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.     

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.     

Residual-based specification of the random-effects distribution for cluster data

We propose a method for specifying the distribution of random effects included in a model for cluster data. The class of models we consider includes mixed models and frailty models whose random effects and explanatory variables are constant within clusters. The method is based on cluster residuals obtained by assuming that the random effects are equal between clusters. We exhibit an asymptotic relationship between the cluster residuals and variations of the random effects as the number of observations increases and the variance of the random effects decreases. The asymptotic relationship is used to specify the random-effects distribution. The method is applied to a frailty model and a model used to describe the spread of plant diseases.     

Nonparametric Modeling Auxiliary Covariates in Random Coefficient Models

Random coefficient model (RCM) is a powerful statistical tool in analyzing correlated data collected from studies with different clusters or from longitudinal studies. In practice, there is a need for statistical methods that allow biomedical researchers to adjust for the measured and unmeasured covariates that might affect the regression model. This article studies two nonparametric methods dealing with auxiliary covariate data in linear random coefficient models. We demonstrate how to estimate the coefficients of the models and how to predict the random effects when the covariates are missing or mismeasured. We employ empirical estimator and kernel smoother to handle a discrete and continuous auxiliary, respectively. Simulation results show that the proposed methods perform better than an alternative method that only uses data in the validation data set and ignores the random effects in the random coefficient model.     

Dynamic Random Effects Models for Times Between Repeated Events

We consider recurrent event data when the duration or gap times between successive event occurrences are of intrinsic interest. Subject heterogeneity not attributed to observed covariates is usually handled by random effects which result in an exchangeable correlation structure for the gap times of a subject. Recently, efforts have been put into relaxing this restriction to allow non-exchangeable correlation. Here we consider dynamic models where random effects can vary stochastically over the gap times. We extend the traditional Gaussian variance components models and evaluate a previously proposed proportional hazards model through a simulation study and some examples. Besides, semiparametric estimation of the proportional hazards models is considered. Both models are easily used. The Gaussian models are easily interpreted in terms of the variance structure. On the other hand, the proportional hazards models would be more appropriate in the context of survival analysis, particularly in the interpretation of the regression parameters. They can be sensitive to the choice of model for random effects but not to the choice of the baseline hazard function.     

Random-effect models with singular precision

We show that smoothing spline, intrinsic autoregression (IAR) and state-space model can be formulated as partially specified random-effect model with singular precision (SP). Various fitting methods have been suggested for the aforementioned models and this paper investigates the relationships among them, once the models have been placed under a single framework. Some methods have been previously shown to give the best linear unbiased predictors (BLUPs) under some random-effect models and here we show that they are in fact uniformly BLUPs (UBLUPs) under a class of models that are generated by the SP of random effects. We offer some new interpretations of the UBLUPs under models of SP and define BLUE and BLUP in these partially specified models without having to specify the covariance. We also show how the full likelihood inferences for random-effect models can be made for these models, so that the maximum likelihood (ML) and restricted maximum likelihood (REML) estimators can be used for the smoothing parameters in splines, etc.     

Evaluation of Bayesian multiple stage estimation under spatial CAR model variants

In this study, an evaluation of Bayesian hierarchical models is made based on simulation scenarios to compare single-stage and multi-stage Bayesian estimations. Simulated datasets of lung cancer disease counts for men aged 65 and older across 44 wards in the London Health Authority were analysed using a range of spatially structured random effect components. The goals of this study are to determine which of these single-stage models perform best given a certain simulating model, how estimation methods (single- vs. multi-stage) compare in yielding posterior estimates of fixed effects in the presence of spatially structured random effects, and finally which of two spatial prior models – the Leroux or ICAR model, perform best in a multi-stage context under different assumptions concerning spatial correlation. Among the fitted single-stage models without covariates, we found that when there is low amount of variability in the distribution of disease counts, the BYM model is relatively robust to misspecification in terms of DIC, while the Leroux model is the least robust to misspecification. When these models were fit to data generated from models with covariates, we found that when there was one set of covariates – either spatially correlated or non-spatially correlated, changing the values of the fixed coefficients affected the ability of either the Leroux or ICAR model to fit the data well in terms of DIC. When there were multiple sets of spatially correlated covariates in the simulating model, however, we could not distinguish the goodness of fit to the data between these single-stage models. We found that the multi-stage modelling process via the Leroux and ICAR models generally reduced the variance of the posterior estimated fixed effects for data generated from models with covariates and a UH term compared to analogous single-stage models. Finally, we found the multi-stage Leroux model compares favourably to the multi-stage ICAR model in terms of DIC. We conclude that the mutli-stage Leroux model should be seriously considered in applications of Bayesian disease mapping when an investigator desires to fit a model with both fixed effects and spatially structured random effects to Poisson count data.     

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.     

