A joint modelling approach for clustered recurrent events and death events

In dental implant research studies, events such as implant complications including pain or infection may be observed recurrently before failure events, i.e. the death of implants. It is natural to assume that recurrent events and failure events are correlated to each other, since they happen on the same implant (subject) and complication times have strong effects on the implant survival time. On the other hand, each patient may have more than one implant. Therefore these recurrent events or failure events are clustered since implant complication times or failure times within the same patient (cluster) are likely to be correlated. The overall implant survival times and recurrent complication times are both interesting to us. In this paper, a joint modelling approach is proposed for modelling complication events and dental implant survival times simultaneously. The proposed method uses a frailty process to model the correlation within cluster and the correlation within subjects. We use Bayesian methods to obtain estimates of the parameters. Performance of the joint models are shown via simulation studies and data analysis.     

Marginal Regression of Multivariate Event Times Based on Linear Transformation Models

Multivariate event time data are common in medical studies and have received much attention recently. In such data, each study subject may potentially experience several types of events or recurrences of the same type of event, or event times may be clustered. Marginal distributions are specified for the multivariate event times in multiple events and clustered events data, and for the gap times in recurrent events data, using the semiparametric linear transformation models while leaving the dependence structures for related events unspecified. We propose several estimating equations for simultaneous estimation of the regression parameters and the transformation function. It is shown that the resulting regression estimators are asymptotically normal, with variance–covariance matrix that has a closed form and can be consistently estimated by the usual plug-in method. Simulation studies show that the proposed approach is appropriate for practical use. An application to the well-known bladder cancer tumor recurrences data is also given to illustrate the methodology.     

Multi-state Models: A Review

Multi-state models are models for a process, for example describing a life history of an individual, which at any time occupies one of a few possible states. This can describe several possible events for a single individual, or the dependence between several individuals. The events are the transitions between the states. This class of models allows for an extremely flexible approach that can model almost any kind of longitudinal failure time data. This is particularly relevant for modeling different events, which have an event-related dependence, like occurrence of disease changing the risk of death. It can also model paired data. It is useful for recurrent events, but has limitations. The Markov models stand out as much simpler than other models from a probability point of view, and this simplifies the likelihood evaluation. However, in many cases, the Markov models do not fit satisfactorily, and happily, it is reasonably simple to study non-Markov models, in particular the Markov extension models. This also makes it possible to consider, whether the dependence is of short-term or long-term nature. Applications include the effect of heart transplantation on the mortality and the mortality among Danish twins.     

Parametric versus semi-parametric models for the analysis of correlated survival data: A case study in veterinary epidemiology

Correlated survival data arise frequently in biomedical and epidemiologic research, because each patient may experience multiple events or because there exists clustering of patients or subjects, such that failure times within the cluster are correlated. In this paper, we investigate the appropriateness of the semi-parametric Cox regression and of the generalized estimating equations as models for clustered failure time data that arise from an epidemiologic study in veterinary medicine. The semi-parametric approach is compared with a proposed fully parametric frailty model. The frailty component is assumed to follow a gamma distribution. Estimates of the fixed covariates effects were obtained by maximizing the likelihood function, while an estimate of the variance component ( frailty parameter) was obtained from a profile likelihood construction.     

The analysis of multivariate recurrent events with partially missing event types

In many clinical studies, subjects are at risk of experiencing more than one type of potentially recurrent event. In some situations, however, the occurrence of an event is observed, but the specific type is not determined. We consider the analysis of this type of incomplete data when the objectives are to summarize features of conditional intensity functions and associated treatment effects, and to study the association between different types of event. Here we describe a likelihood approach based on joint models for the multi-type recurrent events where parameter estimation is obtained from a Monte-Carlo EM algorithm. Simulation studies show that the proposed method gives unbiased estimators for regression coefficients and variance–covariance parameters, and the coverage probabilities of confidence intervals for regression coefficients are close to the nominal level. When the distribution of the frailty variable is misspecified, the method still provides estimators of the regression coefficients with good properties. The proposed method is applied to a motivating data set from an asthma study in which exacerbations were to be sub-typed by cellular analysis of sputum samples as eosinophilic or non-eosinophilic.     

