Sparse integrative clustering of multiple omics data sets

High resolution microarrays and second-generation sequencing platforms are powerful tools to investigate genome-wide alterations in DNA copy number, methylation and gene expression associated with a disease. An integrated genomic profiling approach measures multiple omics data types simultaneously in the same set of biological samples. Such approach renders an integrated data resolution that would not be available with any single data type. In this study, we use penalized latent variable regression methods for joint modeling of multiple omics data types to identify common latent variables that can be used to cluster patient samples into biologically and clinically relevant disease subtypes. We consider lasso [J. Roy. Statist. Soc. Ser. B 58 (1996) 267-288], elastic net [J. R. Stat. Soc. Ser. B Stat. Methodol. 67 (2005) 301-320] and fused lasso [J. R. Stat. Soc. Ser. B Stat. Methodol. 67 (2005) 91-108] methods to induce sparsity in the coefficient vectors, revealing important genomic features that have significant contributions to the latent variables. An iterative ridge regression is used to compute the sparse coefficient vectors. In model selection, a uniform design [Monographs on Statistics and Applied Probability (1994) Chapman & Hall] is used to seek "experimental" points that scattered uniformly across the search domain for efficient sampling of tuning parameter combinations. We compared our method to sparse singular value decomposition (SVD) and penalized Gaussian mixture model (GMM) using both real and simulated data sets. The proposed method is applied to integrate genomic, epigenomic and transcriptomic data for subtype analysis in breast and lung cancer data sets.Comment: Published in at http://dx.doi.org/10.1214/12-AOAS578 the Annals of Applied Statistics (http://www.imstat.org/aoas/) by the Institute of Mathematical Statistics (http://www.imstat.org

Provable Sparse Tensor Decomposition

We propose a novel sparse tensor decomposition method, namely Tensor Truncated Power (TTP) method, that incorporates variable selection into the estimation of decomposition components. The sparsity is achieved via an efficient truncation step embedded in the tensor power iteration. Our method applies to a broad family of high dimensional latent variable models, including high dimensional Gaussian mixture and mixtures of sparse regressions. A thorough theoretical investigation is further conducted. In particular, we show that the final decomposition estimator is guaranteed to achieve a local statistical rate, and further strengthen it to the global statistical rate by introducing a proper initialization procedure. In high dimensional regimes, the obtained statistical rate significantly improves those shown in the existing non-sparse decomposition methods. The empirical advantages of TTP are confirmed in extensive simulated results and two real applications of click-through rate prediction and high-dimensional gene clustering.Comment: To Appear in JRSS-

Machine Learning and Integrative Analysis of Biomedical Big Data.

Recent developments in high-throughput technologies have accelerated the accumulation of massive amounts of omics data from multiple sources: genome, epigenome, transcriptome, proteome, metabolome, etc. Traditionally, data from each source (e.g., genome) is analyzed in isolation using statistical and machine learning (ML) methods. Integrative analysis of multi-omics and clinical data is key to new biomedical discoveries and advancements in precision medicine. However, data integration poses new computational challenges as well as exacerbates the ones associated with single-omics studies. Specialized computational approaches are required to effectively and efficiently perform integrative analysis of biomedical data acquired from diverse modalities. In this review, we discuss state-of-the-art ML-based approaches for tackling five specific computational challenges associated with integrative analysis: curse of dimensionality, data heterogeneity, missing data, class imbalance and scalability issues

Algorithms for nonnegative matrix factorization with the beta-divergence

This paper describes algorithms for nonnegative matrix factorization (NMF) with the beta-divergence (beta-NMF). The beta-divergence is a family of cost functions parametrized by a single shape parameter beta that takes the Euclidean distance, the Kullback-Leibler divergence and the Itakura-Saito divergence as special cases (beta = 2,1,0, respectively). The proposed algorithms are based on a surrogate auxiliary function (a local majorization of the criterion function). We first describe a majorization-minimization (MM) algorithm that leads to multiplicative updates, which differ from standard heuristic multiplicative updates by a beta-dependent power exponent. The monotonicity of the heuristic algorithm can however be proven for beta in (0,1) using the proposed auxiliary function. Then we introduce the concept of majorization-equalization (ME) algorithm which produces updates that move along constant level sets of the auxiliary function and lead to larger steps than MM. Simulations on synthetic and real data illustrate the faster convergence of the ME approach. The paper also describes how the proposed algorithms can be adapted to two common variants of NMF : penalized NMF (i.e., when a penalty function of the factors is added to the criterion function) and convex-NMF (when the dictionary is assumed to belong to a known subspace).Comment: \`a para\^itre dans Neural Computatio