Centered parameterizations and dependence limitations in Markov random field models

Markov random field models incorporate terms representing local statistical dependence among variables in a discrete-index random field. Traditional parameterizations for models based on one-parameter exponential family conditional distributions contain components that would appear to reflect large-scale and small-scale model behaviors, and it is natural to attempt to match these structures with large-scale and small-scale patterns in a set of data. Traditional manners of parameterizing Markov random field models do not allow such correspondence, however. We propose an alternative centered parameterization that, while not leading to different models, allows a correspondence between model structures and data structures to be successfully accomplished. The ability to make these connections is important when incorporating covariate information into a model or if a sequence of models is fit over time to investigate and interpret possible changes in data structure. We demonstrate the improved interpretation that results from use of centered parameterizations. Centered parameterizations also lend themselves to computation of an interpretable decomposition of mean squared error, and this is demonstrated both analytically and through a simulated example. A breakdown in model behavior occurs even with centered parameterizations if dependence parameters in Markov random field models are allowed to become too large. This phenomenon is discussed and illustrated using an auto-logistic model.     

Bayesian outlier analysis in binary regression

We propose alternative approaches to analyze residuals in binary regression models based on random effect components. Our preferred model does not depend upon any tuning parameter, being completely automatic. Although the focus is mainly on accommodation of outliers, the proposed methodology is also able to detect them. Our approach consists of evaluating the posterior distribution of random effects included in the linear predictor. The evaluation of the posterior distributions of interest involves cumbersome integration, which is easily dealt with through stochastic simulation methods. We also discuss different specifications of prior distributions for the random effects. The potential of these strategies is compared in a real data set. The main finding is that the inclusion of extra variability accommodates the outliers, improving the adjustment of the model substantially, besides correctly indicating the possible outliers.     

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.     

Linear Transformations of Linear Mixed-Effects Models

A number of articles have discussed the way lower order polynomial and interaction terms should be handled in linear regression models. Only if all lower order terms are included in the model will the regression model be invariant with respect to coding transformations of the variables. If lower order terms are omitted, the regression model will not be well formulated. In this paper, we extend this work to examine the implications of the ordering of variables in the linear mixed-effects model. We demonstrate how linear transformations of the variables affect the model and tests of significance of fixed effects in the model. We show how the transformations modify the random effects in the model, as well as their covariance matrix and the value of the restricted log-likelihood. We suggest a variable selection strategy for the linear mixed-effects model.     

A Semi-Nonparametric Approach to Model Panel Count Data

In count data models, overdispersion of the dependent variable can be incorporated into the model if a heterogeneity term is added into the mean parameter of the Poisson distribution. We use a nonparametric estimation for the heterogeneity density based on a squared Kth-order polynomial expansion, that we generalize for panel data. A numerical illustration using an insurance dataset is discussed. Even if some statistical analyses showed no clear differences between these new models and the standard Poisson with gamma random effects, we show that the choice of the random effects distribution has a significant influence for interpreting our results.     

Modelling count data with overdispersion and spatial effects

In this paper we consider regression models for count data allowing for overdispersion in a Bayesian framework. We account for unobserved heterogeneity in the data in two ways. On the one hand, we consider more flexible models than a common Poisson model allowing for overdispersion in different ways. In particular, the negative binomial and the generalized Poisson (GP) distribution are addressed where overdispersion is modelled by an additional model parameter. Further, zero-inflated models in which overdispersion is assumed to be caused by an excessive number of zeros are discussed. On the other hand, extra spatial variability in the data is taken into account by adding correlated spatial random effects to the models. This approach allows for an underlying spatial dependency structure which is modelled using a conditional autoregressive prior based on Pettitt et al. in Stat Comput 12(4):353–367, (2002). In an application the presented models are used to analyse the number of invasive meningococcal disease cases in Germany in the year 2004. Models are compared according to the deviance information criterion (DIC) suggested by Spiegelhalter et al. in J R Stat Soc B64(4):583–640, (2002) and using proper scoring rules, see for example Gneiting and Raftery in Technical Report no. 463, University of Washington, (2004). We observe a rather high degree of overdispersion in the data which is captured best by the GP model when spatial effects are neglected. While the addition of spatial effects to the models allowing for overdispersion gives no or only little improvement, spatial Poisson models with spatially correlated or uncorrelated random effects are to be preferred over all other models according to the considered criteria.     

Modelling growth and decline in lung function in Duchenne's muscular dystrophy with an augmented linear mixed effects model

Summary.  Longitudinal modelling of lung function in Duchenne's muscular dystrophy is complicated by a mixture of both growth and decline in lung function within each subject, an unknown point of separation between these phases and significant heterogeneity between individual trajectories. Linear mixed effects models can be used, assuming a single changepoint for all cases; however, this assumption may be incorrect. The paper describes an extension of linear mixed effects modelling in which random changepoints are integrated into the model as parameters and estimated by using a stochastic EM algorithm. We find that use of this 'mixture modelling' approach improves the fit significantly.     

