Identification of Important Nodes in Directed Biological Networks: A Network Motif Approach

Identification of important nodes in complex networks has attracted an increasing attention over the last decade. Various measures have been proposed to characterize the importance of nodes in complex networks, such as the degree, betweenness and PageRank. Different measures consider different aspects of complex networks. Although there are numerous results reported on undirected complex networks, few results have been reported on directed biological networks. Based on network motifs and principal component analysis (PCA), this paper aims at introducing a new measure to characterize node importance in directed biological networks. Investigations on five real-world biological networks indicate that the proposed method can robustly identify actually important nodes in different networks, such as finding command interneurons, global regulators and non-hub but evolutionary conserved actually important nodes in biological networks. Receiver Operating Characteristic (ROC) curves for the five networks indicate remarkable prediction accuracy of the proposed measure. The proposed index provides an alternative complex network metric. Potential implications of the related investigations include identifying network control and regulation targets, biological networks modeling and analysis, as well as networked medicine.

[1]  M S Pepe,et al.  Using a combination of reference tests to assess the accuracy of a new diagnostic test. , 1999, Statistics in medicine.

[2]  Xiaoge Zhang,et al.  A Bio-Inspired Methodology of Identifying Influential Nodes in Complex Networks , 2013, PloS one.

[3]  J. Collins,et al.  Construction of a genetic toggle switch in Escherichia coli , 2000, Nature.

[4]  S. Mangan,et al.  Structure and function of the feed-forward loop network motif , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[5]  Sergey Brin,et al.  The Anatomy of a Large-Scale Hypertextual Web Search Engine , 1998, Comput. Networks.

[6]  S. Shen-Orr,et al.  Networks Network Motifs : Simple Building Blocks of Complex , 2002 .

[7]  Liza Gross Are “Ultraconserved” Genetic Elements Really Indispensable? , 2007, PLoS biology.

[8]  Kwang-Hyun Cho,et al.  Coupled feedback loops form dynamic motifs of cellular networks. , 2008, Biophysical journal.

[9]  E. Wang,et al.  Genetic studies of diseases , 2007, Cellular and Molecular Life Sciences.

[10]  S. Adhya,et al.  The galactose regulon of Escherichia coli , 1993, Molecular microbiology.

[11]  Z N Oltvai,et al.  Evolutionary conservation of motif constituents in the yeast protein interaction network , 2003, Nature Genetics.

[12]  Tore Opsahl,et al.  Prominence and control: the weighted rich-club effect. , 2008, Physical review letters.

[13]  F. Schreiber,et al.  Centrality Analysis Methods for Biological Networks and Their Application to Gene Regulatory Networks , 2008, Gene regulation and systems biology.

[14]  Shelley Lane,et al.  Regulation of Mating and Filamentation Genes by Two Distinct Ste12 Complexes in Saccharomyces cerevisiae , 2006, Molecular and Cellular Biology.

[15]  O. Sporns,et al.  Motifs in Brain Networks , 2004, PLoS biology.

[16]  S. Shen-Orr,et al.  Network motifs in the transcriptional regulation network of Escherichia coli , 2002, Nature Genetics.

[17]  J. Collado-Vides,et al.  Identifying global regulators in transcriptional regulatory networks in bacteria. , 2003, Current opinion in microbiology.

[18]  U. Alon Network motifs: theory and experimental approaches , 2007, Nature Reviews Genetics.

[19]  Xinghuo Yu,et al.  Identification and Evolution of Structurally Dominant Nodes in Protein-Protein Interaction Networks , 2014, IEEE Transactions on Biomedical Circuits and Systems.

[20]  O. Sporns,et al.  Rich Club Organization of Macaque Cerebral Cortex and Its Role in Network Communication , 2012, PloS one.

[21]  P. Bossuyt,et al.  Evaluation of diagnostic tests when there is no gold standard. A review of methods. , 2007, Health technology assessment.

[22]  L. Freeman Centrality in social networks conceptual clarification , 1978 .

[23]  Pei Wang,et al.  Identifying influential spreaders in artificial complex networks , 2014, Journal of Systems Science and Complexity.

[24]  Falk Schreiber,et al.  Ranking of network elements based on functional substructures. , 2007, Journal of theoretical biology.

[25]  M. Elowitz,et al.  A synthetic oscillatory network of transcriptional regulators , 2000, Nature.

[26]  Yicheng Zhang,et al.  Identifying influential nodes in complex networks , 2012 .

[27]  Yi-Cheng Zhang,et al.  Leaders in Social Networks, the Delicious Case , 2011, PloS one.

[28]  Wang Pe,et al.  Control of Genetic Regulatory Networks: Opportunities and Challenges , 2013 .

[29]  Yuval Shavitt,et al.  A model of Internet topology using k-shell decomposition , 2007, Proceedings of the National Academy of Sciences.

[30]  Haiyuan Yu,et al.  Network-based methods for human disease gene prediction. , 2011, Briefings in functional genomics.

[31]  J. E. Kranz,et al.  YPD, PombePD and WormPD: model organism volumes of the BioKnowledge library, an integrated resource for protein information. , 2001, Nucleic acids research.

[32]  S. Mangan,et al.  The coherent feedforward loop serves as a sign-sensitive delay element in transcription networks. , 2003, Journal of molecular biology.

[33]  J. Goldenberg,et al.  The Role of Hubs in the Adoption Process , 2009 .

[34]  Pei Wang,et al.  Control of Genetic Regulatory Networks: Opportunities and Challenges: Control of Genetic Regulatory Networks: Opportunities and Challenges , 2014 .

