Identification of functional gene modules by integrating multi-omics data and known molecular interactions.

Multi-omics data integration has emerged as a promising approach to identify patient subgroups. However, in terms of grouping genes (or gene products) into co-expression modules, data integration methods suffer from two main drawbacks. First, most existing methods only consider genes or samples measured in all different datasets. Second, known molecular interactions (e.g., transcriptional regulatory interactions, protein-protein interactions and biological pathways) cannot be utilized to assist in module detection. Herein, we present a novel data integration framework, Correlation-based Local Approximation of Membership (CLAM), which provides two methodological innovations to address these limitations: 1) constructing a trans-omics neighborhood matrix by integrating multi-omics datasets and known molecular interactions, and 2) using a local approximation procedure to define gene modules from the matrix. Applying Correlation-based Local Approximation of Membership to human colorectal cancer (CRC) and mouse B-cell differentiation multi-omics data obtained from The Cancer Genome Atlas (TCGA), Clinical Proteomics Tumor Analysis Consortium (CPTAC), Gene Expression Omnibus (GEO) and ProteomeXchange database, we demonstrated its superior ability to recover biologically relevant modules and gene ontology (GO) terms. Further investigation of the colorectal cancer modules revealed numerous transcription factors and KEGG pathways that played crucial roles in colorectal cancer progression. Module-based survival analysis constructed four survival-related networks in which pairwise gene correlations were significantly correlated with colorectal cancer patient survival. Overall, the series of evaluations demonstrated the great potential of Correlation-based Local Approximation of Membership for identifying modular biomarkers for complex diseases. We implemented Correlation-based Local Approximation of Membership as a user-friendly application available at https://github.com/free1234hm/CLAM.

Partitioned estimation methodology of biological neuronal networks with topology-based module detection.

Parameter estimation of neuronal networks is closely related with information processing mechanisms in neural systems. Estimation of synaptic parameters for neuronal networks was an time consuming task. Due to complex interactions between neurons, computational efficiency and accuracy of estimation methods is relatively low. Meanwhile, inherent topological properties such as core-periphery and modular structures are not fully considered in estimation. In order to improve the efficiency and accuracy of estimation, this study proposes a two-stage PartitionMLE method which introduces detected neuronal modules as topological constraints in estimation. The proposed PartitionMLE method firstly decomposes the system into multiple non-overlapping neuronal modules, by performing topology-based module detection. Dynamic parameters including intra-modular and inter-modular parameters are estimated in two stages, using detected hubs to connect non-overlapping neuronal modules. The contributions of PartitionMLE method are two-folds: reducing estimation errors and improving the model interpretability. Experiments about neuronal networks consisting of Hodgkin-Huxley (HH) and leaky integrate-and-firing (LIF) neurons validated the effectiveness of the PartitionMLE method, with comparison to the single-stage MLE method.

Test-retest reliability of modular-relevant analysis in brain functional network.

Introduction: The human brain could be modeled as a complex network via functional magnetic resonance imaging (fMRI), and the architecture of these brain functional networks can be studied from multiple spatial scales with different graph theory tools. Detecting modules is an important mesoscale network measuring approach that has provided crucial insights for uncovering how brain organizes itself among different functional subsystems. Despite its successful application in a wide range of brain network studies, the lack of comprehensive reliability assessment prevents its potential extension to clinical trials. Methods: To fill this gap, this paper, using resting-state test-retest fMRI data, systematically explored the reliabilities of five popular network metrics derived from modular structure. Considering the repeatability of network partition depends heavily on network size and module detection algorithm, we constructed three types of brain functional networks for each subject by using a set of coarse-to-fine brain atlases and adopted four methods for single-subject module detection and twelve methods for group-level module detection. Results: The results reported moderate-to-good reliability in modularity, intra- and inter-modular functional connectivities, within-modular degree and participation coefficient at both individual and group levels, indicating modular-relevant network metrics can provide robust evaluation results. Further analysis identified the significant influence of module detection algorithm and node definition approach on reliabilities of network partitions and its derived network analysis results. Discussion: This paper provides important guidance for choosing reliable modular-relevant network metrics and analysis strategies in future studies.

