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.     

Joint Modeling of Event Time and Nonignorable Missing Longitudinal Data

Survival studies usually collect on each participant, both duration until some terminal event and repeated measures of a time-dependent covariate. Such a covariate is referred to as an internal time-dependent covariate. Usually, some subjects drop out of the study before occurence of the terminal event of interest. One may then wish to evaluate the relationship between time to dropout and the internal covariate. The Cox model is a standard framework for that purpose. Here, we address this problem in situations where the value of the covariate at dropout is unobserved. We suggest a joint model which combines a first-order Markov model for the longitudinaly measured covariate with a time-dependent Cox model for the dropout process. We consider maximum likelihood estimation in this model and show how estimation can be carried out via the EM-algorithm. We state that the suggested joint model may have applications in the context of longitudinal data with nonignorable dropout. Indeed, it can be viewed as generalizing Diggle and Kenward's model (1994) to situations where dropout may occur at any point in time and may be censored. Hence we apply both models and compare their results on a data set concerning longitudinal measurements among patients in a cancer clinical trial.     

Non‐Gaussian geostatistical modeling using (skew) t processes

We propose a new model for regression and dependence analysis when addressing spatial data with possibly heavy tails and an asymmetric marginal distribution. We first propose a stationary process with t marginals obtained through scale mixing of a Gaussian process with an inverse square root process with Gamma marginals. We then generalize this construction by considering a skew‐Gaussian process, thus obtaining a process with skew‐t marginal distributions. For the proposed (skew) t process, we study the second‐order and geometrical properties and in the t case, we provide analytic expressions for the bivariate distribution. In an extensive simulation study, we investigate the use of the weighted pairwise likelihood as a method of estimation for the t process. Moreover we compare the performance of the optimal linear predictor of the t process versus the optimal Gaussian predictor. Finally, the effectiveness of our methodology is illustrated by analyzing a georeferenced dataset on maximum temperatures in Australia.     

Quantile Regression For Longitudinal Biomarker Data Subject to Left Censoring and Dropouts

Quantile regression is increasingly used in biomarker analysis to handle nonnormal or heteroscedastic data. However, in some biomedical studies, the biomarker data can be censored by detection limits of the bioassay or missing when the subjects drop out from the study. Inappropriate handling of these two issues leads to biased estimation results. We consider the censored quantile regression approach to account for the censoring data and apply the inverse weighting technique to adjust for dropouts. In particular, we develop a weighted estimating equation for censored quantile regression, where an individual’s contribution is weighted by the inverse probability of dropout at the given occasion. We conduct simulation studies to evaluate the properties of the proposed estimators and demonstrate our method with a real data set from Genetic and Inflammatory Marker of Sepsis (GenIMS) study.     

Modeling statistical dependence of Markov chains via copula models

Conditional probability distributions have been commonly used in modeling Markov chains. In this paper we consider an alternative approach based on copulas to investigate Markov-type dependence structures. Based on the realization of a single Markov chain, we estimate the parameters using one- and two-stage estimation procedures. We derive asymptotic properties of the marginal and copula parameter estimators and compare performance of the estimation procedures based on Monte Carlo simulations. At low and moderate dependence structures the two-stage estimation has comparable performance as the maximum likelihood estimation. In addition we propose a parametric pseudo-likelihood ratio test for copula model selection under the two-stage procedure. We apply the proposed methods to an environmental data set.     

Learning from a lot: Empirical Bayes for high‐dimensional model‐based prediction

Empirical Bayes is a versatile approach to “learn from a lot” in two ways: first, from a large number of variables and, second, from a potentially large amount of prior information, for example, stored in public repositories. We review applications of a variety of empirical Bayes methods to several well‐known model‐based prediction methods, including penalized regression, linear discriminant analysis, and Bayesian models with sparse or dense priors. We discuss “formal” empirical Bayes methods that maximize the marginal likelihood but also more informal approaches based on other data summaries. We contrast empirical Bayes to cross‐validation and full Bayes and discuss hybrid approaches. To study the relation between the quality of an empirical Bayes estimator and p, the number of variables, we consider a simple empirical Bayes estimator in a linear model setting. We argue that empirical Bayes is particularly useful when the prior contains multiple parameters, which model a priori information on variables termed “co‐data”. In particular, we present two novel examples that allow for co‐data: first, a Bayesian spike‐and‐slab setting that facilitates inclusion of multiple co‐data sources and types and, second, a hybrid empirical Bayes–full Bayes ridge regression approach for estimation of the posterior predictive interval.     

Bayesian Analysis of Two-Regime Threshold Autoregressive Moving Average Model with Exogenous Inputs

We consider Bayesian analysis of threshold autoregressive moving average model with exogenous inputs (TARMAX). In order to obtain the desired marginal posterior distributions of all parameters including the threshold value of the two-regime TARMAX model, we use two different Markov chain Monte Carlo (MCMC) methods to apply Gibbs sampler with Metropolis-Hastings algorithm. The first one is used to obtain iterative least squares estimates of the parameters. The second one includes two MCMC stages for estimate the desired marginal posterior distributions and the parameters. Simulation experiments and a real data example show support to our approaches.     

