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1.  MAGNET: MicroArray Gene expression and Network Evaluation Toolkit 
Nucleic Acids Research  2012;40(Web Server issue):W152-W156.
MicroArray Gene expression and Network Evaluation Toolkit (MAGNET) is a web-based application that provides tools to generate and score both protein–protein interaction networks and coexpression networks. MAGNET integrates user-provided experimental measurements with high-throughput proteomic datasets, generating weighted gene–gene and protein–protein interaction networks. MAGNET allows users to weight edges of protein–protein interaction networks using a logistic regression model integrating tissue-specific gene expression data, sub-cellular localization data, co-clustering of interacting proteins and the number of observations of the interaction. This provides a way to quantitatively measure the plausibility of interactions in protein–protein interaction networks given protein/gene expression measurements. Secondly, MAGNET generates filtered coexpression networks, where genes are represented as nodes, and their correlations are represented with edges. Overall, MAGNET provides researchers with a new framework with which to analyze and generate gene–gene and protein–protein interaction networks, based on both the user’s own data and publicly available –omics datasets. The freely available service and documentation can be accessed at or
PMCID: PMC3394302  PMID: 22669910
PLoS ONE  2013;8(3):e58134.
PMCID: PMC3603955  PMID: 23526967
3.  Accuracy improvement in protein complex prediction from protein interaction networks by refining cluster overlaps 
Proteome Science  2012;10(Suppl 1):S3.
PMCID: PMC3380738  PMID: 22759580
Bioinformatics  2009;25(23):3143-3150.
Motivation: Clustering of protein–protein interaction networks is one of the most common approaches for predicting functional modules, protein complexes and protein functions. But, how well does clustering perform at these tasks?
Results: We develop a general framework to assess how well computationally derived clusters in physical interactomes overlap functional modules derived via the Gene Ontology (GO). Using this framework, we evaluate six diverse network clustering algorithms using Saccharomyces cerevisiae and show that (i) the performances of these algorithms can differ substantially when run on the same network and (ii) their relative performances change depending upon the topological characteristics of the network under consideration. For the specific task of function prediction in S.cerevisiae, we demonstrate that, surprisingly, a simple non-clustering guilt-by-association approach outperforms widely used clustering-based approaches that annotate a protein with the overrepresented biological process and cellular component terms in its cluster; this is true over the range of clustering algorithms considered. Further analysis parameterizes performance based on the number of annotated proteins, and suggests when clustering approaches should be used for interactome functional analyses. Overall our results suggest a re-examination of when and how clustering approaches should be applied to physical interactomes, and establishes guidelines by which novel clustering approaches for biological networks should be justified and evaluated with respect to functional analysis.
Supplementary information: Supplementary data are available at Bioinformatics online.
PMCID: PMC3167697  PMID: 19770263
5.  Phylogenetic networks do not need to be complex: using fewer reticulations to represent conflicting clusters 
Bioinformatics  2010;26(12):i124-i131.
Phylogenetic trees are widely used to display estimates of how groups of species are evolved. Each phylogenetic tree can be seen as a collection of clusters, subgroups of the species that evolved from a common ancestor. When phylogenetic trees are obtained for several datasets (e.g. for different genes), then their clusters are often contradicting. Consequently, the set of all clusters of such a dataset cannot be combined into a single phylogenetic tree. Phylogenetic networks are a generalization of phylogenetic trees that can be used to display more complex evolutionary histories, including reticulate events, such as hybridizations, recombinations and horizontal gene transfers. Here, we present the new Cass algorithm that can combine any set of clusters into a phylogenetic network. We show that the networks constructed by Cass are usually simpler than networks constructed by other available methods. Moreover, we show that Cass is guaranteed to produce a network with at most two reticulations per biconnected component, whenever such a network exists. We have implemented Cass and integrated it into the freely available Dendroscope software.
Supplementary information: Supplementary data are available at Bioinformatics online.
PMCID: PMC2881387  PMID: 20529896
6.  Resolving the structure of interactomes with hierarchical agglomerative clustering 
BMC Bioinformatics  2011;12(Suppl 1):S44.
