A parametric multistate model for the analysis of carcinogenicity experiments

A fully parametric multistate model is explored for the analysis of animal carcinogenicity experiments in which the time of tumour onset is not known. This model does not require assumptions about tumour lethality or cause of death judgements and can be fitted in the absence of sacrifice data. The model is constructed as a three-state model with simple parametric forms for the transition rates. Maximum likelihood methods are used to estimate the transition rates and different treatment groups are compared using likelihood ratio tests. Selection of an appropriate model and methods to assess the fit of the model are illustrated with data from animal experiments. Comparisons with standard methods are made.     

Likelihood Imputation

The method of likelihood imputation is devised under the framework of latent structure models where the observation is a statistic of the complete data which can only be specified on a latent basis. The imputed data set is chosen to differ least from the observed one in their information contents—a concept with general implications for the analysis of incomplete-data. In contrast to the standard conditional-mean single imputation, our procedure depends on an entire likelihood region instead of any single point in it, and yields consistent parameter estimators nevertheless. We explain its implementations and illustrate with data from panel surveys and linear regression with censorship. We also discuss its potentials in sensitivity analysis     

Choice between Semi-parametric Estimators of Markov and Non-Markov Multi-state Models from Coarsened Observations

Abstract.  We consider models based on multivariate counting processes, including multi-state models. These models are specified semi-parametrically by a set of functions and real parameters. We consider inference for these models based on coarsened observations, focusing on families of smooth estimators such as produced by penalized likelihood. An important issue is the choice of model structure, for instance, the choice between a Markov and some non-Markov models. We define in a general context the expected Kullback–Leibler criterion and we show that the likelihood-based cross-validation (LCV) is a nearly unbiased estimator of it. We give a general form of an approximate of the leave-one-out LCV. The approach is studied by simulations, and it is illustrated by estimating a Markov and two semi-Markov illness–death models with application on dementia using data of a large cohort study.     

Generalized Linear Factor Models: A New Local EM Estimation Algorithm

In this article, a general approach to latent variable models based on an underlying generalized linear model (GLM) with factor analysis observation process is introduced. We call these models Generalized Linear Factor Models (GLFM). The observations are produced from a general model framework that involves observed and latent variables that are assumed to be distributed in the exponential family. More specifically, we concentrate on situations where the observed variables are both discretely measured (e.g., binomial, Poisson) and continuously distributed (e.g., gamma). The common latent factors are assumed to be independent with a standard multivariate normal distribution. Practical details of training such models with a new local expectation-maximization (EM) algorithm, which can be considered as a generalized EM-type algorithm, are also discussed. In conjunction with an approximated version of the Fisher score algorithm (FSA), we show how to calculate maximum likelihood estimates of the model parameters, and to yield inferences about the unobservable path of the common factors. The methodology is illustrated by an extensive Monte Carlo simulation study and the results show promising performance.     

Analysis of band‐recovery data in a multistate capture‐recapture framework

Dead recoveries of marked animals are commonly used to estimate survival probabilities. Band‐recovery models can be parameterized either by r (the probability of recovering a band conditional on death of the animal) or by f (the probability that an animal will be killed, retrieved, and have its band reported). The T parametrization can be implemented in a capture‐recapture framework with two states (alive and newly dead), mortality being the transition probability between the two states. The authors show here that the f parametrization can also be implemented in a multistate framework by imposing simple constraints on some parameters. They illustrate it using data on the mallard and the snow goose. However, they mention that because it does not entirely separate the individual survival and encounter processes, the f parametrization must be used with care on reduced models, or in the presence of estimates at the boundary of the parameter space. As they show, a multistate framework allows the use of powerful software for model fitting or testing the goodness‐of‐fit of models; it also affords the implementation of complex models such as those based on mixture of information or uncertain states     

Maximum likelihood estimates in the multivariate normal with patterned mean and covariance via the em algorithm

The maximum likelihood equations for a multivariate normal model with structured mean and structured covariance matrix may not have an explicit solution. In some cases the model's error term may be decomposed as the sum of two independent error terms, each having a patterned covariance matrix, such that if one of the unobservable error terms is artificially treated as "missing data", the EM algorithm can be used to compute the maximum likelihood estimates for the original problem. Some decompositions produce likelihood equations which do not have an explicit solution at each iteration of the EM algorithm, but within-iteration explicit solutions are shown for two general classes of models including covariance component models used for analysis of longitudinal data.     