Analysis of spatial frailty models by a weighted estimating equation

Spatially correlated survival data are frequently observed in ecological and epidemiological studies. An assumption in the clustered survival models is inter-cluster independence, which may not be adequate to model the dependence in spatial settings. For survival data, the likelihood function based on a spatial frailty may be complicated. In this paper, we develop a weighted estimating equation for spatially right-censored data. Some large sample properties for the estimate are developed. We also conduct simulations to compare estimation performance with other methods. A data set from a study of forest decline in Wisconsin is used to illustrate the proposed method.     

Rank Regression Analysis of Multivariate Failure Time Data Based on Marginal Linear Models

Abstract.  Multivariate failure time data arises when each study subject can potentially ex-perience several types of failures or recurrences of a certain phenomenon, or when failure times are sampled in clusters. We formulate the marginal distributions of such multivariate data with semiparametric accelerated failure time models (i.e. linear regression models for log-transformed failure times with arbitrary error distributions) while leaving the dependence structures for related failure times completely unspecified. We develop rank-based monotone estimating functions for the regression parameters of these marginal models based on right-censored observations. The estimating equations can be easily solved via linear programming. The resultant estimators are consistent and asymptotically normal. The limiting covariance matrices can be readily estimated by a novel resampling approach, which does not involve non-parametric density estimation or evaluation of numerical derivatives. The proposed estimators represent consistent roots to the potentially non-monotone estimating equations based on weighted log-rank statistics. Simulation studies show that the new inference procedures perform well in small samples. Illustrations with real medical data are provided.     

Implications of Model Misspecification in Robust Tests for Recurrent Events

Chronic disease processes often feature transient recurrent adverse clinical events. Treatment comparisons in clinical trials of such disorders must be based on valid and efficient methods of analysis. We discuss robust strategies for testing treatment effects with recurrent events using methods based on marginal rate functions, partially conditional rate functions, and methods based on marginal failure time models. While all three approaches lead to valid tests of the null hypothesis when robust variance estimates are used, they differ in power. Moreover, some approaches lead to estimators of treatment effect which are more easily interpreted than others. To investigate this, we derive the limiting value of estimators of treatment effect from marginal failure time models and illustrate their dependence on features of the underlying point process, as well as the censoring mechanism. Through simulation, we show that methods based on marginal failure time distributions are shown to be sensitive to treatment effects delaying the occurrence of the very first recurrences. Methods based on marginal or partially conditional rate functions perform well in situations where treatment effects persist or in settings where the aim is to summarizee long-term data on efficacy.     

Integrated likelihoods in parametric survival models for highly clustered censored data

In studies that involve censored time-to-event data, stratification is frequently encountered due to different reasons, such as stratified sampling or model adjustment due to violation of model assumptions. Often, the main interest is not in the clustering variables, and the cluster-related parameters are treated as nuisance. When inference is about a parameter of interest in presence of many nuisance parameters, standard likelihood methods often perform very poorly and may lead to severe bias. This problem is particularly evident in models for clustered data with cluster-specific nuisance parameters, when the number of clusters is relatively high with respect to the within-cluster size. However, it is still unclear how the presence of censoring would affect this issue. We consider clustered failure time data with independent censoring, and propose frequentist inference based on an integrated likelihood. We then apply the proposed approach to a stratified Weibull model. Simulation studies show that appropriately defined integrated likelihoods provide very accurate inferential results in all circumstances, such as for highly clustered data or heavy censoring, even in extreme settings where standard likelihood procedures lead to strongly misleading results. We show that the proposed method performs generally as well as the frailty model, but it is superior when the frailty distribution is seriously misspecified. An application, which concerns treatments for a frequent disease in late-stage HIV-infected people, illustrates the proposed inferential method in Weibull regression models, and compares different inferential conclusions from alternative methods.     

