Patrick E. Meyer

Identification of functional elements and regulatory circuits by Drosophila modENCODE

From Genome to Regulatory Networks For biologists, having a genome in hand is only the beginning—much more investigation is still needed to characterize how the genome is used to help to produce a functional organism (see the Perspective by Blaxter). In this vein, Gerstein et al. (p. 1775) summarize for the Caenorhabditis elegans genome, and The modENCODE Consortium (p. 1787) summarize for the Drosophila melanogaster genome, full transcriptome analyses over developmental stages, genome-wide identification of transcription factor binding sites, and high-resolution maps of chromatin organization. Both studies identified regions of the nematode and fly genomes that show highly occupied targets (or HOT) regions where DNA was bound by more than 15 of the transcription factors analyzed and the expression of related genes were characterized. Overall, the studies provide insights into the organization, structure, and function of the two genomes and provide basic information needed to guide and correlate both focused and genome-wide studies. The Drosophila modENCODE project demonstrates the functional regulatory network of flies. To gain insight into how genomic information is translated into cellular and developmental programs, the Drosophila model organism Encyclopedia of DNA Elements (modENCODE) project is comprehensively mapping transcripts, histone modifications, chromosomal proteins, transcription factors, replication proteins and intermediates, and nucleosome properties across a developmental time course and in multiple cell lines. We have generated more than 700 data sets and discovered protein-coding, noncoding, RNA regulatory, replication, and chromatin elements, more than tripling the annotated portion of the Drosophila genome. Correlated activity patterns of these elements reveal a functional regulatory network, which predicts putative new functions for genes, reveals stage- and tissue-specific regulators, and enables gene-expression prediction. Our results provide a foundation for directed experimental and computational studies in Drosophila and related species and also a model for systematic data integration toward comprehensive genomic and functional annotation.

minet: A R/Bioconductor Package for Inferring Large Transcriptional Networks Using Mutual Information

ResultsThis paper presents the R/Bioconductor package minet (version 1.1.6) which provides a set of functions to infer mutual information networks from a dataset. Once fed with a microarray dataset, the package returns a network where nodes denote genes, edges model statistical dependencies between genes and the weight of an edge quantifies the statistical evidence of a specific (e.g transcriptional) gene-to-gene interaction. Four different entropy estimators are made available in the package minet (empirical, Miller-Madow, Schurmann-Grassberger and shrink) as well as four different inference methods, namely relevance networks, ARACNE, CLR and MRNET. Also, the package integrates accuracy assessment tools, like F-scores, PR-curves and ROC-curves in order to compare the inferred network with a reference one.ConclusionThe package minet provides a series of tools for inferring transcriptional networks from microarray data. It is freely available from the Comprehensive R Archive Network (CRAN) as well as from the Bioconductor website.

Information-theoretic inference of large transcriptional regulatory networks

The paper presents MRNET, an original method for inferring genetic networks from microarray data. The method is based on maximum relevance/minimum redundancy (MRMR), an effective information-theoretic technique for feature selection in supervised learning. The MRMR principle consists in selecting among the least redundant variables the ones that have the highest mutual information with the target. MRNET extends this feature selection principle to networks in order to infer gene-dependence relationships from microarray data. The paper assesses MRNET by benchmarking it against RELNET, CLR, and ARACNE, three state-of-the-art information-theoretic methods for large (up to several thousands of genes) network inference. Experimental results on thirty synthetically generated microarray datasets show that MRNET is competitive with these methods.

Information-Theoretic Feature Selection in Microarray Data Using Variable Complementarity

The paper presents an original filter approach for effective feature selection in microarray data characterized by a large number of input variables and a few samples. The approach is based on the use of a new information-theoretic selection, the double input symmetrical relevance (DISR), which relies on a measure of variable complementarity. This measure evaluates the additional information that a set of variables provides about the output with respect to the sum of each single variable contribution. We show that a variable selection approach based on DISR can be formulated as a quadratic optimization problem: the dispersion sum problem (DSP). To solve this problem, we use a strategy based on backward elimination and sequential replacement (BESR). The combination of BESR and the DISR criterion is compared in theoretical and experimental terms to recently proposed information-theoretic criteria. Experimental results on a synthetic dataset as well as on a set of eleven microarray classification tasks show that the proposed technique is competitive with existing filter selection methods.

