Stochastic Differential Mixed-Effects Models

Abstract.  Stochastic differential equations have been shown useful in describing random continuous time processes. Biomedical experiments often imply repeated measurements on a series of experimental units and differences between units can be represented by incorporating random effects into the model. When both system noise and random effects are considered, stochastic differential mixed-effects models ensue. This class of models enables the simultaneous representation of randomness in the dynamics of the phenomena being considered and variability between experimental units, thus providing a powerful modelling tool with immediate applications in biomedicine and pharmacokinetic/pharmacodynamic studies. In most cases the likelihood function is not available, and thus maximum likelihood estimation of the unknown parameters is not possible. Here we propose a computationally fast approximated maximum likelihood procedure for the estimation of the non-random parameters and the random effects. The method is evaluated on simulations from some famous diffusion processes and on real data sets.     

Modifications of REML algorithm for HGLMs

Hierarchical generalized linear models (HGLMs) have become popular in data analysis. However, their maximum likelihood (ML) and restricted maximum likelihood (REML) estimators are often difficult to compute, especially when the random effects are correlated; this is because obtaining the likelihood function involves high-dimensional integration. Recently, an h-likelihood method that does not involve numerical integration has been proposed. In this study, we show how an h-likelihood method can be implemented by modifying the existing ML and REML procedures. A small simulation study is carried out to investigate the performances of the proposed methods for HGLMs with correlated random effects.     

A note on transformed likelihood approach in linear dynamic panel models

The transformed likelihood approach to estimation of fixed effects dynamic panel data models is shown to present very good inferential properties but it is not directly implemented in the most diffused statistical software. The present paper aims at showing how a simple model reformulation can be adopted to describe the problem in terms of classical linear mixed models. The transformed likelihood approach is based on the first differences data transformation, the following results derive from a convenient reformulation in terms of deviations from the first observations. Given the invariance to data transformation, the likelihood functions defined in the two cases coincide. Resulting in a classical random effect linear model form, the proposed approach significantly improves the number of available estimation procedures and provides a straightforward interpretation for the parameters. Moreover, the proposed model specification allows to consider all the estimation improvements typical of the random effects model literature. Simulation studies are conducted in order to study the robustness of the estimation method to mean stationarity violation.     

SIMULATED MAXIMUM LIKELIHOOD APPLIED TO NON-GAUSSIAN AND NONLINEAR MIXED EFFECTS AND STATE–SPACE MODELS

The paper presents an overview of maximum likelihood estimation using simulated likelihood, including the use of antithetic variables and evaluation of the simulation error of the resulting estimates. It gives a general purpose implementation of simulated maximum likelihood and uses it to re‐visit four models that have previously appeared in the published literature: a state–space model for count data; a nested random effects model for binomial data; a nonlinear growth model with crossed random effects; and a crossed random effects model for binary salamander‐mating data. In the case of the last three examples, this appears to be the first time that maximum likelihood fits of these models have been presented.     

Semiparametric transformation models with random effects for clustered doubly censored data

For right-censored data, Zeng et al. [Semiparametirc transformation modes with random effects for clustered data. Statist Sin. 2008;18:355–377] proposed a class of semiparametric transformation models with random effects to formulate the effects of possibly time-dependent covariates on clustered failure times. In this article, we demonstrate that the approach of Zeng et al. can be extended to analyse clustered doubly censored data. The asymptotic properties of the nonparametric maximum likelihood estimators of the model parameters are derived. A simulation study is conducted to investigate the performance of the proposed estimators.     

Bias‐reduced marginal Akaike information criteria based on a Monte Carlo method for linear mixed‐effects models

In linear mixed‐effects (LME) models, if a fitted model has more random‐effect terms than the true model, a regularity condition required in the asymptotic theory may not hold. In such cases, the marginal Akaike information criterion (AIC) is positively biased for (?2) times the expected log‐likelihood. The asymptotic bias of the maximum log‐likelihood as an estimator of the expected log‐likelihood is evaluated for LME models with balanced design in the context of parameter‐constrained models. Moreover, bias‐reduced marginal AICs for LME models based on a Monte Carlo method are proposed. The performance of the proposed criteria is compared with existing criteria by using example data and by a simulation study. It was found that the bias of the proposed criteria was smaller than that of the existing marginal AIC when a larger model was fitted and that the probability of choosing a smaller model incorrectly was decreased.     

