Regression Analysis for Multistate Models Based on a Pseudo-value Approach, with Applications to Bone Marrow Transplantation Studies

Abstract.  Typically, regression analysis for multistate models has been based on regression models for the transition intensities. These models lead to highly nonlinear and very complex models for the effects of covariates on state occupation probabilities. We present a technique that models the state occupation or transition probabilities in a multistate model directly. The method is based on the pseudo-values from a jackknife statistic constructed from non-parametric estimators for the probability in question. These pseudo-values are used as outcome variables in a generalized estimating equation to obtain estimates of model parameters. We examine this approach and its properties in detail for two special multistate model probabilities, the cumulative incidence function in competing risks and the current leukaemia-free survival used in bone marrow transplants. The latter is the probability a patient is alive and in either a first or second post-transplant remission. The techniques are illustrated on a dataset of leukaemia patients given a marrow transplant. We also discuss extensions of the model that are of current research interest.     

Temporal prediction of future state occupation in a multistate model from high-dimensional baseline covariates via pseudo-value regression

In many complex diseases such as cancer, a patient undergoes various disease stages before reaching a terminal state (say disease free or death). This fits a multistate model framework where a prognosis may be equivalent to predicting the state occupation at a future time t. With the advent of high-throughput genomic and proteomic assays, a clinician may intent to use such high-dimensional covariates in making better prediction of state occupation. In this article, we offer a practical solution to this problem by combining a useful technique, called pseudo-value (PV) regression, with a latent factor or a penalized regression method such as the partial least squares (PLS) or the least absolute shrinkage and selection operator (LASSO), or their variants. We explore the predictive performances of these combinations in various high-dimensional settings via extensive simulation studies. Overall, this strategy works fairly well provided the models are tuned properly. Overall, the PLS turns out to be slightly better than LASSO in most settings investigated by us, for the purpose of temporal prediction of future state occupation. We illustrate the utility of these PV-based high-dimensional regression methods using a lung cancer data set where we use the patients’ baseline gene expression values.     

Nonparametric estimation of quality adjusted lifetime distribution in a simple illness-death model

In this work, we consider the nonparametric estimation of quality adjusted lifetime (QAL) distribution in a simple illness-death model. We first derive the expression of QAL distribution in terms of the distribution of sojourn time in each health state. Next we substitute the estimate of sojourn time distributions in the expression of QAL distribution to obtain its estimate. Consistency and asymptotic normality of the proposed nonparametric estimator are established. Estimation in the presence of some missing data on the transition time to illness is also discussed. We conduct a simulation study to investigate the performance of the proposed estimator. For illustration, we analyse a data set of the Stanford Heart Transplant program. Extension to multistate progressive model is discussed along with an analysis of International Breast Cancer Study Group (IBCSG) Trial V data.     

Direct Modelling of Regression Effects for Transition Probabilities in Multistate Models

Abstract.  A simple and standard approach for analysing multistate model data is to model all transition intensities and then compute a summary measure such as the transition probabilities based on this. This approach is relatively simple to implement but it is difficult to see what the covariate effects are on the scale of interest. In this paper, we consider an alternative approach that directly models the covariate effects on transition probabilities in multistate models. Our new approach is based on binomial modelling and inverse probability of censoring weighting techniques and is very simple to implement by standard software. We show how to do flexible regression models with possibly time-varying covariate effects.     

Nonparametric estimation of waiting time distributions in a Markov model based on current status data

We construct nonparametric estimators of state waiting time distribution functions in a Markov multistate model using current status data. This is a particularly difficult problem since neither the entry nor the exit times of a given state are directly observed. These estimators are obtained, using the Markov property, from estimators of counting processes of state entry and exit times, as well as, the size of “at risk” sets of state entry and transitions out of that state. Consistency of our estimators is established. Finite-sample behavior of our estimators is studied by simulation, in which we show that our estimators based on current status data compare well with those based on complete data. We also illustrate our method using a pubertal development data set obtained from the NHANES III [1997. NHANES III Reference Manuals and Reports (CD-ROM). Analytic and Reporting Guidelines: The Third National Health and Nutrition Examination Survey (1988–94). National Center for Health Statistics, Centers for Disease Control and Prevention, Hyattsville, MD] study.     