MDSN: A Module Detection Method for Identifying High-Order Epistatic Interactions.

Epistatic interactions are referred to as SNPs (single nucleotide polymorphisms) that affect disease development and trait expression nonlinearly, and hence identifying epistatic interactions plays a great role in explaining the pathogenesis and genetic heterogeneity of complex diseases. Many methods have been proposed for epistasis detection; nevertheless, they mainly focus on low-order epistatic interactions, two-order or three-order for instance, and often ignore high-order interactions due to computational burden. In this paper, a module detection method called MDSN is proposed for identifying high-order epistatic interactions. First, an SNP network is constructed by a construction strategy of interaction complementary, which consists of low-order SNP interactions that can be obtained from fast computations. Then, a node evaluation measure that integrates multi-topological features is proposed to improve the node expansion algorithm, where the importance of a node is comprehensively evaluated by the topological characteristics of the neighborhood. Finally, modules are detected in the constructed SNP network, which have high-order epistatic interactions associated with the disease. The MDSN was compared with four state-of-the-art methods on simulation datasets and a real Age-related Macular Degeneration dataset. The results demonstrate that MDSN has higher performance on detecting high-order interactions.

Identification of the Key miRNAs and Genes Associated with the Regulation of Non-Small Cell Lung Cancer: A Network-Based Approach.

Lung cancer is the major cause of cancer-associated deaths across the world in both men and women. Lung cancer consists of two major clinicopathological categories, i.e., small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). Lack of diagnosis of NSCLC at an early stage in addition to poor prognosis results in ineffective treatment, thus, biomarkers for appropriate diagnosis and exact prognosis of NSCLC need urgent attention. The proposed study aimed to reveal essential microRNAs (miRNAs) involved in the carcinogenesis of NSCLC that probably could act as potential biomarkers. The NSCLC-associated expression datasets revealed 12 differentially expressed miRNAs (DEMs). MiRNA-mRNA network identified key miRNAs and their associated genes, for which functional enrichment analysis was applied. Further, survival and validation analysis for key genes was performed and consequently transcription factors (TFs) were predicted. We obtained twelve miRNAs as common DEMs after assessment of all datasets. Further, four key miRNAs and nine key genes were extracted from significant modules based on the centrality approach. The key genes and miRNAs reported in our study might provide some information for potential biomarkers profitable to increased prognosis and diagnosis of lung cancer.

Scalable module detection for attributed networks with applications to breast cancer.

The objective of network module detection is to identify groups of nodes within a network structure that are tightly connected. Nodes in a network often have attributes (aka metadata) associated with them. It is often desirable to identify groups of nodes that are tightly connected in the network structure, but also have strong similarity in their attributes. Utilizing attribute information in module detection is a major challenge because it requires bridging the structural network with attribute data. A Weighted Fast Greedy (WFG) algorithm for attribute-based module detection is proposed. WFG utilizes logistic regression to bridge the structural and attribute spaces. The logistic function naturally emphasizes associations between attributes and network structure accordingly, and can be easily interpreted. A breast cancer application is presented that connects a protein-protein interaction network gene expression data and a survival outcome. This application demonstrates the importance of embedding attribute information into the community detection framework on a breast cancer dataset. Five modules were significant for survival and they contained known pathways and markers for cancer, including cell cycle, p53 pathway, BRCA1, BRCA2, and AURKB, among others. Whereas, neither the gene expression data nor the network structure alone gave rise to these cancer biomarkers and signatures.

Network-based prioritization of cancer biomarkers by phenotype-driven module detection and ranking.