Inferring Multiple Graphical Structures

Gaussian Graphical Models provide a convenient framework for representing dependencies between variables. Recently, this tool has received a high interest for the discovery of biological networks. The literature focuses on the case where a single network is inferred from a set of measurements, but, as wetlab data is typically scarce, several assays, where the experimental conditions affect interactions, are usually merged to infer a single network. In this paper, we propose two approaches for estimating multiple related graphs, by rendering the closeness assumption into an empirical prior or group penalties. We provide quantitative results demonstrating the benefits of the proposed approaches. The methods presented in this paper are embeded in the R package 'simone' from version 1.0-0 and later

Dynamic Tensor Clustering

Dynamic tensor data are becoming prevalent in numerous applications. Existing tensor clustering methods either fail to account for the dynamic nature of the data, or are inapplicable to a general-order tensor. Also there is often a gap between statistical guarantee and computational efficiency for existing tensor clustering solutions. In this article, we aim to bridge this gap by proposing a new dynamic tensor clustering method, which takes into account both sparsity and fusion structures, and enjoys strong statistical guarantees as well as high computational efficiency. Our proposal is based upon a new structured tensor factorization that encourages both sparsity and smoothness in parameters along the specified tensor modes. Computationally, we develop a highly efficient optimization algorithm that benefits from substantial dimension reduction. In theory, we first establish a non-asymptotic error bound for the estimator from the structured tensor factorization. Built upon this error bound, we then derive the rate of convergence of the estimated cluster centers, and show that the estimated clusters recover the true cluster structures with a high probability. Moreover, our proposed method can be naturally extended to co-clustering of multiple modes of the tensor data. The efficacy of our approach is illustrated via simulations and a brain dynamic functional connectivity analysis from an Autism spectrum disorder study.Comment: Accepted at Journal of the American Statistical Associatio

Learning to Discover Sparse Graphical Models

We consider structure discovery of undirected graphical models from observational data. Inferring likely structures from few examples is a complex task often requiring the formulation of priors and sophisticated inference procedures. Popular methods rely on estimating a penalized maximum likelihood of the precision matrix. However, in these approaches structure recovery is an indirect consequence of the data-fit term, the penalty can be difficult to adapt for domain-specific knowledge, and the inference is computationally demanding. By contrast, it may be easier to generate training samples of data that arise from graphs with the desired structure properties. We propose here to leverage this latter source of information as training data to learn a function, parametrized by a neural network that maps empirical covariance matrices to estimated graph structures. Learning this function brings two benefits: it implicitly models the desired structure or sparsity properties to form suitable priors, and it can be tailored to the specific problem of edge structure discovery, rather than maximizing data likelihood. Applying this framework, we find our learnable graph-discovery method trained on synthetic data generalizes well: identifying relevant edges in both synthetic and real data, completely unknown at training time. We find that on genetics, brain imaging, and simulation data we obtain performance generally superior to analytical methods

Foundational principles for large scale inference: Illustrations through correlation mining

When can reliable inference be drawn in the "Big Data" context? This paper presents a framework for answering this fundamental question in the context of correlation mining, with implications for general large scale inference. In large scale data applications like genomics, connectomics, and eco-informatics the dataset is often variable-rich but sample-starved: a regime where the number $n$ of acquired samples (statistical replicates) is far fewer than the number $p$ of observed variables (genes, neurons, voxels, or chemical constituents). Much of recent work has focused on understanding the computational complexity of proposed methods for "Big Data." Sample complexity however has received relatively less attention, especially in the setting when the sample size $n$ is fixed, and the dimension $p$ grows without bound. To address this gap, we develop a unified statistical framework that explicitly quantifies the sample complexity of various inferential tasks. Sampling regimes can be divided into several categories: 1) the classical asymptotic regime where the variable dimension is fixed and the sample size goes to infinity; 2) the mixed asymptotic regime where both variable dimension and sample size go to infinity at comparable rates; 3) the purely high dimensional asymptotic regime where the variable dimension goes to infinity and the sample size is fixed. Each regime has its niche but only the latter regime applies to exa-scale data dimension. We illustrate this high dimensional framework for the problem of correlation mining, where it is the matrix of pairwise and partial correlations among the variables that are of interest. We demonstrate various regimes of correlation mining based on the unifying perspective of high dimensional learning rates and sample complexity for different structured covariance models and different inference tasks