How to understand the cell by breaking it: network analysis of gene perturbation screens

Modern high-throughput gene perturbation screens are key technologies at the forefront of genetic research. Combined with rich phenotypic descriptors they enable researchers to observe detailed cellular reactions to experimental perturbations on a genome-wide scale. This review surveys the current state-of-the-art in analyzing perturbation screens from a network point of view. We describe approaches to make the step from the parts list to the wiring diagram by using phenotypes for network inference and integrating them with complementary data sources. The first part of the review describes methods to analyze one- or low-dimensional phenotypes like viability or reporter activity; the second part concentrates on high-dimensional phenotypes showing global changes in cell morphology, transcriptome or proteome.Comment: Review based on ISMB 2009 tutorial; after two rounds of revisio

Learning Large-Scale Bayesian Networks with the sparsebn Package

Learning graphical models from data is an important problem with wide applications, ranging from genomics to the social sciences. Nowadays datasets often have upwards of thousands---sometimes tens or hundreds of thousands---of variables and far fewer samples. To meet this challenge, we have developed a new R package called sparsebn for learning the structure of large, sparse graphical models with a focus on Bayesian networks. While there are many existing software packages for this task, this package focuses on the unique setting of learning large networks from high-dimensional data, possibly with interventions. As such, the methods provided place a premium on scalability and consistency in a high-dimensional setting. Furthermore, in the presence of interventions, the methods implemented here achieve the goal of learning a causal network from data. Additionally, the sparsebn package is fully compatible with existing software packages for network analysis.Comment: To appear in the Journal of Statistical Software, 39 pages, 7 figure

Inferring cellular networks – a review

In this review we give an overview of computational and statistical methods to reconstruct cellular networks. Although this area of research is vast and fast developing, we show that most currently used methods can be organized by a few key concepts. The first part of the review deals with conditional independence models including Gaussian graphical models and Bayesian networks. The second part discusses probabilistic and graph-based methods for data from experimental interventions and perturbations

Reconstructing gene-regulatory networks from time series, knock-out data, and prior knowledge

BACKGROUND: Cellular processes are controlled by gene-regulatory networks. Several computational methods are currently used to learn the structure of gene-regulatory networks from data. This study focusses on time series gene expression and gene knock-out data in order to identify the underlying network structure. We compare the performance of different network reconstruction methods using synthetic data generated from an ensemble of reference networks. Data requirements as well as optimal experiments for the reconstruction of gene-regulatory networks are investigated. Additionally, the impact of prior knowledge on network reconstruction as well as the effect of unobserved cellular processes is studied. RESULTS: We identify linear Gaussian dynamic Bayesian networks and variable selection based on F-statistics as suitable methods for the reconstruction of gene-regulatory networks from time series data. Commonly used discrete dynamic Bayesian networks perform inferior and this result can be attributed to the inevitable information loss by discretization of expression data. It is shown that short time series generated under transcription factor knock-out are optimal experiments in order to reveal the structure of gene regulatory networks. Relative to the level of observational noise, we give estimates for the required amount of gene expression data in order to accurately reconstruct gene-regulatory networks. The benefit of using of prior knowledge within a Bayesian learning framework is found to be limited to conditions of small gene expression data size. Unobserved processes, like protein-protein interactions, induce dependencies between gene expression levels similar to direct transcriptional regulation. We show that these dependencies cannot be distinguished from transcription factor mediated gene regulation on the basis of gene expression data alone. CONCLUSION: Currently available data size and data quality make the reconstruction of gene networks from gene expression data a challenge. In this study, we identify an optimal type of experiment, requirements on the gene expression data quality and size as well as appropriate reconstruction methods in order to reverse engineer gene regulatory networks from time series data

Modeling Approaches Reveal New Regulatory Networks in <i>Aspergillus fumigatus</i> Metabolism

Systems biology approaches are extensively used to model and reverse-engineer gene regulatory networks from experimental data. Indoleamine 2,3-dioxygenases (IDOs)—belonging in the heme dioxygenase family—degrade l-tryptophan to kynurenines. These enzymes are also responsible for the de novo synthesis of nicotinamide adenine dinucleotide (NAD+). As such, they are expressed by a variety of species, including fungi. Interestingly, Aspergillus may degrade l-tryptophan not only via IDO but also via alternative pathways. Deciphering the molecular interactions regulating tryptophan metabolism is particularly critical for novel drug target discovery designed to control pathogen determinants in invasive infections. Using continuous time Bayesian networks over a time-course gene expression dataset, we inferred the global regulatory network controlling l-tryptophan metabolism. The method unravels a possible novel approach to target fungal virulence factors during infection. Furthermore, this study represents the first application of continuous-time Bayesian networks as a gene network reconstruction method in Aspergillus metabolism. The experiment showed that the applied computational approach may improve the understanding of metabolic networks over traditional pathways

Computational strategies for dissecting the high-dimensional complexity of adaptive immune repertoires

The adaptive immune system recognizes antigens via an immense array of antigen-binding antibodies and T-cell receptors, the immune repertoire. The interrogation of immune repertoires is of high relevance for understanding the adaptive immune response in disease and infection (e.g., autoimmunity, cancer, HIV). Adaptive immune receptor repertoire sequencing (AIRR-seq) has driven the quantitative and molecular-level profiling of immune repertoires thereby revealing the high-dimensional complexity of the immune receptor sequence landscape. Several methods for the computational and statistical analysis of large-scale AIRR-seq data have been developed to resolve immune repertoire complexity in order to understand the dynamics of adaptive immunity. Here, we review the current research on (i) diversity, (ii) clustering and network, (iii) phylogenetic and (iv) machine learning methods applied to dissect, quantify and compare the architecture, evolution, and specificity of immune repertoires. We summarize outstanding questions in computational immunology and propose future directions for systems immunology towards coupling AIRR-seq with the computational discovery of immunotherapeutics, vaccines, and immunodiagnostics.Comment: 27 pages, 2 figure

Penalized Estimation of Directed Acyclic Graphs From Discrete Data

Bayesian networks, with structure given by a directed acyclic graph (DAG), are a popular class of graphical models. However, learning Bayesian networks from discrete or categorical data is particularly challenging, due to the large parameter space and the difficulty in searching for a sparse structure. In this article, we develop a maximum penalized likelihood method to tackle this problem. Instead of the commonly used multinomial distribution, we model the conditional distribution of a node given its parents by multi-logit regression, in which an edge is parameterized by a set of coefficient vectors with dummy variables encoding the levels of a node. To obtain a sparse DAG, a group norm penalty is employed, and a blockwise coordinate descent algorithm is developed to maximize the penalized likelihood subject to the acyclicity constraint of a DAG. When interventional data are available, our method constructs a causal network, in which a directed edge represents a causal relation. We apply our method to various simulated and real data sets. The results show that our method is very competitive, compared to many existing methods, in DAG estimation from both interventional and high-dimensional observational data.Comment: To appear in Statistics and Computin