, collected confounders are not exhaustive, and it is crucial to examine the extent to which the resulting estimate is sensitive to the unmeasured confounders. We consider this problem for survival and competing risks data. Due to the complexity of models for such data, we adapt the simulated potential confounders approach of Carnegie et al. (2016), …
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…
In this article, a general family of bivariate distributions is used to model competing risks data with dependent factors. The general structure of competing risks data considered here includes ties. A comprehensive inferential framework for the proposed model is presented: maximum likelihood estimation, confidence interval construction, and model selection within the bivariate family of distributions for a given dependent competing risks data. The inferential methods are very convenient to implement. Through detailed simulations, the inferential methods are observed to provide quite reasonabl…
We propose a new method for the analysis of competing risks data with long term survivors. The proposed method enables us to estimate the overall survival probability and cure fraction simultaneously. We formulate the effect of covariates on cumulative incidence functions using linear transformation models. Estimating equations based on counting process are developed to estimate regression coefficients. The asymptotic properties of the estimators are studied using martingale theory. An extensive Monte Carlo simulation study is carried out to assess the finite sample performance of the proposed…
The purpose of this paper is to construct confidence intervals for the regression coefficients in the Fine-Gray model for competing risks data with random censoring, where the number of covariates can be larger than the sample size. Despite strong motivation from biomedical applications, a high-dimensional Fine-Gray model has attracted relatively little attention among the methodological or theoretical literature. We fill in this gap by developing confidence intervals based on a one-step bias-correction for a regularized estimation. We develop a theoretical framework for the partial likelihood…
Competing risks model time to first event and type of first event. An example from hospital epidemiology is the incidence of hospital-acquired infection, which has to account for hospital discharge of non-infected patients as a competing risk. An illness-death model would allow to further study hospital outcomes of infected patients. Such a model typically relies on a Markov assumption. However, it is conceivable that the future course of an infected patient does not only depend on the time since hospital admission and current infection status but also on the time since infection. We demonstra…
The analysis and planning methods for competing risks model have been described in the literatures in recent decades, and non-inferiority clinical trials are helpful in current pharmaceutical practice. Analytical methods for non-inferiority clinical trials in the presence of competing risks were investigated by Parpia et al., who indicated that the proportional sub-distribution hazard model is appropriate in the context of biological studies. However, the analytical methods of competing risks model differ from those appropriate for analyzing non-inferiority clinical trials with a single outcom…
Causal treatment effect decompositions with time-to-event outcomes under competing events
University of Turku（图尔库大学）；Finnish Institute for Health and Welfare（芬兰健康福利研究所）；University of Eastern Finland（东芬兰大学）；Karolinska Institutet（卡罗林斯卡学院）；Imperial College London（伦敦帝国理工学院）；Karolinska University Hospital（卡罗林斯卡大学医院）
The Adult Changes in Thought (ACT) study is a long-running prospective study of incident all-cause dementia and Alzheimer's disease (AD). As the cohort ages, death (a terminal event) is a prominent competing risk for AD (a non-terminal event), although the reverse is not the case. As such, analyses of data from ACT can be placed within the semi-competing risks framework. Central to semi-competing risks, and in contrast to standard competing risks, is that one can learn about the dependence structure between the two events. To-date, however, most methods for semi-competing risks treat dependenc…
The methodological advancements made in the field of joint models are numerous. None the less, the case of competing risks joint models have largely been neglected, especially from a practitioner's point of view. In the relevant works on competing risks joint models, the assumptions of Gaussian linear longitudinal series and proportional cause-specific hazard functions, amongst others, have remained unchallenged. In this paper, we provide a framework based on R-INLA to apply competing risks joint models in a unifying way such that non-Gaussian longitudinal data, spatial structures, time depend…
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…
A novel approach for dealing with censored competing risks regression data is proposed. This is implemented by a mixture of accelerated failure time (AFT) models for a competing risks scenario within a cluster-weighted modelling (CWM) framework. Specifically, we make use of the log-normal AFT model here but any commonly used AFT model can be utilized. The alternating expectation conditional maximization algorithm (AECM) is used for parameter estimation and bootstrapping for standard error estimation. Finally, we present our results on some simulated and real competing risks data.