This paper describes an ensemble method with supervised module detection and further module prioritization for reliable network-based biomarker discovery. We design a module detection and ranking method called mRank to discover reliable network modules as cancer diagnostic biomarkers, with two procedures: (1) an iterative supervised module detection guided by phenotypic states in a specific network, (2) a block-based module ranking locally and globally via network topological centrality. We validate its effectiveness and efficiency by identifying hepatocellular carcinoma (HCC) network modules on a comprehensive gene regulatory network with specifying gene interactions by HCC RNA-seq data from the Cancer Genome Atlas (TCGA). These top-ranked modules by mRank get a mean AUC of 0.995 on TCGA HCC dataset with 371 tumor samples and 50 controls by cross-validation SVM. Based on the prior knowledge of cancer dysfunctions enriched in top-ranked modules, 69 genes are identified as HCC candidate biomarkers. They are further validated in independent cohorts with a classifier trained on TCGA HCC dataset. A mean AUC of 0.846 is achieved in distinguishing 976 disease samples from 827 controls. Moreover, some known HCC signatures such as AFP and SPP1 are also included in our identified biomarkers. mRank enables us to find more reliable network modules for cancer diagnosis. For a proof-of-concept study, we validate it in identifying HCC network biomarkers and it is generalizable to other cancers or complex disease. The overall results have demonstrated that mRank can find effective network biomarkers for cancer diagnosis which result in less false positives.

Modular network inference between miRNA-mRNA expression profiles using weighted co-expression network analysis.

Connecting transcriptional and post-transcriptional regulatory networks solves an important puzzle in the elucidation of gene regulatory mechanisms. To decipher the complexity of these connections, we build co-expression network modules for mRNA as well as miRNA expression profiles of breast cancer data. We construct gene and miRNA co-expression modules using the weighted gene co-expression network analysis (WGCNA) method and establish the significance of these modules (Genes/miRNAs) for cancer phenotype. This work also infers an interaction network between the genes of the turquoise module from mRNA expression data and hubs of the turquoise module from miRNA expression data. A pathway enrichment analysis using a miRsystem web tool for miRNA hubs and some of their targets, reveal their enrichment in several important pathways associated with the progression of cancer.

TPSC: a module detection method based on topology potential and spectral clustering in weighted networks and its application in gene co-expression module discovery.

BACKGROUND: Gene co-expression networks are widely studied in the biomedical field, with algorithms such as WGCNA and lmQCM having been developed to detect co-expressed modules. However, these algorithms have limitations such as insufficient granularity and unbalanced module size, which prevent full acquisition of knowledge from data mining. In addition, it is difficult to incorporate prior knowledge in current co-expression module detection algorithms. RESULTS: In this paper, we propose a novel module detection algorithm based on topology potential and spectral clustering algorithm to detect co-expressed modules in gene co-expression networks. By testing on TCGA data, our novel method can provide more complete coverage of genes, more balanced module size and finer granularity than current methods in detecting modules with significant overall survival difference. In addition, the proposed algorithm can identify modules by incorporating prior knowledge. CONCLUSION: In summary, we developed a method to obtain as much as possible information from networks with increased input coverage and the ability to detect more size-balanced and granular modules. In addition, our method can integrate data from different sources. Our proposed method performs better than current methods with complete coverage of input genes and finer granularity. Moreover, this method is designed not only for gene co-expression networks but can also be applied to any general fully connected weighted network.

D-SCRIPT translates genome to phenome with sequence-based, structure-aware, genome-scale predictions of protein-protein interactions.

