Gene Network Inference Research Articles

Gene network inference from incomplete expression data: transcriptional control of hematopoietic commitment

The topology and function of gene regulation networks are commonly inferred from time series of gene expression levels in cell populations. This strategy is usually invalid if the gene expression in different cells of the population is not synchronous. A promising, though technically more demanding alternative is therefore to measure the gene expression levels in single cells individually. The inference of a gene regulation network requires knowledge of the gene expression levels at successive time points, at least before and after a network transition. However, owing to experimental limitations a complete determination of the precursor state is not possible. We investigate a strategy for the inference of gene regulatory networks from incomplete expression data based on dynamic Bayesian networks. This permits prediction of the number of experiments necessary for network inference depending on parameters including noise in the data, prior knowledge and limited attainability of initial states. Our strategy combines a gradual 'Partial Learning' approach based solely on true experimental observations for the network topology with expectation maximization for the network parameters. We illustrate our strategy by extensive computer simulations in a high-dimensional parameter space in a simulated single-cell-based example of hematopoietic stem cell commitment and in random networks of different sizes. We find that the feasibility of network inferences increases significantly with the experimental ability to force the system into different initial network states, with prior knowledge and with noise reduction. Source code is available under: www.izbi.uni-leipzig.de/services/NetwPartLearn.html Supplementary Data are available at Bioinformatics online.

Nonlinear System Identification Using Coevolution of Models and Tests

We present a coevolutionary algorithm for inferring the topology and parameters of a wide range of hidden nonlinear systems with a minimum of experimentation on the target system. The algorithm synthesizes an explicit model directly from the observed data produced by intelligently generated tests. The algorithm is composed of two coevolving populations. One population evolves candidate models that estimate the structure of the hidden system. The second population evolves informative tests that either extract new information from the hidden system or elicit desirable behavior from it. The fitness of candidate models is their ability to explain behavior of the target system observed in response to all tests carried out so far; the fitness of candidate tests is their ability to make the models disagree in their predictions. We demonstrate the generality of this estimation-exploration algorithm by applying it to four different problems-grammar induction, gene network inference, evolutionary robotics, and robot damage recovery-and discuss how it overcomes several of the pathologies commonly found in other coevolutionary algorithms. We show that the algorithm is able to successfully infer and/or manipulate highly nonlinear hidden systems using very few tests, and that the benefit of this approach increases as the hidden systems possess more degrees of freedom, or become more biased or unobservable. The algorithm provides a systematic method for posing synthesis or analysis tasks to a coevolutionary system.

Inferring gene networks from steady-state response to single-gene perturbations

Inferring gene networks from gene expression data is an important step in understanding the molecular machinery of life. Three methods for establishing and quantifying causal relationships between genes based on steady-state measurements in single-gene perturbation experiments have recently been proposed: the regulatory strength method, the local regulatory strength method, and Gardner's method. The theoretical basis of these methods is presented here in a thorough and consistent fashion. In principle, for the same data set all three methods would generate identical networks, but they would quantify the strengths of connections in different ways. The regulatory strength method is shown here to be topology-dependent. It adopts the format of the data collected in gene expression microarray experiments and therefore can be immediately used with this technology. The regulatory strengths obtained by this method can also be used to compute local regulatory strengths. In contrast, Gardner's method requires both measurements of mRNA concentrations and measurements of the applied rate perturbations, which is not usually part of a standard microarray experimental protocol. The results generated by Gardner's method and by the two regulatory strengths methods differ only by scaling constants, but Gardner's method requires more measurements. On the other hand, the explicit use of rate perturbations in Gardner's approach allows one to address new questions with this method, like what perturbations caused given responses of the system. Results of the application of the three techniques to real experimental data are presented and discussed. The comparative analysis presented in this paper can be helpful for identifying an appropriate technique for inferring genetic networks and for interpreting the results of its application to experimental data.

IMPROVING GENE NETWORK INFERENCE BY COMPARING EXPRESSION TIME-SERIES ACROSS SPECIES, DEVELOPMENTAL STAGES OR TISSUES

We present a method for gene network inference and revision based on time-series data. Gene networks are modeled using linear differential equations and a generalized stepwise multiple linear regression procedure is used to recover the interaction coefficients. Our system is designed for the recovery of gene interactions concurrently in many gene regulatory networks related by a tree or a more general graph. We show how this comparative framework can facilitate the recovery of the networks and improve the quality of the solutions inferred.

