We generalize the method proposed by Gelman and Rubin (1992a) for monitoring the convergence of iterative simulations by comparing between and within variances of multiple chains, in order to obtain a family of tests for convergence. We review methods of inference from simulations in order to develop convergence-monitoring summaries that are relevant for the purposes for which the simulations are used. We recommend applying a battery of tests for mixing based on the comparison of inferences from individual sequences and from the mixture of sequences. Finally, we discuss multivariate analogues, for assessing convergence of several parameters simultaneously.

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General methods for monitoring convergence of iterative simulations

Structured additive regression models are perhaps the most commonly used class of models in statistical applications. It includes, among others, (generalized) linear models, (generalized) additive models, smoothing spline models, state space models, semiparametric regression, spatial and spatiotemporal models, log-Gaussian Cox processes and geostatistical and geoadditive models. We consider approximate Bayesian inference in a popular subset of structured additive regression models, latent Gaussian models, where the latent field is Gaussian, controlled by a few hyperparameters and with non-Gaussian response variables. The posterior marginals are not available in closed form owing to the non-Gaussian response variables. For such models, Markov chain Monte Carlo methods can be implemented, but they are not without problems, in terms of both convergence and computational time. In some practical applications, the extent of these problems is such that Markov chain Monte Carlo sampling is simply not an appropriate tool for routine analysis. We show that, by using an integrated nested Laplace approximation and its simplified version, we can directly compute very accurate approximations to the posterior marginals. The main benefit of these approximations is computational: where Markov chain Monte Carlo algorithms need hours or days to run, our approximations provide more precise estimates in seconds or minutes. Another advantage with our approach is its generality, which makes it possible to perform Bayesian analysis in an automatic, streamlined way, and to compute model comparison criteria and various predictive measures so that models can be compared and the model under study can be challenged.

/pdf/approximate-bayesian-inference-for-latent-gaussian-models-by-2m3x22eic2.pdf

Approximate Bayesian inference for latent Gaussian models by using integrated nested Laplace approximations

Genetics and analysis of quantitative traits

The arcsine square root transformation has long been standard procedure when analyzing proportional data in ecology, with applications in data sets containing binomial and non-binomial response variables. Here, we argue that the arcsine transform should not be used in either circumstance. For binomial data, logistic regression has greater interpretability and higher power than analyses of transformed data. However, it is important to check the data for additional unexplained variation, i.e., overdispersion, and to account for it via the inclusion of random effects in the model if found. For non-binomial data, the arcsine transform is undesirable on the grounds of interpretability, and because it can produce nonsensical predictions. The logit transformation is proposed as an alternative approach to address these issues. Examples are presented in both cases to illustrate these advantages, comparing various methods of analyzing proportions including untransformed, arcsine- and logit-transformed linear models and logistic regression (with or without random effects). Simulations demonstrate that logistic regression usually provides a gain in power over other methods.

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The arcsine is asinine: the analysis of proportions in ecology

Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.

Hundreds of variants clustered in genomic loci and biological pathways affect human height

Linear Mixed Models: Part I- Linear Mixed Models: Part II- Generalized Linear Mixed Models: Part I- Generalized Linear Mixed Models: Part II

Linear and Generalized Linear Mixed Models and Their Applications

We describe a general approach using Bayesian analysis for the estimation of parameters in physiological pharmacokinetic models. The chief statistical difficulty in estimation with these models is that any physiological model that is even approximately realistic will have a large number of parameters, often comparable to the number of observations in a typical pharmacokinetic experiment (e.g., 28 measurements and 15 parameters for each subject). In addition, the parameters are generally poorly identified, akin to the well-known ill-conditioned problem of estimating a mixture of declining exponentials. Our modeling includes (a) hierarchical population modeling, which allows partial pooling of information among different experimental subjects; (b) a pharmacokinetic model including compartments for well-perfused tissues, poorly perfused tissues, fat, and the liver; and (c) informative prior distributions for population parameters, which is possible because the parameters represent real physiological...

Physiological Pharmacokinetic Analysis Using Population Modeling and Informative Prior Distributions

Over the last three decades, mixed models have been frequently used in a wide range of small area applications. Such models offer great flexibilities in combining information from various sources, and thus are well suited for solving most small area estimation problems. The present article reviews major research developments in the classical inferential approach for linear and generalized linear mixed models that are relevant to different issues concerning small area estimation and related problems.

Mixed model prediction and small area estimation

The term “empirical predictor” refers to a two-stage predictor of a linear combination of fixed and random effects. In the first stage, a predictor is obtained but it involves unknown parameters; thus, in the second stage, the unknown parameters are replaced by their estimators. In this paper, we consider mean squared errors (MSE) of empirical predictors under a general setup, where ML or REML estimators are used for the second stage. We obtain second-order approximation to the MSE as well as an estimator of the MSE correct to the same order. The general results are applied to mixed linear models to obtain a second-order approximation to the MSE of the empirical best linear unbiased predictor (EBLUP) of a linear mixed effect and an estimator of the MSE of EBLUP whose bias is correct to second order. The general mixed linear model includes the mixed ANOVA model and the longitudinal model as special cases.

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Mean squared error of empirical predictor

The restricted maximum likelihood (REML) estimates of dispersion parameters (variance components) in a general (non-normal) mixed model are defined as solutions of the REML equations. In this paper, we show the REML estimates are consistent if the model is asymptotically identifiable and infinitely informative under the (location) invariant class, and are asymptotically normal (A.N.) if in addition the model is asymptotically nondegenerate. The result does not require normality or boundedness of the rank p of design matrix of fixed effects. Moreover, we give a necessary and sufficient condition for asymptotic normality of Gaussian maximum likelihood estimates (MLE) in non-normal cases. As an application, we show for all unconfounded balanced mixed models of the analysis of variance the REML (ANOVA) estimates are consistent; and are also A.N. provided the models are nondegenerate; the MLE are consistent (A.N.) if and only if certain constraints on p are satisfied.

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Jiming Jiang

Papers

Linear and Generalized Linear Mixed Models and Their Applications

Physiological Pharmacokinetic Analysis Using Population Modeling and Informative Prior Distributions

Mixed model prediction and small area estimation

Mean squared error of empirical predictor

REML estimation: asymptotic behavior and related topics