Disparity-filtered differential correlation network analysis: a case study on CRC metabolomics

Differential network analysis is an important tool to investigate the rewiring of gene interactions under different conditions. Several computational methods have been developed to estimate differential networks from gene expression data, but most of them do not consider that gene network rewiring may be driven by the differential expression of individual genes. New differential network analysis methods that simultaneously take account of the changes in gene interactions and changes in expression levels are needed. : In this article, we propose a differential network analysis method that considers the differential expression of individual genes when identifying differential edges. First, two hypothesis test statistics are used to quantify changes in partial correlations between gene pairs and changes in expression levels for individual genes. Then, an optimization framework is proposed to combine the two test statistics so that the resulting differential network has a hierarchical property, where a differential edge can be considered only if at least one of the two involved genes is differentially expressed. Simulation results indicate that our method outperforms current state-of-the-art methods. We apply our method to identify the differential networks between the luminal A and basal-like subtypes of breast cancer and those between acute myeloid leukemia and normal samples. Hub nodes in the differential networks estimated by our method, including both differentially and nondifferentially expressed genes, have important biological functions. All the datasets underlying this article are publicly available. Processed data and source code can be accessed through the Github repository at https://github.com/Zhangxf-ccnu/chNet. Supplementary data are available at Bioinformatics online.

A growing literature suggests that gene expression can be greatly altered in disease conditions, and identifying those changes will improve the understanding of complex diseases such as cancers or diabetes. A prevailing direction in the analysis of gene expression studies the changes in gene pathways which include sets of related genes. Therefore, introducing structured exploration to differential analysis of gene expression networks may lead to meaningful discoveries. The topic of this paper is differential network analysis, which focuses on capturing the differences between two or more precision matrices. We discuss the connection between the thresholding method and the D-trace loss method on differential network analysis in the case that the precision matrices share the common connected components. Based on this connection, we further propose the cluster D-trace loss method which directly estimates the differential network and achieves model selection consistency. Simulation studies demonstrate its improved performance and computational efficiency. Finally, the usefulness of our proposed estimator is demonstrated by a real-data analysis on non-small cell lung cancer.

The vast majority of primary renal tumors were malignant and had a greater damage to the kidneys. The cause and development of tumor diseases were not only related to a single gene, but also caused by molecular aberrations in a network of complex genes or their generations. In this paper, we used differential network analysis method. The gene chip data of renal tumor related gene from Affymetrix hgu13b was firstly screened to obtain differential expressed genes, and the gene network was constructed separately under disease samples and normal samples. Secondly, the difference between disease network and normal genes was constructed, and the renal tumor related gene was analyzed. In our differential network model, we used a more accurate method than before. What’s more, we used Bayesian information criteria to adjust the parameters, and the gene network under two different conditions was coded as the difference between the precision covariance matrices. More than two hundred pairs of gene pairs were identified from the differential network. Based on the differential network analysis of the central gene, GO enrichment analysis showed that the gene TBX3 had the highest degree of enrichment, indicating that it may be related to the formation of renal tumors. In the KEGG pathway enrichment analysis, it was found that p<0.05 was mainly enriched as a chemokine pathway, and chemokines had an important influence on the occurrence, metastasis and treatment of renal tumors.

Background The rewiring of molecular interactions in various conditions leads to distinct phenotypic outcomes. Differential network analysis (DINA) is dedicated to exploring these rewirings within gene and protein networks. Leveraging statistical learning and graph theory, DINA algorithms scrutinize alterations in interaction patterns derived from experimental data.Results Introducing a novel approach to differential network analysis, we incorporate differential gene expression based on sex and gender attributes. We hypothesize that gene expression can be accurately represented through non-Gaussian processes. Our methodology involves quantifying changes in non-parametric correlations among gene pairs and expression levels of individual genes.ConclusionsApplying our method to public expression datasets concerning diabetes mellitus and atherosclerosis in liver tissue, we identify gender-specific differential networks. Results underscore the biological relevance of our approach in uncovering meaningful molecular distinctions.

BackgroundRecently, erdafitinib (Balversa), the first targeted therapy drug for genetic alteration, was approved to metastatic urothelial carcinoma. Cancer genomics research has been greatly encouraged. Currently, a large number of gene regulatory networks between different states have been constructed, which can reveal the difference states of genes. However, they have not been applied to the subtypes of Muscle-invasive bladder cancer (MIBC).ResultsIn this paper, we propose a method that construct gene regulatory networks under different molecular subtypes of MIBC, and analyse the regulatory differences between different molecular subtypes. Through differential expression analysis and the differential network analysis of the top 100 differential genes in the network, we find that SERPINI1, NOTUM, FGFR1 and other genes have significant differences in expression and regulatory relationship between MIBC subtypes.ConclusionsFurthermore, pathway enrichment analysis and differential network analysis demonstrate that Neuroactive ligand-receptor interaction and Cytokine-cytokine receptor interaction are significantly enriched pathways, and the genes contained in them are significant diversity in the subtypes of bladder cancer.

