Identification of Longitudinal Biomarkers in Survival Analysis for Competing Risks Data

In recent years, joint analysis of longitudinal measurements and survival data has received much attention. However, previous work has primarily focused on a single failure type for the event time. In this article, we consider joint modeling of repeated measurements and competing risks failure time data to allow for more than one distinct failure type in the survival endpoint so we fit a cause-specific hazards sub-model to allow for competing risks, with a separate latent association between longitudinal measurements and each cause of failure. Besides, previous work does not focus on the hypothesis to test a separate latent association between longitudinal measurements and each cause of failure. In this article, we derive a score test to identify longitudinal biomarkers or surrogates for a time to event outcome in competing risks data. With a carefully chosen definition of complete data, the maximum likelihood estimation of the cause-specific hazard functions is performed via an EM algorithm. We extend this work and allow random effects to be present in both the longitudinal biomarker and underlying survival function. The random effects in the biomarker are introduced via an explicit term while the random effect in the underlying survival function is introduced by the inclusion of frailty into the model.

We use simulations to explore how the number of individuals, the number of time points per individual and the functional form of the random effects from the longitudinal biomarkers considering heterogeneous baseline hazards in individuals influence the power to detect the association of a longitudinal biomarker and the survival time.     

Analysis of Competing Risks by Using Bayesian Smoothing

We consider the competing risks set-up. In many practical situations, the conditional probability of the cause of failure given the failure time is of direct interest. We propose to model the competing risks by the overall hazard rate and the conditional probabilities rather than the cause-specific hazards. We adopt a Bayesian smoothing approach for both quantities of interest. Illustrations are given at the end.     

Testing dependence between the failure time and failure modes: An application of enlarged filtration

The model of independent competing risks provides no information for the assessment of competing failure modes if the failure mechanisms underlying these modes are coupled. Models for dependent competing risks in the literature can be distinguished on the basis of the functional behaviour of the conditional probability of failure due to a particular failure mode given that the failure time exceeds a fixed time, as a function of time. There is an interesting link between monotonicity of such conditional probability and dependence between failure time and failure mode, via crude hazard rates. In this paper, we propose tests for testing the dependence between failure time and failure mode using the crude hazards and using the conditional probabilities mentioned above. We establish the equivalence between the two approaches and provide an asymptotically efficient weight function under a sequence of local alternatives. The tests are applied to simulated data and to mortality follow-up data.     

A general joint model for longitudinal measurements and competing risks survival data with heterogeneous random effects

This article studies a general joint model for longitudinal measurements and competing risks survival data. The model consists of a linear mixed effects sub-model for the longitudinal outcome, a proportional cause-specific hazards frailty sub-model for the competing risks survival data, and a regression sub-model for the variance–covariance matrix of the multivariate latent random effects based on a modified Cholesky decomposition. The model provides a useful approach to adjust for non-ignorable missing data due to dropout for the longitudinal outcome, enables analysis of the survival outcome with informative censoring and intermittently measured time-dependent covariates, as well as joint analysis of the longitudinal and survival outcomes. Unlike previously studied joint models, our model allows for heterogeneous random covariance matrices. It also offers a framework to assess the homogeneous covariance assumption of existing joint models. A Bayesian MCMC procedure is developed for parameter estimation and inference. Its performances and frequentist properties are investigated using simulations. A real data example is used to illustrate the usefulness of the approach.     

Inference for cumulative incidence on discrete failure times with competing risks

In the competing risks analysis, most inferences have been developed based on continuous failure time data. However, failure times are sometimes observed as being discrete. We propose nonparametric inferences for the cumulative incidence function for pure discrete data with competing risks. When covariate information is available, we propose semiparametric inferences for direct regression modelling of the cumulative incidence function for grouped discrete failure time data with competing risks. Simulation studies show that the procedures perform well. The proposed methods are illustrated with a study of contraceptive use in Indonesia.     

