Likelihood Inference for Spatial Generalized Linear Mixed Models

Spatial modeling is widely used in environmental sciences, biology, and epidemiology. Generalized linear mixed models are employed to account for spatial variations of point-referenced data called spatial generalized linear mixed models (SGLMMs). Frequentist analysis of these type of data is computationally difficult. On the other hand, the advent of the Markov chain Monte Carlo algorithm has made the Bayesian analysis of SGLMM computationally convenient. Recent introduction of the method of data cloning, which leads to maximum likelihood estimate, has made frequentist analysis of mixed models also equally computationally convenient. Recently, the data cloning was employed to estimate model parameters in SGLMMs, however, the prediction of spatial random effects and kriging are also very important. In this article, we propose a frequentist approach based on data cloning to predict (and provide prediction intervals) spatial random effects and kriging. We illustrate this approach using a real dataset and also by a simulation study.     

Estimation of group means using Bayesian generalized linear mixed models

Generalized linear mixed models (GLMM) are commonly used to model the treatment effect over time while controlling for important clinical covariates. Standard software procedures often provide estimates of the outcome based on the mean of the covariates; however, these estimates will be biased for the true group means in the GLMM. Implementing GLMM in the frequentist framework can lead to issues of convergence. A simulation study demonstrating the use of fully Bayesian GLMM for providing unbiased estimates of group means is shown. These models are very straightforward to implement and can be used for a broad variety of outcomes (eg, binary, categorical, and count data) that arise in clinical trials. We demonstrate the proposed method on a data set from a clinical trial in diabetes.     

Fast two-stage estimator for clustered count data with overdispersion

Clustered count data are commonly analysed by the generalized linear mixed model (GLMM). Here, the correlation due to clustering and some overdispersion is captured by the inclusion of cluster-specific normally distributed random effects. Often, the model does not capture the variability completely. Therefore, the GLMM can be extended by including a set of gamma random effects. Routinely, the GLMM is fitted by maximizing the marginal likelihood. However, this process is computationally intensive. Although feasible with medium to large data, it can be too time-consuming or computationally intractable with very large data. Therefore, a fast two-stage estimator for correlated, overdispersed count data is proposed. It is rooted in the split-sample methodology. Based on a simulation study, it shows good statistical properties. Furthermore, it is computationally much faster than the full maximum likelihood estimator. The approach is illustrated using a large dataset belonging to a network of Belgian general practices.     

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.     

Robust estimation in generalized linear mixed models

Generalized linear mixed models (GLMMs) are widely used to analyse non-normal response data with extra-variation, but non-robust estimators are still routinely used. We propose robust methods for maximum quasi-likelihood and residual maximum quasi-likelihood estimation to limit the influence of outlying observations in GLMMs. The estimation procedure parallels the development of robust estimation methods in linear mixed models, but with adjustments in the dependent variable and the variance component. The methods proposed are applied to three data sets and a comparison is made with the nonparametric maximum likelihood approach. When applied to a set of epileptic seizure data, the methods proposed have the desired effect of limiting the influence of outlying observations on the parameter estimates. Simulation shows that one of the residual maximum quasi-likelihood proposals has a smaller bias than those of the other estimation methods. We further discuss the equivalence of two GLMM formulations when the response variable follows an exponential family. Their extensions to robust GLMMs and their comparative advantages in modelling are described. Some possible modifications of the robust GLMM estimation methods are given to provide further flexibility for applying the method.     

Approximate bounded influence estimation for longitudinal data with outliers and measurement errors

Mixed effects models or random effects models are popular for the analysis of longitudinal data. In practice, longitudinal data are often complex since there may be outliers in both the response and the covariates and there may be measurement errors. The likelihood method is a common approach for these problems but it can be computationally very intensive and sometimes may even be computationally infeasible. In this article, we consider approximate robust methods for nonlinear mixed effects models to simultaneously address outliers and measurement errors. The approximate methods are computationally very efficient. We show the consistency and asymptotic normality of the approximate estimates. The methods can also be extended to missing data problems. An example is used to illustrate the methods and a simulation is conducted to evaluate the methods.     

Power analysis for clustered non-continuous responses in multicenter trials

Power analysis for multi-center randomized control trials is quite difficult to perform for non-continuous responses when site differences are modeled by random effects using the generalized linear mixed-effects model (GLMM). First, it is not possible to construct power functions analytically, because of the extreme complexity of the sampling distribution of parameter estimates. Second, Monte Carlo (MC) simulation, a popular option for estimating power for complex models, does not work within the current context because of a lack of methods and software packages that would provide reliable estimates for fitting such GLMMs. For example, even statistical packages from software giants like SAS do not provide reliable estimates at the time of writing. Another major limitation of MC simulation is the lengthy running time, especially for complex models such as GLMM, especially when estimating power for multiple scenarios of interest. We present a new approach to address such limitations. The proposed approach defines a marginal model to approximate the GLMM and estimates power without relying on MC simulation. The approach is illustrated with both real and simulated data, with the simulation study demonstrating good performance of the method.     