Regression analysis for discrete event history or failure time data

The paper deals with discrete-time regression models to analyze multistate—multiepisode models for event history data or failure time data collected in follow-up studies, retrospective studies, or longitudinal panels. The models are applicable if the events are not dated exactly but only a time interval is recorded. The models include individual specific parameters to account for unobserved heterogeneity. The explantory variables may be time-varying and random with distributions depending on the observed history of the process. Different estimation procedures are considered: Estimation of structural as well as individual specific parameters by maximization of a joint likelihood function, estimation of the structural parameters by maximization of a conditional likelihood function conditioning on a set of sufficient statistics for the individual specific parameters, and estimation of the structural parameters by maximization of a marginal likelihood function assuming that the individual specific parameters follow a distribution. The advantages and limitations of the different approaches are discussed.     

Regression analysis of clustered interval-censored failure time data with linear transformation models in the presence of informative cluster size

This paper discusses regression analysis of clustered interval-censored failure time data, which often occur in medical follow-up studies among other areas. For such data, sometimes the failure time may be related to the cluster size, the number of subjects within each cluster or we have informative cluster sizes. For the problem, we present a within-cluster resampling method for the situation where the failure time of interest can be described by a class of linear transformation models. In addition to the establishment of the asymptotic properties of the proposed estimators of regression parameters, an extensive simulation study is conducted for the assessment of the finite sample properties of the proposed method and suggests that it works well in practical situations. An application to the example that motivated this study is also provided.     

Maximum likelihood estimation for the proportional odds model with mixed interval-censored failure time data

This article discusses regression analysis of mixed interval-censored failure time data. Such data frequently occur across a variety of settings, including clinical trials, epidemiologic investigations, and many other biomedical studies with a follow-up component. For example, mixed failure times are commonly found in the two largest studies of long-term survivorship after childhood cancer, the datasets that motivated this work. However, most existing methods for failure time data consider only right-censored or only interval-censored failure times, not the more general case where times may be mixed. Additionally, among regression models developed for mixed interval-censored failure times, the proportional hazards formulation is generally assumed. It is well-known that the proportional hazards model may be inappropriate in certain situations, and alternatives are needed to analyze mixed failure time data in such cases. To fill this need, we develop a maximum likelihood estimation procedure for the proportional odds regression model with mixed interval-censored data. We show that the resulting estimators are consistent and asymptotically Gaussian. An extensive simulation study is performed to assess the finite-sample properties of the method, and this investigation indicates that the proposed method works well for many practical situations. We then apply our approach to examine the impact of age at cranial radiation therapy on risk of growth hormone deficiency in long-term survivors of childhood cancer.     

Accelerated hazards mixture cure model

We propose a new cure model for survival data with a surviving or cure fraction. The new model is a mixture cure model where the covariate effects on the proportion of cure and the distribution of the failure time of uncured patients are separately modeled. Unlike the existing mixture cure models, the new model allows covariate effects on the failure time distribution of uncured patients to be negligible at time zero and to increase as time goes by. Such a model is particularly useful in some cancer treatments when the treat effect increases gradually from zero, and the existing models usually cannot handle this situation properly. We develop a rank based semiparametric estimation method to obtain the maximum likelihood estimates of the parameters in the model. We compare it with existing models and methods via a simulation study, and apply the model to a breast cancer data set. The numerical studies show that the new model provides a useful addition to the cure model literature.     

Extended complex error correction models for seasonal cointegration

In this paper, we extend the complex error correction model (ECM) of [Cubadda, G. (2001). Complex reduced rank models for seasonally cointegrated time series. Oxford Bulletin of Economics and Statistics, 63, 497–511] to models with two types of deterministic terms: (i) restricted seasonal dummies and constant; (ii) restricted seasonal dummies and unrestricted constant. These types of deterministic terms are most frequently adopted in the analysis of seasonal cointegration by many practitioners and researchers, because the other type–where all seasonal dummies and constant terms are unrestricted–may yield oscillating trends. We obtain the limiting distribution of the likelihood ratio (LR) test for the seasonal cointegrating (CI) rank in the extended models. We also provide asymptotic and finite critical values for the test.     