Modelling Survival Events with Longitudinal Covariates Measured with Error

In survival analysis, time-dependent covariates are usually present as longitudinal data collected periodically and measured with error. The longitudinal data can be assumed to follow a linear mixed effect model and Cox regression models may be used for modelling of survival events. The hazard rate of survival times depends on the underlying time-dependent covariate measured with error, which may be described by random effects. Most existing methods proposed for such models assume a parametric distribution assumption on the random effects and specify a normally distributed error term for the linear mixed effect model. These assumptions may not be always valid in practice. In this article, we propose a new likelihood method for Cox regression models with error-contaminated time-dependent covariates. The proposed method does not require any parametric distribution assumption on random effects and random errors. Asymptotic properties for parameter estimators are provided. Simulation results show that under certain situations the proposed methods are more efficient than the existing methods.     

Structured Modeling for Post-Mortem Brain Tissue Data

Structured means have been used in studying possible covariate effects on responses, whereas patterned covariances deal with random effects, missing data, and differing study designs. In this article, we develop new multivariate models with patterned means and covariance matrices to deal with special structures of the post-mortem brain tissue data collected in the Conte Center for the Neuroscience of Mental Disorders at the University of Pittsburgh. We obtain maximum likelihood estimates via the method of scoring for these new structured models. One-iteration estimators from a consistent starting point are used to derive the asymptotic distributions. The model fitting algorithms, as well as the asymptotic distributions, are examined using simulated data, and are applied to data from post-mortem tissue studies in schizophrenia.     

Analysis of generalized linear mixed models via a stochastic approximation algorithm with Markov chain Monte-Carlo method

In recent years much effort has been devoted to maximum likelihood estimation of generalized linear mixed models. Most of the existing methods use the EM algorithm, with various techniques in handling the intractable E-step. In this paper, a new implementation of a stochastic approximation algorithm with Markov chain Monte Carlo method is investigated. The proposed algorithm is computationally straightforward and its convergence is guaranteed. A simulation and three real data sets, including the challenging salamander data, are used to illustrate the procedure and to compare it with some existing methods. The results indicate that the proposed algorithm is an attractive alternative for problems with a large number of random effects or with high dimensional intractable integrals in the likelihood function.     

Covariate Decomposition Methods for Longitudinal Missing‐at‐Random Data and Predictors Associated with Subject‐Specific Effects

Investigators often gather longitudinal data to assess changes in responses over time within subjects and to relate these changes to within‐subject changes in predictors. Missing data are common in such studies and predictors can be correlated with subject‐specific effects. Maximum likelihood methods for generalized linear mixed models provide consistent estimates when the data are ‘missing at random’ (MAR) but can produce inconsistent estimates in settings where the random effects are correlated with one of the predictors. On the other hand, conditional maximum likelihood methods (and closely related maximum likelihood methods that partition covariates into between‐ and within‐cluster components) provide consistent estimation when random effects are correlated with predictors but can produce inconsistent covariate effect estimates when data are MAR. Using theory, simulation studies, and fits to example data this paper shows that decomposition methods using complete covariate information produce consistent estimates. In some practical cases these methods, that ostensibly require complete covariate information, actually only involve the observed covariates. These results offer an easy‐to‐use approach to simultaneously protect against bias from both cluster‐level confounding and MAR missingness in assessments of change.     