EXPONENTIAL SMOOTHING AND NON‐NEGATIVE DATA

The most common forecasting methods in business are based on exponential smoothing, and the most common time series in business are inherently non‐negative. Therefore it is of interest to consider the properties of the potential stochastic models underlying exponential smoothing when applied to non‐negative data. We explore exponential smoothing state space models for non‐negative data under various assumptions about the innovations, or error, process. We first demonstrate that prediction distributions from some commonly used state space models may have an infinite variance beyond a certain forecasting horizon. For multiplicative error models that do not have this flaw, we show that sample paths will converge almost surely to zero even when the error distribution is non‐Gaussian. We propose a new model with similar properties to exponential smoothing, but which does not have these problems, and we develop some distributional properties for our new model. We then explore the implications of our results for inference, and compare the short‐term forecasting performance of the various models using data on the weekly sales of over 300 items of costume jewelry. The main findings of the research are that the Gaussian approximation is adequate for estimation and one‐step‐ahead forecasting. However, as the forecasting horizon increases, the approximate prediction intervals become increasingly problematic. When the model is to be used for simulation purposes, a suitably specified scheme must be employed.     

Low-dimensional confounder adjustment and high-dimensional penalized estimation for survival analysis

High-throughput profiling is now common in biomedical research. In this paper we consider the layout of an etiology study composed of a failure time response, and gene expression measurements. In current practice, a widely adopted approach is to select genes according to a preliminary marginal screening and a follow-up penalized regression for model building. Confounders, including for example clinical risk factors and environmental exposures, usually exist and need to be properly accounted for. We propose covariate-adjusted screening and variable selection procedures under the accelerated failure time model. While penalizing the high-dimensional coefficients to achieve parsimonious model forms, our procedure also properly adjust the low-dimensional confounder effects to achieve more accurate estimation of regression coefficients. We establish the asymptotic properties of our proposed methods and carry out simulation studies to assess the finite sample performance. Our methods are illustrated with a real gene expression data analysis where proper adjustment of confounders produces more meaningful results.     

Α Markov model for longitudinal studies with incomplete dichotomous outcomes

Missing outcome data constitute a serious threat to the validity and precision of inferences from randomized controlled trials. In this paper, we propose the use of a multistate Markov model for the analysis of incomplete individual patient data for a dichotomous outcome reported over a period of time. The model accounts for patients dropping out of the study and also for patients relapsing. The time of each observation is accounted for, and the model allows the estimation of time‐dependent relative treatment effects. We apply our methods to data from a study comparing the effectiveness of 2 pharmacological treatments for schizophrenia. The model jointly estimates the relative efficacy and the dropout rate and also allows for a wide range of clinically interesting inferences to be made. Assumptions about the missingness mechanism and the unobserved outcomes of patients dropping out can be incorporated into the analysis. The presented method constitutes a viable candidate for analyzing longitudinal, incomplete binary data.     

Efficient estimation for the proportional hazards model with bivariate current status data

We consider efficient estimation of regression and association parameters jointly for bivariate current status data with the marginal proportional hazards model. Current status data occur in many fields including demographical studies and tumorigenicity experiments and several approaches have been proposed for regression analysis of univariate current status data. We discuss bivariate current status data and propose an efficient score estimation approach for the problem. In the approach, the copula model is used for joint survival function with the survival times assumed to follow the proportional hazards model marginally. Simulation studies are performed to evaluate the proposed estimates and suggest that the approach works well in practical situations. A real life data application is provided for illustration.     

A Likelihood Based Estimating Equation for the Clayton–Oakes Model with Marginal Proportional Hazards

Multivariate failure time data arise when data consist of clusters in which the failure times may be dependent. A popular approach to such data is the marginal proportional hazards model with estimation under the working independence assumption. In this paper, we consider the Clayton–Oakes model with marginal proportional hazards and use the full model structure to improve on efficiency compared with the independence analysis. We derive a likelihood based estimating equation for the regression parameters as well as for the correlation parameter of the model. We give the large sample properties of the estimators arising from this estimating equation. Finally, we investigate the small sample properties of the estimators through Monte Carlo simulations.     

Fitting semiparametric accelerated failure time models for nested case–control data

A nested case–control (NCC) study is an efficient cohort-sampling design in which a subset of controls are sampled from the risk set at each event time. Since covariate measurements are taken only for the sampled subjects, time and efforts of conducting a full scale cohort study can be saved. In this paper, we consider fitting a semiparametric accelerated failure time model to failure time data from a NCC study. We propose to employ an efficient induced smoothing procedure for rank-based estimating method for regression parameters estimation. For variance estimation, we propose to use an efficient resampling method that utilizes the robust sandwich form. We extend our proposed methods to a generalized NCC study that allows a sampling of cases. Finite sample properties of the proposed estimators are investigated via an extensive stimulation study. An application to a tumor study illustrates the utility of the proposed method in routine data analysis.     