Graphs provide a natural framework for visualizing and analyzing networks of many types, including biological networks. Network clustering is a valuable approach for summarizing the structure in large networks, for predicting unobserved interactions, and for predicting functional annotations. Many current clustering algorithms suffer from a common set of limitations: poor resolution of top-level clusters; over-splitting of bottom-level clusters; requirements to pre-define the number of clusters prior to analysis; and an inability to jointly cluster over multiple interaction types.
A new algorithm, Hierarchical Agglomerative Clustering (HAC), is developed for fast clustering of heterogeneous interaction networks. This algorithm uses maximum likelihood to drive the inference of a hierarchical stochastic block model for network structure. Bayesian model selection provides a principled method for collapsing the fine-structure within the smallest groups, and for identifying the top-level groups within a network. Model scores are additive over independent interaction types, providing a direct route for simultaneous analysis of multiple interaction types. In addition to inferring network structure, this algorithm generates link predictions that with cross-validation provide a quantitative assessment of performance for real-world examples.
When applied to genome-scale data sets representing several organisms and interaction types, HAC provides the overall best performance in link prediction when compared with other clustering methods and with model-free graph diffusion kernels. Investigation of performance on genome-scale yeast protein interactions reveals roughly 100 top-level clusters, with a long-tailed distribution of cluster sizes. These are in turn partitioned into 1000 fine-level clusters containing 5 proteins on average, again with a long-tailed size distribution. Top-level clusters correspond to broad biological processes, whereas fine-level clusters correspond to discrete complexes. Surprisingly, link prediction based on joint clustering of physical and genetic interactions performs worse than predictions based on individual data sets, suggesting a lack of synergy in current high-throughput data.
PMCID: PMC3044301  PMID: 21342576
7.  MINE: Module Identification in Networks 
BMC Bioinformatics  2011;12:192.
PMCID: PMC3123237  PMID: 21605434
8.  Interaction Networks as Scaffolds for Organizing and Interpreting Proteomes 
Genes and proteins do not operate in isolation, but form components of highly integrated biological processes such as metabolic networks, protein complexes or signal transduction pathways. Identifying the connections between these components enables the construction of a valuable scaffold onto which additional metadata may be readily mapped.A significant challenge is the lack of large scale high quality data detailing component interactions. Here, using E. coli as a model, I will illustrate how existing lower quality datasets may be integrated to derive a highly reliable network of protein interactions. Such networks may be readily organized into discrete functional modules using graph clustering algorithms, to reveal biologically meaningful complexes and pathways. Using additional network examples, I will also show how these datasets may be used as frameworks for organizing additional metadata sets such as protein function, expression and conservation, to yield unique insights into the operation and evolution of biological processes.
PMCID: PMC2918101
BMC Systems Biology  2009;3:10.
PMCID: PMC2637233  PMID: 19154595
10.  Prediction of Human Disease-Related Gene Clusters by Clustering Analysis 
Since genes associated with similar diseases/disorders show an increased tendency for their protein products to interact with each other through protein-protein interactions (PPI), clustering analysis obviously as an efficient technique can be easily used to predict human disease-related gene clusters/subnetworks. Firstly, we used clustering algorithms, Markov cluster algorithm (MCL), Molecular complex detection (MCODE) and Clique percolation method (CPM) to decompose human PPI network into dense clusters as the candidates of disease-related clusters, and then a log likelihood model that integrates multiple biological evidences was proposed to score these dense clusters. Finally, we identified disease-related clusters using these dense clusters if they had higher scores. The efficiency was evaluated by a leave-one-out cross validation procedure. Our method achieved a success rate with 98.59% and recovered the hidden disease-related clusters in 34.04% cases when removed one known disease gene and all its gene-disease associations. We found that the clusters decomposed by CPM outperformed MCL and MCODE as the candidates of disease-related clusters with well-supported biological significance in biological process, molecular function and cellular component of Gene Ontology (GO) and expression of human tissues. We also found that most of the disease-related clusters consisted of tissue-specific genes that were highly expressed only in one or several tissues, and a few of those were composed of housekeeping genes (maintenance genes) that were ubiquitously expressed in most of all the tissues.