A semiparametric stochastic mixed effects model for bivariate cyclic longitudinal data

We propose a flexible semiparametric stochastic mixed effects model for bivariate cyclic longitudinal data. The model can handle either single cycle or, more generally, multiple consecutive cycle data. The approach models the mean of responses by parametric fixed effects and a smooth nonparametric function for the underlying time effects, and the relationship across the bivariate responses by a bivariate Gaussian random field and a joint distribution of random effects. The proposed model not only can model complicated individual profiles, but also allows for more flexible within-subject and between-response correlations. The fixed effects regression coefficients and the nonparametric time functions are estimated using maximum penalized likelihood, where the resulting estimator for the nonparametric time function is a cubic smoothing spline. The smoothing parameters and variance components are estimated simultaneously using restricted maximum likelihood. Simulation results show that the parameter estimates are close to the true values. The fit of the proposed model on a real bivariate longitudinal dataset of pre-menopausal women also performs well, both for a single cycle analysis and for a multiple consecutive cycle analysis. The Canadian Journal of Statistics 48: 471–498; 2020 © 2020 Statistical Society of Canada     

Cox Regression with Incomplete Covariate Measurements using the EM-algorithm

Ibrahim (1990) used the EM-algorithm to obtain maximum likelihood estimates of the regression parameters in generalized linear models with partially missing covariates. The technique was termed EM by the method of weights. In this paper, we generalize this technique to Cox regression analysis with missing values in the covariates. We specify a full model letting the unobserved covariate values be random and then maximize the observed likelihood. The asymptotic covariance matrix is estimated by the inverse information matrix. The missing data are allowed to be missing at random but also the non-ignorable non-response situation may in principle be considered. Simulation studies indicate that the proposed method is more efficient than the method suggested by Paik & Tsai (1997). We apply the procedure to a clinical trials example with six covariates with three of them having missing values.     

Mixed effects smoothing spline analysis of variance

We propose a general family of nonparametric mixed effects models. Smoothing splines are used to model the fixed effects and are estimated by maximizing the penalized likelihood function. The random effects are generic and are modelled parametrically by assuming that the covariance function depends on a parsimonious set of parameters. These parameters and the smoothing parameter are estimated simultaneously by the generalized maximum likelihood method. We derive a connection between a nonparametric mixed effects model and a linear mixed effects model. This connection suggests a way of fitting a nonparametric mixed effects model by using existing programs. The classical two-way mixed models and growth curve models are used as examples to demonstrate how to use smoothing spline analysis-of-variance decompositions to build nonparametric mixed effects models. Similarly to the classical analysis of variance, components of these nonparametric mixed effects models can be interpreted as main effects and interactions. The penalized likelihood estimates of the fixed effects in a two-way mixed model are extensions of James–Stein shrinkage estimates to correlated observations. In an example three nested nonparametric mixed effects models are fitted to a longitudinal data set.     

Local influence of nonlinear mixed effects model based on M-estimation

Abstract

In this work we mainly study the local influence in nonlinear mixed effects model with M-estimation. A robust method to obtain maximum likelihood estimates for parameters is presented, and the local influence of nonlinear mixed models based on robust estimation (M-estimation) by use of the curvature method is systematically discussed. The counting formulas of curvature for case weights perturbation, response variable perturbation and random error covariance perturbation are derived. Simulation studies are carried to access performance of the methods we proposed. We illustrate the diagnostics by an example presented in Davidian and Giltinan, which was analyzed under the non-robust situation.     

Variance component models for longitudinal count data with baseline information: epilepsy data revisited

Random effect models have often been used in longitudinal data analysis since they allow for association among repeated measurements due to unobserved heterogeneity. Various approaches have been proposed to extend mixed models for repeated count data to include dependence on baseline counts. Dependence between baseline counts and individual-specific random effects result in a complex form of the (conditional) likelihood. An approximate solution can be achieved ignoring this dependence, but this approach could result in biased parameter estimates and in wrong inferences. We propose a computationally feasible approach to overcome this problem, leaving the random effect distribution unspecified. In this context, we show how the EM algorithm for nonparametric maximum likelihood (NPML) can be extended to deal with dependence of repeated measures on baseline counts.     