We combine advances in neural language modeling and structurally motivated design to develop D-SCRIPT, an interpretable and generalizable deep-learning model, which predicts interaction between two proteins using only their sequence and maintains high accuracy with limited training data and across species. We show that a D-SCRIPT model trained on 38,345 human PPIs enables significantly improved functional characterization of fly proteins compared with the state-of-the-art approach. Evaluating the same D-SCRIPT model on protein complexes with known 3D structure, we find that the inter-protein contact map output by D-SCRIPT has significant overlap with the ground truth. We apply D-SCRIPT to screen for PPIs in cow (Bos taurus) at a genome-wide scale and focusing on rumen physiology, identify functional gene modules related to metabolism and immune response. The predicted interactions can then be leveraged for function prediction at scale, addressing the genome-to-phenome challenge, especially in species where little data are available.

TPQCI: A topology potential-based method to quantify functional influence of copy number variations.

Copy number variation (CNV) is a major type of chromosomal structural variation that play important roles in many diseases including cancers. Due to genome instability, a large number of CNV events can be detected in diseases such as cancer. Therefore, it is important to identify the functionally important CNVs in diseases, which currently still poses a challenge in genomics. One of the critical steps to solve the problem is to define the influence of CNV. In this paper, we provide a topology potential based method, TPQCI, to quantify this kind of influence by integrating statistics, gene regulatory associations, and biological function information. We used this metric to detect functionally enriched genes on genomic segments with CNV in breast cancer and multiple myeloma and discovered biological functions influenced by CNV. Our results demonstrate that, by using our proposed TPQCI metric, we can detect disease-specific genes that are influenced by CNVs. Source codes of TPQCI are provided in Github (https://github.com/usos/TPQCI).

Dynamic Analyses of Contagion Risk and Module Evolution on the SSE A-Shares Market Based on Minimum Information Entropy.

The interactive effect is significant in the Chinese stock market, exacerbating the abnormal market volatilities and risk contagion. Based on daily stock returns in the Shanghai Stock Exchange (SSE) A-shares, this paper divides the period between 2005 and 2018 into eight bull and bear market stages to investigate interactive patterns in the Chinese financial market. We employ the Least Absolute Shrinkage and Selection Operator (LASSO) method to construct the stock network, compare the heterogeneity of bull and bear markets, and further use the Map Equation method to analyse the evolution of modules in the SSE A-shares market. Empirical results show that (1) the connected effect is more significant in bear markets than bull markets and gives rise to abnormal volatilities in the stock market; (2) a system module can be found in the network during the first four stages, and the industry aggregation effect leads to module differentiation in the last four stages; (3) some stocks have leading effects on others throughout eight periods, and medium- and small-cap stocks with poor financial conditions are more likely to become risk sources, especially in bear markets. Our conclusions are beneficial to improving investment strategies and making regulatory policies.

Secondary analysis of transcriptomes of SARS-CoV-2 infection models to characterize COVID-19.

Standard transcriptomic analyses alone have limited power in capturing the molecular mechanisms driving disease pathophysiology and outcomes. To overcome this, unsupervised network analyses are used to identify clusters of genes that can be associated with distinct molecular mechanisms and outcomes for a disease. In this study, we developed an integrated network analysis framework that integrates transcriptional signatures from multiple model systems with protein-protein interaction data to find gene modules. Through a meta-analysis of different enriched features from these gene modules, we extract communities of highly interconnected features. These clusters of higher-order features, working as a multifeatured machine, enable collective assessment of their contribution for disease or phenotype characterization. We show the utility of this workflow using transcriptomics data from three different models of SARS-CoV-2 infection and identify several pathways and biological processes that could enable understanding or hypothesizing molecular signatures inducing pathophysiological changes, risks, or sequelae of COVID-19.

A framework for stability-based module detection in correlation graphs.

