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.     

Comparison of models for average bioequivalence in replicated crossover designs

Average bioequivalence (ABE) has been the regulatory standard for bioequivalence (BE) since the 1990s. BE studies are commonly two-period crossovers, but may also use replicated designs. The replicated crossover will provide greater power for the ABE assessment. FDA has recommended that ABE analysis of replicated crossovers use a model which includes terms for separate within- and between-subject components for each formulation and which allows for a subject x formulation interaction component. Our simulation study compares the performance of four alternative mixed effects models: the FDA model, a three variance component model proposed by Ekbohm and Melander (EM), a random intercepts and slopes model (RIS) proposed by Patterson and Jones, and a simple model that contains only two variance components. The simple model fails (when not 'true') to provide adequate coverage and it accepts the hypothesis of equivalence too often. FDA and EM models are frequently indistinguishable and often provide the best performance with respect to coverage and probability of concluding BE. The RIS model concludes equivalence too often when both the within- and between-subject variance components differ between formulations. The FDA analysis model is recommended because it provides the most detail regarding components of variability and has a slight advantage over the EM model in confidence interval length.     

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.     

Parameter estimation for generalized random coefficient autoregressive processes

A generalized random coefficient autoregressive (GRCA) process is introduced in which the random coefficients are permitted to be correlated with the error process. The ordinary random coefficient autoregressive process, the Markovian bilinear model and its generalization, and the random coefficient exponential autoregressive process, among others, are seen to be special cases of the GRCA process. Conditional least squares, and weighted least-squares estimators of the mean of the random coefficient vector are derived and their limit distributions are studied. Estimators of the variance-covariance parameters are also discussed. A simulation study is presented which shows that the weighted least-squares estimator dominates the unweighted least-squares estimator.     

Nonparametric survival regression using the beta-Stacy process

A novel class of hierarchical nonparametric Bayesian survival regression models for time-to-event data with uninformative right censoring is introduced. The survival curve is modeled as a random function whose prior distribution is defined using the beta-Stacy (BS) process. The prior mean of each survival probability and its prior variance are linked to a standard parametric survival regression model. This nonparametric survival regression can thus be anchored to any reference parametric form, such as a proportional hazards or an accelerated failure time model, allowing substantial departures of the predictive survival probabilities when the reference model is not supported by the data. Also, under this formulation the predictive survival probabilities will be close to the empirical survival distribution near the mode of the reference model and they will be shrunken towards its probability density in the tails of the empirical distribution.     

Prediction in linear mixed models

Following estimation of effects from a linear mixed model, it is often useful to form predicted values for certain factor/variate combinations. The process has been well defined for linear models, but the introduction of random effects into the model means that a decision has to be made about the inclusion or exclusion of random model terms from the predictions. This paper discusses the interpretation of predictions formed including or excluding random terms. Four datasets are used to illustrate circumstances where different prediction strategies may be appropriate: in an orthogonal design, an unbalanced nested structure, a model with cubic smoothing spline terms and for kriging after spatial analysis. The examples also show the need for different weighting schemes that recognize nesting and aliasing during prediction, and the necessity of being able to detect inestimable predictions.     

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.     

Maximum likelihood estimation of variance components of heteroscedastic random anova model

the estimation of variance components of heteroscedastic random model is discussed in this paper. Maximum Likelihood (ML) is described for one-way heteroscedastic random models. The proportionality condition that cell variance is proportional to the cell sample size, is used to eliminate the efffect of heteroscedasticity. The algebraic expressions of the estimators are obtained for the model. It is seen that the algebraic expressions of the estimators depend mainly on the inverse of the variance-covariance matrix of the observation vector. So, the variance-covariance matrix is obtained and the formulae for the inversions are given. A Monte Carlo study is conducted. Five different variance patterns with different numbers of cells are considered in this study. For each variance pattern, 1000 Monte Carlo samples are drawn. Then the Monte Carlo biases and Monte Carlo MSE’s of the estimators of variance components are calculated. In respect of both bias and MSE, the Maximum Likelihood (ML) estimators of variance components are found to be sufficiently good.     

A revisit to two-way factorial ANOVA with mixed effects and interactions

Abstract

Two mixed models exist in analysis of two-way factorial ANOVA with mixed effects and interactions: the constrained and unconstrained models. The constrained model is unfavored because there is no convincing rationale for the enforced constraints on its random interactions and a lack of clear interpretation about its variance components. The purpose of this study is to further explore the relationship between these two models. We reveal some nice features of the constrained model on partition of the responsive variance. An alternative formulation of ANOVA that follows from this exploration is also presented.     

Estimation of group means in generalized linear mixed models

In this study, we investigate the concept of the mean response for a treatment group mean as well as its estimation and prediction for generalized linear models with a subject‐wise random effect. Generalized linear models are commonly used to analyze categorical data. The model‐based mean for a treatment group usually estimates the response at the mean covariate. However, the mean response for the treatment group for studied population is at least equally important in the context of clinical trials. New methods were proposed to estimate such a mean response in generalized linear models; however, this has only been done when there are no random effects in the model. We suggest that, in a generalized linear mixed model (GLMM), there are at least two possible definitions of a treatment group mean response that can serve as estimation/prediction targets. The estimation of these treatment group means is important for healthcare professionals to be able to understand the absolute benefit vs risk. For both of these treatment group means, we propose a new set of methods that suggests how to estimate/predict both of them in a GLMMs with a univariate subject‐wise random effect. Our methods also suggest an easy way of constructing corresponding confidence and prediction intervals for both possible treatment group means. Simulations show that proposed confidence and prediction intervals provide correct empirical coverage probability under most circumstances. Proposed methods have also been applied to analyze hypoglycemia data from diabetes clinical trials.     