Differential network analysis investigates how the network of connected genes changes from one condition to another and has become a prevalent tool to provide a deeper and more comprehensive understanding of the molecular etiology of complex diseases. Based on the asymptotically normal estimation of large Gaussian graphical model (GGM) in the high-dimensional setting, we developed a computationally efficient test for differential network analysis through testing the equality of two precision matrices, which summarize the conditional dependence network structures of the genes. Additionally, we applied a multiple testing procedure to infer the differential network structure with false discovery rate (FDR) control. Through extensive simulation studies with different combinations of parameters including sample size, number of vertices, level of heterogeneity and graph structure, we demonstrated that our method performed much better than the current available methods in terms of accuracy and computational time. In real data analysis on lung adenocarcinoma, we revealed a differential network with 3503 nodes and 2550 edges, which consisted of 50 clusters with an FDR threshold at 0.05. Many of the top gene pairs in the differential network have been reported relevant to human cancers. Our method represents a powerful tool of network analysis for high-dimensional biological data.

BackgroundThe recent emergence of COVID-19, rapid worldwide spread, and incomplete knowledge of molecular mechanisms underlying SARS-CoV-2 infection have limited development of therapeutic strategies. Our objective was to systematically investigate molecular regulatory mechanisms of COVID-19, using a combination of high throughput RNA-sequencing-based transcriptomics and systems biology approaches.MethodsRNA-Seq data from peripheral blood mononuclear cells (PBMCs) of healthy persons, mild and severe 17 COVID-19 patients were analyzed to generate a gene expression matrix. Weighted gene co-expression network analysis (WGCNA) was used to identify co-expression modules in healthy samples as a reference set. For differential co-expression network analysis, module preservation and module-trait relationships approaches were used to identify key modules. Then, protein-protein interaction (PPI) networks, based on co-expressed hub genes, were constructed to identify hub genes/TFs with the highest information transfer (hub-high traffic genes) within candidate modules.ResultsBased on differential co-expression network analysis, connectivity patterns and network density, 72% (15 of 21) of modules identified in healthy samples were altered by SARS-CoV-2 infection. Therefore, SARS-CoV-2 caused systemic perturbations in host biological gene networks. In functional enrichment analysis, among 15 non-preserved modules and two significant highly-correlated modules (identified by MTRs), 9 modules were directly related to the host immune response and COVID-19 immunopathogenesis. Intriguingly, systemic investigation of SARS-CoV-2 infection identified signaling pathways and key genes/proteins associated with COVID-19’s main hallmarks, e.g., cytokine storm, respiratory distress syndrome (ARDS), acute lung injury (ALI), lymphopenia, coagulation disorders, thrombosis, and pregnancy complications, as well as comorbidities associated with COVID-19, e.g., asthma, diabetic complications, cardiovascular diseases (CVDs), liver disorders and acute kidney injury (AKI). Topological analysis with betweenness centrality (BC) identified 290 hub-high traffic genes, central in both co-expression and PPI networks. We also identified several transcriptional regulatory factors, including NFKB1, HIF1A, AHR, and TP53, with important immunoregulatory roles in SARS-CoV-2 infection. Moreover, several hub-high traffic genes, including IL6, IL1B, IL10, TNF, SOCS1, SOCS3, ICAM1, PTEN, RHOA, GDI2, SUMO1, CASP1, IRAK3, HSPA5, ADRB2, PRF1, GZMB, OASL, CCL5, HSP90AA1, HSPD1, IFNG, MAPK1, RAB5A, and TNFRSF1A had the highest rates of information transfer in 9 candidate modules and central roles in COVID-19 immunopathogenesis.ConclusionThis study provides comprehensive information on molecular mechanisms of SARS-CoV-2-host interactions and identifies several hub-high traffic genes as promising therapeutic targets for the COVID-19 pandemic.