Graphs can be used to represent the direct and indirect relationships between variables, and elucidate complex relationships and interdependencies. Detecting structure within a graph is a challenging problem. This problem is studied over a range of fields and is sometimes termed community detection, module detection, or graph partitioning. A popular class of algorithms for module detection relies on optimizing a function of modularity to identify the structure. In practice, graphs are often learned from the data, and thus prone to uncertainty. In these settings, the uncertainty of the network structure can become exaggerated by giving unreliable estimates of the module structure. In this work, we begin to address this challenge through the use of a nonparametric bootstrap approach to assessing the stability of module detection in a graph. Estimates of stability are presented at the level of the individual node, the inferred modules, and as an overall measure of performance for module detection in a given graph. Furthermore, bootstrap stability estimates are derived for complexity parameter selection that ultimately defines a graph from data in a way that optimizes stability. This approach is utilized in connection with correlation graphs but is generalizable to other graphs that are defined through the use of dissimilarity measures. We demonstrate our approach using a broad range of simulations and on a metabolomics dataset from the Beijing Olympics Air Pollution study. These approaches are implemented using bootcluster package that is available in the R programming language.

Recommendations for the analysis of gene expression data to identify intrinsic differences between similar tissues.

Identifying genes involved in functional differences between similar tissues from expression profiles is challenging, because the expected differences in expression levels are small. To exemplify this challenge, we studied the expression profiles of two skeletal muscles, deltoid and biceps, in healthy individuals. We provide a series of guides and recommendations for the analysis of this type of studies. These include how to account for batch effects and inter-individual differences to optimize the detection of gene signatures associated with tissue function. We provide guidance on the selection of optimal settings for constructing gene co-expression networks through parameter sweeps of settings and calculation of the overlap with an established knowledge network. Our main recommendation is to use a combination of the data-driven approaches, such as differential gene expression analysis and gene co-expression network analysis, and hypothesis-driven approaches, such as gene set connectivity analysis. Accordingly, we detected differences in metabolic gene expression between deltoid and biceps that were supported by both data- and hypothesis-driven approaches. Finally, we provide a bioinformatic framework that support the biological interpretation of expression profiles from related tissues from this combination of approaches, which is available at github.com/tabbassidaloii/AnalysisFrameworkSimilarTissues.

Refining modules to determine functionally significant clusters in molecular networks.

BACKGROUND: Module detection algorithms relying on modularity maximization suffer from an inherent resolution limit that hinders detection of small topological modules, especially in molecular networks where most biological processes are believed to form small and compact communities. We propose a novel modular refinement approach that helps finding functionally significant modules of molecular networks. RESULTS: The module refinement algorithm improves the quality of topological modules in protein-protein interaction networks by finding biologically functionally significant modules. The algorithm is based on the fact that functional modules in biology do not necessarily represent those corresponding to maximum modularity. Larger modules corresponding to maximal modularity are incrementally re-modularized again under specific constraints so that smaller yet topologically and biologically valid modules are recovered. We show improvement in quality and functional coverage of modules using experiments on synthetic and real protein-protein interaction networks. We also compare our results with six existing methods available for clustering biological networks. CONCLUSION: The proposed algorithm finds smaller but functionally relevant modules that are undetected by classical quality maximization approaches for modular detection. The refinement procedure helps to detect more functionally enriched modules in protein-protein interaction networks, which are also more coherent with functionally characterised gene sets.

Enriching Human Interactome with Functional Mutations to Detect High-Impact Network Modules Underlying Complex Diseases.

Rapid progress in high-throughput -omics technologies moves us one step closer to the datacalypse in life sciences. In spite of the already generated volumes of data, our knowledge of the molecular mechanisms underlying complex genetic diseases remains limited. Increasing evidence shows that biological networks are essential, albeit not sufficient, for the better understanding of these mechanisms. The identification of disease-specific functional modules in the human interactome can provide a more focused insight into the mechanistic nature of the disease. However, carving a disease network module from the whole interactome is a difficult task. In this paper, we propose a computational framework, Discovering most IMpacted SUbnetworks in interactoMe (DIMSUM), which enables the integration of genome-wide association studies (GWAS) and functional effects of mutations into the protein-protein interaction (PPI) network to improve disease module detection. Specifically, our approach incorporates and propagates the functional impact of non-synonymous single nucleotide polymorphisms (nsSNPs) on PPIs to implicate the genes that are most likely influenced by the disruptive mutations, and to identify the module with the greatest functional impact. Comparison against state-of-the-art seed-based module detection methods shows that our approach could yield modules that are biologically more relevant and have stronger association with the studied disease. We expect for our method to become a part of the common toolbox for the disease module analysis, facilitating the discovery of new disease markers.