Gene networks inference using dynamic Bayesian networks.

This article deals with the identification of gene regulatory networks from experimental data using a statistical machine learning approach. A stochastic model of gene interactions capable of handling missing variables is proposed. It can be described as a dynamic Bayesian network particularly well suited to tackle the stochastic nature of gene regulation and gene expression measurement. Parameters of the model are learned through a penalized likelihood maximization implemented through an extended version of EM algorithm. Our approach is tested against experimental data relative to the S.O.S. DNA Repair network of the Escherichia coli bacterium. It appears to be able to extract the main regulations between the genes involved in this network. An added missing variable is found to model the main protein of the network. Good prediction abilities on unlearned data are observed. These first results are very promising: they show the power of the learning algorithm and the ability of the model to capture gene interactions.

Genetic network inference: the effects of preprocessing

Clustering of gene expression data and gene network inference from such data has been a major research topic in recent years. In clustering, pairwise measurements are performed when calculating the distance matrix upon which the clustering is based. Pairwise measurements can also be used for gene network inference, by deriving potential interactions above a certain correlation or distance threshold. Our experiments show how interaction networks derived by this simple approach exhibit low—but significant—sensitivity and specificity. We also explore the effects that normalization and prefiltering have on the results of methods for identifying interactions from expression data. Before derivation of interactions or clustering, preprocessing is often performed by applying normalization to rescale the expression profiles and prefiltering where genes that do not appear to contribute to regulation are removed. In this paper, different ways of normalizing in combination with different distance measurements are tested on both unfiltered and prefiltered data, different prefiltering criteria are considered.

Inferring gene networks from time series microarray data using dynamic Bayesian networks

Dynamic Bayesian networks (DBNs) are considered as a promising model for inferring gene networks from time series microarray data. DBNs have overtaken Bayesian networks (BNs) as DBNs can construct cyclic regulations using time delay information. In this paper, a general framework for DBN modelling is outlined. Both discrete and continuous DBN models are constructed systematically and criteria for learning network structures are introduced from a Bayesian statistical viewpoint. This paper reviews the applications of DBNs over the past years. Real data applications for Saccharomyces cerevisiae time series gene expression data are also shown.

Evolutionary modeling and inference of gene network

This paper describes an Evolutionary Modeling (EM) approach to building causal model of differential equation system from time series data. The main target of the modeling is the gene regulatory network. A hybrid method of Genetic Programming (GP) and statistical analysis is featured in our work. GP and Least Mean Square method (LMS) were combined to identify a concise form of regulation between the variables from a given set of time series. Our approach was evaluated in several real-world problems. Further, Monte Carlo analysis is applied to indicate the robust and significant influence from the results for gene network analysis purpose.

Quantifying gene networks with regulatory strengths.

A gene network is the collection of regulatory relationships between all genes in a genome. Gene networks are high-level descriptions of cellular biochemistry and show the phenomenological interactions between gene activities. These interactions are mediated by proteins and metabolites. In the gene network approach, only the transcriptome is considered and all biochemistry underlying gene-gene interactions is only implicitly present. In a previous work, we presented a method for inferring gene networks from experimental data, quantifying gene-gene interactions with regulatory strengths. Here, we show how to express these regulatory strengths in terms of properties of the whole biochemical network.

Dynamic Bayesian Network and Nonparametric Regression Model for Inferring Gene Networks

A Bayesian network is a powerful tool for modeling relations among a large number of random variables. Therefore the Bayesian network has received considerable attention from the studies of gene network estimation using microarray gene expression data. Imoto et al. [1, 2] proposed a Bayesian network and nonparametric regression model for capturing nonlinear relations between genes from the continuous gene expression data. However, a Bayesian network still has a problem that it cannot construct cyclic regulations, while real gene networks have cyclic regulations. For a solution of this problem, in this paper, we propose a dynamic Bayesian network and nonparametric regression model for estimating a gene network with cyclic regulations from time series microarray data. We also derive a criterion for selecting a network from Bayes approach. The effectiveness of our method is displayed though the analysis of the Saccharomyces cerevisiae gene expression data.

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