A Baseline-free Procedure for Transformation Models Under Interval Censorship

An important property of Cox regression model is that the estimation of regression parameters using the partial likelihood procedure does not depend on its baseline survival function. We call such a procedure baseline-free. Using marginal likelihood, we show that an baseline-free procedure can be derived for a class of general transformation models under interval censoring framework. The baseline-free procedure results a simplified and stable computation algorithm for some complicated and important semiparametric models, such as frailty models and heteroscedastic hazard/rank regression models, where the estimation procedures so far available involve estimation of the infinite dimensional baseline function. A detailed computational algorithm using Markov Chain Monte Carlo stochastic approximation is presented. The proposed procedure is demonstrated through extensive simulation studies, showing the validity of asymptotic consistency and normality. We also illustrate the procedure with a real data set from a study of breast cancer. A heuristic argument showing that the score function is a mean zero martingale is provided.     

A Partial Likelihood Estimator of Vaccine Efficacy

A partial likelihood method is proposed for estimating vaccine efficacy for a general epidemic model. In contrast to the maximum likelihood estimator (MLE) which requires complete observation of the epidemic, the suggested method only requires information on the sequence in which individuals are infected and not the exact infection times. A simulation study shows that the method performs almost as well as the MLE. The method is applied to data on the infectious disease mumps.     

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.     

Skewness of maximum likelihood estimators in dispersion models

We introduce the dispersion models with a regression structure to extend the generalized linear models, the exponential family nonlinear models (Cordeiro and Paula, 1989) and the proper dispersion models (Jørgensen, 1997a). We provide a matrix expression for the skewness of the maximum likelihood estimators of the regression parameters in dispersion models. The formula is suitable for computer implementation and can be applied for several important submodels discussed in the literature. Expressions for the skewness of the maximum likelihood estimators of the precision and dispersion parameters are also derived. In particular, our results extend previous formulas obtained by Cordeiro and Cordeiro (2001) and Cavalcanti et al. (2009). A simulation study is performed to show the practice importance of our results.     

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.     

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.     

Conditional Likelihood Estimators for Hidden Markov Models and Stochastic Volatility Models

ABSTRACT.  This paper develops a new contrast process for parametric inference of general hidden Markov models, when the hidden chain has a non-compact state space. This contrast is based on the conditional likelihood approach, often used for ARCH-type models. We prove the strong consistency of the conditional likelihood estimators under appropriate conditions. The method is applied to the Kalman filter (for which this contrast and the exact likelihood lead to asymptotically equivalent estimators) and to the discretely observed stochastic volatility models.     

Estimating functions in indirect inference

Summary.  There are models for which the evaluation of the likelihood is infeasible in practice. For these models the Metropolis–Hastings acceptance probability cannot be easily computed. This is the case, for instance, when only departure times from a G / G /1 queue are observed and inference on the arrival and service distributions are required. Indirect inference is a method to estimate a parameter θ in models whose likelihood function does not have an analytical closed form, but from which random samples can be drawn for fixed values of θ . First an auxiliary model is chosen whose parameter β can be directly estimated. Next, the parameters in the auxiliary model are estimated for the original data, leading to an estimate     . The parameter β is also estimated by using several sampled data sets, simulated from the original model for different values of the original parameter θ . Finally, the parameter θ which leads to the best match to     is chosen as the indirect inference estimate. We analyse which properties an auxiliary model should have to give satisfactory indirect inference. We look at the situation where the data are summarized in a vector statistic T , and the auxiliary model is chosen so that inference on β is drawn from T only. Under appropriate assumptions the asymptotic covariance matrix of the indirect estimators is proportional to the asymptotic covariance matrix of T and componentwise inversely proportional to the square of the derivative, with respect to θ , of the expected value of T . We discuss how these results can be used in selecting good estimating functions. We apply our findings to the queuing problem.     

Profile likelihood approaches for semiparametric copula and frailty models for clustered survival data

ABSTRACT

In clustered survival data, the dependence among individual survival times within a cluster has usually been described using copula models and frailty models. In this paper we propose a profile likelihood approach for semiparametric copula models with different cluster sizes. We also propose a likelihood ratio method based on profile likelihood for testing the absence of association parameter (i.e. test of independence) under the copula models, leading to the boundary problem of the parameter space. For this purpose, we show via simulation study that the proposed likelihood ratio method using an asymptotic chi-square mixture distribution performs well as sample size increases. We compare the behaviors of the two models using the profile likelihood approach under a semiparametric setting. The proposed method is demonstrated using two well-known data sets.     