Analysis of correlation-based biomolecular networks from different omics data by fitting stochastic block models.

Background: Biological entities such as genes, promoters, mRNA, metabolites or proteins do not act alone, but in concert in their network context. Modules, i.e., groups of nodes with similar topological properties in these networks characterize important biological functions of the underlying biomolecular system. Edges in such molecular networks represent regulatory and physical interactions, and comparing them between conditions provides valuable information on differential molecular mechanisms. However, biological data is inherently noisy and network reduction techniques can propagate errors particularly to the level of edges. We aim to improve the analysis of networks of biological molecules by deriving modules together with edge relevance estimations that are based on global network characteristics.  Methods: We propose to fit the networks to stochastic block models (SBM), a method that has not yet been investigated for the analysis of biomolecular networks. This procedure both delivers modules of the networks and enables the derivation of edge confidence scores. We apply it to correlation-based networks of breast cancer data originating from high-throughput measurements of diverse molecular layers such as transcriptomics, proteomics, and metabolomics. The networks were reduced by thresholding for correlation significance or by requirements on scale-freeness.  Results and discussion: We find that the networks are best represented by the hierarchical version of the SBM, and many of the predicted blocks have a biological meaning according to functional annotation. The edge confidence scores are overall in concordance with the biological evidence given by the measurements. As they are based on global network connectivity characteristics and potential hierarchies within the biomolecular networks are taken into account, they could be used as additional, integrated features in network-based data comparisons. Their tight relationship to edge existence probabilities can be exploited to predict missing or spurious edges in order to improve the network representation of the underlying biological system.

A Network Hierarchy-Based method for functional module detection in protein-protein interaction networks.

In the post-genomic era, one of the important tasks is to identify protein complexes and functional modules from high-throughput protein-protein interaction data, so that we can systematically analyze and understand the molecular functions and biological processes of cells. Although a lot of functional module detection studies have been proposed, how to design correctly and efficiently functional modules detection algorithms is still a challenging and important scientific problem in computational biology. In this paper, we present a novel Network Hierarchy-Based method to detect functional modules in PPI networks (named NHB-FMD). NHB-FMD first constructs the hierarchy tree corresponding to the PPI network and then encodes the tree such that genetic algorithm is employed to obtain the hierarchy tree with Maximum Likelihood. After that functional module partitioning is performed based on it and the best partitioning is selected as the result. Experimental results in the real PPI networks have shown that the proposed algorithm not only significantly outperforms the state-of-the-art methods but also can detect protein modules more effectively and accurately.

The Reconstruction and Analysis of Gene Regulatory Networks.

In post-genomic era, an important task is to explore the function of individual biological molecules (i.e., gene, noncoding RNA, protein, metabolite) and their organization in living cells. For this end, gene regulatory networks (GRNs) are constructed to show relationship between biological molecules, in which the vertices of network denote biological molecules and the edges of network present connection between nodes (Strogatz, Nature 410:268-276, 2001; Bray, Science 301:1864-1865, 2003). Biologists can understand not only the function of biological molecules but also the organization of components of living cells through interpreting the GRNs, since a gene regulatory network is a comprehensively physiological map of living cells and reflects influence of genetic and epigenetic factors (Strogatz, Nature 410:268-276, 2001; Bray, Science 301:1864-1865, 2003). In this paper, we will review the inference methods of GRN reconstruction and analysis approaches of network structure. As a powerful tool for studying complex diseases and biological processes, the applications of the network method in pathway analysis and disease gene identification will be introduced.