PMCID: PMC3030143  PMID: 21278917
Disease-related gene cluster; Clustering analysis; PPI network; Gene expression data
BMC Bioinformatics  2010;11:117.
PMCID: PMC2846907  PMID: 20202218
12.  Scalable global alignment for multiple biological networks 
BMC Bioinformatics  2012;13(Suppl 3):S11.
PMCID: PMC3311098  PMID: 22536895
13.  Improving the quality of protein similarity network clustering algorithms using the network edge weight distribution 
Bioinformatics  2010;27(3):326-333.
Motivation: Clustering protein sequence data into functionally specific families is a difficult but important problem in biological research. One useful approach for tackling this problem involves representing the sequence dataset as a protein similarity network, and afterwards clustering the network using advanced graph analysis techniques. Although a multitude of such network clustering algorithms have been developed over the past few years, comparing algorithms is often difficult because performance is affected by the specifics of network construction. We investigate an important aspect of network construction used in analyzing protein superfamilies and present a heuristic approach for improving the performance of several algorithms.
Results: We analyzed how the performance of network clustering algorithms relates to thresholding the network prior to clustering. Our results, over four different datasets, show how for each input dataset there exists an optimal threshold range over which an algorithm generates its most accurate clustering output. Our results further show how the optimal threshold range correlates with the shape of the edge weight distribution for the input similarity network. We used this correlation to develop an automated threshold selection heuristic in order to most optimally filter a similarity network prior to clustering. This heuristic allows researchers to process their protein datasets with runtime efficient network clustering algorithms without sacrificing the clustering accuracy of the final results.
Availability: Python code for implementing the automated threshold selection heuristic, together with the datasets used in our analysis, are available at
Supplementary information: Supplementary data are available at Bioinformatics online.
PMCID: PMC3031030  PMID: 21118823
14.  FUSE: a profit maximization approach for functional summarization of biological networks 
BMC Bioinformatics  2012;13(Suppl 3):S10.
The availability of large-scale curated protein interaction datasets has given rise to the opportunity to investigate higher level organization and modularity within the protein interaction network (PPI) using graph theoretic analysis. Despite the recent progress, systems level analysis of PPIS remains a daunting task as it is challenging to make sense out of the deluge of high-dimensional interaction data. Specifically, techniques that automatically abstract and summarize PPIS at multiple resolutions to provide high level views of its functional landscape are still lacking. We present a novel data-driven and generic algorithm called FUSE (Functional Summary Generator) that generates functional maps of a PPI at different levels of organization, from broad process-process level interactions to in-depth complex-complex level interactions, through a pro t maximization approach that exploits Minimum Description Length (MDL) principle to maximize information gain of the summary graph while satisfying the level of detail constraint.
We evaluate the performance of FUSE on several real-world PPIS. We also compare FUSE to state-of-the-art graph clustering methods with GO term enrichment by constructing the biological process landscape of the PPIS. Using AD network as our case study, we further demonstrate the ability of FUSE to quickly summarize the network and identify many different processes and complexes that regulate it. Finally, we study the higher-order connectivity of the human PPI.
By simultaneously evaluating interaction and annotation data, FUSE abstracts higher-order interaction maps by reducing the details of the underlying PPI to form a functional summary graph of interconnected functional clusters. Our results demonstrate its effectiveness and superiority over state-of-the-art graph clustering methods with GO term enrichment.
PMCID: PMC3402926  PMID: 22536894
BMC Bioinformatics  2010;11:504.
PMCID: PMC2965181  PMID: 20939868
16.  Simultaneous supervised clustering and feature selection over a graph 
Biometrika  2012;99(4):899-914.