On a mixture autoregressive model

We generalize the Gaussian mixture transition distribution (GMTD) model introduced by Le and co-workers to the mixture autoregressive (MAR) model for the modelling of non-linear time series. The models consist of a mixture of K stationary or non-stationary AR components. The advantages of the MAR model over the GMTD model include a more full range of shape changing predictive distributions and the ability to handle cycles and conditional heteroscedasticity in the time series. The stationarity conditions and autocorrelation function are derived. The estimation is easily done via a simple EM algorithm and the model selection problem is addressed. The shape changing feature of the conditional distributions makes these models capable of modelling time series with multimodal conditional distributions and with heteroscedasticity. The models are applied to two real data sets and compared with other competing models. The MAR models appear to capture features of the data better than other competing models do.     

Joint modelling of longitudinal response and time-to-event data using conditional distributions: a Bayesian perspective

Over the last 20 or more years a lot of clinical applications and methodological development in the area of joint models of longitudinal and time-to-event outcomes have come up. In these studies, patients are followed until an event, such as death, occurs. In most of the work, using subject-specific random-effects as frailty, the dependency of these two processes has been established. In this article, we propose a new joint model that consists of a linear mixed-effects model for longitudinal data and an accelerated failure time model for the time-to-event data. These two sub-models are linked via a latent random process. This model will capture the dependency of the time-to-event on the longitudinal measurements more directly. Using standard priors, a Bayesian method has been developed for estimation. All computations are implemented using OpenBUGS. Our proposed method is evaluated by a simulation study, which compares the conditional model with a joint model with local independence by way of calibration. Data on Duchenne muscular dystrophy (DMD) syndrome and a set of data in AIDS patients have been analysed.     

Vertical modeling: analysis of competing risks data with a cure fraction

In this paper, we extend the vertical modeling approach for the analysis of survival data with competing risks to incorporate a cure 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-parametric mixture cure model in ordinary survival analysis; thus, causes of failure are assigned only if a failure occurs. This contrasts with the existing mixture cure model for competing risks of Larson and Dinse, which conditions at the onset on the future status presumably attained. Regression parameter estimates are obtained using an EM-algorithm. The performance of the estimators is evaluated in a simulation study. The method is illustrated using a melanoma cancer data set.

     

Consistency of the Generalized MLE with Interval-Censored and Masked Competing Risks Data

We consider nonparametric estimation based on interval-censored competing risks data with masked failure cause. The generalized maximum likelihood estimator of the joint survival function of the failure time and the failure cause is studied under mixed case interval censorship and random partition masking. Strong consistency in the L ₁(μ)-topology is established for some finite measure μ which is derived from the joint censoring and masking distribution. Under additional regularity assumptions we also establish the strong consistencies in the topologies of weak convergence, point-wise convergence, and uniform convergence.     

Bayesian Analysis of Masked Series System Lifetime Data

The problem of analyzing series system lifetime data with masked or partial information on cause of failure is recent, compared to that of the standard competing risks model. A generic Gibbs sampling scheme is developed in this article towards a Bayesian analysis for a general parametric competing risks model with masked cause of failure data. The masking probabilities are not subjected to the symmetry assumption and independent Dirichlet priors are used to marginalize these nuisance parameters. The developed methodology is illustrated for the case where the components of a series system have independent log-Normal life distributions by employing independent Normal-Gamma priors for these component lifetime parameters. The Gibbs sampling scheme developed for the required analysis can also be used to provide a Bayesian analysis of data arising from the conventional competing risks model of independent log-Normals, which interestingly has so far remained by and large neglected in the literature. The developed methodology is deployed to analyze a masked lifetime data of PS/2 computer systems.     

