Inferring gene regression networks with model trees

Background: Novel strategies are required in order to handle the huge amount of data produced by microarray technologies. To infer gene regulatory networks, the first step is to find direct regulatory relationships between genes building the so-called gene co-expression networks. They are typically generated using correlation statistics as pairwise similarity measures. Correlation-based methods are very useful in order to determine whether two genes have a strong global similarity but do not detect local similarities. Results: We propose model trees as a method to identify gene interaction networks. While correlation-based methods analyze each pair of genes, in our approach we generate a single regression tree for each gene from the remaining genes. Finally, a graph from all the relationships among output and input genes is built taking into account whether the pair of genes is statistically significant. For this reason we apply a statistical procedure to control the false discovery rate. The performance of our approach, named REGNET, is experimentally tested on two well-known data sets: Saccharomyces Cerevisiae and E.coli data set. First, the biological coherence of the results are tested. Second the E.coli transcriptional network (in the Regulon database) is used as control to compare the results to that of a correlation-based method. This experiment shows that REGNET performs more accurately at detecting true gene associations than the Pearson and Spearman zeroth and first-order correlation-based methods. Conclusions: REGNET generates gene association networks from gene expression data, and differs from correlation-based methods in that the relationship between one gene and others is calculated simultaneously. Model trees are very useful techniques to estimate the numerical values for the target genes by linear regression functions. They are very often more precise than linear regression models because they can add just different linear regressions to separate areas of the search space favoring to infer localized similarities over a more global similarity. Furthermore, experimental results show the good performance of REGNET.Ministerio de Ciencia e Innovación TIN2011-68084-C02-00Ministerio de Ciencia e Innovación PCI2006-A7-0575Junta de Andalucia P07-TIC- 02611Junta de Andalucía TIC-20

Inferring gene regression networks with model trees

<p>Abstract</p> <p>Background</p> <p>Novel strategies are required in order to handle the huge amount of data produced by microarray technologies. To infer gene regulatory networks, the first step is to find direct regulatory relationships between genes building the so-called gene co-expression networks. They are typically generated using correlation statistics as pairwise similarity measures. Correlation-based methods are very useful in order to determine whether two genes have a strong global similarity but do not detect local similarities.</p> <p>Results</p> <p>We propose model trees as a method to identify gene interaction networks. While correlation-based methods analyze each pair of genes, in our approach we generate a single regression tree for each gene from the remaining genes. Finally, a graph from all the relationships among output and input genes is built taking into account whether the pair of genes is statistically significant. For this reason we apply a statistical procedure to control the false discovery rate. The performance of our approach, named R<smcaps>EG</smcaps>N<smcaps>ET</smcaps>, is experimentally tested on two well-known data sets: <it>Saccharomyces Cerevisiae </it>and E.coli data set. First, the biological coherence of the results are tested. Second the E.coli transcriptional network (in the Regulon database) is used as control to compare the results to that of a correlation-based method. This experiment shows that R<smcaps>EG</smcaps>N<smcaps>ET</smcaps> performs more accurately at detecting true gene associations than the Pearson and Spearman zeroth and first-order correlation-based methods.</p> <p>Conclusions</p> <p>R<smcaps>EG</smcaps>N<smcaps>ET</smcaps> generates gene association networks from gene expression data, and differs from correlation-based methods in that the relationship between one gene and others is calculated simultaneously. Model trees are very useful techniques to estimate the numerical values for the target genes by linear regression functions. They are very often more precise than linear regression models because they can add just different linear regressions to separate areas of the search space favoring to infer localized similarities over a more global similarity. Furthermore, experimental results show the good performance of R<smcaps>EG</smcaps>N<smcaps>ET</smcaps>.</p

Validating module network learning algorithms using simulated data

In recent years, several authors have used probabilistic graphical models to learn expression modules and their regulatory programs from gene expression data. Here, we demonstrate the use of the synthetic data generator SynTReN for the purpose of testing and comparing module network learning algorithms. We introduce a software package for learning module networks, called LeMoNe, which incorporates a novel strategy for learning regulatory programs. Novelties include the use of a bottom-up Bayesian hierarchical clustering to construct the regulatory programs, and the use of a conditional entropy measure to assign regulators to the regulation program nodes. Using SynTReN data, we test the performance of LeMoNe in a completely controlled situation and assess the effect of the methodological changes we made with respect to an existing software package, namely Genomica. Additionally, we assess the effect of various parameters, such as the size of the data set and the amount of noise, on the inference performance. Overall, application of Genomica and LeMoNe to simulated data sets gave comparable results. However, LeMoNe offers some advantages, one of them being that the learning process is considerably faster for larger data sets. Additionally, we show that the location of the regulators in the LeMoNe regulation programs and their conditional entropy may be used to prioritize regulators for functional validation, and that the combination of the bottom-up clustering strategy with the conditional entropy-based assignment of regulators improves the handling of missing or hidden regulators.Comment: 13 pages, 6 figures + 2 pages, 2 figures supplementary informatio