[35]  Alessandro Vespignani,et al.  Epidemic spreading in scale-free networks. , 2000, Physical review letters.

[36]  Uri Alon,et al.  Efficient sampling algorithm for estimating subgraph concentrations and detecting network motifs , 2004, Bioinform..

[37]  S. Shen-Orr,et al.  Superfamilies of Evolved and Designed Networks , 2004, Science.

[38]  S. Shen-Orr,et al.  Network motifs: simple building blocks of complex networks. , 2002, Science.

[39]  Denis Thieffry,et al.  RegulonDB: a database on transcriptional regulation in Escherichia coli , 1998, Nucleic Acids Res..

[40]  Lav R. Varshney,et al.  Structural Properties of the Caenorhabditis elegans Neuronal Network , 2009, PLoS Comput. Biol..

[41]  Lev Muchnik,et al.  Identifying influential spreaders in complex networks , 2010, 1001.5285.

[42]  O. Sporns,et al.  Rich-Club Organization of the Human Connectome , 2011, The Journal of Neuroscience.

[43]  D. Chklovskii,et al.  Wiring optimization can relate neuronal structure and function. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[44]  Alessandro Vespignani,et al.  Detecting rich-club ordering in complex networks , 2006, physics/0602134.

[45]  Tore Opsahl,et al.  Publisher's Note: Prominence and Control: The Weighted Rich-Club Effect [Phys. Rev. Lett. 101, 168702 (2008)] , 2008 .

[46]  Jiawei Han,et al.  gSpan: graph-based substructure pattern mining , 2002, 2002 IEEE International Conference on Data Mining, 2002. Proceedings..

[47]  Olaf Sporns,et al.  Complex network measures of brain connectivity: Uses and interpretations , 2010, NeuroImage.

[48]  Albert-László Barabási,et al.  Error and attack tolerance of complex networks , 2000, Nature.

[49]  E. Dubois,et al.  TEC1, a gene involved in the activation of Ty1 and Ty1-mediated gene expression in Saccharomyces cerevisiae: cloning and molecular analysis , 1990, Molecular and cellular biology.

[50]  Marcel Salathé,et al.  Dynamics and Control of Diseases in Networks with Community Structure , 2010, PLoS Comput. Biol..

[51]  M. P. van den Heuvel,et al.  Rich Club Organization and Intermodule Communication in the Cat Connectome , 2013, The Journal of Neuroscience.

[52]  Shiva Kintali,et al.  Betweenness Centrality : Algorithms and Lower Bounds , 2008, ArXiv.

[53]  Xinghuo Yu,et al.  Duplication and Divergence Effect on Network Motifs in Undirected Bio-Molecular Networks , 2015, IEEE Transactions on Biomedical Circuits and Systems.

[54]  Marek S. Skrzypek,et al.  YPDTM, PombePDTM and WormPDTM: model organism volumes of the BioKnowledgeTM Library, an integrated resource for protein information , 2001, Nucleic Acids Res..

[55]  O. Sporns,et al.  Identification and Classification of Hubs in Brain Networks , 2007, PloS one.

[56]  Jinhu Lu,et al.  Consensus of Discrete-Time Second-Order Multiagent Systems Based on Infinite Products of General Stochastic Matrices , 2013, SIAM J. Control. Optim..

[57]  Maciej Ogorzalek,et al.  Global relative parameter sensitivities of the feed-forward loops in genetic networks , 2012, Neurocomputing.

[58]  Stefan Wuchty,et al.  Interaction and domain networks of yeast , 2002, Proteomics.

[59]  Emma K. Towlson,et al.  The Rich Club of the C. elegans Neuronal Connectome , 2013, The Journal of Neuroscience.

[60]  Florian Probst,et al.  Who will lead and who will follow: Identifying Influential Users in Online Social Networks , 2013, Business & Information Systems Engineering.

[61]  Karl Pearson F.R.S. LIII. On lines and planes of closest fit to systems of points in space , 1901 .

[62]  U. Alon,et al.  The incoherent feedforward loop can provide fold-change detection in gene regulation. , 2009, Molecular cell.

[63]  Falk Schreiber,et al.  MAVisto: a tool for the exploration of network motifs , 2005, Bioinform..

[64]  Tom Fawcett,et al.  An introduction to ROC analysis , 2006, Pattern Recognit. Lett..

[65]  Charles E. Heckler,et al.  Applied Multivariate Statistical Analysis , 2005, Technometrics.

[66]  Jinhu Lu,et al.  Consensus of discrete-time multi-agent systems with transmission nonlinearity , 2013, Autom..

[67]  Mark E. J. Newman,et al.  The Structure and Function of Complex Networks , 2003, SIAM Rev..

[68]  Wang Pei,et al.  Global relative input-output sensitivities of the feed-forward loops in genetic networks , 2012, Proceedings of the 31st Chinese Control Conference.

[69]  Shi Zhou,et al.  The rich-club phenomenon in the Internet topology , 2003, IEEE Communications Letters.

[70]  Sebastian Wernicke,et al.  FANMOD: a tool for fast network motif detection , 2006, Bioinform..

[71]  Massimo Marchiori,et al.  Error and attacktolerance of complex network s , 2004 .

[72]  Claudia Canali,et al.  A quantitative methodology based on component analysis to identify key users in social networks , 2012, Int. J. Soc. Netw. Min..

[73]  Wojciech Szpankowski,et al.  An efficient algorithm for detecting frequent subgraphs in biological networks , 2004, ISMB/ECCB.