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. Author manuscript; available in PMC: 2014 Jun 1.
Published in final edited form as: Pharmacol Ther. 2013 Feb 4;138(3):333–408. doi: 10.1016/j.pharmthera.2013.01.016

Table 3.

Network-based predictions of disease-related genes as biomarkers

  • Type of prediction methods*

  • Type of data used

Name and additional description, website References
  • similarity-based

  • protein structure descriptor-related QSAR

new disease-related proteins are predicted by their structural similarity to known disease-related proteins Vilar et al., 2009
  • interaction-based

  • (predicted) interactome

new disease-related genes are predicted by their interactome neighborhood Krauthammer et al., 2004; Chen et al., 2006a; Oti et al., 2006; Xu & Li, 2006
  • iterative summary of interactome and disease neighborhood

  • disease similarity network, interactome

measures the neighborhood association in both the interactome and disease similarity networks and iteratively calculates the similarity of the node to diseases Guo et al., 2011
  • semantic similarity score

  • semantic similarity networks of diseases and related genes

calculates a semantic similarity score between gene ontology terms as well as human genes associated with them Jiang et al., 2011
  • summarized network neighborhood of several candidate genes

  • disease, gene-descriptions, disease related genes, interactome, mRNA co-expressions, pathways

constructs an integrative network and predicts candidate genes by their network closeness to known disease-related genes; Prioritizer: http://129.125.135.180/prioritizer Franke et al., 2006
  • shortest path length

  • disease, gene-descriptions, disease related genes, interactome, mRNA co-expressions

uses a maximum expectation gene cover algorithm finding small gene sets to predict associated new disease-related genes Karni et al., 2009
  • user-defined path distance from known disease-related genes

  • up to 10 integrated interactomes

new disease-related genes are predicted by their interactome closeness to known disease-related proteins; Genes2Networks: http://actin.pharm.mssm.edu/genes2networks Berger et al., 2007
  • interaction-based

  • disease-related mutations, domain-domain resolved interactome

new disease-related genes are predicted by their association to previously known disease-related genes at protein-protein domains affected by the disease-associated mutations of the known disease related gene Sharma et al., 2010a; Song & Lee, 2012
  • interaction-based

  • disease-related mutations, 3D structurally resolved interactome

new disease-related genes are predicted by their association to previously known disease-related genes at 3D modeled protein-protein interfaces affected by the disease-associated mutations of the known disease related gene Wang et al., 2012b
  • clustering

  • disease-related genes, interactome

  • closeness

  • disease-related genes, disease network, interactome

new disease-related genes are predicted by their common protein-protein interaction network module with previous disease-related genes closeness of unrelated proteins is calculated in the interactome from protein products of disease-related genes, and compared with phenotype similarity profile: large closeness marks a potential new disease-related gene; CIPHER: http://rulai.cshl.edu/tools/cipher Navlakha & Kingsford, 2010; Wu et al., 2008
  • random walk

  • disease-related genes, disease network, interactome

random walks in the interactome are started from protein products of disease-related genes: frequent visits of a previously unrelated protein mark a potential new disease-related gene; Cytoscape plug-in GPEC: http://sourceforge.net/p/gpec Kohler et al., 2008; Chen et al., 2009b; Le & Kwon, 2012
  • iterative network propagation

  • disease-related genes, disease network, interactome

iterative steps of information flow from disease-related and between interacting proteins: after convergence a large flow of a previously unrelated protein marks potential new disease-related gene; Cytoscape plug-in PRINCIPLE/PRINCE: http://www.cs.tau.ac.il/~bnet/software/PrincePlugin Vanunu et al., 2010; Gottlieb et al., 2011b
  • random walk with re-starts in both networks

  • disease-related genes, disease network, interactome

random walk in both the interactome and the disease networks: number of frequent visits marks candidate genes Li & Patra, 2010
  • NetworkBlast algorithm to align interactome and disease networks

  • disease-related genes, disease network, interactome

after alignment of the interactome and disease networks finds high scoring subnetworks (bi-modules); candidate genes have the highest scoring bi-modules Wu et al., 2009a
  • information flow with statistical correction

  • disease-related genes, interactome

statistically corrects random walk- based prediction with the degree distribution of the network; DADA: http://compbio.case.edu/dada Erten et al., 2011a
  • topological network similarity

  • disease-related genes

calculates neighborhood similarity in the interactome and prioritizes candidate genes; VAVIEN: http://diseasegenes.org Erten et al., 2011b
  • neighborhood similarity

  • disease-related genes, interactome, expression patterns

calculates expression weighted neighborhood similarity (using Katz centrality or other methods) in the interactome Zhao et al., 2011b; Wu et al., 2012
  • semantic-based centrality

  • disease-related genes, interactome, pathways

calculates data-type weighted centrality in the integrated network and uses it as a rank of candidate genes Gudivala et al., 2008
  • direct neighbor-based Bayesian predictor

  • disease-related genes, disease network, interactome, pathways

constructs candidate protein complexes in a virtual pull-down experiment, and scores candidates by measuring the similarity between the phenotype in the complex and disease phenotype Lage et al., 2007
  • genetic linkage analysis of gene network clusters

  • disease-related genes, text mining-based associations (binding, phosphorylation, methylation, etc.)

calculates genetic linkage analysis of connected clusters in a text mining-derived direct interaction network Iossifov et al., 2008
  • random forest learning

  • disease, disease related genes, disease networks, single-nucleotide polymorphisms (SNPs)

predict deleterious SNPs and disease genes using the random forest learning method, uses interactomes and deleterious SNPs to predict disease-related genes by random forest learning Care et al., 2009
  • random walk, iterative network propagation (PRINCE/PRINCIPLE)

  • disease, disease related genes, interactome, protein/DNA interaction, tissue, drug

a Cytoscape plug-in to construct an integrative network of diseases, associated genes, drugs and tissues; iCTNet: http://www.cs.queensu.ca/ictnet Wang et al., 2011b
  • machine learning

  • disease, disease related genes, gene annotations, interactome, expression levels, sequences

integrative methods using similarities of neighbors or shortest paths in multiple data sources including interactomes; Endeavour: http://esat.kuleuven.be/endeavour; Phenopred: http://www.phenopred.org Radijovac et al., 2008; Tranchevent et al., 2008; Linghu et al., 2009; Costa et al., 2010
  • rank coherence with target disease and unrelated disease networks

  • disease, disease related genes, gene annotations, interactome, expression levels, genome-wide association studies

Calculates rank coherences between the integrated network characteristic to the target disease and unrelated diseases; rcNet: http://phegenex.cs.umn.edu/Nano Hwang et al., 2011
*

The Table summarizes methods using networks as data representations. We excluded those methods, like neural network or Bayesian network-based methods, which decipher associations between various, not network-assembled data. Several methods are included in the excellent reviews of Wang et al. (2011a) and Doncheva et al. (2012a).