Semiparametric analysis of mixture regression models with competing risks data

In the analysis of competing risks data, cumulative incidence function is a useful summary of the overall crude risk for a failure type of interest. Mixture regression modeling has served as a natural approach to performing covariate analysis based on this quantity. However, existing mixture regression methods with competing risks data either impose parametric assumptions on the conditional risks or require stringent censoring assumptions. In this article, we propose a new semiparametric regression approach for competing risks data under the usual conditional independent censoring mechanism. We establish the consistency and asymptotic normality of the resulting estimators. A simple resampling method is proposed to approximate the distribution of the estimated parameters and that of the predicted cumulative incidence functions. Simulation studies and an analysis of a breast cancer dataset demonstrate that our method performs well with realistic sample sizes and is appropriate for practical use.     

On the NBU ageing notion within the competing risks model

The classical competing risks model deals with failure times of items subject to multiple causes of failure. We propose a version of the well-known ‘new better than used’ and ‘new worse than used’ ageing notions for random lifetimes within a specific cause of failure in the competing risks set up. Various properties of these new notions are studied, including the closure under time-dependent scale changes, as well as their connection to the hazard rate functions of the competing risks model. A data analytic example is finally provided.     

The Bernstein–von Mises theorem in semiparametric competing risks models

Semiparametric Bayesian models are nowadays a popular tool in event history analysis. An important area of research concerns the investigation of frequentist properties of posterior inference. In this paper, we propose novel semiparametric Bayesian models for the analysis of competing risks data and investigate the Bernstein–von Mises theorem for differentiable functionals of model parameters. The model is specified by expressing the cause-specific hazard as the product of the conditional probability of a failure type and the overall hazard rate. We take the conditional probability as a smooth function of time and leave the cumulative overall hazard unspecified. A prior distribution is defined on the joint parameter space, which includes a beta process prior for the cumulative overall hazard. We first develop the large-sample properties of maximum likelihood estimators by giving simple sufficient conditions for them to hold. Then, we show that, under the chosen priors, the posterior distribution for any differentiable functional of interest is asymptotically equivalent to the sampling distribution derived from maximum likelihood estimation. A simulation study is provided to illustrate the coverage properties of credible intervals on cumulative incidence functions.     

Joint models with multiple longitudinal outcomes and a time-to-event outcome: a corrected two-stage approach

Joint models for longitudinal and survival data have gained a lot of attention in recent years, with the development of myriad extensions to the basic model, including those which allow for multivariate longitudinal data, competing risks and recurrent events. Several software packages are now also available for their implementation. Although mathematically straightforward, the inclusion of multiple longitudinal outcomes in the joint model remains computationally difficult due to the large number of random effects required, which hampers the practical application of this extension. We present a novel approach that enables the fitting of such models with more realistic computational times. The idea behind the approach is to split the estimation of the joint model in two steps: estimating a multivariate mixed model for the longitudinal outcomes and then using the output from this model to fit the survival submodel. So-called two-stage approaches have previously been proposed and shown to be biased. Our approach differs from the standard version, in that we additionally propose the application of a correction factor, adjusting the estimates obtained such that they more closely resemble those we would expect to find with the multivariate joint model. This correction is based on importance sampling ideas. Simulation studies show that this corrected two-stage approach works satisfactorily, eliminating the bias while maintaining substantial improvement in computational time, even in more difficult settings.

     

Fully exponential Laplace approximations for the joint modelling of survival and longitudinal data

Summary.  A common objective in longitudinal studies is the joint modelling of a longitudinal response with a time-to-event outcome. Random effects are typically used in the joint modelling framework to explain the interrelationships between these two processes. However, estimation in the presence of random effects involves intractable integrals requiring numerical integration. We propose a new computational approach for fitting such models that is based on the Laplace method for integrals that makes the consideration of high dimensional random-effects structures feasible. Contrary to the standard Laplace approximation, our method requires much fewer repeated measurements per individual to produce reliable results.     