In this article, we propose a regression method for simultaneous supervised clustering and feature selection over a given undirected graph, where homogeneous groups or clusters are estimated as well as informative predictors, with each predictor corresponding to one node in the graph and a connecting path indicating a priori possible grouping among the corresponding predictors. The method seeks a parsimonious model with high predictive power through identifying and collapsing homogeneous groups of regression coefficients. To address computational challenges, we present an efficient algorithm integrating the augmented Lagrange multipliers, coordinate descent and difference convex methods. We prove that the proposed method not only identifies the true homogeneous groups and informative features consistently but also leads to accurate parameter estimation. A gene network dataset is analysed to demonstrate that the method can make a difference by exploring dependency structures among the genes.
PMCID: PMC3629856  PMID: 23843673
Expression quantitative trait loci data; High-dimensional data; Nonconvex minimization; Prediction
17.  A systematic comparison of genome-scale clustering algorithms 
BMC Bioinformatics  2012;13(Suppl 10):S7.
PMCID: PMC3382433  PMID: 22759431
18.  A structural approach for finding functional modules from large biological networks 
BMC Bioinformatics  2008;9(Suppl 9):S19.
Biological systems can be modeled as complex network systems with many interactions between the components. These interactions give rise to the function and behavior of that system. For example, the protein-protein interaction network is the physical basis of multiple cellular functions. One goal of emerging systems biology is to analyze very large complex biological networks such as protein-protein interaction networks, metabolic networks, and regulatory networks to identify functional modules and assign functions to certain components of the system. Network modules do not occur by chance, so identification of modules is likely to capture the biologically meaningful interactions in large-scale PPI data. Unfortunately, existing computer-based clustering methods developed to find those modules are either not so accurate or too slow.
We devised a new methodology called SCAN (Structural Clustering Algorithm for Networks) that can efficiently find clusters or functional modules in complex biological networks as well as hubs and outliers. More specifically, we demonstrated that we can find functional modules in complex networks and classify nodes into various roles based on their structures. In this study, we showed the effectiveness of our methodology using the budding yeast (Saccharomyces cerevisiae) protein-protein interaction network. To validate our clustering results, we compared our clusters with the known functions of each protein. Our predicted functional modules achieved very high purity comparing with state-of-the-art approaches. Additionally the theoretical and empirical analysis demonstrated a linear running-time of the algorithm, which is the fastest approach for networks.
We compare our algorithm with well-known modularity based clustering algorithm CNM. We successfully detect functional groups that are annotated with putative GO terms. Top-10 clusters with minimum p-value theoretically prove that newly proposed algorithm partitions network more accurately then CNM. Furthermore, manual interpretations of functional groups found by SCAN show superior performance over CNM.
PMCID: PMC2537570  PMID: 18793464
19.  Predicting and characterizing selective multiple drug treatments for metabolic diseases and cancer 
BMC Systems Biology  2012;6:115.
In the field of drug discovery, assessing the potential of multidrug therapies is a difficult task because of the combinatorial complexity (both theoretical and experimental) and because of the requirements on the selectivity of the therapy. To cope with this problem, we have developed a novel method for the systematic in silico investigation of synergistic effects of currently available drugs on genome-scale metabolic networks.
The algorithm finds the optimal combination of drugs which guarantees the inhibition of an objective function, while minimizing the side effect on the other cellular processes. Two different applications are considered: finding drug synergisms for human metabolic diseases (like diabetes, obesity and hypertension) and finding antitumoral drug combinations with minimal side effect on the normal human cell. The results we obtain are consistent with some of the available therapeutic indications and predict new multiple drug treatments. A cluster analysis on all possible interactions among the currently available drugs indicates a limited variety on the metabolic targets for the approved drugs.
The in silico prediction of drug synergisms can represent an important tool for the repurposing of drugs in a realistic perspective which considers also the selectivity of the therapy. Moreover, for a more profitable exploitation of drug-drug interactions, we have shown that also experimental drugs which have a different mechanism of action can be reconsider as potential ingredients of new multicompound therapeutic indications. Needless to say the clues provided by a computational study like ours need in any case to be thoroughly evaluated experimentally.
