Comparison of Selected Methods for Modeling of Multi-State Disease Progression Processes: A Simulation Study

Prognostic studies are essential to understand the role of particular prognostic factors and, thus, improve prognosis. In most studies, disease progression trajectories of individual patients may end up with one of mutually exclusive endpoints or can involve a sequence of different events.

One challenge in such studies concerns separating the effects of putative prognostic factors on these different endpoints and testing the differences between these effects.

In this article, we systematically evaluate and compare, through simulations, the performance of three alternative multivariable regression approaches in analyzing competing risks and multiple-event longitudinal data. The three approaches are: (1) fitting separate event-specific Cox's proportional hazards models; (2) the extension of Cox's model to competing risks proposed by Lunn and McNeil; and (3) Markov multi-state model.

The simulation design is based on a prognostic study of cancer progression, and several simulated scenarios help investigate different methodological issues relevant to the modeling of multiple-event processes of disease progression. The results highlight some practically important issues. Specifically, the decreased precision of the observed timing of intermediary (non fatal) events has a strong negative impact on the accuracy of regression coefficients estimated with either the Cox's or Lunn-McNeil models, while the Markov model appears to be quite robust, under the same circumstances. Furthermore, the tests based on both Markov and Lunn-McNeil models had similar power for detecting a difference between the effects of the same covariate on the hazards of two mutually exclusive events. The Markov approach yields also accurate Type I error rate and good empirical power for testing the hypothesis that the effect of a prognostic factor on changes after an intermediary event, which cannot be directly tested with the Lunn-McNeil method. Bootstrap-based standard errors improve the coverage rates for Markov model estimates. Overall, the results of our simulations validate Markov multi-state model for a wide range of data structures encountered in prognostic studies of disease progression, and may guide end users regarding the choice of model(s) most appropriate for their specific application.     

A semiparametric approach to hidden Markov models under longitudinal observations

We propose a hidden Markov model for longitudinal count data where sources of unobserved heterogeneity arise, making data overdispersed. The observed process, conditionally on the hidden states, is assumed to follow an inhomogeneous Poisson kernel, where the unobserved heterogeneity is modeled in a generalized linear model (GLM) framework by adding individual-specific random effects in the link function. Due to the complexity of the likelihood within the GLM framework, model parameters may be estimated by numerical maximization of the log-likelihood function or by simulation methods; we propose a more flexible approach based on the Expectation Maximization (EM) algorithm. Parameter estimation is carried out using a non-parametric maximum likelihood (NPML) approach in a finite mixture context. Simulation results and two empirical examples are provided.     

贝叶斯隐马尔科夫异质面板模型及应用研究

针对不可观测异质性非时变假设导致的删失变量偏差及推断无效问题,构建贝叶斯隐马尔科夫异质面板模型,刻画截面个体间的动态时变不可观测异质性,诊断经济系统环境中可能存在的隐性变点,设计相应的马尔科夫链蒙特卡洛抽样算法估计模型参数,并对中国各地区的金融发展与城乡收入差距关系进行实证分析,捕捉到金融发展与城乡收入差距间长期稳定关系的隐性变化,发现了区域个体不可观测异质性存在的动态时变特征。研究结果表明各参数的迭代轨迹收敛且估计误差非常小,验证了贝叶斯隐马尔科夫异质面板模型的有效性。     

Specification Tests for Random-effects Transition Models: An Application to a Model of the British Youth Training Scheme

We develop diagnostic tests for random-effects multi-spell multi-state models focusing on: independence between the unobserved heterogeneity and observed covariates; mutual independence of heterogeneity terms; and distributional form. They are applied to a transition model of the British youth labor market, revealing significant misspecifications in our initial model, and allowing us to develop a considerably better-fitting specification that would have been difficult to reach by other means. The improved specification implies reduced estimates of the effectiveness of the youth training scheme (YTS), but we nevertheless retain the conclusion of significant positive effects of YTS on employment prospects.     