The complexity of cancer diseases demands bioinformatic techniques and translational research based on big data and personalized medicine. Open data enables researchers to accelerate cancer studies, save resources and foster collaboration. Several tools and programming approaches are available for analyzing data, including annotation, clustering, comparison and extrapolation, merging, enrichment, functional association and statistics. We exploit openly available data via cancer gene expression analysis, we apply refinement as well as enrichment analysis via gene ontology and conclude with graph-based visualization of involved protein interaction networks as a basis for signaling. The different databases allowed for the construction of huge networks or specified ones consisting of high-confidence interactions only. Several genes associated to glioma were isolated via a network analysis from top hub nodes as well as from an outlier analysis. The latter approach highlights a mitogen-activated protein kinase next to a member of histondeacetylases and a protein phosphatase as genes uncommonly associated with glioma. Cluster analysis from top hub nodes lists several identified glioma-associated gene products to function within protein complexes, including epidermal growth factors as well as cell cycle proteins or RAS proto-oncogenes. By using selected exemplary tools and open-access resources for cancer research and differential network analysis, we highlight disturbed signaling components in brain cancer subtypes of glioma.

Colon cancer has been well studied using a variety of molecular techniques, including whole genome sequencing. However, genetic markers that could be used to predict lymph node (LN) involvement, which is the most important prognostic factor for colon cancer, have not been identified. In the present study, we compared LN(+) and LN(−) colon cancer patients using differential gene expression and network analysis. Colon cancer gene expression data were obtained from the Cancer Genome Atlas and divided into two groups, LN(+) and LN(−). Gene expression networks were constructed using LASSO (Least Absolute Shrinkage and Selection Operator) regression. We identified hub genes, such as APBB1, AHSA2, ZNF767, and JAK2, that were highly differentially expressed. Survival analysis using selected hub genes, such as AHSA2, CDK10, and CWC22, showed that their expression levels were significantly associated with the survival rate of colon cancer patients, which indicates their possible use as prognostic markers. In addition, protein-protein interaction network, GO enrichment, and KEGG pathway analysis were performed with selected hub genes from each group to investigate the regulatory relationships between hub genes and LN involvement in colon cancer; these analyses revealed differences between the LN(−) and LN(+) groups. Our network analysis may help narrow down the search for novel candidate genes for the treatment of colon cancer, in addition to improving our understanding of the biological processes underlying LN involvement. All R implementation codes are available at journal website as Supplementary Materials.

BackgroundGenes might have different gene interactions in different cell conditions, which might be mapped into different networks. Differential analysis of gene networks allows spotting condition-specific interactions that, for instance, form disease networks if the conditions are a disease, such as cancer, and normal. This could potentially allow developing better and subtly targeted drugs to cure cancer. Differential network analysis with direct physical gene interactions needs to be explored in this endeavour.ResultsC3NET is a recently introduced information theory based gene network inference algorithm that infers direct physical gene interactions from expression data, which was shown to give consistently higher inference performances over various networks than its competitors. In this paper, we present, DC3net, an approach to employ C3NET in inferring disease networks. We apply DC3net on a synthetic and real prostate cancer datasets, which show promising results. With loose cutoffs, we predicted 18583 interactions from tumor and normal samples in total. Although there are no reference interactions databases for the specific conditions of our samples in the literature, we found verifications for 54 of our predicted direct physical interactions from only four of the biological interaction databases. As an example, we predicted that RAD50 with TRF2 have prostate cancer specific interaction that turned out to be having validation from the literature. It is known that RAD50 complex associates with TRF2 in the S phase of cell cycle, which suggests that this predicted interaction may promote telomere maintenance in tumor cells in order to allow tumor cells to divide indefinitely. Our enrichment analysis suggests that the identified tumor specific gene interactions may be potentially important in driving the growth in prostate cancer. Additionally, we found that the highest connected subnetwork of our predicted tumor specific network is enriched for all proliferation genes, which further suggests that the genes in this network may serve in the process of oncogenesis.ConclusionsOur approach reveals disease specific interactions. It may help to make experimental follow-up studies more cost and time efficient by prioritizing disease relevant parts of the global gene network.

The stomach is inhabited by diverse microbial communities, co-existing in a dynamic balance. Long-term use of drugs such as proton pump inhibitors (PPIs), or bacterial infection such as Helicobacter pylori, cause significant microbial alterations. Yet, studies revealing how the commensal bacteria re-organize, due to these perturbations of the gastric environment, are in early phase and rely principally on linear techniques for multivariate analysis. Here we disclose the importance of complementing linear dimensionality reduction techniques with nonlinear ones to unveil hidden patterns that remain unseen by linear embedding. Then, we prove the advantages to complete multivariate pattern analysis with differential network analysis, to reveal mechanisms of bacterial network re-organizations which emerge from perturbations induced by a medical treatment (PPIs) or an infectious state (H. pylori). Finally, we show how to build bacteria-metabolite multilayer networks that can deepen our understanding of the metabolite pathways significantly associated to the perturbed microbial communities.

