Dataset Information

Integrative enrichment analysis: a new computational method to detect dysregulated pathways in heterogeneous samples.

ABSTRACT: Pathway enrichment analysis is a useful tool to study biology and biomedicine, due to its functional screening on well-defined biological procedures rather than separate molecules. The measurement of malfunctions of pathways with a phenotype change, e.g., from normal to diseased, is the key issue when applying enrichment analysis on a pathway. The differentially expressed genes (DEGs) are widely focused in conventional analysis, which is based on the great purity of samples. However, the disease samples are usually heterogeneous, so that, the genes with great differential expression variance (DEVGs) are becoming attractive and important to indicate the specific state of a biological system. In the context of differential expression variance, it is still a challenge to measure the enrichment or status of a pathway. To address this issue, we proposed Integrative Enrichment Analysis (IEA) based on a novel enrichment measurement.The main competitive ability of IEA is to identify dysregulated pathways containing DEGs and DEVGs simultaneously, which are usually under-scored by other methods. Next, IEA provides two additional assistant approaches to investigate such dysregulated pathways. One is to infer the association among identified dysregulated pathways and expected target pathways by estimating pathway crosstalks. The other one is to recognize subtype-factors as dysregulated pathways associated to particular clinical indices according to the DEVGs' relative expressions rather than conventional raw expressions. Based on a previously established evaluation scheme, we found that, in particular cohorts (i.e., a group of real gene expression datasets from human patients), a few target disease pathways can be significantly high-ranked by IEA, which is more effective than other state-of-the-art methods. Furthermore, we present a proof-of-concept study on Diabetes to indicate: IEA rather than conventional ORA or GSEA can capture the under-estimated dysregulated pathways full of DEVGs and DEGs; these newly identified pathways could be significantly linked to prior-known disease pathways by estimated crosstalks; and many candidate subtype-factors recognized by IEA also have significant relation with the risk of subtypes of genotype-phenotype associations.Totally, IEA supplies a new tool to carry on enrichment analysis in the complicate context of clinical application (i.e., heterogeneity of disease), as a necessary complementary and cooperative approach to conventional ones.

SUBMITTER: Yu X

PROVIDER: S-EPMC4641376 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Integrative enrichment analysis: a new computational method to detect dysregulated pathways in heterogeneous samples.

Yu Xiangtian X Zeng Tao T Li Guojun G

BMC genomics 20151110

<h4>Background</h4>Pathway enrichment analysis is a useful tool to study biology and biomedicine, due to its functional screening on well-defined biological procedures rather than separate molecules. The measurement of malfunctions of pathways with a phenotype change, e.g., from normal to diseased, is the key issue when applying enrichment analysis on a pathway. The differentially expressed genes (DEGs) are widely focused in conventional analysis, which is based on the great purity of samples. H ...[more]

PMID: 26556243

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Project description:BACKGROUND: Although there are a lot of researches focusing on cancer prognosis or prediction of cancer metastases, it is still a big challenge to predict the risks of cancer metastasizing to a specific organ such as bone. In fact, little work has been published for such a purpose nowadays. METHODS: In this work, we propose a Dysregulated Pathway Based prediction Model (DPBM) built on a merged data set with 855 samples. First, we use bootstrapping strategy to select bone metastasis related genes. Based on the selected genes, we then detect out the dysregulated pathways involved in the process of bone metastasis via enrichment analysis. And then we use the discriminative genes in each dysregulated pathway, called as dysregulated genes, to construct a sub-model to forecast the risk of bone metastasis. Finally we combine all sub-models as an ensemble model (DPBM) to predict the risk of bone metastasis. RESULTS: We have validated DPBM on the training, test and independent sets separately, and the results show that DPBM can significantly distinguish the bone metastases risks of patients (with p-values of 3.82E-10, 0.00007 and 0.0003 on three sets respectively). Moreover, the dysregulated genes are generally with higher topological coefficients (degree and betweenness centrality) in the PPI network, which means that they may play critical roles in the biological functions. Further functional analysis of these genes demonstrates that the immune system seems to play an important role in bone-specific metastasis of breast cancer. CONCLUSIONS: Each of the dysregulated pathways that are enriched with bone metastasis related genes may uncover one critical aspect of influencing the bone metastasis of breast cancer, thus the ensemble strategy can help to describe the comprehensive view of bone metastasis mechanism. Therefore, the constructed DPBM is robust and able to significantly distinguish the bone metastases risks of patients in both test set and independent set. Moreover, the dysregulated genes in the dysregulated pathways tend to play critical roles in the biological process of bone metastasis of breast cancer.

Project description:Complex diseases such as cancer are usually the result of a combination of environmental factors and one or several biological pathways consisting of sets of genes. Each biological pathway exerts its function by delivering signaling through the gene network. Theoretically, a pathway is supposed to have a robust topological structure under normal physiological conditions. However, the pathway's topological structure could be altered under some pathological condition. It is well known that a normal biological network includes a small number of well-connected hub nodes and a large number of nodes that are non-hubs. In addition, it is reported that the loss of connectivity is a common topological trait of cancer networks, which is an assumption of our method. Hence, from normal to cancer, the process of the network losing connectivity might be the process of disrupting the structure of the network, namely, the number of hub genes might be altered in cancer compared to that in normal or the distribution of topological ranks of genes might be altered. Based on this, we propose a new PageRank-based method called Pathways of Topological Rank Analysis (PoTRA) to detect pathways involved in cancer. We use PageRank to measure the relative topological ranks of genes in each biological pathway, then select hub genes for each pathway, and use Fisher's exact test to test if the number of hub genes in each pathway is altered from normal to cancer. Alternatively, if the distribution of topological ranks of gene in a pathway is altered between normal and cancer, this pathway might also be involved in cancer. Hence, we use the Kolmogorov-Smirnov test to detect pathways that have an altered distribution of topological ranks of genes between two phenotypes. We apply PoTRA to study hepatocellular carcinoma (HCC) and several subtypes of HCC. Very interestingly, we discover that all significant pathways in HCC are cancer-associated generally, while several significant pathways in subtypes of HCC are HCC subtype-associated specifically. In conclusion, PoTRA is a new approach to explore and discover pathways involved in cancer. PoTRA can be used as a complement to other existing methods to broaden our understanding of the biological mechanisms behind cancer at the system-level.

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Integrative enrichment analysis: a new computational method to detect dysregulated pathways in heterogeneous samples.

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Integrative enrichment analysis: a new computational method to detect dysregulated pathways in heterogeneous samples.

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