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Bioinformatics Prediction for Network-Based Integrative Multi-Omics Expression Data Analysis in Hirschsprung Disease.

ABSTRACT: Hirschsprung's disease (HSCR) is a rare developmental disorder in which enteric ganglia are missing along a portion of the intestine. HSCR has a complex inheritance, with RET as the major disease-causing gene. However, the pathogenesis of HSCR is still not completely understood. Therefore, we applied a computational approach based on multi-omics network characterization and clustering analysis for HSCR-related gene/miRNA identification and biomarker discovery. Protein-protein interaction (PPI) and miRNA-target interaction (MTI) networks were analyzed by DPClusO and BiClusO, respectively, and finally, the biomarker potential of miRNAs was computationally screened by miRNA-BD. In this study, a total of 55 significant gene-disease modules were identified, allowing us to propose 178 new HSCR candidate genes and two biological pathways. Moreover, we identified 12 key miRNAs with biomarker potential among 137 predicted HSCR-associated miRNAs. Functional analysis of new candidates showed that enrichment terms related to gene ontology (GO) and pathways were associated with HSCR. In conclusion, this approach has allowed us to decipher new clues of the etiopathogenesis of HSCR, although molecular experiments are further needed for clinical validations.

SUBMITTER: Lucena-Padros H

PROVIDER: S-EPMC10886964 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature

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Bioinformatics Prediction for Network-Based Integrative Multi-Omics Expression Data Analysis in Hirschsprung Disease.

Lucena-Padros Helena H Bravo-Gil Nereida N Tous Cristina C Rojano Elena E Seoane-Zonjic Pedro P Fernández Raquel María RM Ranea Juan A G JAG Antiñolo Guillermo G Borrego Salud S

Biomolecules 20240130 2

Hirschsprung's disease (HSCR) is a rare developmental disorder in which enteric ganglia are missing along a portion of the intestine. HSCR has a complex inheritance, with <i>RET</i> as the major disease-causing gene. However, the pathogenesis of HSCR is still not completely understood. Therefore, we applied a computational approach based on multi-omics network characterization and clustering analysis for HSCR-related gene/miRNA identification and biomarker discovery. Protein-protein interaction ...[more]

PMID: 38397401

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Project description:BackgroundCOVID-19 disease is characterized by a spectrum of disease phases (mild, moderate, and severe). Each disease phase is marked by changes in omics profiles with corresponding changes in the expression of features (biosignatures). However, integrative analysis of multiple omics data from different experiments across studies to investigate biosignatures at various disease phases is limited. Exploring an integrative multi-omics profile analysis through a network approach could be used to determine biosignatures associated with specific disease phases and enable the examination of the relationships between the biosignatures.AimTo identify and characterize biosignatures underlying various COVID-19 disease phases in an integrative multi-omics data analysis.MethodWe leveraged a multi-omics network-based approach to integrate transcriptomics, metabolomics, proteomics, and lipidomics data. The World Health Organization Ordinal Scale WHO Ordinal Scale was used as a disease severity reference to harmonize COVID-19 patient metadata across two studies with independent data. A unified COVID-19 knowledge graph was constructed by assembling a disease-specific interactome from the literature and databases. Disease-state specific omics-graphs were constructed by integrating multi-omics data with the unified COVID-19 knowledge graph. We expanded on the network layers of multiXrank, a random walk with restart on multilayer network algorithm, to explore disease state omics-specific graphs and perform enrichment analysis.ResultsNetwork analysis revealed the biosignatures involved in inducing chemokines and inflammatory responses as hubs in the severe and moderate disease phases. We observed distinct biosignatures between severe and moderate disease phases as compared to mild-moderate and mild-severe disease phases. Mild COVID-19 cases were characterized by a unique biosignature comprising C-C Motif Chemokine Ligand 4 (CCL4), and Interferon Regulatory Factor 1 (IRF1). Hepatocyte Growth Factor (HGF), Matrix Metallopeptidase 12 (MMP12), Interleukin 10 (IL10), Nuclear Factor Kappa B Subunit 1 (NFKB1), and suberoylcarnitine form hubs in the omics network that characterizes the moderate disease state. The severe cases were marked by biosignatures such as Signal Transducer and Activator of Transcription 1 (STAT1), Superoxide Dismutase 2 (SOD2), HGF, taurine, lysophosphatidylcholine, diacylglycerol, triglycerides, and sphingomyelin that characterize the disease state.ConclusionThis study identified both biosignatures of different omics types enriched in disease-related pathways and their associated interactions (such as protein-protein, protein-transcript, protein-metabolite, transcript-metabolite, and lipid-lipid interactions) that are unique to mild, moderate, and severe COVID-19 disease states. These biosignatures include molecular features that underlie the observed clinical heterogeneity of COVID-19 and emphasize the need for disease-phase-specific treatment strategies. The approach implemented here can be used to find associations between transcripts, proteins, lipids, and metabolites in other diseases.

Project description:Recent technological advances and international efforts, such as The Cancer Genome Atlas (TCGA), have made available several pan-cancer datasets encompassing multiple omics layers with detailed clinical information in large collection of samples. The need has thus arisen for the development of computational methods aimed at improving cancer subtyping and biomarker identification from multi-modal data. Here we apply the Integrative Network Fusion (INF) pipeline, which combines multiple omics layers exploiting Similarity Network Fusion (SNF) within a machine learning predictive framework. INF includes a feature ranking scheme (rSNF) on SNF-integrated features, used by a classifier over juxtaposed multi-omics features (juXT). In particular, we show instances of INF implementing Random Forest (RF) and linear Support Vector Machine (LSVM) as the classifier, and two baseline RF and LSVM models are also trained on juXT. A compact RF model, called rSNFi, trained on the intersection of top-ranked biomarkers from the two approaches juXT and rSNF is finally derived. All the classifiers are run in a 10x5-fold cross-validation schema to warrant reproducibility, following the guidelines for an unbiased Data Analysis Plan by the US FDA-led initiatives MAQC/SEQC. INF is demonstrated on four classification tasks on three multi-modal TCGA oncogenomics datasets. Gene expression, protein expression and copy number variants are used to predict estrogen receptor status (BRCA-ER, N = 381) and breast invasive carcinoma subtypes (BRCA-subtypes, N = 305), while gene expression, miRNA expression and methylation data is used as predictor layers for acute myeloid leukemia and renal clear cell carcinoma survival (AML-OS, N = 157; KIRC-OS, N = 181). In test, INF achieved similar Matthews Correlation Coefficient (MCC) values and 97% to 83% smaller feature sizes (FS), compared with juXT for BRCA-ER (MCC: 0.83 vs. 0.80; FS: 56 vs. 1801) and BRCA-subtypes (0.84 vs. 0.80; 302 vs. 1801), improving KIRC-OS performance (0.38 vs. 0.31; 111 vs. 2319). INF predictions are generally more accurate in test than one-dimensional omics models, with smaller signatures too, where transcriptomics consistently play the leading role. Overall, the INF framework effectively integrates multiple data levels in oncogenomics classification tasks, improving over the performance of single layers alone and naive juxtaposition, and provides compact signature sizes.

Dataset Information

Bioinformatics Prediction for Network-Based Integrative Multi-Omics Expression Data Analysis in Hirschsprung Disease.

Publications

Bioinformatics Prediction for Network-Based Integrative Multi-Omics Expression Data Analysis in Hirschsprung Disease.

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