Functional Modules In Protein-protein Interaction Networks Research Articles

SEMtree: tree-based structure learning methods with structural equation models.

With the exponential growth of expression and protein-protein interaction (PPI) data, the identification of functional modules in PPI networks that show striking changes in molecular activity or phenotypic signatures becomes of particular interest to reveal process-specific information that is correlated with cellular or disease states. This requires both the identification of network nodes with reliability scores and the availability of an efficient technique to locate the network regions with the highest scores. In the literature, a number of heuristic methods have been suggested. We propose SEMtree(), a set of tree-based structure discovery algorithms, combining graph and statistically interpretable parameters together with a user-friendly R package based on structural equation models framework. Condition-specific changes from differential expression and gene-gene co-expression are recovered with statistical testing of node, directed edge, and directed path difference between groups. In the end, from a list of seed (i.e. disease) genes or gene P-values, the perturbed modules with undirected edges are generated with five state-of-the-art active subnetwork detection methods. The latter are supplied to causal additive trees based on Chu-Liu-Edmonds' algorithm (Chow and Liu, Approximating discrete probability distributions with dependence trees. IEEE Trans Inform Theory 1968;14:462-7) in SEMtree() to be converted in directed trees. This conversion allows to compare the methods in terms of directed active subnetworks. We applied SEMtree() to both Coronavirus disease (COVID-19) RNA-seq dataset (GEO accession: GSE172114) and simulated datasets with various differential expression patterns. Compared to existing methods, SEMtree() is able to capture biologically relevant subnetworks with simple visualization of directed paths, good perturbation extraction, and classifier performance. SEMtree() function is implemented in the R package SEMgraph, easily available at https://CRAN.R-project.org/package=SEMgraph.

AdaPPI: identification of novel protein functional modules via adaptive graph convolution networks in a protein–protein interaction network

Identifying unknown protein functional modules, such as protein complexes and biological pathways, from protein-protein interaction (PPI) networks, provides biologists with an opportunity to efficiently understand cellular function and organization. Finding complex nonlinear relationships in underlying functional modules may involve a long-chain of PPI and pose great challenges in a PPI network with an unevenly sparse and dense node distribution. To overcome these challenges, we propose AdaPPI, an adaptive convolution graph network in PPI networks to predict protein functional modules. We first suggest an attributed graph node presentation algorithm. It can effectively integrate protein gene ontology attributes and network topology, and adaptively aggregates low- or high-order graph structural information according to the node distribution by considering graph node smoothness. Based on the obtained node representations, core cliques and expansion algorithms are applied to find functional modules in PPI networks. Comprehensive performance evaluations and case studies indicate that the framework significantly outperforms state-of-the-art methods. We also presented potential functional modules based on their confidence.

A Robust Algorithm Based on Link Label Propagation for Identifying Functional Modules From Protein-Protein Interaction Networks.

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.

Module overlapping structure detection in PPI using an improved link similarity-based Markov clustering algorithm

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.

Simplified Swarm Optimization-Based Function Module Detection in Protein–Protein Interaction Networks

Proteomics research has become one of the most important topics in the field of life science and natural science. At present, research on protein–protein interaction networks (PPIN) mainly focuses on detecting protein complexes or function modules. However, existing approaches are either ineffective or incomplete. In this paper, we investigate detection mechanisms of functional modules in PPIN, including open database, existing detection algorithms, and recent solutions. After that, we describe the proposed approach based on the simplified swarm optimization (SSO) algorithm and the knowledge of Gene Ontology (GO). The proposed solution implements the SSO algorithm for clustering proteins with similar function, and imports biological gene ontology knowledge for further identifying function complexes and improving detection accuracy. Furthermore, we use four different categories of species datasets for experiment: fruitfly, mouse, scere, and human. The testing and analysis result show that the proposed solution is feasible, efficient, and could achieve a higher accuracy of prediction than existing approaches.

NCMine: Core-peripheral based functional module detection using near-clique mining.

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.

Detecting Functional Modules Based on a Multiple-Grain Model in Large-Scale Protein-Protein Interaction Networks.

Detecting functional modules from a Protein-Protein Interaction (PPI) network is a fundamental and hot issue in proteomics research, where many computational approaches have played an important role in recent years. However, how to effectively and efficiently detect functional modules in large-scale PPI networks is still a challenging problem. We present a new framework, based on a multiple-grain model of PPI networks, to detect functional modules in PPI networks. First, we give a multiple-grain representation model of a PPI network, which has a smaller scale with super nodes. Next, we design the protein grain partitioning method, which employs a functional similarity or a structural similarity to merge some proteins layer by layer. Thirdly, a refining mechanism with border node tests is proposed to address the protein overlapping of different modules during the grain eliminating process. Finally, systematic experiments are conducted on five large-scale yeast and human networks. The results show that the framework not only significantly reduces the running time of functional module detection, but also effectively identifies overlapping modules while keeping some competitive performances, thus it is highly competent to detect functional modules in large-scale PPI networks.