PMCID: PMC3744170  PMID: 22932283
Metabolic network; Drug synergism; Flux balance analysis; Metabolic diseases; Cancer
20.  A novel subgradient-based optimization algorithm for blockmodel functional module identification 
BMC Bioinformatics  2013;14(Suppl 2):S23.
Functional module identification in biological networks may provide new insights into the complex interactions among biomolecules for a better understanding of cellular functional organization. Most of existing functional module identification methods are based on the optimization of network modularity and cluster networks into groups of nodes within which there are a higher-than-expectation number of edges. However, module identification simply based on this topological criterion may not discover certain kinds of biologically meaningful modules within which nodes are sparsely connected but have similar interaction patterns with the rest of the network. In order to unearth more biologically meaningful functional modules, we propose a novel efficient convex programming algorithm based on the subgradient method with heuristic path generation to solve the problem in a recently proposed framework of blockmodel module identification. We have implemented our algorithm for large-scale protein-protein interaction (PPI) networks, including Saccharomyces cerevisia and Homo sapien PPI networks collected from the Database of Interaction Proteins (DIP) and Human Protein Reference Database (HPRD). Our experimental results have shown that our algorithm achieves comparable network clustering performance in comparison to the more time-consuming simulated annealing (SA) optimization. Furthermore, preliminary results for identifying fine-grained functional modules in both biological networks and the comparison with the commonly adopted Markov Clustering (MCL) algorithm have demonstrated the potential of our algorithm to discover new types of modules, within which proteins are sparsely connected but with significantly enriched biological functionalities.
PMCID: PMC3549836  PMID: 23368964
21.  Inferring protein–protein interaction complexes from immunoprecipitation data 
BMC Research Notes  2013;6:468.
Protein–protein interactions in cells are widely explored using small–scale experiments. However, the search for protein complexes and their interactions in data from high throughput experiments such as immunoprecipitation is still a challenge. We present "4N", a novel method for detecting protein complexes in such data. Our method is a heuristic algorithm based on Near Neighbor Network (3N) clustering. It is written in R, it is faster than model-based methods, and has only a small number of tuning parameters. We explain the application of our new method to real immunoprecipitation results and two artificial datasets. We show that the method can infer protein complexes from protein immunoprecipitation datasets of different densities and sizes.
4N was applied on the immunoprecipitation dataset that was presented by the authors of the original 3N in Cell 145:787–799, 2011. The test with our method shows that it can reproduce the original clustering results with fewer manually adapted parameters and, in addition, gives direct insight into the complex–complex interactions. We also tested 4N on the human "Tip49a/b" dataset. We conclude that 4N can handle the contaminants and can correctly infer complexes from this very dense dataset. Further tests were performed on two artificial datasets of different sizes. We proved that the method predicts the reference complexes in the two artificial datasets with high accuracy, even when the number of samples is reduced.
4N has been implemented in R. We provide the sourcecode of 4N and a user-friendly toolbox including two example calculations. Biologists can use this 4N-toolbox even if they have a limited knowledge of R. There are only a few tuning parameters to set, and each of these parameters has a biological interpretation. The run times for medium scale datasets are in the order of minutes on a standard desktop PC. Large datasets can typically be analyzed within a few hours.
PMCID: PMC3874675  PMID: 24237943
Protein–protein interactions; Proteomics; Protein complexes; Immunoprecipitation
BMC Bioinformatics  2007;8:408.
Nowadays modern biology aims at unravelling the strands of complex biological structures such as the protein-protein interaction (PPI) networks. A key concept in the organization of PPI networks is the existence of dense subnetworks (functional modules) in them. In recent approaches clustering algorithms were applied at these networks and the resulting subnetworks were evaluated by estimating the coverage of well-established protein complexes they contained. However, most of these algorithms elaborate on an unweighted graph structure which in turn fails to elevate those interactions that would contribute to the construction of biologically more valid and coherent functional modules.