A gradient-based algorithm for semiparametric models with missing covariates

In the parametric regression model, the covariate missing problem under missing at random is considered. It is often desirable to use flexible parametric or semiparametric models for the covariate distribution, which can reduce a potential misspecification problem. Recently, a completely nonparametric approach was developed by [H.Y. Chen, Nonparametric and semiparametric models for missing covariates in parameter regression, J. Amer. Statist. Assoc. 99 (2004), pp. 1176–1189; Z. Zhang and H.E. Rockette, On maximum likelihood estimation in parametric regression with missing covariates, J. Statist. Plann. Inference 47 (2005), pp. 206–223]. Although it does not require a model for the covariate distribution or the missing data mechanism, the proposed method assumes that the covariate distribution is supported only by observed values. Consequently, their estimator is a restricted maximum likelihood estimator (MLE) rather than the global MLE. In this article, we show the restricted semiparametric MLE could be very misleading in some cases. We discuss why this problem occurs and suggest an algorithm to obtain the global MLE. Then, we assess the performance of the proposed method via some simulation experiments.     

Multilevel and nonlinear panel data models

Summary This paper presents a selective survey on panel data methods. The focus is on new developments. In particular, linear multilevel models, specific nonlinear, nonparametric and semiparametric models are at the center of the survey. In contrast to linear models there do not exist unified methods for nonlinear approaches. In this case conditional maximum likelihood methods dominate for fixed effects models. Under random effects assumptions it is sometimes possible to employ conventional maximum likelihood methods using Gaussian quadrature to reduce a T-dimensional integral. Alternatives are generalized methods of moments and simulated estimators. If the nonlinear function is not exactly known, nonparametric or semiparametric methods should be preferred. Helpful comments and suggestions from an unknown referee are gratefully acknowledged.     

The Weibull Marshall–Olkin family: Regression model and application to censored data

We introduce a new class of distributions called the Weibull Marshall–Olkin-G family. We obtain some of its mathematical properties. The special models of this family provide bathtub-shaped, decreasing-increasing, increasing-decreasing-increasing, decreasing-increasing-decreasing, monotone, unimodal and bimodal hazard functions. The maximum likelihood method is adopted for estimating the model parameters. We assess the performance of the maximum likelihood estimators by means of two simulation studies. We also propose a new family of linear regression models for censored and uncensored data. The flexibility and importance of the proposed models are illustrated by means of three real data sets.     

Umvu estimators for the population mean and variance based on random effects models for lognormal data

Cross-classified data are often obtained in controlled experimental situations and in epidemiologic studies. As an example of the latter, occupational health studies sometimes require personal exposure measurements on a random sample of workers from one or more job groups, in one or more plant locations, on several different sampling dates. Because the marginal distributions of exposure data from such studies are generally right-skewed and well-approximated as lognormal, researchers in this area often consider the use of ANOVA models after a logarithmic transformation. While it is then of interest to estimate original-scale population parameters (e.g., the overall mean and variance), standard candidates such as maximum likelihood estimators (MLEs) can be unstable and highly biased. Uniformly minimum variance unbiased (UMVU) cstiniators offer a viable alternative, and are adaptable to sampling schemes that are typiral of experimental or epidemiologic studies. In this paper, we provide UMVU estimators for the mean and variance under two random effects ANOVA models for logtransformed data. We illustrate substantial mean squared error gains relative to the MLE when estimating the mean under a one-way classification. We illustrate that the results can readily be extended to encompass a useful class of purely random effects models, provided that the study data are balanced.     

Two-step and likelihood methods for joint models of longitudinal and survival data

We compare the commonly used two-step methods and joint likelihood method for joint models of longitudinal and survival data via extensive simulations. The longitudinal models include LME, GLMM, and NLME models, and the survival models include Cox models and AFT models. We find that the full likelihood method outperforms the two-step methods for various joint models, but it can be computationally challenging when the dimension of the random effects in the longitudinal model is not small. We thus propose an approximate joint likelihood method which is computationally efficient. We find that the proposed approximation method performs well in the joint model context, and it performs better for more “continuous” longitudinal data. Finally, a real AIDS data example shows that patients with higher initial viral load or lower initial CD4 are more likely to drop out earlier during an anti-HIV treatment.