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

BackgroundStudies of functional modules in a Protein-Protein Interaction (PPI) network contribute greatly to the understanding of biological mechanisms. With the development of computing science, computational approaches have played an important role in detecting functional modules.ResultsWe present a new approach using multi-agent evolution for detection of functional modules in PPI networks. The proposed approach consists of two stages: the solution construction for agents in a population and the evolutionary process of computational agents in a lattice environment, where each agent corresponds to a candidate solution to the detection problem of functional modules in a PPI network. First, the approach utilizes a connection-based encoding scheme to model an agent, and employs a random-walk behavior merged topological characteristics with functional information to construct a solution. Next, it applies several evolutionary operators, i.e., competition, crossover, and mutation, to realize information exchange among agents as well as solution evolution. Systematic experiments have been conducted on three benchmark testing sets of yeast networks. Experimental results show that the approach is more effective compared to several other existing algorithms.ConclusionsThe algorithm has the characteristics of outstanding recall, F-measure, sensitivity and accuracy while keeping other competitive performances, so it can be applied to the biological study which requires high accuracy.

C-element: A New Clustering Algorithm to Find High Quality Functional Modules in PPI 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.

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

Mining functional modules in a protein–protein interaction (PPI) network contributes greatly to the understanding of biological mechanism, thus how to effectively detect functional modules in a PPI network has a significant application. In this paper, we present a hybrid approach using ant colony optimization and multi-agent evolution for detection functional modules in PPI networks. The proposed algorithm enhances the performance of ant colony optimization by incorporating multi-agent evolution for detecting functional modules. In the ant colony optimization process, a new heuristic, which merges topological characteristics with functional information function, is introduced to effectively conduct ants searching in finding optimal results. Thereafter, the multi-agent evolutionary process based on an energy function is performed to move out of local optima and obtain some enclosed connecting subgraphs which represent functional modules mined in a PPI network. Finally, systematic experiments have been conducted on four benchmark testing sets of yeast networks. Experimental results show that the hybrid approach is more effective compared to several other existing algorithms.

Identification of Hierarchical and Overlapping Functional Modules in PPI Networks

Various evidences have demonstrated that functional modules are overlapping and hierarchically organized in protein-protein interaction (PPI) networks. Up to now, few methods are able to identify both overlapping and hierarchical functional modules in PPI networks. In this paper, a new hierarchical clustering algorithm, called OH-PIN, is proposed based on the overlapping M_clusters, λ-module, and a new concept of clustering coefficient between two clusters. By recursively merging two clusters with the maximum clustering coefficient, OH-PIN finally assembles all M_clusters into λ -modules. Since M_clusters are overlapping, λ -modules based on them are also overlapping. Thus, OH-PIN can detect a hierarchical organization of overlapping modules by tuning the value of λ. The hierarchical organization is similar to the hierarchical organization of GO annotations and that of the known complexes in MIPS. To compare the performance of OH-PIN and other existing competing algorithms, we apply them to the yeast PPI network. The experimental results show that OH-PIN outperforms the existing algorithms in terms of the functional enrichment and matching with known protein complexes.

CLUSTERING ALGORITHMS FOR DETECTING FUNCTIONAL MODULES IN PROTEIN INTERACTION NETWORKS

Protein-Protein Interaction (PPI) networks are believed to be important sources of information related to biological processes and complex metabolic functions of the cell. When studying the workings of a biological cell, it is useful to be able to detect known and predict still undiscovered protein complexes within the cell's PPI networks. Such predictions may be used as an inexpensive tool to direct biological experiments. The increasing amount of available PPI data necessitate a fast, accurate approach to biological complex identification. Because of its importance in the studies of protein interaction network, there are different models and algorithms in identifying functional modules in PPI networks. In this paper, we review some representative algorithms, focusing on the algorithms underlying the approaches and how the algorithms relate to each other. In particular, a comparison is given based on the property of the algorithms. Since the PPI network is noisy and still incomplete, some methods which consider other additional properties for preprocessing and purifying of PPI data are presented. We also give a discussion about the functional annotation and validation of protein complexes. Finally, new progress and future research directions are discussed from the computational viewpoint.

Identifying functional modules in protein–protein interaction networks: an integrated exact approach

Motivation: With the exponential growth of expression and protein–protein interaction (PPI) data, the frontier of research in systems biology shifts more and more to the integrated analysis of these large datasets. Of particular interest is the identification of functional modules in PPI networks, sharing common cellular function beyond the scope of classical pathways, by means of detecting differentially expressed regions in PPI networks. This requires on the one hand an adequate scoring of the nodes in the network to be identified and on the other hand the availability of an effective algorithm to find the maximally scoring network regions. Various heuristic approaches have been proposed in the literature.Results: Here we present the first exact solution for this problem, which is based on integer-linear programming and its connection to the well-known prize-collecting Steiner tree problem from Operations Research. Despite the NP-hardness of the underlying combinatorial problem, our method typically computes provably optimal subnetworks in large PPI networks in a few minutes. An essential ingredient of our approach is a scoring function defined on network nodes. We propose a new additive score with two desirable properties: (i) it is scalable by a statistically interpretable parameter and (ii) it allows a smooth integration of data from various sources.We apply our method to a well-established lymphoma microarray dataset in combination with associated survival data and the large interaction network of HPRD to identify functional modules by computing optimal-scoring subnetworks. In particular, we find a functional interaction module associated with proliferation over-expressed in the aggressive ABC subtype as well as modules derived from non-malignant by-stander cells.Availability: Our software is available freely for non-commercial purposes at http://www.planet-lisa.net.Contact: tobias.mueller@biozentrum.uni-wuerzburg.de