CAUSAL GRAPHICAL MODELS IN SYSTEMS GENETICS: A UNIFIED FRAMEWORK FOR JOINT INFERENCE OF CAUSAL NETWORK AND GENETIC ARCHITECTURE FOR CORRELATED PHENOTYPES

Causal inference approaches in systems genetics exploit quantitative trait loci (QTL) genotypes to infer causal relationships among phenotypes. The genetic architecture of each phenotype may be complex, and poorly estimated genetic architectures may compromise the inference of causal relationships among phenotypes. Existing methods assume QTLs are known or inferred without regard to the phenotype network structure. In this paper we develop a QTL-driven phenotype network method (QTLnet) to jointly infer a causal phenotype network and associated genetic architecture for sets of correlated phenotypes. Randomization of alleles during meiosis and the unidirectional influence of genotype on phenotype allow the inference of QTLs causal to phenotypes. Causal relationships among phenotypes can be inferred using these QTL nodes, enabling us to distinguish among phenotype networks that would otherwise be distribution equivalent. We jointly model phenotypes and QTLs using homogeneous conditional Gaussian regression models, and we derive a graphical criterion for distribution equivalence. We validate the QTLnet approach in a simulation study. Finally, we illustrate with simulated data and a real example how QTLnet can be used to infer both direct and indirect effects of QTLs and phenotypes that co-map to a genomic region.     

Objective Bayes Covariate‐Adjusted Sparse Graphical Model Selection

We present an objective Bayes method for covariance selection in Gaussian multivariate regression models having a sparse regression and covariance structure, the latter being Markov with respect to a directed acyclic graph (DAG). Our procedure can be easily complemented with a variable selection step, so that variable and graphical model selection can be performed jointly. In this way, we offer a solution to a problem of growing importance especially in the area of genetical genomics (eQTL analysis). The input of our method is a single default prior, essentially involving no subjective elicitation, while its output is a closed form marginal likelihood for every covariate‐adjusted DAG model, which is constant over each class of Markov equivalent DAGs; our procedure thus naturally encompasses covariate‐adjusted decomposable graphical models. In realistic experimental studies, our method is highly competitive, especially when the number of responses is large relative to the sample size.     

Checking the censored two-sample accelerated life model using integrated cumulative hazard difference

In this paper, new statistical tests for the censored two-sample accelerated life model are discussed. From the estimating functions using integrated cumulative hazard difference, stochastic processes are constructed. They can be described by martingale residuals, and, given the data, conditional distributions can be approximated by zero mean Gaussian processes. The new methods, based on these processes, provide asymptotically consistent tests against a general departure from the model. A graphical method is also discussed. In various numerical studies, the new tests performed better than the existing method, especially when the hazard curves cross. The proposed procedures are illustrated with two real data sets.     

Sparse group lasso for multiclass functional logistic regression models

Sparsity-inducing penalties are useful tools for variable selection and are also effective for regression problems where the data are functions. We consider the problem of selecting not only variables but also decision boundaries in multiclass logistic regression models for functional data, using sparse regularization. The parameters of the functional logistic regression model are estimated in the framework of the penalized likelihood method with the sparse group lasso-type penalty, and then tuning parameters for the model are selected using the model selection criterion. The effectiveness of the proposed method is investigated through simulation studies and the analysis of a gene expression data set.     

Continuous covariate frailty models for censored and truncated clustered data

Using some logarithmic and integral transformation we transform a continuous covariate frailty model into a polynomial regression model with a random effect. The responses of this mixed model can be ‘estimated’ via conditional hazard function estimation. The random error in this model does not have zero mean and its variance is not constant along the covariate and, consequently, these two quantities have to be estimated. Since the asymptotic expression for the bias is complicated, the two-large-bandwidth trick is proposed to estimate the bias. The proposed transformation is very useful for clustered incomplete data subject to left truncation and right censoring (and for complex clustered data in general). Indeed, in this case no standard software is available to fit the frailty model, whereas for the transformed model standard software for mixed models can be used for estimating the unknown parameters in the original frailty model. A small simulation study illustrates the good behavior of the proposed method. This method is applied to a bladder cancer data set.     

