Direct estimation of differential networks under high‐dimensional nonparanormal graphical models

A sparse precision matrix can be directly translated into a sparse Gaussian graphical model under the assumption that the data follow a joint normal distribution. This neat property makes high-dimensional precision matrix estimation very appealing in many applications. However, in practice we often face nonnormal data, and variable transformation is often used to achieve normality. In this paper we consider the nonparanormal model that assumes that the variables follow a joint normal distribution after a set of unknown monotone transformations. The nonparanormal model is much more flexible than the normal model while retaining the good interpretability of the latter in that each zero entry in the sparse precision matrix of the nonparanormal model corresponds to a pair of conditionally independent variables. In this paper we show that the nonparanormal graphical model can be efficiently estimated by using a rank-based estimation scheme which does not require estimating these unknown transformation functions. In particular, we study the rank-based graphical lasso, the rank-based neighborhood Dantzig selector and the rank-based CLIME. We establish their theoretical properties in the setting where the dimension is nearly exponentially large relative to the sample size. It is shown that the proposed rank-based estimators work as well as their oracle counterparts defined with the oracle data. Furthermore, the theory motivates us to consider the adaptive version of the rank-based neighborhood Dantzig selector and the rank-based CLIME that are shown to enjoy graphical model selection consistency without assuming the irrepresentable condition for the oracle and rank-based graphical lasso. Simulated and real data are used to demonstrate the finite performance of the rank-based estimators.

We propose Bayesian methods for Gaussian graphical models that lead to sparse and adaptively shrunk estimators of the precision (inverse covariance) matrix. Our methods are based on lasso-type regularization priors leading to parsimonious parameterization of the precision matrix, which is essential in several applications involving learning relationships among the variables. In this context, we introduce a novel type of selection prior that develops a sparse structure on the precision matrix by making most of the elements exactly zero, in addition to ensuring positive definiteness - thus conducting model selection and estimation simultaneously. More importantly, we extend these methods to analyze clustered data using finite mixtures of Gaussian graphical model and infinite mixtures of Gaussian graphical models. We discuss appropriate posterior simulation schemes to implement posterior inference in the proposed models, including the evaluation of normalizing constants that are functions of parameters of interest, which result from the restriction of positive definiteness on the correlation matrix. We evaluate the operating characteristics of our method via several simulations and demonstrate the application to real data examples in genomics.

Gene regulatory networks (GRNs) are often inferred based on Gaussian graphical models that could identify the conditional dependence among genes by estimating the corresponding precision matrix. Classical Gaussian graphical models are usually designed for single network estimation and ignore existing knowledge such as pathway information. Therefore, they can neither make use of the common information shared by multiple networks, nor can they utilize useful prior information to guide the estimation. In this paper, we propose a new weighted fused pathway graphical lasso (WFPGL) to jointly estimate multiple networks by incorporating prior knowledge derived from known pathways and gene interactions. Based on the assumption that two genes are less likely to be connected if they do not participate together in any pathways, a pathway-based constraint is considered in our model. Moreover, we introduce a weighted fused lasso penalty in our model to take into account prior gene interaction data and common information shared by multiple networks. Our model is optimized based on the alternating direction method of multipliers (ADMM). Experiments on synthetic data demonstrate that our method outperforms other five state-of-the-art graphical models. We then apply our model to two real datasets. Hub genes in our identified state-specific networks show some shared and specific patterns, which indicates the efficiency of our model in revealing the underlying mechanisms of complex diseases.

This paper introduces a MATLAB toolbox, MGraph, which applies graphical models as a natural environment to formulate and solve problems in microarray data analysis. MGraph with its graphical interface allows the user to predict genetic regulatory networks by a graphical gaussian model (GGM), and to quantify the effects of different experimental treatment conditions on gene expression profiles by a graphical log-linear model (GLM). The power of graphical models was explored and illustrated through two example applications. First, four MAPK pathways in yeast were meaningfully reconstructed through GGM. Second, GLM was used to quantify the contributions of sex, genotype and age to transcriptional variance in Drosophila melanogaster. This application may provide a valuable aid in the prediction of genetic regulatory networks, as well as in investigations of various experimental conditions that affect global gene expression profiles. The MATLAB program MGraph is freely available at http://www.uio.no/~junbaiw/mgraph/mgraph.html for academics.

