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166
An Empirical Bayes Approach to Inferring LargeScale Gene Association Networks
 BIOINFORMATICS
, 2004
"... Motivation: Genetic networks are often described statistically by graphical models (e.g. Bayesian networks). However, inferring the network structure offers a serious challenge in microarray analysis where the sample size is small compared to the number of considered genes. This renders many standar ..."
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Cited by 210 (6 self)
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Motivation: Genetic networks are often described statistically by graphical models (e.g. Bayesian networks). However, inferring the network structure offers a serious challenge in microarray analysis where the sample size is small compared to the number of considered genes. This renders many standard algorithms for graphical models inapplicable, and inferring genetic networks an “illposed” inverse problem. Methods: We introduce a novel framework for smallsample inference of graphical models from gene expression data. Specifically, we focus on socalled graphical Gaussian models (GGMs) that are now frequently used to describe gene association networks and to detect conditionally dependent genes. Our new approach is based on (i) improved (regularized) smallsample point estimates of partial correlation, (ii) an exact test of edge inclusion with adaptive estimation of the degree of freedom, and (iii) a heuristic network search based on false discovery rate multiple testing. Steps (ii) and (iii) correspond to an empirical Bayes estimate of the network topology. Results: Using computer simulations we investigate the sensitivity (power) and specificity (true negative rate) of the proposed framework to estimate GGMs from microarray data. This shows that it is possible to recover the true network topology with high accuracy even for smallsample data sets. Subsequently, we analyze gene expression data from a breast cancer tumor study and illustrate our approach by inferring a corresponding largescale gene association network for 3,883 genes. Availability: The authors have implemented the approach in the R package “GeneTS ” that is freely available from
Firstorder methods for sparse covariance selection
 SIAM Journal on Matrix Analysis and Applications
"... Abstract. Given a sample covariance matrix, we solve a maximum likelihood problem penalized by the number of nonzero coefficients in the inverse covariance matrix. Our objective is to find a sparse representation of the sample data and to highlight conditional independence relationships between the ..."
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Cited by 98 (1 self)
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Abstract. Given a sample covariance matrix, we solve a maximum likelihood problem penalized by the number of nonzero coefficients in the inverse covariance matrix. Our objective is to find a sparse representation of the sample data and to highlight conditional independence relationships between the sample variables. We first formulate a convex relaxation of this combinatorial problem, we then detail two efficient firstorder algorithms with low memory requirements to solve largescale, dense problem instances.
Convex optimization techniques for fitting sparse gaussian graphical models
 In Proceedings of the 23rd International Conference on Machine Learning
, 2006
"... We consider the problem of fitting a largescale covariance matrix to multivariate Gaussian data in such a way that the inverse is sparse, thus providing model selection. Beginning with a dense empirical covariance matrix, we solve a maximum likelihood problem with an l1norm penalty term added to e ..."
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Cited by 62 (0 self)
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We consider the problem of fitting a largescale covariance matrix to multivariate Gaussian data in such a way that the inverse is sparse, thus providing model selection. Beginning with a dense empirical covariance matrix, we solve a maximum likelihood problem with an l1norm penalty term added to encourage sparsity in the inverse. For models with tens of nodes, the resulting problem can be solved using standard interiorpoint algorithms for convex optimization, but these methods scale poorly with problem size. We present two new algorithms aimed at solving problems with a thousand nodes. The first, based on Nesterov’s firstorder algorithm, yields a rigorous complexity estimate for the problem, with a much better dependence on problem size than interiorpoint methods. Our second algorithm uses block coordinate descent, updating row/columns of the covariance matrix sequentially. Experiments with genomic data show that our method is able to uncover biologically interpretable connections among genes. 1.
Projected Subgradient Methods for Learning Sparse Gaussians
"... Gaussian Markov random fields (GMRFs) are useful in a broad range of applications. In this paper we tackle the problem of learning a sparse GMRF in a highdimensional space. Our approach uses the ℓ1norm as a regularization on the inverse covariance matrix. We utilize a novel projected gradient meth ..."
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Cited by 58 (0 self)
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Gaussian Markov random fields (GMRFs) are useful in a broad range of applications. In this paper we tackle the problem of learning a sparse GMRF in a highdimensional space. Our approach uses the ℓ1norm as a regularization on the inverse covariance matrix. We utilize a novel projected gradient method, which is faster than previous methods in practice and equal to the best performing of these in asymptotic complexity. We also extend the ℓ1regularized objective to the problem of sparsifying entire blocks within the inverse covariance matrix. Our methods generalize fairly easily to this case, while other methods do not. We demonstrate that our extensions give better generalization performance on two real domains—biological network analysis and a 2Dshape modeling image task. 1
A robust procedure for gaussian graphical model search from microarray data with p larger than n
 Journal of Machine Learning Research
, 2006
"... Learning of largescale networks of interactions from microarray data is an important and challenging problem in bioinformatics. A widely used approach is to assume that the available data constitute a random sample from a multivariate distribution belonging to a Gaussian graphical model. As a conse ..."