Mammographic screening and prophylactic surgery such as risk-reducing salpingo oophorectomy (RRSO) can potentially reduce breast cancer risks among mutation carriers of BRCA families. The evaluation of these interventions is usually complicated by the fact that their effects on breast cancer may change over time and by the presence of competing risks. We introduce a correlated competing risks model to model breast and ovarian cancer risks within BRCA1 families that accounts for time-varying covariates (TVCs). Different parametric forms for these TVCs are proposed for more flexibility and a cor…
A typical situation in competing risks analysis is that the researcher is only interested in a subset of risks. This paper considers a depending competing risks model with the distribution of one risk being a parametric or semi-parametric model, while the model for the other risks being unknown. Identifiability is shown for popular classes of parametric models and the semiparametric proportional hazards model. The identifiability of the parametric models does not require a covariate, while the semiparametric model requires at least one. Estimation approaches are suggested which are shown to be…
Under adaptive progressive Type-II censoring schemes, order restricted inference based on competing risks data is discussed in this article. The latent failure lifetimes for the competing causes are assumed to follow Weibull distributions, with an order restriction on the scale parameters of the distributions. The practical implication of this order restriction is that one of the risk factors is dominant, as often observed in competing risks scenarios. In this setting, likelihood estimation for the model parameters, along with bootstrap based techniques for constructing asymptotic confidence i…
When considering a genetic disease with variable age at onset (ex: diabetes , familial amyloid neuropathy, cancers, etc.), computing the individual risk of the disease based on family history (FH) is of critical interest both for clinicians and patients. Such a risk is very challenging to compute because: 1) the genotype X of the individual of interest is in general unknown; 2) the posterior distribution P(X|FH, T > t) changes with t (T is the age at disease onset for the targeted individual); 3) the competing risk of death is not negligible. In this work, we present a modeling of this problem…
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 …
Scoring rules are used to evaluate the quality of predictions that take the form of probability distributions. A scoring rule is strictly proper if its expected value is uniquely minimized by the true probability distribution. One of the most well-known and widely used strictly proper scoring rules is the logarithmic scoring rule. We propose a version of the logarithmic scoring rule for competing risks data and show that it remains strictly proper under non-informative censoring.
In this paper, we extend the vertical modeling approach for the analysis of survival data with competing risks to incorporate a cured fraction in the population, that is, a proportion of the population for which none of the competing events can occur. The proposed method has three components: the proportion of cure, the risk of failure, irrespective of the cause, and the relative risk of a certain cause of failure, given a failure occurred. Covariates may affect each of these components. An appealing aspect of the method is that it is a natural extension to competing risks of the semi-parametr…
Random forests are a sensible non-parametric model to predict competing risk data according to some covariates. However, there are currently no packages that can adequately handle large datasets ($n > 100,000$). We introduce a new R package, largeRCRF, using the random competing risks forest theory developed by Ishwaran et al. (2014). We verify our package's validity and accuracy through simulation studies and show that its results are similar enough to randomForestSRC while taking less time to run. We also demonstrate the package on a large dataset that was previously inaccessible, using hard…
Analysis of competing risks data plays an important role in the lifetime data analysis. Recently Feizjavadian and Hashemi (Computational Statistics and Data Analysis, vol. 82, 19-34, 2015) provided a classical inference of a competing risks data set using four-parameter Marshall-Olkin bivariate Weibull distribution when the failure of an unit at a particular time point can happen due to more than one cause. The aim of this paper is to provide the Bayesian analysis of the same model based on a very flexible Gamma-Dirichlet prior on the scale parameters. It is observed that the Bayesian inferenc…
McCombs School of Business（麦克库姆斯商学院）；The University of Texas at Austin（德克萨斯大学奥斯汀分校）
We propose Lomax delegate racing (LDR) to explicitly model the mechanism of survival under competing risks and to interpret how the covariates accelerate or decelerate the time to event. LDR explains non-monotonic covariate effects by racing a potentially infinite number of sub-risks, and consequently relaxes the ubiquitous proportional-hazards assumption which may be too restrictive. Moreover, LDR is naturally able to model not only censoring, but also missing event times or event types. For inference, we develop a Gibbs sampler under data augmentation for moderately sized data, along with a …
Competing risks data with discrete lifetime comes up in practice. However, only limited literature exists for such data. In this paper, we propose a non-parametric test based on U-statistics for testing independence of time to failure and cause of failure of competing risks data when the lifetime is a discrete random variable. Asymptotic distribution of the proposed test statistic is derived. An extensive Monte Carlo simulation study is conducted to assess the finite sample performance of the proposed test. The flexibility of the testing procedure is illustrated using real data sets on oral ca…
We apply Gaussian process (GP) regression, which provides a powerful non-parametric probabilistic method of relating inputs to outputs, to survival data consisting of time-to-event and covariate measurements. In this context, the covariates are regarded as the `inputs' and the event times are the `outputs'. This allows for highly flexible inference of non-linear relationships between covariates and event times. Many existing methods, such as the ubiquitous Cox proportional hazards model, focus primarily on the hazard rate which is typically assumed to take some parametric or semi-parametric fo…