A graphical model selection tool for mixed models

ABSTRACT

Model selection can be defined as the task of estimating the performance of different models in order to choose the most parsimonious one, among a potentially very large set of candidate statistical models. We propose a graphical representation to be considered as an extension to the class of mixed models of the deviance plot proposed in the literature within the framework of classical and generalized linear models. This graphical representation allows, once a reduced number of models have been selected, to identify important covariates focusing only on the fixed effects component, assuming the random part properly specified. Nevertheless, we suggest also a standalone figure representing the residual random variance ratio: a cross-evaluation of the two graphical representations will allow to derive some conclusions on the random part specification of the model and a more accurate selection of the final model.     

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.     

Using continuation-ratio logits to analyze the variation of the age composition of fish catches

Major sources of information for the estimation of the size of the fish stocks and the rate of their exploitation are samples from which the age composition of catches may be determined. However, the age composition in the catches often varies as a result of several factors. Stratification of the sampling is desirable, because it leads to better estimates of the age composition, and the corresponding variances and covariances. The analysis is impeded by the fact that the response is ordered categorical. This paper introduces an easily applicable method to analyze such data. The method combines continuation-ratio logits and the theory for generalized linear mixed models. Continuation-ratio logits are designed for ordered multinomial response and have the feature that the associated log-likelihood splits into separate terms for each category levels. Thus, generalized linear mixed models can be applied separately to each level of the logits. The method is illustrated by the analysis of age-composition data collected from the Danish sandeel fishery in the North Sea in 1993. The significance of possible sources of variation is evaluated, and formulae for estimating the proportions of each age group and their variance-covariance matrix are derived.     

Bayesian parsimonious covariance estimation for hierarchical linear mixed models

We consider a non-centered parameterization of the standard random-effects model, which is based on the Cholesky decomposition of the variance-covariance matrix. The regression type structure of the non-centered parameterization allows us to use Bayesian variable selection methods for covariance selection. We search for a parsimonious variance-covariance matrix by identifying the non-zero elements of the Cholesky factors. With this method we are able to learn from the data for each effect whether it is random or not, and whether covariances among random effects are zero. An application in marketing shows a substantial reduction of the number of free elements in the variance-covariance matrix.     

Spatio‐temporal modelling of disease mapping of rates

This paper studies generalized linear mixed models (GLMMs) for the analysis of geographic and temporal variability of disease rates. This class of models adopts spatially correlated random effects and random temporal components. Spatio‐temporal models that use conditional autoregressive smoothing across the spatial dimension and autoregressive smoothing over the temporal dimension are developed. The model also accommodates the interaction between space and time. However, the effect of seasonal factors has not been previously addressed and in some applications (e.g., health conditions), these effects may not be negligible. The authors incorporate the seasonal effects of month and possibly year as part of the proposed model and estimate model parameters through generalized estimating equations. The model provides smoothed maps of disease risk and eliminates the instability of estimates in low‐population areas while maintaining geographic resolution. They illustrate the approach using a monthly data set of the number of asthma presentations made by children to Emergency Departments (EDs) in the province of Alberta, Canada, during the period 2001–2004. The Canadian Journal of Statistics 38: 698–715; 2010 © 2010 Statistical Society of Canada     

Analyzing Permanent and Transient Influences in Multiple Time Series Models

Several multiple time series models are developed and applied to the analysis and forecasting of the M1 and M2 money supply aggregates. These models feature a decomposition of the time series into permanent and transient influences or components. This decomposition appears to enhance forecasting accuracy and is associated with a variance-covariance allocation parameter that is also estimated from the data. Conditional maximum likelihood estimates for model parameters are presented as well as a numerical algorithm that is an adaptation of Marquardt's algorithm.     

Random effects regression models for count data with excess zeros in caries research

We extend the family of Poisson and negative binomial models to derive the joint distribution of clustered count outcomes with extra zeros. Two random effects models are formulated. The first model assumes a shared random effects term between the conditional probability of perfect zeros and the conditional mean of the imperfect state. The second formulation relaxes the shared random effects assumption by relating the conditional probability of perfect zeros and the conditional mean of the imperfect state to two different but correlated random effects variables. Under the conditional independence and the missing data at random assumption, a direct optimization of the marginal likelihood and an EM algorithm are proposed to fit the proposed models. Our proposed models are fitted to dental caries counts of children under the age of six in the city of Detroit.     

Prediction in a class of mixed models with two variance components

A best unbiased predictor (BUP) of an arbitrary linear combination of fixed and random effects in mixed linear models is available when the true values of the variance ratios are known. When the true values are unknown, a two-stage predictor, obtained from the BUP by replacing the true values by estimated values, can be used. In this article, exact mean squared errors of two-stage predictors are obtained for a class of mixed models with two variance components that includes the balanced one-way random model and other analysis-of-variance models with proportional frequencies and one balanced random factor.     

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.     

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.