MAE-FMD: multi-agent evolutionary method for functional module detection in protein-protein interaction networks.

Graph clustering algorithms are widely used in the analysis of biological networks. Extracting functional modules in protein-protein interaction (PPI) networks is one such use. Most clustering algorithms whose focuses are on finding functional modules try either to find a clique like sub networks or to grow clusters starting from vertices with high degrees as seeds. These algorithms do not make any difference between a biological network and any other networks. In the current research, we present a new procedure to find functional modules in PPI networks. Our main idea is to model a biological concept and to use this concept for finding good functional modules in PPI networks. In order to evaluate the quality of the obtained clusters, we compared the results of our algorithm with those of some other widely used clustering algorithms on three high throughput PPI networks from Sacchromyces Cerevisiae, Homo sapiens and Caenorhabditis elegans as well as on some tissue specific networks. Gene Ontology (GO) analyses were used to compare the results of different algorithms. Each algorithm's result was then compared with GO-term derived functional modules. We also analyzed the effect of using tissue specific networks on the quality of the obtained clusters. The experimental results indicate that the new algorithm outperforms most of the others, and this improvement is more significant when tissue specific networks are used.

Identifying functional modules in protein-protein interaction (PPI) networks elucidates cellular organization and mechanism. Various methods have been proposed to identify the functional modules in PPI networks, but most of these methods do not consider the noisy links in PPI networks. They achieve a competitive performance on the PPI networks without noisy links, but the performance of these methods considerably deteriorates in the noisy PPI networks. Furthermore, the noisy links are inevitable in the PPI networks. In this paper, we propose a novel link-driven label propagation algorithm (LLPA) to identify functional modules in PPI networks. The LLPA first find link clusters in PPI networks, and then the functional modules are identified from the link clusters. Two strategies aimed to ensure the robustness of LLPA are proposed. One strategy involves the proposed LLPA updating the link labels in accordance with the designed weight of the link, which can reduce the incidence of noisy links. The other strategy involves the filtration of some noisy labels from the link clusters to further reduce the influence of noisy links. The performance evaluation on three real PPI networks shows that LLPA outperforms other eight state-of-the-art detection algorithms in terms of accuracy and robustness.

HAM-FMD: Mining functional modules in protein–protein interaction networks using ant colony optimization and multi-agent evolution

Motivation: The identification of functional modules from protein–protein interaction (PPI) networks is an important step toward understanding the biological features of PPI networks. The detection of functional modules in PPI networks is often performed by identifying internally densely connected subnetworks, and often produces modules with “core” and “peripheral” proteins. The core proteins are the ones having dense connections to each other in a module. The difference between core and peripheral proteins is important to understand the functional roles of proteins in modules, but there are few methods to explicitly elucidate the internal structure of functional modules at gene level.Results: We propose NCMine, which is a novel network clustering method and visualization tool for the core-peripheral structure of functional modules. It extracts near-complete subgraphs from networks based on a node-weighting scheme using degree centrality, and reports subgroups as functional modules. We implemented this method as a plugin of Cytoscape, which is widely used to visualize and analyze biological networks. The plugin allows users to extract functional modules from PPI networks and interactively filter modules of interest. We applied the method to human PPI networks, and found several examples with the core-peripheral structure of modules that may be related to cancer development.Availability and Implementation: The Cytoscape plugin and tutorial are available at Cytoscape AppStore. (http://apps.cytoscape.org/apps/ncmine).Contact:kengo@ecei.tohoku.ac.jpSupplementary information:Supplementary data are available at Bioinformatics online.

The identification and analysis of functional modules in protein–protein interaction (PPI) networks provide insight into understanding the organization and function of biological systems. A lot of overlapping structures are shared by the functional modules in PPI networks, which indicates there are some proteins play indispensable roles in different biological processes. Markov clustering (MCL) is a popular algorithm for clustering networks in bioinformatics. In this paper, to identify the overlapping structures among the functional modules and find more modules with biological significance in PPI networks, we propose a Markov clustering algorithm based on link similarity (MLS). First of all, the weighted link similarity is calculated and the link similarity matrix which measures the association strength of the protein interactions can be gotten. Then, the link similarity matrix is divided by applying Markov clustering, and the clustering results are mapped to original networks to analyze the protein modules. The method has been experimented on three databases, including DIP, Gavin and Krogan. Our results show that the MLS cannot only accurately identify the functional modules, but also outperform the original MCL algorithm and the F-measure value improved 5–10% compared with it.

Functional module identification in a Protein-Protein Interaction (PPI) network is one of the most important and challenging tasks in computational biology. For detecting functional modules, it is difficult to solve the problem directly and always results in a low accuracy and a large discard rate. In this paper, we present a novel algorithm of ant colony optimization with multi-agent evolution for detecting functional modules. The proposed ACO-MAE algorithm enhances the performance of ant colony optimization (ACO) by incorporating multi-agent evolution (MAE). First, the ant colony optimization for solving Traveling Salesman Problems (TSP) is conducted to construct primary clustering results. Then, the multi-agent evolutionary process is performed to move out of local optima. From simulation results, it is shown that the proposed ACO-MAE algorithm has superior performance when compared to other existing algorithms.