The graphical lasso [5] is an algorithm for learning the structure in an undirected Gaussian graphical model, using ℓ1 regularization to control the number of zeros in the precision matrix Θ = Σ-1 [2, 11]. The R package GLASSO [5] is popular, fast, and allows one to efficiently build a path of models for different values of the tuning parameter. Convergence of GLASSO can be tricky; the converged precision matrix might not be the inverse of the estimated covariance, and occasionally it fails to converge with warm starts. In this paper we explain this behavior, and propose new algorithms that appear to outperform GLASSO. By studying the "normal equations" we see that, GLASSO is solving the dual of the graphical lasso penalized likelihood, by block coordinate ascent; a result which can also be found in [2]. In this dual, the target of estimation is Σ, the covariance matrix, rather than the precision matrix Θ. We propose similar primal algorithms P-GLASSO and DP-GLASSO, that also operate by block-coordinate descent, where Θ is the optimization target. We study all of these algorithms, and in particular different approaches to solving their coordinate sub-problems. We conclude that DP-GLASSO is superior from several points of view.

Large-scale precision matrix estimation is of fundamental importance yet challenging in many contemporary applications for recovering Gaussian graphical models. In this paper, we suggest a new approach of innovated scalable efficient estimation (ISEE) for estimating large precision matrix. Motivated by the innovated transformation, we convert the original problem into that of large covariance matrix estimation. The suggested method combines the strengths of recent advances in high-dimensional sparse modeling and large covariance matrix estimation. Compared to existing approaches, our method is scalable and can deal with much larger precision matrices with simple tuning. Under mild regularity conditions, we establish that this procedure can recover the underlying graphical structure with significant probability and provide efficient estimation of link strengths. Both computational and theoretical advantages of the procedure are evidenced through simulation and real data examples.

It is often of interest to understand how the structure of a genetic network differs between two conditions. In this paper, each condition-specific network is modeled using the precision matrix of a multivariate normal random vector, and a method is proposed to directly estimate the difference of the precision matrices. In contrast to other approaches, such as separate or joint estimation of the individual matrices, direct estimation does not require those matrices to be sparse, and thus can allow the individual networks to contain hub nodes. Under the assumption that the true differential network is sparse, the direct estimator is shown to be consistent in support recovery and estimation. It is also shown to outperform existing methods in simulations, and its properties are illustrated on gene expression data from late-stage ovarian cancer patients.

The covariance matrix (or its inverse, the precision matrix) is central to many chemometric techniques. Traditional sample estimators perform poorly for high‐dimensional data such as metabolomics data. Because of this, many traditional inference techniques break down or produce unreliable results. In this paper, we selectively review several modern estimators of the covariance and precision matrix that improve upon the traditional sample estimator. We focus on 3 general techniques: eigenvalue‐shrinkage estimation, ridge‐type estimation, and structured estimation. These methods rely on different assumptions regarding the structure of the covariance or precision matrix. Various examples, in particular using metabolomics data, are used to compare these techniques and to demonstrate that in concert with, eg, principal component analysis, multivariate analysis of variance, and Gaussian graphical models, better results are obtained.

Gaussian Graphical Models (GGMs) are extensively used in many research areas, such as genomics, proteomics, neuroimaging, and psychology, to study the partial correlation structure of a set of variables. This structure is visualized by drawing an undirected network, in which the variables constitute the nodes and the partial correlations the edges. In many applications, it makes sense to impose sparsity (i.e., some of the partial correlations are forced to zero) as sparsity is theoretically meaningful and/or because it improves the predictive accuracy of the fitted model. However, as we will show by means of extensive simulations, state-of-the-art estimation approaches for imposing sparsity on GGMs, such as the Graphical lasso, ℓ1 regularized nodewise regression, and joint sparse regression, fall short because they often yield too many false positives (i.e., partial correlations that are not properly set to zero). In this paper we present a new estimation approach that allows to control the false positive rate better. Our approach consists of two steps: First, we estimate an undirected network using one of the three state-of-the-art estimation approaches. Second, we try to detect the false positives, by flagging the partial correlations that are smaller in absolute value than a given threshold, which is determined through cross-validation; the flagged correlations are set to zero. Applying this new approach to the same simulated data, shows that it indeed performs better. We also illustrate our approach by using it to estimate (1) a gene regulatory network for breast cancer data, (2) a symptom network of patients with a diagnosis within the nonaffective psychotic spectrum and (3) a symptom network of patients with PTSD.

This paper introduces Polynomial Graphical Lasso (PGL), a new approach to learning graph structures from nodal signals. Our key contribution lies in modeling the signals as Gaussian and stationary on the graph, enabling the development of a graph learning formulation that combines the strengths of graphical lasso with a more encompassing model. Specifically, we assume that the precision matrix can take any polynomial form of the sought graph, allowing for increased flexibility in modeling nodal relationships. Given the inherent complexity and nonconvexity of the optimization problem, we (i) propose a low-complexity algorithm that alternates between estimating the graph and precision matrices, and (ii) characterize its convergence. We evaluate the performance of PGL through comprehensive numerical simulations using both synthetic and real data, demonstrating its superiority over several alternatives. Overall, this approach presents a significant advancement in graph learning and holds promise for various applications in graph-aware signal analysis and beyond.

