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.     

Small area estimation under unit-level temporal linear mixed models

Data from past time periods and temporal correlation are rich sources of information for estimating small area parameters at the current period. This paper investigates the use of unit-level temporal linear mixed models for estimating linear parameters. Two models are considered, with domain and domain-time random effects. The first model assumes time independency and the second one AR(1)-type time correlation. They are fitted by a Fisher-scoring algorithm that calculates the residual maximum likelihood estimators of the model parameters. Based on the introduced models, empirical best linear unbiased predictors of small area linear parameters are studied, and analytic estimators for evaluating the performance of their mean squared errors are proposed. Three simulation experiments are carried out to study the behaviour of the fitting algorithm, the small area predictors and the estimators of the mean squared error. By using data of the Spanish surveys of income and living conditions of 2004–2008, an application to the estimation of 2008 average normalized net annual incomes in Spanish provinces by sex is given.     

High dimensional multivariate mixed models for binary questionnaire data

Summary.  Questionnaires that are used to measure the effect of an intervention often consist of different sets of items, each set possibly measuring another concept. Mixed models with set-specific random effects are a flexible tool to model the different sets of items jointly. However, computational problems typically arise as the number of sets increases. This is especially true when the random-effects distribution cannot be integrated out analytically, as with mixed models for binary data. A pairwise modelling strategy, in which all possible bivariate mixed models are fitted and where inference follows from pseudolikelihood theory, has been proposed as a solution. This approach has been applied to assess the effect of physical activity on psychocognitive functioning, the latter measured by a battery of questionnaires.     

Impact of missing data on type 1 error rates in non‐inferiority trials

In this paper, a simulation study is conducted to systematically investigate the impact of different types of missing data on six different statistical analyses: four different likelihood‐based linear mixed effects models and analysis of covariance (ANCOVA) using two different data sets, in non‐inferiority trial settings for the analysis of longitudinal continuous data. ANCOVA is valid when the missing data are completely at random. Likelihood‐based linear mixed effects model approaches are valid when the missing data are at random. Pattern‐mixture model (PMM) was developed to incorporate non‐random missing mechanism. Our simulations suggest that two linear mixed effects models using unstructured covariance matrix for within‐subject correlation with no random effects or first‐order autoregressive covariance matrix for within‐subject correlation with random coefficient effects provide well control of type 1 error (T1E) rate when the missing data are completely at random or at random. ANCOVA using last observation carried forward imputed data set is the worst method in terms of bias and T1E rate. PMM does not show much improvement on controlling T1E rate compared with other linear mixed effects models when the missing data are not at random but is markedly inferior when the missing data are at random. Copyright © 2009 John Wiley & Sons, Ltd.     

Sparse optimization for nonconvex group penalized estimation

We consider a linear regression model where there are group structures in covariates. The group LASSO has been proposed for group variable selections. Many nonconvex penalties such as smoothly clipped absolute deviation and minimax concave penalty were extended to group variable selection problems. The group coordinate descent (GCD) algorithm is used popularly for fitting these models. However, the GCD algorithms are hard to be applied to nonconvex group penalties due to computational complexity unless the design matrix is orthogonal. In this paper, we propose an efficient optimization algorithm for nonconvex group penalties by combining the concave convex procedure and the group LASSO algorithm. We also extend the proposed algorithm for generalized linear models. We evaluate numerical efficiency of the proposed algorithm compared to existing GCD algorithms through simulated data and real data sets.     

Bayesian inference for generalized additive mixed models based on Markov random field priors

Most regression problems in practice require flexible semiparametric forms of the predictor for modelling the dependence of responses on covariates. Moreover, it is often necessary to add random effects accounting for overdispersion caused by unobserved heterogeneity or for correlation in longitudinal or spatial data. We present a unified approach for Bayesian inference via Markov chain Monte Carlo simulation in generalized additive and semiparametric mixed models. Different types of covariates, such as the usual covariates with fixed effects, metrical covariates with non-linear effects, unstructured random effects, trend and seasonal components in longitudinal data and spatial covariates, are all treated within the same general framework by assigning appropriate Markov random field priors with different forms and degrees of smoothness. We applied the approach in several case-studies and consulting cases, showing that the methods are also computationally feasible in problems with many covariates and large data sets. In this paper, we choose two typical applications.     