SummaryThe package implements a novel functionality for “multivariable” differential co-abundance network (DN, hereafter) analyses of microbiome data. It incorporates a regression approach that adjusts for additional covariates for DN analyses. This distinguishes from previous prominent approaches in DN analyses such as and which do not feature a covariate adjustment of finding taxa that are differentially connected (DC, hereafter) between individuals with different clinical and phenotypic characteristics.Availability and implementation with a vignette is available on CRAN repository https://CRAN.R-project.org/package=SOHPIE and published under General Public License (GPL) version 3 license.

Non-functioning pituitary adenomas (NFPAs) are tumors with clinically challenging features since they have insidious progression. A complex network of gene interactions is thought to have roles in tumor formation and progression. Therefore, revealing the genetic network behind NFPA tumorigenesis is not only essential to attain further knowledge of tumor biology, but also plays a fundamental role in the development of efficacious treatment strategies. Differential co-expression network analysis is an outstanding approach for elucidation of groups of genes which show distinct co-expression patterns among phenotypes. In this study, we carried out a differential co-expression network analysis of NFPA-associated transcriptome dataset (n = 40) considering invasive (n = 22) and non-invasive (n = 18) phenotypes. Furthermore, we identified differentially co-expressed and co-regulated mRNA modules, which might be considered as potential systems biomarkers for NFPA prognosis and invasiveness. As a result, we have identified a novel 13-gene module, including CEACAM6, CYP4B1, EIF2S2, HID1, IFFO1, MYO18A, PDCD2, SGIP1, SWSAP1, and four unknown genes (A_24_P127621, A_24_P255786, A_24_P683553, and A_24_P916979), which was able to categorize the patients into two groups as invasive and non-invasive NFPA with distinct prognosis. The prognostic core module genes were associated with progression and prognosis of brain and glandular based cancers as well. Furthermore, these module genes were also expressed in blood, salivary gland, and spinal cord tissues. These results may provide the evidence on featured gene module which might play a prominent role in NFPA prognosis and sub-typing as effective biomarkers and therapeutic targets in the future.

Atypical frontotemporal lobar degeneration with ubiquitin-positive inclusions (aFTLD-U) is a rare cause of frontotemporal lobar degeneration (FTLD), characterized postmortem by neuronal inclusions of the FET family of proteins (FTLD-FET). The recent discovery of TAF15 amyloid filaments in aFTLD-U brains represents a significant step toward improved diagnostic and therapeutic strategies. However, our understanding of the etiology of this FTLD subtype remains limited, which severely hampers translational research efforts. To explore the transcriptomic changes in aFTLD-U, we performed bulk RNA sequencing on the frontal cortex tissue of 21 aFTLD-U patients and 20 control individuals. Cell-type deconvolution revealed loss of excitatory neurons and a higher proportion of astrocytes in aFTLD-U relative to controls. Differential gene expression and co-expression network analysis, adjusted for the shift in cell-type proportions, showed dysregulation of mitochondrial pathways, transcriptional regulators, and upregulation of the Sonic hedgehog (Shh) pathway, including the GLI1 transcription factor, in aFTLD-U. Overall, oligodendrocyte and astrocyte-enriched genes were significantly over-represented among the differentially expressed genes. Differential splicing analysis confirmed the dysregulation of non-neuronal cell types with significant splicing alterations, particularly in oligodendrocyte-enriched genes, including myelin basic protein (MBP), a crucial component of myelin. Immunohistochemistry in frontal cortex brain tissue also showed reduced myelin levels in aFTLD-U patients compared to controls. Together, these findings highlight a central role for glial cells, particularly astrocytes and oligodendrocytes, in the pathogenesis of aFTLD-U, with disruptions in mitochondrial activity, RNA metabolism, Shh signaling, and myelination as possible disease mechanisms. This study offers the first transcriptomic insight into aFTLD-U and presents new avenues for research into FTLD-FET.Supplementary InformationThe online version contains supplementary material available at 10.1007/s00401-025-02919-x.

Developing improved approaches for diagnosis, treatment, and prevention of diseases is a major goal of biomedical research. Therefore, the discovery of biomarker signatures from high-throughput "omics" data is an active research topic in the field of bioinformatics and systems medicine. A major issue is the low reproducibility and the limited biological interpretability of candidate biomarker signatures identified from high-throughput data. This impedes the use of discovered biomarker signatures into clinical applications. Currently, much focus is placed on developing strategies to improve reproducibility and interpretability. Researchers have fruitfully started to incorporate prior knowledge derived from pathways and molecular networks into the process of biomarker identification. In this chapter, after giving a general introduction to the problem of disease classification and biomarker discovery, we will review two types of network-assisted approaches: (1) approaches inferring activity scores for specific pathways which are subsequently used for classification and (2) approaches identifying subnetworks or modules of molecular networks by differential network analysis which can serve as biomarker signatures.