Biological networks are important for the analysis of human diseases, which summarize the regulatory interactions and other relationships between different molecules. Understanding and constructing networks for molecules, such as DNA, RNA and proteins, can help elucidate the mechanisms of complex biological systems. The Gaussian Graphical Models (GGMs) are popular tools for the estimation of biological networks. Nonetheless, reconstructing GGMs from high-dimensional datasets is still challenging. The current methods cannot handle the sparsity and high-dimensionality issues arising from datasets very well. Here, we developed a new GGM, called the GR2D2 (Graphical $R^2$-induced Dirichlet Decomposition) model, based on the R2D2 priors for linear models. Besides, we provided a data-augmented block Gibbs sampler algorithm. The R code is available at https://github.com/RavenGan/GR2D2. The GR2D2 estimator shows superior performance in estimating the precision matrices compared with the existing techniques in various simulation settings. When the true precision matrix is sparse and of high dimension, the GR2D2 provides the estimates with smallest information divergence from the underlying truth. We also compare the GR2D2 estimator with the graphical horseshoe estimator in five cancer RNA-seq gene expression datasets grouped by three cancer types. Our results show that GR2D2 successfully identifies common cancer pathways and cancer-specific pathways for each dataset.

In this paper, we consider the problem of fitting a sparse precision matrix to multivariate Gaussian data. The zero elements in the precision matrix correspond to conditional independencies between variables. We focus on the estimation of a class of sparse precision matrix which represents the scale-free networks. It has been demonstrated that some of the important networks display features similar to scale-free graphs. We propose a new log-likelihood formulation, which promotes the sparseness of the precision matrix as well as the topological structure of scale-free networks. To optimize this new energy formulation, the alternating direction method of multipliers form is used with the general \(L_1\)-regularized loss optimization. We tested our proposed method on various databases. Our proposed method exhibits better estimation performance with various number of samples, N, and different selection of sparsity parameter, \(\rho \).

Functional data capture a wide range of processes, including growth curves and spectral absorption patterns. In this study, we analyse air pollution data from the In-service Aircraft for a Global Observing System, focusing on the spatial interactions among atmospheric chemicals and their dependence on meteorological conditions. This analysis necessitates functional regression, where both response and covariates are functional objects evolving throughout the troposphere. Quantifying both the functional dependencies between the response and covariates and the interdependencies among multivariate response functions poses significant challenges. To address these challenges, we introduce a functional Gaussian graphical regression model, which extends conditional Gaussian graphical models to partially separable functional data. We propose a doubly penalized estimator for model inference and develop a novel adaptation of Kullback–Leibler cross-validation, specifically tailored for graphical estimators. This criterion, named joint Kullback–Leibler cross-validation, simultaneously accounts for both precision and regression matrices, particularly in scenarios where the population comprises multiple sub-groups. Model performance is evaluated in terms of Kullback–Leibler divergence and graph recovery power.

Graphical models are well established in providing compact conditional probability descriptions of complex multivariable interactions. In the Gaussian case, graphical models are determined by zeros in the precision or concentration matrix, i.e. the inverse of the covariance matrix. Hence, there has been much recent interest in sparse precision matrices in areas such as statistics, machine learning, computer vision, pattern recognition and signal processing. In this paper we propose a simple new algorithm for constructing a sparse estimator for the precision matrix from multivariate data where the sparsity is enforced by an l 0 penalty. We compare and test the quality of our method on a synthetic graphical model.

Inferring gene regulatory networks can elucidate how genes work cooperatively. The gene-gene collaboration information is often learned by Gaussian graphical models (GGM) that aim to identify whether the expression levels of any pair of genes are dependent, given other genes’ expression values. One basic assumption that guarantees the validity of GGM is data normality, and this often holds for bulk-level expression data which aggregate biological signals from a collection of cells. However, fine-grained cell-level expression profiles collected in single-cell RNA-sequencing (scRNA-seq) reveal nonnormality features—cellular heterogeneity and zero inflation. We propose a Bayesian latent mixture GGM to jointly estimate multiple gene regulatory networks accounting for the zero inflation and unknown heterogeneity of single-cell expression data. The proposed approach outperforms competing methods on synthetic data in terms of network structure and precision matrix estimation accuracy and provides biological insights when applied to two real-world scRNA-seq datasets. An R package implementing the proposed model is available on GitHub https://github.com/WgitU/BLGGM.