Inferring Regulatory Networks by Combining Perturbation Screens and Steady State Gene Expression Profiles

Reconstructing transcriptional regulatory networks is an important task in functional genomics. Data obtained from experiments that perturb genes by knockouts or RNA interference contain useful information for addressing this reconstruction problem. However, such data can be limited in size and/or are expensive to acquire. On the other hand, observational data of the organism in steady state (e.g. wild-type) are more readily available, but their informational content is inadequate for the task at hand. We develop a computational approach to appropriately utilize both data sources for estimating a regulatory network. The proposed approach is based on a three-step algorithm to estimate the underlying directed but cyclic network, that uses as input both perturbation screens and steady state gene expression data. In the first step, the algorithm determines causal orderings of the genes that are consistent with the perturbation data, by combining an exhaustive search method with a fast heuristic that in turn couples a Monte Carlo technique with a fast search algorithm. In the second step, for each obtained causal ordering, a regulatory network is estimated using a penalized likelihood based method, while in the third step a consensus network is constructed from the highest scored ones. Extensive computational experiments show that the algorithm performs well in reconstructing the underlying network and clearly outperforms competing approaches that rely only on a single data source. Further, it is established that the algorithm produces a consistent estimate of the regulatory network.Comment: 24 pages, 4 figures, 6 table

RIDDLE: Race and ethnicity Imputation from Disease history with Deep LEarning

Anonymized electronic medical records are an increasingly popular source of research data. However, these datasets often lack race and ethnicity information. This creates problems for researchers modeling human disease, as race and ethnicity are powerful confounders for many health exposures and treatment outcomes; race and ethnicity are closely linked to population-specific genetic variation. We showed that deep neural networks generate more accurate estimates for missing racial and ethnic information than competing methods (e.g., logistic regression, random forest). RIDDLE yielded significantly better classification performance across all metrics that were considered: accuracy, cross-entropy loss (error), and area under the curve for receiver operating characteristic plots (all $p < 10^{-6}$). We made specific efforts to interpret the trained neural network models to identify, quantify, and visualize medical features which are predictive of race and ethnicity. We used these characterizations of informative features to perform a systematic comparison of differential disease patterns by race and ethnicity. The fact that clinical histories are informative for imputing race and ethnicity could reflect (1) a skewed distribution of blue- and white-collar professions across racial and ethnic groups, (2) uneven accessibility and subjective importance of prophylactic health, (3) possible variation in lifestyle, such as dietary habits, and (4) differences in background genetic variation which predispose to diseases

Advances in Learning Bayesian Networks of Bounded Treewidth

This work presents novel algorithms for learning Bayesian network structures with bounded treewidth. Both exact and approximate methods are developed. The exact method combines mixed-integer linear programming formulations for structure learning and treewidth computation. The approximate method consists in uniformly sampling $k$-trees (maximal graphs of treewidth $k$), and subsequently selecting, exactly or approximately, the best structure whose moral graph is a subgraph of that $k$-tree. Some properties of these methods are discussed and proven. The approaches are empirically compared to each other and to a state-of-the-art method for learning bounded treewidth structures on a collection of public data sets with up to 100 variables. The experiments show that our exact algorithm outperforms the state of the art, and that the approximate approach is fairly accurate.Comment: 23 pages, 2 figures, 3 table

Layered Label Propagation: A MultiResolution Coordinate-Free Ordering for Compressing Social Networks

We continue the line of research on graph compression started with WebGraph, but we move our focus to the compression of social networks in a proper sense (e.g., LiveJournal): the approaches that have been used for a long time to compress web graphs rely on a specific ordering of the nodes (lexicographical URL ordering) whose extension to general social networks is not trivial. In this paper, we propose a solution that mixes clusterings and orders, and devise a new algorithm, called Layered Label Propagation, that builds on previous work on scalable clustering and can be used to reorder very large graphs (billions of nodes). Our implementation uses overdecomposition to perform aggressively on multi-core architecture, making it possible to reorder graphs of more than 600 millions nodes in a few hours. Experiments performed on a wide array of web graphs and social networks show that combining the order produced by the proposed algorithm with the WebGraph compression framework provides a major increase in compression with respect to all currently known techniques, both on web graphs and on social networks. These improvements make it possible to analyse in main memory significantly larger graphs

PReaCH: A Fast Lightweight Reachability Index using Pruning and Contraction Hierarchies

We develop the data structure PReaCH (for Pruned Reachability Contraction Hierarchies) which supports reachability queries in a directed graph, i.e., it supports queries that ask whether two nodes in the graph are connected by a directed path. PReaCH adapts the contraction hierarchy speedup techniques for shortest path queries to the reachability setting. The resulting approach is surprisingly simple and guarantees linear space and near linear preprocessing time. Orthogonally to that, we improve existing pruning techniques for the search by gathering more information from a single DFS-traversal of the graph. PReaCH-indices significantly outperform previous data structures with comparable preprocessing cost. Methods with faster queries need significantly more preprocessing time in particular for the most difficult instances

Improving Optimization Bounds using Machine Learning: Decision Diagrams meet Deep Reinforcement Learning

Finding tight bounds on the optimal solution is a critical element of practical solution methods for discrete optimization problems. In the last decade, decision diagrams (DDs) have brought a new perspective on obtaining upper and lower bounds that can be significantly better than classical bounding mechanisms, such as linear relaxations. It is well known that the quality of the bounds achieved through this flexible bounding method is highly reliant on the ordering of variables chosen for building the diagram, and finding an ordering that optimizes standard metrics is an NP-hard problem. In this paper, we propose an innovative and generic approach based on deep reinforcement learning for obtaining an ordering for tightening the bounds obtained with relaxed and restricted DDs. We apply the approach to both the Maximum Independent Set Problem and the Maximum Cut Problem. Experimental results on synthetic instances show that the deep reinforcement learning approach, by achieving tighter objective function bounds, generally outperforms ordering methods commonly used in the literature when the distribution of instances is known. To the best knowledge of the authors, this is the first paper to apply machine learning to directly improve relaxation bounds obtained by general-purpose bounding mechanisms for combinatorial optimization problems.Comment: Accepted and presented at AAAI'1

Sparse Linear Identifiable Multivariate Modeling

In this paper we consider sparse and identifiable linear latent variable (factor) and linear Bayesian network models for parsimonious analysis of multivariate data. We propose a computationally efficient method for joint parameter and model inference, and model comparison. It consists of a fully Bayesian hierarchy for sparse models using slab and spike priors (two-component delta-function and continuous mixtures), non-Gaussian latent factors and a stochastic search over the ordering of the variables. The framework, which we call SLIM (Sparse Linear Identifiable Multivariate modeling), is validated and bench-marked on artificial and real biological data sets. SLIM is closest in spirit to LiNGAM (Shimizu et al., 2006), but differs substantially in inference, Bayesian network structure learning and model comparison. Experimentally, SLIM performs equally well or better than LiNGAM with comparable computational complexity. We attribute this mainly to the stochastic search strategy used, and to parsimony (sparsity and identifiability), which is an explicit part of the model. We propose two extensions to the basic i.i.d. linear framework: non-linear dependence on observed variables, called SNIM (Sparse Non-linear Identifiable Multivariate modeling) and allowing for correlations between latent variables, called CSLIM (Correlated SLIM), for the temporal and/or spatial data. The source code and scripts are available from http://cogsys.imm.dtu.dk/slim/.Comment: 45 pages, 17 figure