Wavelet‐based estimators for mixture regression

We consider a process that is observed as a mixture of two random distributions, where the mixing probability is an unknown function of time. The setup is built upon a wavelet‐based mixture regression. Two linear wavelet estimators are proposed. Furthermore, we consider three regularizing procedures for each of the two wavelet methods. We also discuss regularity conditions under which the consistency of the wavelet methods is attained and derive rates of convergence for the proposed estimators. A Monte Carlo simulation study is conducted to illustrate the performance of the estimators. Various scenarios for the mixing probability function are used in the simulations, in addition to a range of sample sizes and resolution levels. We apply the proposed methods to a data set consisting of array Comparative Genomic Hybridization from glioblastoma cancer studies.     

Bivariate degradation modelling with marginal heterogeneous stochastic processes

In this paper, we consider that the degradation of two performance characteristics of a product can be modelled by stochastic processes and jointly by copula functions, but different stochastic processes govern the behaviour of each performance characteristic (PC) degradation. Different heterogeneous and homogeneous models are presented considering copula functions and different combinations of the most used stochastic processes in degradation analysis as marginal distributions. This is an important aspect to consider because the behaviour of the degradation of each PC may be different in its nature. As the joint distributions of the proposed models result in complex distributions, the estimation of the parameters of interest is performed via MCMC. A simulation study is performed to compare heterogeneous and homogeneous models. In addition, the proposed models are implemented to crack propagation data of two terminals of an electronic device, and some insights are provided about the product reliability under heterogeneous models.     

Time‐change models for asymmetric processes

Many records in environmental sciences exhibit asymmetric trajectories. The physical mechanisms behind these records may lead for example to sample paths with different characteristics at high and low levels (up–down asymmetries) or in the ascending and descending phases leading to time irreversibility (front–back asymmetries). Such features are important for many applications, and there is a need for simple and tractable models that can reproduce them. In this paper, we explore original time‐change models where the clock is a stochastic process that depends on the observed trajectory. The ergodicity of the proposed model is established under general conditions, and this result is used to develop nonparametric estimation procedures based on the joint distribution of the process and its derivative. The methodology is illustrated on meteorological and oceanographic data sets. We show that, combined with a marginal transformation, the proposed methodology is able to reproduce important characteristics of the data set such as marginal distributions, up‐crossing intensity, and up–down and front–back asymmetries.     

Pair‐copula constructions for non‐Gaussian DAG models

We propose a new type of multivariate statistical model that permits non‐Gaussian distributions as well as the inclusion of conditional independence assumptions specified by a directed acyclic graph. These models feature a specific factorisation of the likelihood that is based on pair‐copula constructions and hence involves only univariate distributions and bivariate copulas, of which some may be conditional. We demonstrate maximum‐likelihood estimation of the parameters of such models and compare them to various competing models from the literature. A simulation study investigates the effects of model misspecification and highlights the need for non‐Gaussian conditional independence models. The proposed methods are finally applied to modeling financial return data. The Canadian Journal of Statistics 40: 86–109; 2012 © 2012 Statistical Society of Canada     

A nonlinear mixed-effects model for multivariate longitudinal data with partially observed outcomes with application to HIV disease dynamics

The measurable multiple bio-markers for a disease are used as indicators for studying the response variable of interest in order to monitor and model disease progression. However, it is common for subjects to drop out of the studies prematurely resulting in unbalanced data and hence complicating the inferences involving such data. In this paper we consider a case where data are unbalanced among subjects and also within a subject because for some reason only a subset of the multiple outcomes of the response variable are observed at any one occasion. We propose a nonlinear mixed-effects model for the multivariate response variable data and derive a joint likelihood function that takes into account the partial dropout of the outcomes of the response variable. We further show how the methodology can be used in the estimation of the parameters that characterise HIV disease dynamics. An approximation technique of the parameters is also given and illustrated using a routine observational HIV dataset.     

Semiparametric Likelihood Estimation in the Clayton–Oakes Failure Time Model

Multivariate failure time data arise when the sample consists of clusters and each cluster contains several possibly dependent failure times. The Clayton–Oakes model (Clayton, 1978; Oakes, 1982) for multivariate failure times characterizes the intracluster dependence parametrically but allows arbitrary specification of the marginal distributions. In this paper, we discuss estimation in the Clayton–Oakes model when the marginal distributions are modeled to follow the Cox (1972) proportional hazards regression model. Parameter estimation is based on an approximate generalized maximum likelihood estimator. We illustrate the model's application with example datasets.