Robust multivariate mixture regression models with incomplete data

Multivariate mixture regression models can be used to investigate the relationships between two or more response variables and a set of predictor variables by taking into consideration unobserved population heterogeneity. It is common to take multivariate normal distributions as mixing components, but this mixing model is sensitive to heavy-tailed errors and outliers. Although normal mixture models can approximate any distribution in principle, the number of components needed to account for heavy-tailed distributions can be very large. Mixture regression models based on the multivariate t distributions can be considered as a robust alternative approach. Missing data are inevitable in many situations and parameter estimates could be biased if the missing values are not handled properly. In this paper, we propose a multivariate t mixture regression model with missing information to model heterogeneity in regression function in the presence of outliers and missing values. Along with the robust parameter estimation, our proposed method can be used for (i) visualization of the partial correlation between response variables across latent classes and heterogeneous regressions, and (ii) outlier detection and robust clustering even under the presence of missing values. We also propose a multivariate t mixture regression model using MM-estimation with missing information that is robust to high-leverage outliers. The proposed methodologies are illustrated through simulation studies and real data analysis.     

Pareto Regression: A Bayesian Analysis

Abstract

In this article, a new model is presented that is based on the Pareto distribution of the second kind, when the location parameter depends on covariates as well as unobserved heterogeneity. Bayesian analysis of the model can be performed using Markov Chain Monte Carlo techniques. The new procedures are illustrated in the context of artificial data as well as international output data.     

Gamma shared frailty model based on reversed hazard rate

Abstract

Frailty models are used in survival analysis to account for unobserved heterogeneity in individual risks to disease and death. To analyze bivariate data on related survival times (e.g., matched pairs experiments, twin, or family data), shared frailty models were suggested. Shared frailty models are frequently used to model heterogeneity in survival analysis. The most common shared frailty model is a model in which hazard function is a product of random factor(frailty) and baseline hazard function which is common to all individuals. There are certain assumptions about the baseline distribution and distribution of frailty. In this paper, we introduce shared gamma frailty models with reversed hazard rate. We introduce Bayesian estimation procedure using Markov Chain Monte Carlo (MCMC) technique to estimate the parameters involved in the model. We present a simulation study to compare the true values of the parameters with the estimated values. Also, we apply the proposed model to the Australian twin data set.     

Bayesian analysis of Cannabis offences using generalized Poisson geometric process model with flexible dispersion

ABSTRACT

This paper derives models to analyse Cannabis offences count series from New South Wales, Australia. The data display substantial overdispersion as well as underdispersion for a subset, trend movement and population heterogeneity. To describe the trend dynamic in the data, the Poisson geometric process model is first adopted and is extended to the generalized Poisson geometric process model to capture both over- and underdispersion. By further incorporating mixture effect, the model accommodates population heterogeneity and enables classification of homogeneous units. The model is implemented using Markov chain Monte Carlo algorithms via the user-friendly WinBUGS software and its performance is evaluated through a simulation study.     

Testing for Homogeneity in an Exponential Mixture Model

This paper studies diagnostic procedures to test for homogeneity against unobserved heterogeneity in an exponential mixture model. The procedures include a dispersion score test, a likelihood ratio test, a moment likelihood approach and several goodness-of-fit tests. The paper compares the empirical power of these tests on a broad range of alternatives and proposes a new test that combines the dispersion score test with a properly chosen goodness-of-fit procedure; its empirical power comes close to the power of the best of the other tests.     

A shared parameter model of longitudinal measurements and survival time with heterogeneous random-effects distribution

Typical joint modeling of longitudinal measurements and time to event data assumes that two models share a common set of random effects with a normal distribution assumption. But, sometimes the underlying population that the sample is extracted from is a heterogeneous population and detecting homogeneous subsamples of it is an important scientific question. In this paper, a finite mixture of normal distributions for the shared random effects is proposed for considering the heterogeneity in the population. For detecting whether the unobserved heterogeneity exits or not, we use a simple graphical exploratory diagnostic tool proposed by Verbeke and Molenberghs [34] to assess whether the traditional normality assumption for the random effects in the mixed model is adequate. In the joint modeling setting, in the case of evidence against normality (homogeneity), a finite mixture of normals is used for the shared random-effects distribution. A Bayesian MCMC procedure is developed for parameter estimation and inference. The methodology is illustrated using some simulation studies. Also, the proposed approach is used for analyzing a real HIV data set, using the heterogeneous joint model for this data set, the individuals are classified into two groups: a group with high risk and a group with moderate risk.     