Reconstructing dynamical networks via feature ranking

Empirical data on real complex systems are becoming increasingly available. Parallel to this is the need for new methods of reconstructing (inferring) the topology of networks from time-resolved observations of their node-dynamics. The methods based on physical insights often rely on strong assumptions about the properties and dynamics of the scrutinized network. Here, we use the insights from machine learning to design a new method of network reconstruction that essentially makes no such assumptions. Specifically, we interpret the available trajectories (data) as features, and use two independent feature ranking approaches -- Random forest and RReliefF -- to rank the importance of each node for predicting the value of each other node, which yields the reconstructed adjacency matrix. We show that our method is fairly robust to coupling strength, system size, trajectory length and noise. We also find that the reconstruction quality strongly depends on the dynamical regime

Variable selection for BART: An application to gene regulation

We consider the task of discovering gene regulatory networks, which are defined as sets of genes and the corresponding transcription factors which regulate their expression levels. This can be viewed as a variable selection problem, potentially with high dimensionality. Variable selection is especially challenging in high-dimensional settings, where it is difficult to detect subtle individual effects and interactions between predictors. Bayesian Additive Regression Trees [BART, Ann. Appl. Stat. 4 (2010) 266-298] provides a novel nonparametric alternative to parametric regression approaches, such as the lasso or stepwise regression, especially when the number of relevant predictors is sparse relative to the total number of available predictors and the fundamental relationships are nonlinear. We develop a principled permutation-based inferential approach for determining when the effect of a selected predictor is likely to be real. Going further, we adapt the BART procedure to incorporate informed prior information about variable importance. We present simulations demonstrating that our method compares favorably to existing parametric and nonparametric procedures in a variety of data settings. To demonstrate the potential of our approach in a biological context, we apply it to the task of inferring the gene regulatory network in yeast (Saccharomyces cerevisiae). We find that our BART-based procedure is best able to recover the subset of covariates with the largest signal compared to other variable selection methods. The methods developed in this work are readily available in the R package bartMachine.Comment: Published in at http://dx.doi.org/10.1214/14-AOAS755 the Annals of Applied Statistics (http://www.imstat.org/aoas/) by the Institute of Mathematical Statistics (http://www.imstat.org

ABC random forests for Bayesian parameter inference

This preprint has been reviewed and recommended by Peer Community In Evolutionary Biology (http://dx.doi.org/10.24072/pci.evolbiol.100036). Approximate Bayesian computation (ABC) has grown into a standard methodology that manages Bayesian inference for models associated with intractable likelihood functions. Most ABC implementations require the preliminary selection of a vector of informative statistics summarizing raw data. Furthermore, in almost all existing implementations, the tolerance level that separates acceptance from rejection of simulated parameter values needs to be calibrated. We propose to conduct likelihood-free Bayesian inferences about parameters with no prior selection of the relevant components of the summary statistics and bypassing the derivation of the associated tolerance level. The approach relies on the random forest methodology of Breiman (2001) applied in a (non parametric) regression setting. We advocate the derivation of a new random forest for each component of the parameter vector of interest. When compared with earlier ABC solutions, this method offers significant gains in terms of robustness to the choice of the summary statistics, does not depend on any type of tolerance level, and is a good trade-off in term of quality of point estimator precision and credible interval estimations for a given computing time. We illustrate the performance of our methodological proposal and compare it with earlier ABC methods on a Normal toy example and a population genetics example dealing with human population evolution. All methods designed here have been incorporated in the R package abcrf (version 1.7) available on CRAN.Comment: Main text: 24 pages, 6 figures Supplementary Information: 14 pages, 5 figure

Getting started in probabilistic graphical models

Probabilistic graphical models (PGMs) have become a popular tool for computational analysis of biological data in a variety of domains. But, what exactly are they and how do they work? How can we use PGMs to discover patterns that are biologically relevant? And to what extent can PGMs help us formulate new hypotheses that are testable at the bench? This note sketches out some answers and illustrates the main ideas behind the statistical approach to biological pattern discovery.Comment: 12 pages, 1 figur