On the use of between–within models to adjust for confounding due to unmeasured cluster-level covariates

Between–within models are generalized linear mixed models (GLMMs) for clustered data that incorporate a random intercept together with fixed effects for within-cluster and between-cluster covariates; the between-cluster covariates represent the cluster means of the within-cluster covariates. One popular use of these models is to adjust for confounding of the effect of within-cluster covariates due to unmeasured between-cluster covariates. Previous research has shown via simulations that using this approach can yield inconsistent estimators. We present theory and simulations as evidence that a primary cause of the inconsistency is heteroscedasticity of the linearized version of the GLMM used for estimation.     

Bayesian regularisation in geoadditive expectile regression

Regression modelling beyond the mean of the response has found a lot of attention in the last years. Expectile regression is a special and computationally convenient case of this type of models where expectiles offer a quantile-like characterisation of the complete distribution and include the mean as a special case. In the frequentist framework, expectile regression could be combined with covariate effects of quite different forms and in particular nonlinear and spatial effects. We propose Bayesian expectile regression based on the asymmetric normal distribution as an auxiliary likelihood to allow for the additional inclusion of Bayesian regularisation priors for covariates with linear effects. Proposal densities based on iteratively weighted least squares updates for the resulting Markov chain Monte Carlo simulation algorithm are developed and evaluated in both simulations and an application. A special focus of the simulations lies on the evaluation of coverage properties of the Bayesian credible bands and the quantification of the detrimental effect arising from the misspecification of the auxiliary likelihood.     

Choice of link and variance function for generalized linear mixed models: a case study with binomial response in proteomics

Abstract

Non-normality is a common phenomenon in data from agricultural and biological research, especially in molecular data (for example; -omics, RNAseq, flow cytometric data, etc.). For over half a century, the leading paradigm called for using analysis of variance (ANOVA) after applying a data transformation. The introduction of generalized linear mixed models (GLMM) provides a new way of analyzing non-normal data. Selecting an apt link function in GLMM can be quite influential, however, and is as critical as selecting an appropriate transformation for ANOVA. In this paper, we assess the performance of different parametric link families available in literature. Then, we propose a new estimation method for selecting an appropriate link function with a suitable variance function in a quasi-likelihood framework. We apply these methods to a proteomics data set, showing that GLMMs provide a very flexible framework for analyzing these kinds of data.     

Semi‐parametric small‐area estimation by combining time‐series and cross‐sectional data methods

In survey sampling, policymaking regarding the allocation of resources to subgroups (called small areas) or the determination of subgroups with specific properties in a population should be based on reliable estimates. Information, however, is often collected at a different scale than that of these subgroups; hence, the estimation can only be obtained on finer scale data. Parametric mixed models are commonly used in small‐area estimation. The relationship between predictors and response, however, may not be linear in some real situations. Recently, small‐area estimation using a generalised linear mixed model (GLMM) with a penalised spline (P‐spline) regression model, for the fixed part of the model, has been proposed to analyse cross‐sectional responses, both normal and non‐normal. However, there are many situations in which the responses in small areas are serially dependent over time. Such a situation is exemplified by a data set on the annual number of visits to physicians by patients seeking treatment for asthma, in different areas of Manitoba, Canada. In cases where covariates that can possibly predict physician visits by asthma patients (e.g. age and genetic and environmental factors) may not have a linear relationship with the response, new models for analysing such data sets are required. In the current work, using both time‐series and cross‐sectional data methods, we propose P‐spline regression models for small‐area estimation under GLMMs. Our proposed model covers both normal and non‐normal responses. In particular, the empirical best predictors of small‐area parameters and their corresponding prediction intervals are studied with the maximum likelihood estimation approach being used to estimate the model parameters. The performance of the proposed approach is evaluated using some simulations and also by analysing two real data sets (precipitation and asthma).     

基于MCMC模拟和伪似然估计法的交叉分类信度模型费率厘定简

针对传统交叉分类信度模型计算复杂且在结构参数先验信息不足的情况下不能得到参数无偏后验估计的问题，利用MCMC模拟和GLMM方法，对交叉分类信度模型进行实证分析证明模型的有效性。结果表明：基于MCMC方法能够动态模拟参数的后验分布，并可提高模型估计的精度；基于GLMM能大大简化计算过程且操作方便，可利用图形和其它诊断工具选择模型，并对模型实用性做出评价。     

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.     