A Bayesian model for estimating the malaria transition probabilities considering individuals lost to follow-up

It is known that patients may cease participating in a longitudinal study and become lost to follow-up. The objective of this article is to present a Bayesian model to estimate the malaria transition probabilities considering individuals lost to follow-up. We consider a homogeneous population, and it is assumed that the considered period of time is small enough to avoid two or more transitions from one state of health to another. The proposed model is based on a Gibbs sampling algorithm that uses information of lost to follow-up at the end of the longitudinal study. To simulate the unknown number of individuals with positive and negative states of malaria at the end of the study and lost to follow-up, two latent variables were introduced in the model. We used a real data set and a simulated data to illustrate the application of the methodology. The proposed model showed a good fit to these data sets, and the algorithm did not show problems of convergence or lack of identifiability. We conclude that the proposed model is a good alternative to estimate probabilities of transitions from one state of health to the other in studies with low adherence to follow-up.     

Targeted estimation of state occupation probabilities for the non-Markov illness-death model

We use semi-parametric efficiency theory to derive a class of estimators for the state occupation probabilities of the continuous-time irreversible illness-death model. We consider both the setting with and without additional baseline information available, where we impose no specific functional form on the intensity functions of the model. We show that any estimator in the class is asymptotically linear under suitable assumptions about the estimators of the intensity functions. In particular, the assumptions are weak enough to allow the use of data-adaptive methods, which is important for making the identifying assumption of coarsening at random plausible in realistic settings. We suggest a flexible method for estimating the transition intensity functions of the illness-death model based on penalized Poisson regression. We apply this method to estimate the nuisance parameters of an illness-death model in a simulation study and a real-world application.     

Estimation of extreme survival probabilities with cox model

We propose an extension of the regular Cox's proportional hazards model which allows the estimation of the probabilities of rare events. It is known that when the data are heavily censored, the estimation of the tail of the survival distribution is not reliable. To improve the estimate of the baseline survival function in the range of the largest observed data and to extend it outside, we adjust the tail of the baseline distribution beyond some threshold by an extreme value model under appropriate assumptions. The survival distributions conditioned to the covariates are easily computed from the baseline. A procedure allowing an automatic choice of the threshold and an aggregated estimate of the survival probabilities are also proposed. The performance is studied by simulations and an application on two data sets is given.     

Inference for outcome probabilities in multi-state models

In bone marrow transplantation studies, patients are followed over time and a number of events may be observed. These include both ultimate events like death and relapse and transient events like graft versus host disease and graft recovery. Such studies, therefore, lend themselves for using an analytic approach based on multi-state models. We will give a review of such methods with emphasis on regression models for both transition intensities and transition- and state occupation probabilities. Both semi-parametric models, like the Cox regression model, and parametric models based on piecewise constant intensities will be discussed.     

Multistate recapture models: Modelling incomplete individual histories

Multistate capture-recapture models are a natural generalization of the usual one-site recapture models. Similarly, individuals are sampled on discrete occasions, at which they may be captured or not. However, contrary to the one-site case, the individuals can move within a finite set of states between occasions. The growing interest in spatial aspects of population dynamics presently contributes to making multistate models a very promising tool for population biology. We review first the interest and the potential of multistate models, in particular when they are used with individual states as well as geographical sites. Multistate models indeed constitute canonical capture-recapture models for individual categorical covariates changing over time, and can be linked to longitudinal studies with missing data and models such as hidden Markov chains. Multistate models also provide a promising tool for handling heterogeneity of capture, provided states related to capturability can be defined and used. Such an approach could be relevant for population size estimation in closed populations. Multistate models also constitute a natural framework for mixtures of information in individual history data. Presently, most models can be fit using program MARK. As an example, we present a canonical model for multisite accession to reproduction, which fully generalizes a classical one-site model. In the generalization proposed, one can estimate simultaneously age-dependent rates of accession to reproduction, natal and breeding dispersal. Finally, we discuss further generalizations - such as a multistate generalization of growth rate models and models for data where the state in which an individual is detected is known with uncertainty - and prospects for software development.     