Multilevel models for longitudinal variables prognostic for survival

The issue of modelling the joint distribution of survival time and of prognostic variables measured periodically has recently become of interest in the AIDS literature but is of relevance in other applications. The focus of this paper is on clinical trials where follow-up measurements of potentially prognostic variables are often collected but not routinely used. These measurements can be used to study the biological evolution of the disease of interest; in particular the effect of an active treatment can be examined by comparing the time profiles of patients in the active and placebo group. It is proposed to use multilevel regression analysis to model the individual repeated observations as function of time and, possibly, treatment. To address the problem of informative drop-out—which may arise if deaths (or any other censoring events) are related to the unobserved values of the prognostic variables—we analyse sequentially overlapping portions of the follow-up information. An example arising from a randomized clinical trial for the treatment of primary biliary cirrhosis is examined in detail.     

Exact inference for competing risks model with generalized type-I hybrid censored exponential data

Recently, exact inference under hybrid censoring scheme has attracted extensive attention in the field of reliability analysis. However, most of the authors neglect the possibility of competing risks model. This paper mainly discusses the exact likelihood inference for the analysis of generalized type-I hybrid censoring data with exponential competing failure model. Based on the maximum likelihood estimates for unknown parameters, we establish the exact conditional distribution of parameters by conditional moment generating function, and then obtain moment properties as well as exact confidence intervals (CIs) for parameters. Furthermore, approximate CIs are constructed by asymptotic distribution and bootstrap method as well. We also compare their performances with exact method through the use of Monte Carlo simulations. And finally, a real data set is analysed to illustrate the validity of all the methods developed here.     

Bounds for the hazard gradients in the competing risks set up

The joint survival function of the latent lifetimes in the dependent competing risks set up is nonidentifiable from the joint probability distribution of the observation (failure time, cause of failure). This paper concentrates on the hazard gradients associated with the joint survival function, for which we provide bounds in the general dependent case and improve these in case the type of dependence (e.g., RTI, RCSI, etc.) is known. This leads to bounds on net (marginal) hazard rates in terms of cause-specific hazard rates which are identifiable. The problem of estimation of these bounds is discussed at the end.     

Planning and analyzing clinical trials with competing risks: Recommendations for choosing appropriate statistical methodology

In the analysis of time‐to‐event data, competing risks occur when multiple event types are possible, and the occurrence of a competing event precludes the occurrence of the event of interest. In this situation, statistical methods that ignore competing risks can result in biased inference regarding the event of interest. We review the mechanisms that lead to bias and describe several statistical methods that have been proposed to avoid bias by formally accounting for competing risks in the analyses of the event of interest. Through simulation, we illustrate that Gray's test should be used in lieu of the logrank test for nonparametric hypothesis testing. We also compare the two most popular models for semiparametric modelling: the cause‐specific hazards (CSH) model and Fine‐Gray (F‐G) model. We explain how to interpret estimates obtained from each model and identify conditions under which the estimates of the hazard ratio and subhazard ratio differ numerically. Finally, we evaluate several model diagnostic methods with respect to their sensitivity to detect lack of fit when the CSH model holds, but the F‐G model is misspecified and vice versa. Our results illustrate that adequacy of model fit can strongly impact the validity of statistical inference. We recommend analysts incorporate a model diagnostic procedure and contingency to explore other appropriate models when designing trials in which competing risks are anticipated.     

Estimation and inference of the joint conditional distribution for multivariate longitudinal data using nonparametric copulas

In this paper we study estimating the joint conditional distributions of multivariate longitudinal outcomes using regression models and copulas. For the estimation of marginal models, we consider a class of time-varying transformation models and combine the two marginal models using nonparametric empirical copulas. Our models and estimation method can be applied in many situations where the conditional mean-based models are not good enough. Empirical copulas combined with time-varying transformation models may allow quite flexible modelling for the joint conditional distributions for multivariate longitudinal data. We derive the asymptotic properties for the copula-based estimators of the joint conditional distribution functions. For illustration we apply our estimation method to an epidemiological study of childhood growth and blood pressure.