Weighting Method for a Linear Mixed Model

Maximum likelihood is a widely used estimation method in statistics. This method is model dependent and as such is criticized as being non robust. In this article, we consider using weighted likelihood method to make robust inferences for linear mixed models where weights are determined at both the subject level and the observation level. This approach is appropriate for problems where maximum likelihood is the basic fitting technique, but a subset of data points is discrepant with the model. It allows us to reduce the impact of outliers without complicating the basic linear mixed model with normally distributed random effects and errors. The weighted likelihood estimators are shown to be robust and asymptotically normal. Our simulation study demonstrates that the weighted estimates are much better than the unweighted ones when a subset of data points is far away from the rest. Its application to the analysis of deglutition apnea duration in normal swallows shows that the differences between the weighted and unweighted estimates are due to large amount of outliers in the data set.     

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.     

Generalised additive mixed models analysis via gammSlice

We demonstrate the use of our R package, gammSlice, for Bayesian fitting and inference in generalised additive mixed model analysis. This class of models includes generalised linear mixed models and generalised additive models as special cases. Accurate Bayesian inference is achievable via sufficiently large Markov chain Monte Carlo (MCMC) samples. Slice sampling is a key component of the MCMC scheme. Comparisons with existing generalised additive mixed model software shows that gammSlice offers improved inferential accuracy, albeit at the cost of longer computational time.     

Variable selection for generalized linear mixed models by L 1-penalized estimation

Generalized linear mixed models are a widely used tool for modeling longitudinal data. However, their use is typically restricted to few covariates, because the presence of many predictors yields unstable estimates. The presented approach to the fitting of generalized linear mixed models includes an L ₁-penalty term that enforces variable selection and shrinkage simultaneously. A gradient ascent algorithm is proposed that allows to maximize the penalized log-likelihood yielding models with reduced complexity. In contrast to common procedures it can be used in high-dimensional settings where a large number of potentially influential explanatory variables is available. The method is investigated in simulation studies and illustrated by use of real data sets.     

Bayesian quantile regression for skew-normal linear mixed models

Linear mixed models have been widely used to analyze repeated measures data which arise in many studies. In most applications, it is assumed that both the random effects and the within-subjects errors are normally distributed. This can be extremely restrictive, obscuring important features of within-and among-subject variations. Here, quantile regression in the Bayesian framework for the linear mixed models is described to carry out the robust inferences. We also relax the normality assumption for the random effects by using a multivariate skew-normal distribution, which includes the normal ones as a special case and provides robust estimation in the linear mixed models. For posterior inference, we propose a Gibbs sampling algorithm based on a mixture representation of the asymmetric Laplace distribution and multivariate skew-normal distribution. The procedures are demonstrated by both simulated and real data examples.     

Particle filtering for partially observed Gaussian state space models

Summary. Solving Bayesian estimation problems where the posterior distribution evolves over time through the accumulation of data has many applications for dynamic models. A large number of algorithms based on particle filtering methods, also known as sequential Monte Carlo algorithms, have recently been proposed to solve these problems. We propose a special particle filtering method which uses random mixtures of normal distributions to represent the posterior distributions of partially observed Gaussian state space models. This algorithm is based on a marginalization idea for improving efficiency and can lead to substantial gains over standard algorithms. It differs from previous algorithms which were only applicable to conditionally linear Gaussian state space models. Computer simulations are carried out to evaluate the performance of the proposed algorithm for dynamic tobit and probit models.     

A test of separate hypotheses for comparing linear mixed models with non nested fixed effects

As researchers increasingly rely on linear mixed models to characterize longitudinal data, there is a need for improved techniques for selecting among this class of models which requires specification of both fixed and random effects via a mean model and variance-covariance structure. The process is further complicated when fixed and/or random effects are non nested between models. This paper explores the development of a hypothesis test to compare non nested linear mixed models based on extensions of the work begun by Sir David Cox. We assess the robustness of this approach for comparing models containing correlated measures of body fat for predicting longitudinal cardiometabolic risk.     

Fast EM-type implementations for mixed effects models

The mixed effects model, in its various forms, is a common model in applied statistics. A useful strategy for fitting this model implements EM-type algorithms by treating the random effects as missing data. Such implementations, however, can be painfully slow when the variances of the random effects are small relative to the residual variance. In this paper, we apply the 'working parameter' approach to derive alternative EM-type implementations for fitting mixed effects models, which we show empirically can be hundreds of times faster than the common EM-type implementations. In our limited simulations, they also compare well with the routines in S-PLUS® and Stata® in terms of both speed and reliability. The central idea of the working parameter approach is to search for efficient data augmentation schemes for implementing the EM algorithm by minimizing the augmented information over the working parameter, and in the mixed effects setting this leads to a transfer of the mixed effects variances into the regression slope parameters. We also describe a variation for computing the restricted maximum likelihood estimate and an adaptive algorithm that takes advantage of both the standard and the alternative EM-type implementations.     