Likelihood analysis for a class of beta mixed models

Beta regression is a suitable choice for modelling continuous response variables taking values on the unit interval. Data structures such as hierarchical, repeated measures and longitudinal typically induce extra variability and/or dependence and can be accounted for by the inclusion of random effects. In this sense, Statistical inference typically requires numerical methods, possibly combined with sampling algorithms. A class of Beta mixed models is adopted for the analysis of two real problems with grouped data structures. We focus on likelihood inference and describe the implemented algorithms. The first is a study on the life quality index of industry workers with data collected according to an hierarchical sampling scheme. The second is a study assessing the impact of hydroelectric power plants upon measures of water quality indexes up, downstream and at the reservoirs of the dammed rivers, with a nested and longitudinal data structure. Results from different algorithms are reported for comparison including from data-cloning, an alternative to numerical approximations which also allows assessing identifiability. Confidence intervals based on profiled likelihoods are compared with those obtained by asymptotic quadratic approximations, showing relevant differences for parameters related to the random effects. In both cases, the scientific hypothesis of interest was investigated by comparing alternative models, leading to relevant interpretations of the results within each context.     

Estimating multiple-membership logit models with mixed effects: indirect inference versus data cloning

Multiple-membership logit models with random effects are models for clustered binary data, where each statistical unit can belong to more than one group. The likelihood function of these models is analytically intractable. We propose two different approaches for parameter estimation: indirect inference and data cloning (DC). The former is a non-likelihood-based method which uses an auxiliary model to select reasonable estimates. We propose an auxiliary model with the same dimension of parameter space as the target model, which is particularly convenient to reach good estimates very fast. The latter method computes maximum likelihood estimates through the posterior distribution of an adequate Bayesian model, fitted to cloned data. We implement a DC algorithm specifically for multiple-membership models. A Monte Carlo experiment compares the two methods on simulated data. For further comparison, we also report Bayesian posterior mean and Integrated Nested Laplace Approximation hybrid DC estimates. Simulations show a negligible loss of efficiency for the indirect inference estimator, compensated by a relevant computational gain. The approaches are then illustrated with two real examples on matched paired data.     

Mixed models for data from thorough QT studies: part 1. assessment of marginal QT prolongation

We investigate mixed models for repeated measures data from cross-over studies in general, but in particular for data from thorough QT studies. We extend both the conventional random effects model and the saturated covariance model for univariate cross-over data to repeated measures cross-over (RMC) data; the resulting models we call the RMC model and Saturated model, respectively. Furthermore, we consider a random effects model for repeated measures cross-over data previously proposed in the literature. We assess the standard errors of point estimates and the coverage properties of confidence intervals for treatment contrasts under the various models. Our findings suggest: (i) Point estimates of treatment contrasts from all models considered are similar; (ii) Confidence intervals for treatment contrasts under the random effects model previously proposed in the literature do not have adequate coverage properties; the model therefore cannot be recommended for analysis of marginal QT prolongation; (iii) The RMC model and the Saturated model have similar precision and coverage properties; both models are suitable for assessment of marginal QT prolongation; and (iv) The Akaike Information Criterion (AIC) is not a reliable criterion for selecting a covariance model for RMC data in the following sense: the model with the smallest AIC is not necessarily associated with the highest precision for the treatment contrasts, even if the model with the smallest AIC value is also the most parsimonious model.     

ANOVA models for Brownian motion

We investigate longitudinal models having Brownian-motion covariance structure. We show that any such model can be viewed as arising from a related “timeless” classical linear model where sample sizes correspond to longitudinal observation times. This relationship is of practical impact when there are closed-form ANOVA tables for the related classical model. Such tables can be directly transformed into the analogous tables for the original longitudinal model. We in particular provide complete results for one-way fixed and random effects ANOVA on the drift parameter in Brownian motion, and illustrate its use in estimating heterogeneity in tumor growth rates.     

Modeling proportions and marginal counts simultaneously for clustered multinomial data with random cluster sizes

Clustered multinomial data with random cluster sizes commonly appear in health, environmental and ecological studies. Traditional approaches for analyzing clustered multinomial data contemplate two assumptions. One of these assumptions is that cluster sizes are fixed, whereas the other demands cluster sizes to be positive. Randomness of the cluster sizes may be the determinant of the within-cluster correlation and between-cluster variation. We propose a baseline-category mixed model for clustered multinomial data with random cluster sizes based on Poisson mixed models. Our orthodox best linear unbiased predictor approach to this model depends only on the moment structure of unobserved distribution-free random effects. Our approach also consolidates the marginal and conditional modeling interpretations. Unlike the traditional methods, our approach can accommodate both random and zero cluster sizes. Two real-life multinomial data examples, crime data and food contamination data, are used to manifest our proposed methodology.