Multistate recapture models: modelling incomplete individual histories

Multistate capture-recapture models are a natural generalization of the usual one-site recapture models. Similarly, individuals are sampled on discrete occasions, at which they may be captured or not. However, contrary to the one-site case, the individuals can move within a finite set of states between occasions. The growing interest in spatial aspects of population dynamics presently contributes to making multistate models a very promising tool for population biology. We review first the interest and the potential of multistate models, in particular when they are used with individual states as well as geographical sites. Multistate models indeed constitute canonical capture-recapture models for individual categorical covariates changing over time, and can be linked to longitudinal studies with missing data and models such as hidden Markov chains. Multistate models also provide a promising tool for handling heterogeneity of capture, provided states related to capturability can be defined and used. Such an approach could be relevant for population size estimation in closed populations. Multistate models also constitute a natural framework for mixtures of information in individual history data. Presently, most models can be fit using program MARK. As an example, we present a canonical model for multisite accession to reproduction, which fully generalizes a classical one-site model. In the generalization proposed, one can estimate simultaneously age-dependent rates of accession to reproduction, natal and breeding dispersal. Finally, we discuss further generalizations - such as a multistate generalization of growth rate models and models for data where the state in which an individual is detected is known with uncertainty - and prospects for software development.     

A semi-Markov multistate model for estimation of the mean quality-adjusted survival for non-progressive processes

We discuss the estimation of the expected value of the quality-adjusted survival, based on multistate models. We generalize an earlier work, considering the sojourn times in health states are not identically distributed, for a given vector of covariates. Approaches based on semiparametric and parametric (exponential and Weibull distributions) methodologies are considered. A simulation study is conducted to evaluate the performance of the proposed estimator and the jackknife resampling method is used to estimate the variance of such estimator. An application to a real data set is also included.     

Non-homogeneous Markov models in the analysis of survival after breast cancer

A cohort of 300 women with breast cancer who were submitted for surgery is analysed by using a non-homogeneous Markov process. Three states are onsidered: no relapse, relapse and death. As relapse times change over time, we have extended previous approaches for a time homogeneous model to a non omogeneous multistate process. The trends of the hazard rate functions of transitions between states increase and then decrease, showing that a changepoint can be considered. Piecewise Weibull distributions are introduced as transition intensity functions. Covariates corresponding to treatments are incorporated in the model multiplicatively via these functions. The likelihood function is built for a general model with k changepoints and applied to the data set, the parameters are estimated and life-table and transition probabilities for treatments in different periods of time are given. The survival probability functions for different treatments are plotted and compared with the corresponding function for the homogeneous model. The survival functions for the various cohorts submitted for treatment are fitted to the mpirical survival functions.     

ESTIMATING PROCESSES OF COUNTS FROM CROSS-SECTIONAL AGGREGATE DATA, WITH AN APPLICATION TO MULTISTATE LIFE TABLES AND HEALTH EXPECTANCIES

This paper discusses the estimation of time‐dependent probabilities of a finite state‐space discrete‐time process using aggregate cross‐sectional data. A large‐sample version of multistate logistic regression is described and shown to be useful for analysing multistate life tables. The technique is applied to the estimation of disability‐free, severely disabled and other disabled survival curves and health expectancies in Australia, based on data from national health surveys in 1988, 1993 and 1998. A conclusion is that there has been a general upward trend in the future time expected to be spent in a state of disability, the picture being more pessimistic for males than females. For example, during 1988‐1998 the estimated increase in male life expectancy at birth of 2.7 years is decomposed as a decrease of 1.2 years in disability‐free health (life) expectancy and increases of 1.3 and 2.6 years, respectively, in states of severe disability and other disability.     