Sampling from the posterior distribution in generalized linear mixed models

Generalized linear mixed models provide a unified framework for treatment of exponential family regression models, overdispersed data and longitudinal studies. These problems typically involve the presence of random effects and this paper presents a new methodology for making Bayesian inference about them. The approach is simulation-based and involves the use of Markov chain Monte Carlo techniques. The usual iterative weighted least squares algorithm is extended to include a sampling step based on the Metropolis–Hastings algorithm thus providing a unified iterative scheme. Non-normal prior distributions for the regression coefficients and for the random effects distribution are considered. Random effect structures with nesting required by longitudinal studies are also considered. Particular interests concern the significance of regression coefficients and assessment of the form of the random effects. Extensions to unknown scale parameters, unknown link functions, survival and frailty models are outlined.     

Maximum-likelihood estimation and influence analysis in multivariate skew-normal reproductive dispersion mixed models for longitudinal data

Various mixed models were developed to capture the features of between- and within-individual variation for longitudinal data under the normality assumption of the random effect and the within-individual random error. However, the normality assumption may be violated in some applications. To this end, this article assumes that the random effect follows a skew-normal distribution and the within-individual error is distributed as a reproductive dispersion model. An expectation conditional maximization (ECME) algorithm together with the Metropolis-Hastings (MH) algorithm within the Gibbs sampler is presented to simultaneously obtain estimates of parameters and random effects. Several diagnostic measures are developed to identify the potentially influential cases and assess the effect of minor perturbation to model assumptions via the case-deletion method and local influence analysis. To reduce the computational burden, we derive the first-order approximations to case-deletion diagnostics. Several simulation studies and a real data example are presented to illustrate the newly developed methodologies.     

Parameter estimation of nonlinear mixed-effects models using first-order conditional linearization and the EM algorithm

Nonlinear mixed-effects (NLME) models are flexible enough to handle repeated-measures data from various disciplines. In this article, we propose both maximum-likelihood and restricted maximum-likelihood estimations of NLME models using first-order conditional expansion (FOCE) and the expectation–maximization (EM) algorithm. The FOCE-EM algorithm implemented in the ForStat procedure SNLME is compared with the Lindstrom and Bates (LB) algorithm implemented in both the SAS macro NLINMIX and the S-Plus/R function nlme in terms of computational efficiency and statistical properties. Two realworld data sets an orange tree data set and a Chinese fir (Cunninghamia lanceolata) data set, and a simulated data set were used for evaluation. FOCE-EM converged for all mixed models derived from the base model in the two realworld cases, while LB did not, especially for the models in which random effects are simultaneously considered in several parameters to account for between-subject variation. However, both algorithms had identical estimated parameters and fit statistics for the converged models. We therefore recommend using FOCE-EM in NLME models, particularly when convergence is a concern in model selection.     

Mixed models for data from thorough QT studies: part 2. One-step assessment of conditional QT prolongation

We investigate mixed analysis of covariance models for the 'one-step' assessment of conditional QT prolongation. Initially, we consider three different covariance structures for the data, where between-treatment covariance of repeated measures is modelled respectively through random effects, random coefficients, and through a combination of random effects and random coefficients. In all three of those models, an unstructured covariance pattern is used to model within-treatment covariance. In a fourth model, proposed earlier in the literature, between-treatment covariance is modelled through random coefficients but the residuals are assumed to be independent identically distributed (i.i.d.). Finally, we consider a mixed model with saturated covariance structure. We investigate the precision and robustness of those models by fitting them to a large group of real data sets from thorough QT studies. Our findings suggest: (i) Point estimates of treatment contrasts from all five models are similar. (ii) The random coefficients model with i.i.d. residuals is not robust; the model potentially leads to both under- and overestimation of standard errors of treatment contrasts and therefore cannot be recommended for the analysis of conditional QT prolongation. (iii) The combined random effects/random coefficients model does not always converge; in the cases where it converges, its precision is generally inferior to the other models considered. (iv) Both the random effects and the random coefficients model are robust. (v) The random effects, the random coefficients, and the saturated model have similar precision and all three models are suitable for the one-step assessment of conditional QT prolongation.     

Double hierarchical generalized linear models (with discussion)

Summary.  We propose a class of double hierarchical generalized linear models in which random effects can be specified for both the mean and dispersion. Heteroscedasticity between clusters can be modelled by introducing random effects in the dispersion model, as is heterogeneity between clusters in the mean model. This class will, among other things, enable models with heavy-tailed distributions to be explored, providing robust estimation against outliers. The h -likelihood provides a unified framework for this new class of models and gives a single algorithm for fitting all members of the class. This algorithm does not require quadrature or prior probabilities.