Incomplete covariates data in generalized linear models

We consider regression analysis when part of covariates are incomplete in generalized linear models. The incomplete covariates could be due to measurement error or missing for some study subjects. We assume there exists a validation sample in which the data is complete and is a simple random subsample from the whole sample. Based on the idea of projection-solution method in Heyde (1997, Quasi-Likelihood and its Applications: A General Approach to Optimal Parameter Estimation. Springer, New York), a class of estimating functions is proposed to estimate the regression coefficients through the whole data. This method does not need to specify a correct parametric model for the incomplete covariates to yield a consistent estimate, and avoids the ‘curse of dimensionality’ encountered in the existing semiparametric method. Simulation results shows that the finite sample performance and efficiency property of the proposed estimates are satisfactory. Also this approach is computationally convenient hence can be applied to daily data analysis.     

A new look at the difference between the GEE and the GLMM when modeling longitudinal count responses

Poisson log-linear regression is a popular model for count responses. We examine two popular extensions of this model – the generalized estimating equations (GEE) and the generalized linear mixed-effects model (GLMM) – to longitudinal data analysis and complement the existing literature on characterizing the relationship between the two dueling paradigms in this setting. Unlike linear regression, the GEE and the GLMM carry significant conceptual and practical implications when applied to modeling count data. Our findings shed additional light on the differences between the two classes of models when used for count data. Our considerations are demonstrated by both real study and simulated data.     

Some asymptotic results for semiparametric nonlinear mixed-effects models with incomplete data

In modeling complex longitudinal data, semiparametric nonlinear mixed-effects (SNLME) models are very flexible and useful. Covariates are often introduced in the models to partially explain the inter-individual variations. In practice, data are often incomplete in the sense that there are often measurement errors and missing data in longitudinal studies. The likelihood method is a standard approach for inference for these models but it can be computationally very challenging, so computationally efficient approximate methods are quite valuable. However, the performance of these approximate methods is often based on limited simulation studies, and theoretical results are unavailable for many approximate methods. In this article, we consider a computationally efficient approximate method for a class of SNLME models with incomplete data and investigate its theoretical properties. We show that the estimates based on the approximate method are consistent and asymptotically normally distributed.     

Restricted likelihood inference for generalized linear mixed models

We aim to promote the use of the modified profile likelihood function for estimating the variance parameters of a GLMM in analogy to the REML criterion for linear mixed models. Our approach is based on both quasi-Monte Carlo integration and numerical quadrature, obtaining in either case simulation-free inferential results. We will illustrate our idea by applying it to regression models with binary responses or count data and independent clusters, covering also the case of two-part models. Two real data examples and three simulation studies support the use of the proposed solution as a natural extension of REML for GLMMs. An R package implementing the methodology is available online.     

Robust methods for the analysis of spatially autocorrelated data

In this paper we propose a new robust technique for the analysis of spatial data through simultaneous autoregressive (SAR) models, which extends the Forward Search approach of Cerioli and Riani (1999) and Atkinson and Riani (2000). Our algorithm starts from a subset of outlier-free observations and then selects additional observations according to their degree of agreement with the postulated model. A number of useful diagnostics which are monitored along the search help to identify masked spatial outliers and high leverage sites. In contrast to other robust techniques, our method is particularly suited for the analysis of complex multidimensional systems since each step is performed through statistically and computationally efficient procedures, such as maximum likelihood. The main contribution of this paper is the development of joint robust estimation of both trend and autocorrelation parameters in spatial linear models. For this purpose we suggest a novel definition of the elemental sets of the Forward Search, which relies on blocks of contiguous spatial locations.     

Bayesian nonparametric density estimation under length bias

A density estimation method in a Bayesian nonparametric framework is presented when recorded data are not coming directly from the distribution of interest, but from a length biased version. From a Bayesian perspective, efforts to computationally evaluate posterior quantities conditionally on length biased data were hindered by the inability to circumvent the problem of a normalizing constant. In this article, we present a novel Bayesian nonparametric approach to the length bias sampling problem that circumvents the issue of the normalizing constant. Numerical illustrations as well as a real data example are presented and the estimator is compared against its frequentist counterpart, the kernel density estimator for indirect data of Jones.     

Approximate composite marginal likelihood inference in spatial generalized linear mixed models

Non-Gaussian spatial responses are usually modeled using spatial generalized linear mixed model with spatial random effects. The likelihood function of this model cannot usually be given in a closed form, thus the maximum likelihood approach is very challenging. There are numerical ways to maximize the likelihood function, such as Monte Carlo Expectation Maximization and Quadrature Pairwise Expectation Maximization algorithms. They can be applied but may in such cases be computationally very slow or even prohibitive. Gauss–Hermite quadrature approximation only suitable for low-dimensional latent variables and its accuracy depends on the number of quadrature points. Here, we propose a new approximate pairwise maximum likelihood method to the inference of the spatial generalized linear mixed model. This approximate method is fast and deterministic, using no sampling-based strategies. The performance of the proposed method is illustrated through two simulation examples and practical aspects are investigated through a case study on a rainfall data set.