Bayesian model-averaged regularization for Gaussian graphical models

The graphical lasso has now become a useful tool to estimate high-dimensional Gaussian graphical models, but its practical applications suffer from the problem of choosing regularization parameters in a data-dependent way. In this article, we propose a model-averaged method for estimating sparse inverse covariance matrices for Gaussian graphical models. We consider the graphical lasso regularization path as the model space for Bayesian model averaging and use Markov chain Monte Carlo techniques for the regularization path point selection. Numerical performance of our method is investigated using both simulated and real datasets, in comparison with some state-of-art model selection procedures.     

A SINful approach to Gaussian graphical model selection

Multivariate Gaussian graphical models are defined in terms of Markov properties, i.e., conditional independences, corresponding to missing edges in the graph. Thus model selection can be accomplished by testing these independences, which are equivalent to zero values of corresponding partial correlation coefficients. For concentration graphs, acyclic directed graphs, and chain graphs (both LWF and AMP classes), we apply Fisher's z-transform, Šidák's correlation inequality, and Holm's step-down procedure to simultaneously test the multiple hypotheses specified by these zero values. This simple method for model selection controls the overall error rate for incorrect edge inclusion. Prior information about the presence and/or absence of particular edges can be readily incorporated.     

Composite conditional likelihood for sparse clustered data

Summary.  Sparse clustered data arise in finely stratified genetic and epidemiologic studies and pose at least two challenges to inference. First, it is difficult to model and interpret the full joint probability of dependent discrete data, which limits the utility of full likelihood methods. Second, standard methods for clustered data, such as pairwise likelihood and the generalized estimating function approach, are unsuitable when the data are sparse owing to the presence of many nuisance parameters. We present a composite conditional likelihood for use with sparse clustered data that provides valid inferences about covariate effects on both the marginal response probabilities and the intracluster pairwise association. Our primary focus is on sparse clustered binary data, in which case the method proposed utilizes doubly discordant quadruplets drawn from each stratum to conduct inference about the intracluster pairwise odds ratios.     

ESTIMATING BAYESIAN NETWORKS FOR HIGH‐DIMENSIONAL DATA WITH COMPLEX MEAN STRUCTURE AND RANDOM EFFECTS

The estimation of Bayesian networks given high‐dimensional data, in particular gene expression data, has been the focus of much recent research. Whilst there are several methods available for the estimation of such networks, these typically assume that the data consist of independent and identically distributed samples. It is often the case, however, that the available data have a more complex mean structure, plus additional components of variance, which must then be accounted for in the estimation of a Bayesian network. In this paper, score metrics that take account of such complexities are proposed for use in conjunction with score‐based methods for the estimation of Bayesian networks. We propose first, a fully Bayesian score metric, and second, a metric inspired by the notion of restricted maximum likelihood. We demonstrate the performance of these new metrics for the estimation of Bayesian networks using simulated data with known complex mean structures. We then present the analysis of expression levels of grape‐berry genes adjusting for exogenous variables believed to affect the expression levels of the genes. Demonstrable biological effects can be inferred from the estimated conditional independence relationships and correlations amongst the grape‐berry genes.     

Stratified Gaussian graphical models

Gaussian graphical models represent the backbone of the statistical toolbox for analyzing continuous multivariate systems. However, due to the intrinsic properties of the multivariate normal distribution, use of this model family may hide certain forms of context-specific independence that are natural to consider from an applied perspective. Such independencies have been earlier introduced to generalize discrete graphical models and Bayesian networks into more flexible model families. Here, we adapt the idea of context-specific independence to Gaussian graphical models by introducing a stratification of the Euclidean space such that a conditional independence may hold in certain segments but be absent elsewhere. It is shown that the stratified models define a curved exponential family, which retains considerable tractability for parameter estimation and model selection.     

Shrinkage tuning parameter selection in precision matrices estimation

Recent literature provides many computational and modeling approaches for covariance matrices estimation in a penalized Gaussian graphical models but relatively little study has been carried out on the choice of the tuning parameter. This paper tries to fill this gap by focusing on the problem of shrinkage parameter selection when estimating sparse precision matrices using the penalized likelihood approach. Previous approaches typically used K-fold cross-validation in this regard. In this paper, we first derived the generalized approximate cross-validation for tuning parameter selection which is not only a more computationally efficient alternative, but also achieves smaller error rate for model fitting compared to leave-one-out cross-validation. For consistency in the selection of nonzero entries in the precision matrix, we employ a Bayesian information criterion which provably can identify the nonzero conditional correlations in the Gaussian model. Our simulations demonstrate the general superiority of the two proposed selectors in comparison with leave-one-out cross-validation, 10-fold cross-validation and Akaike information criterion.     

