Dataset Information

CTpathway: a CrossTalk-based pathway enrichment analysis method for cancer research.

ABSTRACT:

Background

Pathway enrichment analysis (PEA) is a common method for exploring functions of hundreds of genes and identifying disease-risk pathways. Moreover, different pathways exert their functions through crosstalk. However, existing PEA methods do not sufficiently integrate essential pathway features, including pathway crosstalk, molecular interactions, and network topologies, resulting in many risk pathways that remain uninvestigated.

Methods

To overcome these limitations, we develop a new crosstalk-based PEA method, CTpathway, based on a global pathway crosstalk map (GPCM) with >440,000 edges by combing pathways from eight resources, transcription factor-gene regulations, and large-scale protein-protein interactions. Integrating gene differential expression and crosstalk effects in GPCM, we assign a risk score to genes in the GPCM and identify risk pathways enriched with the risk genes.

Results

Analysis of >8300 expression profiles covering ten cancer tissues and blood samples indicates that CTpathway outperforms the current state-of-the-art methods in identifying risk pathways with higher accuracy, reproducibility, and speed. CTpathway recapitulates known risk pathways and exclusively identifies several previously unreported critical pathways for individual cancer types. CTpathway also outperforms other methods in identifying risk pathways across all cancer stages, including early-stage cancer with a small number of differentially expressed genes. Moreover, the robust design of CTpathway enables researchers to analyze both bulk and single-cell RNA-seq profiles to predict both cancer tissue and cell type-specific risk pathways with higher accuracy.

Conclusions

Collectively, CTpathway is a fast, accurate, and stable pathway enrichment analysis method for cancer research that can be used to identify cancer risk pathways. The CTpathway interactive web server can be accessed here http://www.jianglab.cn/CTpathway/ . The stand-alone program can be accessed here https://github.com/Bioccjw/CTpathway .

SUBMITTER: Liu H

PROVIDER: S-EPMC9563764 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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Publications

CTpathway: a CrossTalk-based pathway enrichment analysis method for cancer research.

Liu Haizhou H Yuan Mengqin M Mitra Ramkrishna R Zhou Xu X Long Min M Lei Wanyue W Zhou Shunheng S Huang Yu-E YE Hou Fei F Eischen Christine M CM Jiang Wei W

Genome medicine 20221013 1

<h4>Background</h4>Pathway enrichment analysis (PEA) is a common method for exploring functions of hundreds of genes and identifying disease-risk pathways. Moreover, different pathways exert their functions through crosstalk. However, existing PEA methods do not sufficiently integrate essential pathway features, including pathway crosstalk, molecular interactions, and network topologies, resulting in many risk pathways that remain uninvestigated.<h4>Methods</h4>To overcome these limitations, we ...[more]

PMID: 36229842

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Project description:BackgroundPathway enrichment analysis is extensively used in high-throughput experimental studies to gain insight into the functional roles of pre-defined subsets of genes, proteins and metabolites. Methods that leverages information on the topology of the underlying pathways outperform simpler methods that only consider pathway membership, leading to improved performance. Among all the proposed software tools, there's the need to combine high statistical power together with a user-friendly framework, making it difficult to choose the best method for a particular experimental environment.ResultsWe propose SEMgsa, a topology-based algorithm developed into the framework of structural equation models. SEMgsa combine the SEM p values regarding node-specific group effect estimates in terms of activation or inhibition, after statistically controlling biological relations among genes within pathways. We used SEMgsa to identify biologically relevant results in a Coronavirus disease (COVID-19) RNA-seq dataset (GEO accession: GSE172114) together with a frontotemporal dementia (FTD) DNA methylation dataset (GEO accession: GSE53740) and compared its performance with some existing methods. SEMgsa is highly sensitive to the pathways designed for the specific disease, showing low p values ([Formula: see text]) and ranking in high positions, outperforming existing software tools. Three pathway dysregulation mechanisms were used to generate simulated expression data and evaluate the performance of methods in terms of type I error followed by their statistical power. Simulation results confirm best overall performance of SEMgsa.ConclusionsSEMgsa is a novel yet powerful method for identifying enrichment with regard to gene expression data. It takes into account topological information and exploits pathway perturbation statistics to reveal biological information. SEMgsa is implemented in the R package SEMgraph, easily available at https://CRAN.R-project.org/package=SEMgraph .

Project description:BackgroundPathway enrichment extensively used in the analysis of Omics data for gaining biological insights into the functional roles of pre-defined subsets of genes, proteins and metabolites. A large number of methods have been proposed in the literature for this task. The vast majority of these methods use as input expression levels of the biomolecules under study together with their membership in pathways of interest. The latest generation of pathway enrichment methods also leverages information on the topology of the underlying pathways, which as evidence from their evaluation reveals, lead to improved sensitivity and specificity. Nevertheless, a systematic empirical comparison of such methods is still lacking, making selection of the most suitable method for a specific experimental setting challenging. This comparative study of nine network-based methods for pathway enrichment analysis aims to provide a systematic evaluation of their performance based on three real data sets with different number of features (genes/metabolites) and number of samples.ResultsThe findings highlight both methodological and empirical differences across the nine methods. In particular, certain methods assess pathway enrichment due to differences both across expression levels and in the strength of the interconnectedness of the members of the pathway, while others only leverage differential expression levels. In the more challenging setting involving a metabolomics data set, the results show that methods that utilize both pieces of information (with NetGSA being a prototypical one) exhibit superior statistical power in detecting pathway enrichment.ConclusionThe analysis reveals that a number of methods perform equally well when testing large size pathways, which is the case with genomic data. On the other hand, NetGSA that takes into consideration both differential expression of the biomolecules in the pathway, as well as changes in the topology exhibits a superior performance when testing small size pathways, which is usually the case for metabolomics data.

Dataset Information

CTpathway: a CrossTalk-based pathway enrichment analysis method for cancer research.

Background

Methods

Results

Conclusions

Publications

CTpathway: a CrossTalk-based pathway enrichment analysis method for cancer research.

Similar Datasets

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