Estimation in a model for a semi-Markov process with covariates under right-censoring

A semi-Markov model with covariates is proposed for a multi-state process with a finite number of states such that the transition probabilities between the states and the distribution functions of the duration times between the occurrence of two states depend on a discrete covariate. The hazard rates for the time elapsed between two successive states depend on the covariate through a proportional hazards model involving a set of regression parameters, while the transition probabilities depend on the covariate in an unspecified way. We propose estimators for these parameters and for the cumulative hazard functions of the sojourn times. A difficulty comes from the fact that when a sojourn time in a state is right-censored, the next state is unknown. We prove that our estimators are consistent and asymptotically Gaussian under the model constraints.     

The time‐dependent “cure‐death” model investigating two equally important endpoints simultaneously in trials treating high‐risk patients with resistant pathogens

A variety of primary endpoints are used in clinical trials treating patients with severe infectious diseases, and existing guidelines do not provide a consistent recommendation. We propose to study simultaneously two primary endpoints, cure and death, in a comprehensive multistate cure‐death model as starting point for a treatment comparison. This technique enables us to study the temporal dynamic of the patient‐relevant probability to be cured and alive. We describe and compare traditional and innovative methods suitable for a treatment comparison based on this model. Traditional analyses using risk differences focus on one prespecified timepoint only. A restricted logrank‐based test of treatment effect is sensitive to ordered categories of responses and integrates information on duration of response. The pseudo‐value regression provides a direct regression model for examination of treatment effect via difference in transition probabilities. Applied to a topical real data example and simulation scenarios, we demonstrate advantages and limitations and provide an insight into how these methods can handle different kinds of treatment imbalances. The cure‐death model provides a suitable framework to gain a better understanding of how a new treatment influences the time‐dynamic cure and death process. This might help the future planning of randomised clinical trials, sample size calculations, and data analyses.     

A New lifetime model for multivariate survival data with a surviving fraction

In this paper we propose a new lifetime model for multivariate survival data with a surviving fraction. We develop this model assuming that there are m types of unobservable competing risks, where each risk is related to a time of the occurrence of an event of interest. We explore the use of Markov chain Monte Carlo methods to develop a Bayesian analysis for the proposed model. We also perform a simulation study in order to analyse the frequentist coverage probabilities of credible interval derived from posteriors. Our modelling is illustrated through a real data set.     

A Multistate Transition Model for Osteoarthritis Pain Change

Pain severity of knees is assessed using an ordinal scale in patients with musculoskeletal diseases and often changes over time. Assessment of the effect of a particular risk factor on the change in pain severity will shed light on our understanding of biological mechanisms and provide guidance for rational clinical intervention for recurrent pain. The multistate transition model allows transitions between several different states of pain severity and estimates the transitional intensity using an extension of the Cox proportional hazards model. Using data from a longitudinal study, we applied this model to assess the relation of two psychological factors to the change in knee pain severity over time among patients with osteoarthritis and demonstrated that the multistate transition model can be a valuable tool for rheumatic disease studies.     

Efficient Semiparametric Bayesian Estimation of Multivariate Discrete Proportional Hazards Model with Random Effects

We incorporate a random effect into a multivariate discrete proportional hazards model and propose an efficient semiparametric Bayesian estimation method. By introducing a prior process for the parameters of baseline hazards, we consider a nonparametric estimation of baseline hazards function. Using a state space representation, we derive a dynamic modeling of baseline hazards function and propose an efficient block sampler for Markov chain Monte Carlo method. A numerical example using kidney patients data is given.     

Nonparametric estimation of the sojourn time distributions for a multipath model

Summary. We use a multipath (multistate) model to describe data with multiple end points. Statistical inference based on the intermediate end point is challenging because of the problems of nonidentifiability and dependent censoring. We study nonparametric estimation for the path probability and the sojourn time distributions between the states. The methodology proposed can be applied to analyse cure models which account for the competing risk of death. Asymptotic properties of the estimators proposed are derived. Simulation shows that the methods proposed have good finite sample performance. The methodology is applied to two data sets.