MULTILEVEL DISCRETE‐TIME EVENT HISTORY MODELS WITH APPLICATIONS TO THE ANALYSIS OF RECURRENT EMPLOYMENT TRANSITIONS

Data on the timing of events such as births, residential moves and changes in employment status are collected in many longitudinal surveys. These data often have a highly complex structure, with events of several types occurring repeatedly over time to an individual and interdependences between different event processes (e.g. births and employment transitions). The aim of this paper is to review a general class of multilevel discrete‐time event history models for handling recurrent events and transitions between multiple states. It is also shown how standard methods can be extended to allow for time‐varying covariates that are outcomes of an event process that is jointly determined with the process of interest. The considerable potential of these methods for studying transitions through the life course is illustrated in analyses of the effect of the presence and age of children on women's employment transitions, using data from the British Household Panel Survey.     

Correcting for non-compliance in randomized trials using rank preserving structural failure time models

We propose correcting for non-compliance in randomized trials by estimating the parameters of a class of semi-parametric failure time models, the rank preserving structural failure time models, using a class of rank estimators. These models are the structural or strong version of the “accelerated failure time model with time-dependent covariates” of Cox and Oakes (1984). In this paper we develop a large sample theory for these estimators, derive the optimal estimator within this class, and briefly consider the construction of “partially adaptive” estimators whose efficiency may approach that of the optimal estimator. We show that in the absence of censoring the optimal estimator attains the semiparametric efficiency bound for the model.     

Methods for the estimation of failure distributions and rates from automobile warranty data

We consider the occurrence of warranty claims for automobiles when both age and mileage accumulation may affect failure. The presence of both age and mileage limits on warranties creates interesting problems for the analysis of failures. We propose a family of models that relates failure to time and mileage accumulation. Methods for fitting the models based on warranty data and supplementary information about mileage accumulation are presented and illustrated on some real data. The general problem of modelling failures in equipment when both time and usage are factors is discussed.     

Buckley–James-type estimation of quantile regression with recurrent gap time data

In longitudinal studies, an individual may potentially undergo a series of repeated recurrence events. The gap times, which are referred to as the times between successive recurrent events, are typically the outcome variables of interest. Various regression models have been developed in order to evaluate covariate effects on gap times based on recurrence event data. The proportional hazards model, additive hazards model, and the accelerated failure time model are all notable examples. Quantile regression is a useful alternative to the aforementioned models for survival analysis since it can provide great flexibility to assess covariate effects on the entire distribution of the gap time. In order to analyze recurrence gap time data, we must overcome the problem of the last gap time subjected to induced dependent censoring, when numbers of recurrent events exceed one time. In this paper, we adopt the Buckley–James-type estimation method in order to construct a weighted estimation equation for regression coefficients under the quantile model, and develop an iterative procedure to obtain the estimates. We use extensive simulation studies to evaluate the finite-sample performance of the proposed estimator. Finally, analysis of bladder cancer data is presented as an illustration of our proposed methodology.     

Some applications of nonlinear and non-Gaussian state–space modelling by means of hidden Markov models

Nonlinear and non-Gaussian state–space models (SSMs) are fitted to different types of time series. The applications include homogeneous and seasonal time series, in particular earthquake counts, polio counts, rainfall occurrence data, glacial varve data and daily returns on a share. The considered SSMs comprise Poisson, Bernoulli, gamma and Student-t distributions at the observation level. Parameter estimations for the SSMs are carried out using a likelihood approximation that is obtained after discretization of the state space. The approximation can be made arbitrarily accurate, and the approximated likelihood is precisely that of a finite-state hidden Markov model (HMM). The proposed method enables us to apply standard HMM techniques. It is easy to implement and can be extended to all kinds of SSMs in a straightforward manner.     

Constant Stress Accelerated Life Test on a Multiple-Component Series System under Weibull Lifetime Distributions

We will discuss the reliability analysis of the constant stress accelerated life test on a series system connected with multiple components under independent Weibull lifetime distributions whose scale parameters are log-linear in the level of the stress variable. The system lifetimes are collected under Type I censoring but the components that cause the systems to fail may or may not be observed. The data are so called masked for the latter case. Maximum likelihood approach and the Bayesian method are considered when the data are masked. Statistical inference on the estimation of the underlying model parameters as well as the mean time to failure and the reliability function will be addressed. Simulation study for a three-component case shows that Bayesian analysis outperforms the maximum likelihood approach especially when the data are highly masked.