In the current study, we present a method that corroborates the integration of protein interaction and microarray data via the discovery of biologically valid functional modules. Initially the gene expression information is overlaid as weights onto the PPI network and the enriched PPI graph allows us to exploit its topological aspects, while simultaneously highlights enhanced functional association in specific pairs of proteins. Then we present an algorithm that unveils the functional modules of the weighted graph by expanding a kernel protein set, which originates from a given 'seed' protein used as starting-point.
The integrated data and the concept of our approach provide reliable functional modules. We give proofs based on yeast data that our method manages to give accurate results in terms both of structural coherency, as well as functional consistency.
PMCID: PMC2233647  PMID: 17956603
23.  Multi-objective dynamic population shuffled frog-leaping biclustering of microarray data 
BMC Genomics  2012;13(Suppl 3):S6.
Multi-objective optimization (MOO) involves optimization problems with multiple objectives. Generally, theose objectives is used to estimate very different aspects of the solutions, and these aspects are often in conflict with each other. MOO first gets a Pareto set, and then looks for both commonality and systematic variations across the set. For the large-scale data sets, heuristic search algorithms such as EA combined with MOO techniques are ideal. Newly DNA microarray technology may study the transcriptional response of a complete genome to different experimental conditions and yield a lot of large-scale datasets. Biclustering technique can simultaneously cluster rows and columns of a dataset, and hlep to extract more accurate information from those datasets. Biclustering need optimize several conflicting objectives, and can be solved with MOO methods. As a heuristics-based optimization approach, the particle swarm optimization (PSO) simulate the movements of a bird flock finding food. The shuffled frog-leaping algorithm (SFL) is a population-based cooperative search metaphor combining the benefits of the local search of PSO and the global shuffled of information of the complex evolution technique. SFL is used to solve the optimization problems of the large-scale datasets.
This paper integrates dynamic population strategy and shuffled frog-leaping algorithm into biclustering of microarray data, and proposes a novel multi-objective dynamic population shuffled frog-leaping biclustering (MODPSFLB) algorithm to mine maximum bicluesters from microarray data. Experimental results show that the proposed MODPSFLB algorithm can effectively find significant biological structures in terms of related biological processes, components and molecular functions.
The proposed MODPSFLB algorithm has good diversity and fast convergence of Pareto solutions and will become a powerful systematic functional analysis in genome research.
PMCID: PMC3394423  PMID: 22759615
24.  Mining functional subgraphs from cancer protein-protein interaction networks 
BMC Systems Biology  2012;6(Suppl 3):S2.
PMCID: PMC3524085  PMID: 23282132
BMC Bioinformatics  2008;9:458.
The analysis of large-scale data sets via clustering techniques is utilized in a number of applications. Biclustering in particular has emerged as an important problem in the analysis of gene expression data since genes may only jointly respond over a subset of conditions. Biclustering algorithms also have important applications in sample classification where, for instance, tissue samples can be classified as cancerous or normal. Many of the methods for biclustering, and clustering algorithms in general, utilize simplified models or heuristic strategies for identifying the "best" grouping of elements according to some metric and cluster definition and thus result in suboptimal clusters.
In this article, we present a rigorous approach to biclustering, OREO, which is based on the Optimal RE-Ordering of the rows and columns of a data matrix so as to globally minimize the dissimilarity metric. The physical permutations of the rows and columns of the data matrix can be modeled as either a network flow problem or a traveling salesman problem. Cluster boundaries in one dimension are used to partition and re-order the other dimensions of the corresponding submatrices to generate biclusters. The performance of OREO is tested on (a) metabolite concentration data, (b) an image reconstruction matrix, (c) synthetic data with implanted biclusters, and gene expression data for (d) colon cancer data, (e) breast cancer data, as well as (f) yeast segregant data to validate the ability of the proposed method and compare it to existing biclustering and clustering methods.
We demonstrate that this rigorous global optimization method for biclustering produces clusters with more insightful groupings of similar entities, such as genes or metabolites sharing common functions, than other clustering and biclustering algorithms and can reconstruct underlying fundamental patterns in the data for several distinct sets of data matrices arising in important biological applications.
PMCID: PMC2605474  PMID: 18954459

Results 1-25 (868328)