Protein-protein interaction (PPI) networks carry vital information on the organization of molecular interactions in cellular systems. The identification of functionally relevant modules in PPI networks is one of the most important applications of biological network analysis. Computational analysis is becoming an indispensable tool to understand large-scale biomolecular interaction networks. Several types of computational methods have been developed and employed for the analysis of PPI networks. Of these computational methods, graph comparison and module detection are the two most commonly used strategies. This review summarizes current literature on graph kernel and graph alignment methods for graph comparison strategies, as well as module detection approaches including seed-and-extend, hierarchical clustering, optimization-based, probabilistic, and frequent subgraph methods. Herein, we provide a comprehensive review of the major algorithms employed under each theme, including our recently published frequent subgraph method, for detecting functional modules commonly shared across multiple cancer PPI networks.

BackgroundThe sparse connectivity of protein-protein interaction data sets makes identification of functional modules challenging. The purpose of this study is to critically evaluate a novel clustering technique for clustering and detecting functional modules in protein-protein interaction networks, termed STM.ResultsSTM selects representative proteins for each cluster and iteratively refines clusters based on a combination of the signal transduced and graph topology. STM is found to be effective at detecting clusters with a diverse range of interaction structures that are significant on measures of biological relevance. The STM approach is compared to six competing approaches including the maximum clique, quasi-clique, minimum cut, betweeness cut and Markov Clustering (MCL) algorithms. The clusters obtained by each technique are compared for enrichment of biological function. STM generates larger clusters and the clusters identified have p-values that are approximately 125-fold better than the other methods on biological function. An important strength of STM is that the percentage of proteins that are discarded to create clusters is much lower than the other approaches.ConclusionSTM outperforms competing approaches and is capable of effectively detecting both densely and sparsely connected, biologically relevant functional modules with fewer discards.

The identification of disease-associated modules based on protein-protein interaction networks (PPINs) and gene expression data has provided new insights into the mechanistic nature of diverse diseases. However, their identification is hampered by the detection of protein communities within large-scale, whole-genome PPINs. A presented successful strategy detects a PPIN’s community structure based on the maximal clique enumeration problem (MCE), which is a non-deterministic polynomial time-hard problem. This renders the approach computationally challenging for large PPINs implying the need for new strategies. We present ModuleDiscoverer, a novel approach for the identification of regulatory modules from PPINs and gene expression data. Following the MCE-based approach, ModuleDiscoverer uses a randomization heuristic-based approximation of the community structure. Given a PPIN of Rattus norvegicus and public gene expression data, we identify the regulatory module underlying a rodent model of non-alcoholic steatohepatitis (NASH), a severe form of non-alcoholic fatty liver disease (NAFLD). The module is validated using single-nucleotide polymorphism (SNP) data from independent genome-wide association studies and gene enrichment tests. Based on gene enrichment tests, we find that ModuleDiscoverer performs comparably to three existing module-detecting algorithms. However, only our NASH-module is significantly enriched with genes linked to NAFLD-associated SNPs. ModuleDiscoverer is available at http://www.hki-jena.de/index.php/0/2/490 (Others/ModuleDiscoverer).

Identifying functional modules in protein-protein interaction (PPI) networks is fundamental to understand cellular organization, processes, and functions. As an emerging evolutionary computational technology, swarm intelligence approaches are now becoming a new research hotspot in identifying functional modules. This paper proposes a new computational approach based on bacterial biological mechanisms for functional module detection in PPI networks (called as BBM-FMD). In BBM-FMD, each bacterium is first initialized to a candidate module partition by a random walk behavior. Then four biological mechanisms of bacteria including chemotaxis, conjugation, reproduction, and elimination and dispersal are simulated to iteratively search for better protein module partitions. At last, two post-processing steps are carried out to refine the obtained module partition. The experimental results on two PPI datasets demonstrate the superior performance of BBM-FMD in detecting functional modules compared with several other algorithms.