Multilevel Mixed Linear Models for Survival Data

For the analysis of correlated survival data mixed linear models are useful alternatives to frailty models. By their use the survival times can be directly modelled, so that the interpretation of the fixed and random effects is straightforward. However, because of intractable integration involved with the use of marginal likelihood the class of models in use has been severely restricted. Such a difficulty can be avoided by using hierarchical-likelihood, which provides a statistically efficient and fast fitting algorithm for multilevel models. The proposed method is illustrated using the chronic granulomatous disease data. A simulation study is carried out to evaluate the performance.     

Estimation of prolongation of hospital stay attributable to nosocomial infections: New approaches based on multistate models

Evaluation of the impact of nosocomial infection on duration of hospital stay usually relies on estimates obtained in prospective cohort studies. However, the statistical methods used to estimate the extra length of stay are usually not adequate. A naive comparison of duration of stay in infected and non-infected patients is not adequate to estimate the extra hospitalisation time due to nosocomial infections. Matching for duration of stay prior to infection can compensate in part for the bias of ad hoc methods. New model-based approaches have been developed to estimate the excess length of stay. It will be demonstrated that statistical models based on multivariate counting processes provide an appropriate framework to analyse the occurrence and impact of nosocomial infections. We will propose and investigate new approaches to estimate the extra time spent in hospitals attributable to nosocomial infections based on functionals of the transition probabilities in multistate models. Additionally, within the class of structural nested failure time models an alternative approach to estimate the extra stay due to nosocomial infections is derived. The methods are illustrated using data from a cohort study on 756 patients admitted to intensive care units at the University Hospital in Freiburg.     

ML, PL, QL in Markov Chain Models

Abstract.  In many spatial and spatial-temporal models, and more generally in models with complex dependencies, it may be too difficult to carry out full maximum-likelihood (ML) analysis. Remedies include the use of pseudo-likelihood (PL) and quasi-likelihood (QL) (also called the composite likelihood). The present paper studies the ML, PL and QL methods for general Markov chain models, partly motivated by the desire to understand the precise behaviour of the PL and QL methods in settings where this can be analysed. We present limiting normality results and compare performances in different settings. For Markov chain models, the PL and QL methods can be seen as maximum penalized likelihood methods. We find that QL is typically preferable to PL, and that it loses very little to ML, while sometimes earning in model robustness. It has also appeal and potential as a modelling tool. Our methods are illustrated for consonant-vowel transitions in poetry and for analysis of DNA sequence evolution-type models.     

Semicompeting risks in aging research: methods,issues and needs

A semicompeting risks problem involves two-types of events: a nonterminal and a terminal event (death). Typically, the nonterminal event is the focus of the study, but the terminal event can preclude the occurrence of the nonterminal event. Semicompeting risks are ubiquitous in studies of aging. Examples of semicompeting risk dyads include: dementia and death, frailty syndrome and death, disability and death, and nursing home placement and death. Semicompeting risk models can be divided into two broad classes: models based only on observables quantities (class \(\mathcal {O}\) ) and those based on potential (latent) failure times (class \(\mathcal {L}\) ). The classical illness-death model belongs to class \(\mathcal {O}\) . This model is a special case of the multistate models, which has been an active area of methodology development. During the past decade and a half, there has also been a flurry of methodological activity on semicompeting risks based on latent failure times ( \(\mathcal {L}\) models). These advances notwithstanding, the semicompeting risks methodology has not penetrated biomedical research, in general, and gerontological research, in particular. Some possible reasons for this lack of uptake are: the methods are relatively new and sophisticated, conceptual problems associated with potential failure time models are difficult to overcome, paucity of expository articles aimed at educating practitioners, and non-availability of readily usable software. The main goals of this review article are: (i) to describe the major types of semicompeting risks problems arising in aging research, (ii) to provide a brief survey of the semicompeting risks methods, (iii) to suggest appropriate methods for addressing the problems in aging research, (iv) to highlight areas where more work is needed, and (v) to suggest ways to facilitate the uptake of the semicompeting risks methodology by the broader biomedical research community.