Mixture modelling of recurrent event times with long-term survivors: Analysis of Hutterite birth intervals

We propose a mixture model that combines a discrete-time survival model for analyzing the correlated times between recurrent events, e.g. births, with a logistic regression model for the probability of never experiencing the event of interest, i.e., being a long-term survivor. The proposed survival model incorporates both observed and unobserved heterogeneity in the probability of experiencing the event of interest. We use Gibbs sampling for the fitting of such mixture models, which leads to a computationally intensive solution to the problem of fitting survival models for multiple event time data with long-term survivors. We illustrate our Bayesian approach through an analysis of Hutterite birth histories.     

Multilevel regression mixture analysis

Summary.  A two-level regression mixture model is discussed and contrasted with the conventional two-level regression model. Simulated and real data shed light on the modelling alternatives. The real data analyses investigate gender differences in mathematics achievement from the US National Education Longitudinal Survey. The two-level regression mixture analyses show that unobserved heterogeneity should not be presupposed to exist only at level 2 at the expense of level 1. Both the simulated and the real data analyses show that level 1 heterogeneity in the form of latent classes can be mistaken for level 2 heterogeneity in the form of the random effects that are used in conventional two-level regression analysis. Because of this, mixture models have an important role to play in multilevel regression analyses. Mixture models allow heterogeneity to be investigated more fully, more correctly attributing different portions of the heterogeneity to the different levels.     

Testing Inference from Logistic Regression Models in Data with Unobserved Heterogeneity at Cluster Levels

Clustering due to unobserved heterogeneity may seriously impact on inference from binary regression models. We examined the performance of the logistic, and the logistic-normal models for data with such clustering. The total variance of unobserved heterogeneity rather than the level of clustering determines the size of bias of the maximum likelihood (ML) estimator, for the logistic model. Incorrect specification of clustering as level 2, using the logistic-normal model, provides biased estimates of the structural and random parameters, while specifying level 1, provides unbiased estimates for the former, and adequately estimates the latter. The proposed procedure appeals to many research areas.     

Shared frailty models based on reversed hazard rate for modified inverse Weibull distribution as baseline distribution

The unknown or unobservable risk factors in the survival analysis cause heterogeneity between individuals. Frailty models are used in the survival analysis to account for the unobserved heterogeneity in individual risks to disease and death. To analyze the bivariate data on related survival times, the shared frailty models were suggested. The most common shared frailty model is a model in which frailty act multiplicatively on the hazard function. In this paper, we introduce the shared gamma frailty model and the inverse Gaussian frailty model with the reversed hazard rate. We introduce the Bayesian estimation procedure using Markov chain Monte Carlo (MCMC) technique to estimate the parameters involved in the model. We present a simulation study to compare the true values of the parameters with the estimated values. We also apply the proposed models to the Australian twin data set and a better model is suggested.     

Mixture inverse Gaussian for unobserved heterogeneity in the autoregressive conditional duration model

In this paper, we assume that the duration of a process has two different intrinsic components or phases which are independent. The first is the time it takes for a trade to be initiated in the market (for example, the time during which agents obtain knowledge about the market in which they are operating and accumulate information, which is coherent with Brownian motion) and the second is the subsequent time required for the trade to develop into a complete duration. Of course, if the first time is zero then the trade is initiated immediately and no initial knowledge is required. If we assume a specific compound Bernoulli distribution for the first time and an inverse Gaussian distribution for the second, the resulting convolution model has a mixture of an inverse Gaussian distribution with its reciprocal, which allows us to specify and test the unobserved heterogeneity in the autoregressive conditional duration (ACD) model.

Our proposals make it possible not only to capture various density shapes of the durations but also easily to accommodate the behaviour of the tail of the distribution and the non monotonic hazard function. The proposed model is easy to fit and characterizes the behaviour of the conditional durations reasonably well in terms of statistical criteria based on point and density forecasts.     

A comparison of non-homogeneous Markov regression models with application to Alzheimer's disease progression

Markov regression models are useful tools for estimating the impact of risk factors on rates of transition between multiple disease states. Alzheimer's disease (AD) is an example of a multi-state disease process in which great interest lies in identifying risk factors for transition. In this context, non-homogeneous models are required because transition rates change as subjects age. In this report we propose a non-homogeneous Markov regression model that allows for reversible and recurrent disease states, transitions among multiple states between observations, and unequally spaced observation times. We conducted simulation studies to demonstrate performance of estimators for covariate effects from this model and compare performance with alternative models when the underlying non-homogeneous process was correctly specified and under model misspecification. In simulation studies, we found that covariate effects were biased if non-homogeneity of the disease process was not accounted for. However, estimates from non-homogeneous models were robust to misspecification of the form of the non-homogeneity. We used our model to estimate risk factors for transition to mild cognitive impairment (MCI) and AD in a longitudinal study of subjects included in the National Alzheimer's Coordinating Center's Uniform Data Set. Using our model, we found that subjects with MCI affecting multiple cognitive domains were significantly less likely to revert to normal cognition.     