Advances in proteomic technologies combined with sophisticated computing and modeling methods have generated an unprecedented amount of high-throughput data for system-scale analysis. As a result, the study of protein-protein interaction (PPI) networks has garnered much attention in recent years. One of the most fundamental problems in studying PPI networks is to understand how their architecture originated and evolved to their current state. By investigating how proteins of different ages are connected in the yeast PPI networks, one can deduce their expansion procedure in evolution and how the ancient primitive network expanded and evolved. Studies have shown that proteins are often connected to other proteins of a similar age, suggesting a high degree of age preference between interacting proteins. Though several theories have been proposed to explain this phenomenon, none of them considered protein-clusters as a contributing factor. Here we first investigate the age-dependency of the proteins from the perspective of network motifs. Our analysis confirms that proteins of the same age groups tend to form interacting network motifs; furthermore, those proteins within motifs tend to be within protein complexes and the interactions among them largely contribute to the observed age preference in the yeast PPI networks. In light of these results, we describe a new modeling approach, based on "network motifs", whereby topologically connected protein clusters in the network are treated as single evolutionary units. Instead of modeling single proteins, our approach models the connections and evolutionary relationships of multiple related protein clusters or "network motifs" that are collectively integrated into an existing PPI network. Through simulation studies, we found that the "network motif" modeling approach can capture yeast PPI network properties better than if individual proteins were considered to be the simplest evolutionary units. Our approach provides a fresh perspective on modeling the evolution of yeast PPI networks, specifically that PPI networks may have a much higher age-dependency of interaction density than had been previously envisioned.

Signal flow direction is one of the most important features of the protein-protein interactions in signaling networks. However, almost all the outcomes of current high-throughout techniques for protein-protein interactions mapping are usually supposed to be non-directional. Based on the pairwise interaction domains, here we defined a novel parameter protein interaction directional score and then used it to predict the direction of signal flow between proteins in proteome-wide signaling networks. Using 5-fold cross-validation, our approach obtained a satisfied performance with the accuracy 89.79%, coverage 48.08%, and error ratio 16.91%. As an application, we established an integrated human directional protein interaction network, including 2,237 proteins and 5,530 interactions, and inferred a large amount of novel signaling pathways. Directional protein interaction network was strongly supported by the known signaling pathways literature (with the 87.5% accuracy) and further analyses on the biological annotation, subcellular localization, and network topology property. Thus, this study provided an effective method to define the upstream/downstream relations of interacting protein pairs and a powerful tool to unravel the unknown signaling pathways.

Accumulating evidence suggests that biological systems are composed of interacting, separable, functional modules-groups of vertices within which connections are dense but between which they are sparse. Identifying these modules is likely through capturing the biologically meaningful interactions. In recent years, many algorithms have been developed for detecting such structures. These algorithms, however, are computationally demanding, which limits their applications. In this paper, we propose a fast iterative-clique percolation method (ICPM) for identifying overlapping functional modules in protein-protein interaction (PPI) networks. Our method is based on clique percolation method (CPM), and it not only considers the degree of nodes to minimize the search space (the vertices in k-cliques must have the degree of k − 1 at least), but also converts k-cliques to (k − 1)-cliques. It finds k-cliques by appending one node to (k − 1)-cliques. By testing our method on PPI networks, our analysis of the yeast PPI network suggests that most of these modules have well-supported biological significance.

Although the main treatments of inflammatory bowel disease (IBD) aim at the induction and maintenance of clinical remission, several studies have demonstrated inflammation still present in clinical remission. The goal of this study was to analyze the gene expression profiles between the pediatric IBD and control samples, aiming to further investigate the underlying therapeutic target in remission. Gene expression profiles data of GSE33943 were downloaded from Gene Expression Omnibus, which included 45 pediatric IBD samples and 13 control samples. The differentially expressed genes (DEGs) between IBD and control samples were identified by LIMMA package in R and the function of DEGs were predicted by Gene Ontology and KEGG pathway enrichment analyses using GeneAnswer package. Furthermore, a protein-protein interaction (PPI) network was constructed through the STRING database and functional module was obtained using ClusterONE. A total of 224 DEGs were screened between IBD and control samples. These DEGs (e.g. up-regulated FAS and down-regulated CCL5) were mainly enriched in cytokine‒cytokine receptor interaction and chemokine signaling pathway. In addition, some hub genes (e.g. up-regulated PSMA2 and PSMA6) were obtained through PPI network and functional module. These two genes were involved in Proteasome alpha-subunit and conserved site by functional module analysis. The immune and Proteasome mechanisms are still active during remission and FAS, PMSF6 and PMSF2 may be underlying targets for therapy of this disease.

We know that protein-protein interaction (PPI) network is an extremely important biological molecular relationship network in life activities, at present, it has become an important research topic in bioinformatics to detect functional modules from PPI network by computational methods. In this context, this paper studies the implementation of fast algorithm based on GN algorithm in PPI network. Based on GN algorithm, this paper proposes a fast algorithm based on GN algorithm and applies it to PPI network. In the research, we first analyze the performance of the fast algorithm based on GN algorithm, and select MIPS database as PPI data set, compare the proposed method with GN algorithm, and evaluate the accuracy, recall rate, F measure, sensitivity, positive prediction rate and coverage. The results show that the F measure of the fast algorithm based on GN algorithm is 0.70, and the recall rate of GN algorithm is 0.63. The F measure of this algorithm is larger than that of GN algorithm. In addition, the fast algorithm based on GN algorithm is better than GN algorithm in other evaluation indexes. It can be seen that this method has great advantages in the implementation of PPI network.KeywordsGN algorithmFast algorithmPPI networkF measure