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Detection for disease tipping points by landscape dynamic network biomarkers.

ABSTRACT: A new model-free method has been developed and termed the landscape dynamic network biomarker (l-DNB) methodology. The method is based on bifurcation theory, which can identify tipping points prior to serious disease deterioration using only single-sample omics data. Here, we show that l-DNB provides early-warning signals of disease deterioration on a single-sample basis and also detects critical genes or network biomarkers (i.e. DNB members) that promote the transition from normal to disease states. As a case study, l-DNB was used to predict severe influenza symptoms prior to the actual symptomatic appearance in influenza virus infections. The l-DNB approach was then also applied to three tumor disease datasets from the TCGA and was used to detect critical stages prior to tumor deterioration using an individual DNB for each patient. The individual DNBs were further used as individual biomarkers in the analysis of physiological data, which led to the identification of two biomarker types that were surprisingly effective in predicting the prognosis of tumors. The biomarkers can be considered as common biomarkers for cancer, wherein one indicates a poor prognosis and the other indicates a good prognosis.

SUBMITTER: Liu X

PROVIDER: S-EPMC8291500 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Detection for disease tipping points by landscape dynamic network biomarkers.

Liu Xiaoping X Chang Xiao X Leng Siyang S Tang Hui H Aihara Kazuyuki K Chen Luonan L

National science review 20181228 4

A new model-free method has been developed and termed the landscape dynamic network biomarker (<i>l</i>-DNB) methodology. The method is based on bifurcation theory, which can identify tipping points prior to serious disease deterioration using only single-sample omics data. Here, we show that <i>l</i>-DNB provides early-warning signals of disease deterioration on a single-sample basis and also detects critical genes or network biomarkers (i.e. DNB members) that promote the transition from normal ...[more]

PMID: 34691933

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Project description:Hepatocellular carcinoma (HCC) is a complex disease with a multi-step carcinogenic process from preneoplastic lesions, including cirrhosis, low-grade dysplastic nodules (LGDNs), and high-grade dysplastic nodules (HGDNs) to HCC. There is only an elemental understanding of its molecular pathogenesis, for which a key problem is to identify when and how the critical transition happens during the HCC initiation period at a molecular level. In this work, for the first time, we revealed that LGDNs is the tipping point (i.e., pre-HCC state rather than HCC state) of hepatocarcinogenesis based on a series of gene expression profiles by a new mathematical model termed dynamic network biomarkers (DNB)-a group of dominant genes or molecules for the transition. Different from the conventional biomarkers based on the differential expressions of the observed genes (or molecules) for diagnosing a disease state, the DNB model exploits collective fluctuations and correlations of the observed genes, thereby predicting the imminent disease state or diagnosing the critical state. Our results show that DNB composed of 59 genes signals the tipping point of HCC (i.e., LGDNs). On the other hand, there are a large number of differentially expressed genes between cirrhosis and HGDNs, which highlighted the stark differences or drastic changes before and after the tipping point or LGDNs, implying the 59 DNB members serving as the early-warning signals of the upcoming drastic deterioration for HCC. We further identified the biological pathways responsible for this transition, such as the type I interferon signaling pathway, Janus kinase-signal transducers and activators of transcription (JAK-STAT) signaling pathway, transforming growth factor (TGF)-β signaling pathway, retinoic acid-inducible gene I (RIG-I)-like receptor signaling pathway, cell adhesion molecules, and cell cycle. In particular, pathways related to immune system reactions and cell adhesion were downregulated, and pathways related to cell growth and death were upregulated. Furthermore, DNB was validated as an effective predictor of prognosis for HCV-induced HCC patients by survival analysis on independent data, suggesting a potential clinical application of DNB. This work provides biological insights into the dynamic regulations of the critical transitions during multistep hepatocarcinogenesis.

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Detection for disease tipping points by landscape dynamic network biomarkers.

Publications

Detection for disease tipping points by landscape dynamic network biomarkers.

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