Quasi‐Symmetric Graphical Log‐Linear Models

Abstract. We propose an extension of graphical log‐linear models to allow for symmetry constraints on some interaction parameters that represent homologous factors. The conditional independence structure of such quasi‐symmetric (QS) graphical models is described by an undirected graph with coloured edges, in which a particular colour corresponds to a set of equality constraints on a set of parameters. Unlike standard QS models, the proposed models apply with contingency tables for which only some variables or sets of the variables have the same categories. We study the graphical properties of such models, including conditions for decomposition of model parameters and of maximum likelihood estimates.     

Statistical inference concerning weighted Poisson rates under some natural order restrictions

A conditional Poisson model is proposed for situations where one wants to compare the rate parameters for several populations, adjusting for a 'size' parameter and the random e ects of the subjects. Sometimes the physical nature of the problem makes it logical to consider some order restrictions on the rate parameters. The rate parameters are estimated and tested for under such order restrictions. This investigation is motivated by a real-life example on butterfly behavior, and the estimation and tests of hypotheses are illustrated over this data set.     

Clustering gene expression time course data using mixtures of multivariate t-distributions

Clustering gene expression time course data is an important problem in bioinformatics because understanding which genes behave similarly can lead to the discovery of important biological information. Statistically, the problem of clustering time course data is a special case of the more general problem of clustering longitudinal data. In this paper, a very general and flexible model-based technique is used to cluster longitudinal data. Mixtures of multivariate t-distributions are utilized, with a linear model for the mean and a modified Cholesky-decomposed covariance structure. Constraints are placed upon the covariance structure, leading to a novel family of mixture models, including parsimonious models. In addition to model-based clustering, these models are also used for model-based classification, i.e., semi-supervised clustering. Parameters, including the component degrees of freedom, are estimated using an expectation-maximization algorithm and two different approaches to model selection are considered. The models are applied to simulated data to illustrate their efficacy; this includes a comparison with their Gaussian analogues—the use of these Gaussian analogues with a linear model for the mean is novel in itself. Our family of multivariate t mixture models is then applied to two real gene expression time course data sets and the results are discussed. We conclude with a summary, suggestions for future work, and a discussion about constraining the degrees of freedom parameter.     

Graphical modelling and the Mahalanobis distance

I consider the problem of estimating the Mahalanobis distance between multivariate normal populations when the population covariance matrix satisfies a graphical model. In addition to providing a clear understanding of the dependencies in a multivariate data set, the use of graphical models can reduce the variability of the estimated distances and improve inferences. I derive the asymptotic distribution of the estimated Mahalanobis distance under a general covariance model, which includes graphical models as a special case. Two examples are discussed.     

On the impact of contaminations in graphical Gaussian models

This paper analyzes the impact of some kinds of contaminant on model selection in graphical Gaussian models. We investigate four different kinds of contaminants, in order to consider the effect of gross errors, model deviations, and model misspecification. The aim of the work is to assess against which kinds of contaminant a model selection procedure for graphical Gaussian models has a more robust behavior. The analysis is based on simulated data. The simulation study shows that relatively few contaminated observations in even just one of the variables can have a significant impact on correct model selection, especially when the contaminated variable is a node in a separating set of the graph.     

Sparse Functional Principal Component Analysis via Regularized Basis Expansions and Its Application

This article introduces principal component analysis for multidimensional sparse functional data, utilizing Gaussian basis functions. Our multidimensional model is estimated by maximizing a penalized log-likelihood function, while previous mixed-type models were estimated by maximum likelihood methods for one-dimensional data. The penalized estimation performs well for our multidimensional model, while maximum likelihood methods yield unstable parameter estimates and some of the parameter estimates are infinite. Numerical experiments are conducted to investigate the effectiveness of our method for some types of missing data. The proposed method is applied to handwriting data, which consist of the XY coordinates values in handwritings.