Modelling survival data using mixtures of frailties

Frailty models are often used to describe the extra heterogeneity in survival data by introducing an individual random, unobserved effect. The frailty term is usually assumed to act multiplicatively on a baseline hazard function common to all individuals. In order to apply the frailty model, a specific frailty distribution has to be assumed. If at least one of the latent variables is continuous, the frailty must follow a continuous distribution. In this paper, a finite mixture of continuous frailty distributions is used in order to describe situations in which one (or more) of the latent variables separates the population in study into two (or more) subpopulations. Closure properties of the unobserved quantity are given along with the maximum-likelihood estimates under the most common choices of frailty distributions. The model is illustrated on a set of lifetime data.     

Dynamic latent trait models with mixed hidden Markov structure for mixed longitudinal outcomes

We propose a general Bayesian joint modeling approach to model mixed longitudinal outcomes from the exponential family for taking into account any differential misclassification that may exist among categorical outcomes. Under this framework, outcomes observed without measurement error are related to latent trait variables through generalized linear mixed effect models. The misclassified outcomes are related to the latent class variables, which represent unobserved real states, using mixed hidden Markov models (MHMMs). In addition to enabling the estimation of parameters in prevalence, transition and misclassification probabilities, MHMMs capture cluster level heterogeneity. A transition modeling structure allows the latent trait and latent class variables to depend on observed predictors at the same time period and also on latent trait and latent class variables at previous time periods for each individual. Simulation studies are conducted to make comparisons with traditional models in order to illustrate the gains from the proposed approach. The new approach is applied to data from the Southern California Children Health Study to jointly model questionnaire-based asthma state and multiple lung function measurements in order to gain better insight about the underlying biological mechanism that governs the inter-relationship between asthma state and lung function development.     

Estimation of drug effect in radiographic progression for rheumatoid arthritis and psoriatic arthritis

To demonstrate the treatment effect on structural damage in rheumatoid arthritis (RA) and psoriatic arthritis (PsA), radiographic images of hands and feet are scored according to Sharp scoring systems in randomized clinical trials. However, the quantification of such an effect is challenging because the overall mean progression is lack of clinical interpretation. This article attempts to shed a light on the statistical challenges resulted from its scoring methods and heterogeneity of the study population and proposes a mixture distribution model approach to fit radiographic progression data. With such a model, the drug effect is fully captured by the mean progression of those patients who would progress in the study period under the control treatment. The resulting regression model also lends a tool in examining prognostic factors for radiographic progression. Simulations have been carried out to evaluate the precision of the parameter estimation procedure. Using the data examples from RA and PsA, we will show that the mixture distribution approach provides a better goodness of fit and leads to a casual inference of the study drug, hence a clinically meaningful interpretation.     

Bayesian spectral analysis models for quantile regression with Dirichlet process mixtures

This paper presents a Bayesian analysis of partially linear additive models for quantile regression. We develop a semiparametric Bayesian approach to quantile regression models using a spectral representation of the nonparametric regression functions and the Dirichlet process (DP) mixture for error distribution. We also consider Bayesian variable selection procedures for both parametric and nonparametric components in a partially linear additive model structure based on the Bayesian shrinkage priors via a stochastic search algorithm. Based on the proposed Bayesian semiparametric additive quantile regression model referred to as BSAQ, the Bayesian inference is considered for estimation and model selection. For the posterior computation, we design a simple and efficient Gibbs sampler based on a location-scale mixture of exponential and normal distributions for an asymmetric Laplace distribution, which facilitates the commonly used collapsed Gibbs sampling algorithms for the DP mixture models. Additionally, we discuss the asymptotic property of the sempiparametric quantile regression model in terms of consistency of posterior distribution. Simulation studies and real data application examples illustrate the proposed method and compare it with Bayesian quantile regression methods in the literature.