Predictive regulatory models in Drosophila melanogaster by integrative inference of transcriptional networks

Gaining insights on gene regulation from large-scale functional data sets is a grand challenge in systems biology. In this article, we develop and apply methods for transcriptional regulatory network inference from diverse functional genomics data sets and demonstrate their value for gene function and gene expression prediction. We formulate the network inference problem in a machine-learning framework and use both supervised and unsupervised methods to predict regulatory edges by integrating transcription factor (TF) binding, evolutionarily conserved sequence motifs, gene expression, and chromatin modification data sets as input features. Applying these methods to Drosophila melanogaster, we predict ∼300,000 regulatory edges in a network of ∼600 TFs and 12,000 target genes. We validate our predictions using known regulatory interactions, gene functional annotations, tissue-specific expression, protein-protein interactions, and three-dimensional maps of chromosome conformation. We use the inferred network to identify putative functions for hundreds of previously uncharacterized genes, including many in nervous system development, which are independently confirmed based on their tissue-specific expression patterns. Last, we use the regulatory network to predict target gene expression levels as a function of TF expression, and find significantly higher predictive power for integrative networks than for motif or ChIP-based networks. Our work reveals the complementarity between physical evidence of regulatory interactions (TF binding, motif conservation) and functional evidence (coordinated expression or chromatin patterns) and demonstrates the power of data integration for network inference and studies of gene regulation at the systems level.

On the use of the Choquet integral with fuzzy numbers in multiple criteria decision support

This paper presents a multiple criteria decision support approach in order to build a ranking and suggest a best choice on a set of alternatives. The partial evaluations of the alternatives on the points of view can be fuzzy numbers. The aggregation is performed through the use of a fuzzy extension of the Choquet integral. We detail how to assess the coefficients of the aggregation operator by using alternatives which are well-known to the decision maker, and which originate from his domain of expertise.

On the use of variable complementarity for feature selection in cancer classification

The paper presents an original filter approach for effective feature selection in classification tasks with a very large number of input variables. The approach is based on the use of a new information theoretic selection criterion: the double input symmetrical relevance (DISR). The rationale of the criterion is that a set of variables can return an information on the output class that is higher than the sum of the informations of each variable taken individually. This property will be made explicit by defining the measure of variable complementarity. A feature selection filter based on the DISR criterion is compared in theoretical and experimental terms to recently proposed information theoretic criteria. Experimental results on a set of eleven microarray classification tasks show that the proposed technique is competitive with existing filter selection methods.

Sorting multi-attribute alternatives: the TOMASO method

We analyze a recently proposed ordinal sorting procedure (TOMASO) for the assignment of alternatives to graded classes and we present a freeware constructed from this procedure. We illustrate it by two examples, and do some testing in order to show its usefulness.

On the impact of entropy estimation on transcriptional regulatory network inference based on mutual information

The reverse engineering of transcription regulatory networks from expression data is gaining large interest in the bioinformatics community. An important family of inference techniques is represented by algorithms based on information theoretic measures which rely on the computation of pairwise mutual information. This paper aims to study the impact of the entropy estimator on the quality of the inferred networks. This is done by means of a comprehensive study which takes into consideration three state-of-the-art mutual information algorithms: ARACNE, CLR, and MRNET. Two different setups are considered in this work. The first one considers a set of 12 synthetically generated datasets to compare 8 different entropy estimators and three network inference algorithms. The two methods emerging as the most accurate ones from the first set of experiments are the MRNET method combined with the newly applied Spearman correlation and the CLR method combined with the Pearson correlation. The validation of these two techniques is then carried out on a set of 10 public domain microarray datasets measuring the transcriptional regulatory activity in the yeast organism.

Choice, Ranking and Sorting in Fuzzy Multiple Criteria Decision Aid

In this chapter we survey several approaches to derive a recommendation from some preference models for multiple criteria decision aid. Depending on the specificities of the decision problem, the recommendation can be a selection of the best alternatives, a ranking of these alternatives or a sorting. We detail a sorting procedure for the assignment of alternatives to graded classes when the available information is given by interacting points of view and a subset of prototypic alternatives whose assignment is given beforehand. A software dedicated to that approach (TOMASO) is briefly presented. Finally we define the concepts of good and bad choices based on dominant and absorbant kernels in the valued digraph that corresponds to an ordinal valued outranking relation. Aggregation with fuzzy environment, fuzzy choice, ordinal ordered sorting, choquet integral, TOMASO.