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Cited by 41 (6 self)
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Learning of largescale networks of interactions from microarray data is an important and challenging problem in bioinformatics. A widely used approach is to assume that the available data constitute a random sample from a multivariate distribution belonging to a Gaussian graphical model. As a consequence, the prime objects of inference are fullorder partial correlations which are partial correlations between two variables given the remaining ones. In the context of microarray data the number of variables exceed the sample size and this precludes the application of traditional structure learning procedures because a sampling version of fullorder partial correlations does not exist. In this paper we consider limitedorder partial correlations, these are partial correlations computed on marginal distributions of manageable size, and provide a set of rules that allow one to assess the usefulness of these quantities to derive the independence structure of the underlying Gaussian graphical model. Furthermore, we introduce a novel structure learning procedure based on a quantity, obtained from limitedorder partial correlations, that we call the nonrejection rate. The applicability and usefulness of the procedure are demonstrated by both simulated and real data.
Temporal Causal Modeling with Graphical Granger Methods
 In Proceedings of the 13th Int. Conference on Knowledge Discovery and Data Mining, 66 – 75: Association for Computing Machinery
, 2007
"... The need for mining causality, beyond mere statistical correlations, for real world problems has been recognized widely. Many of these applications naturally involve temporal data, which raises the challenge of how best to leverage the temporal information for causal modeling. Recently graphical mod ..."
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Cited by 39 (6 self)
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The need for mining causality, beyond mere statistical correlations, for real world problems has been recognized widely. Many of these applications naturally involve temporal data, which raises the challenge of how best to leverage the temporal information for causal modeling. Recently graphical modeling with the concept of “Granger causality”, based on the intuition that a cause helps predict its effects in the future, has gained attention in many domains involving time series data analysis. With the surge of interest in model selection methodologies for regression, such as the Lasso, as practical alternatives to solving structural learning of graphical models, the question arises whether and how to combine these two notions into a practically viable approach for temporal causal modeling. In this paper, we examine a host of related
Entropy Inference and the JamesStein Estimator, with Application to Nonlinear Gene Association Networks
"... We present a procedure for effective estimation of entropy and mutual information from smallsample data, and apply it to the problem of inferring highdimensional gene association networks. Specifically, we develop a JamesSteintype shrinkage estimator, resulting in a procedure that is highly effic ..."
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Cited by 37 (1 self)
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We present a procedure for effective estimation of entropy and mutual information from smallsample data, and apply it to the problem of inferring highdimensional gene association networks. Specifically, we develop a JamesSteintype shrinkage estimator, resulting in a procedure that is highly efficient statistically as well as computationally. Despite its simplicity, we show that it outperforms eight other entropy estimation procedures across a diverse range of sampling scenarios and datagenerating models, even in cases of severe undersampling. We illustrate the approach by analyzing E. coli gene expression data and computing an entropybased geneassociation network from gene expression data. A computer program is available that implements the proposed shrinkage estimator. Keywords: entropy, shrinkage estimation, JamesStein estimator, “small n, large p ” setting, mutual information, gene association network
Smooth optimization approach for sparse covariance selection
 SIAM J. Optim
"... In this paper we first study a smooth optimization approach for solving a class of nonsmooth strictly concave maximization problems whose objective functions admit smooth convex minimization reformulations. In particular, we apply Nesterov’s smooth optimization technique [19, 21] to their dual coun ..."
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Cited by 36 (3 self)
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In this paper we first study a smooth optimization approach for solving a class of nonsmooth strictly concave maximization problems whose objective functions admit smooth convex minimization reformulations. In particular, we apply Nesterov’s smooth optimization technique [19, 21] to their dual counterparts that are smooth convex problems. It is shown that the resulting approach has O(1 / √ ǫ) iteration complexity for finding an ǫoptimal solution to both primal and dual problems. We then discuss the application of this approach to sparse covariance selection that is approximately solved as a l1norm penalized maximum likelihood estimation problem, and also propose a variant of this approach which has substantially outperformed the latter one in our computational experiments. We finally compare the performance of these approaches with other firstorder methods, namely, Nesterov’s O(1/ǫ) smooth approximation scheme and blockcoordinate descent method studied in [9, 15] for sparse covariance selection on a set of randomly generated instances. It shows that our smooth optimization approach substantially outperforms the first method above, and moreover, its variant substantially outperforms both methods above.
Objective Bayesian model selection in Gaussian graphical models
, 2007
"... This paper presents a default modelselection procedure for Gaussian graphical models that involves two new developments. First, we develop a default version of the hyperinverse Wishart prior for restricted covariance matrices, called the hyperinverse Wishart gprior, and show how it corresponds t ..."
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Cited by 34 (3 self)
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This paper presents a default modelselection procedure for Gaussian graphical models that involves two new developments. First, we develop a default version of the hyperinverse Wishart prior for restricted covariance matrices, called the hyperinverse Wishart gprior, and show how it corresponds to the implied fractional prior for covariance selection using fractional Bayes factors. Second, we apply a class of priors that automatically handles the problem of multiple hypothesis testing implied by covariance selection. We demonstrate our methods on a variety of simulated examples, concluding with a real example analysing covariation in mutualfund returns. These studies reveal that the combined use of a multiplicitycorrection prior on graphs and fractional Bayes factors for computing marginal likelihoods yields better performance than existing Bayesian methods. Some key words: covariance selection; hyperinverse Wishart distribution; fractional Bayes factors; Bayesian model selection; multiple hypothesis testing.