- Biological network inference
Many types of biological networks exist. Few such networks are known in anything approaching their complete structure, even in the simplest

bacteria . Still less is known on the parameters governing the behavior of such networks over time, how the networks at different levels in a cell interact, and how to predict the complete state description of a eukaryotic cell or bacterial organism at a given point in the future.Systems biology , in this sense, is still in its infancy. Prediction is the subject ofdynamic modeling . This article focuses on a necessary prerequisite to dynamic modeling of a network: inference of thetopology , that is, prediction of the "wiring diagram" of the network. More specifically, we focus here on inference of biological network structure using the growing sets of high-throughput expression data forgene s,protein s, and metabolites.Briefly, methods using high-throughput data for inference of regulatory networks rely on searching for patterns of partial correlation or conditional probabilities that indicate causal influence [

*cite book |author= Sprites, P., Glymour, C. & Scheines, R.|year=2000 |title= Causation, prediction, and search: Adaptive computation and machine learning. 2nd ed.|publisher= MIT Press|location=Cambridge, MA*] . Such patterns of partial correlations found in the high-throughput data, possibly combined with other supplemental data on the genes or proteins in the proposed networks, or combined with other information on the organism, form the basis upon which suchalgorithm s work.Such algorithms can be of use in inferring the topology of any network where the change in state of onenode can affect the state of other nodes.**Computational inference methods**In a topological sense, a network is a set of nodes and a set of directed or undirected edges between the nodes. Biological networks currently under study using such computational inference methods include:

1) Transcriptional regulatory networks. Genes are the nodes and the edges are directed. A gene serves as the source of a direct regulatory edge to a target gene by producing an

RNA or protein molecule that functions as a transcriptional activator or inhibitor of the target gene. If the gene is an activator, then it is the source of a positive regulatory connection; if an inhibitor, then it is the source of a negative regulatory connection. Computational algorithms used to infer the topology take as primary input the data from a set ofmicroarray runs measuring themRNA expression levels of the genes under consideration for inclusion in the network.As of 2007, the great bulk of high-throughput data being fed into correlation-based algorithms comes from microarray experiments, and such analysis is the most fruitful point of biological application for such algorithms. (This is reflected in the reference list at bottom, where almost all bioinformatic algorithm references are directed toward use of microarray data.) Clustering or some form of statistical classification is typically employed to perform an initial organization of the high-throughput mRNA expression values derived from microarray experiments. The question then arises: how can the clustering or classification results be connected to the underlying biology? Such results can be useful for pattern classification – for example, to classify subtypes of

cancer , or to predict differential responses to adrug (pharmacogenomics). But to understand the relationships between the genes, that is, to more precisely define the influence of each gene on the others, the scientist typically attempts to reconstruct the transcriptional regulatory network. This can be done by using background literature, or information in publicdatabase s, combined with the clustering results. It can also be done by the application of a correlation-based inference algorithm, as will be discussed below, an approach which is having increased success as the size of the available microarray sets keeps increasing [*cite journal | author = Faith, J.J., et al. | year = 2007 | title = Large-Scale Mapping and Validation of Escherichia coli Transcriptional Regulation from a Compendium of Expression Profiles | journal = PLoS Biology | volume = 5 | issue = 1 | pages = 54–66 | doi = 10.1371/journal.pbio.0050008*] [*cite journal | author = Hayete, B., T.S. Gardner, and J.J. Collins | year = 2007 | title = Size matters: network inference tackles the genome scale | journal = Molecular Systems Biology | volume = 3 | pages = 77 | doi = 10.1038/msb4100118*]2)

Signal transduction networks (very important in the biology of cancer). Proteins are the nodes and the edges are directed. Primary input into the inference algorithm would be data from a set of experiments measuring protein activation / inactivation (e.g.,phosphorylation / dephosphorylation) across a set of proteins.3)

Metabolite networks. Metabolites are the nodes and the edges are directed. Primary input into an algorithm would be data from a set of experiments measuring metabolite levels.4) Intraspecies or interspecies communication networks in microbial communities. Nodes are excreted organic compounds and the edges are directed. Input into an inference algorithm is data from a set of experiments measuring levels of excreted molecules.

Protein-protein interaction networks are also under very active study. However, reconstruction of these networks does not use correlation-based inference in the sense discussed for the networks already described (interaction does not necessarily imply a change in protein state), and a description of such interaction network reconstruction is left to other articles.

**Co-relation-based inference algorithms**1) from classical statistics - STUB - baseline:

Pearson correlation 2) from information theory - STUB concept of mutual information - ARACNE algorithm - CLR algorithm - MRNET algorithm

3) from graphical probabilistic models - STUB -

Bayesian network structure learning - K2 alg - needs a node ordering - BANJO toolkitDREAM project - stub

Platforms for network inference - STUB - geWorkbench, Columbia - SEBINI

Visualization of inferred network - STUB -

Cytoscape toolExpansion of inferred network using public databases - data integration - STUB - CABIN tool

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*Bansal, M., G.D. Gatta, and D. di Bernardo, Inference of gene regulatory networks and compound mode of action from time course gene expression profiles. Bioinformatics, 2006. 22(7): p. 815-822.

*Faith, J.J., et al., Large-Scale Mapping and Validation of Escherichia coli Transcriptional Regulation from a Compendium of Expression Profiles. PLoS Biology, 2007. 5(1): p. 54-66.

*Barrett, C.L. and B.O. Palsson, Iterative Reconstruction of Transcriptional Regulatory Networks: An Algorithmic Approach. PLoS Comput. Biol., 2006. 2(5): p. e52.

*Basso, K., et al., Reverse engineering of regulatory networks in human B cells. Nat. Genet., 2005. 37(4): p. 382-390. (uses ARACNE algorithm)

*Bonneau, R., et al., The Inferelator: an algorithm for learning parsimonious regulatory networks from systems-biology data sets de novo. Genome Biology, 2006. 7(5, Article R36).

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