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研究生: 丁白龍
Carlos R. Arias
論文名稱: Network Based Disease Gene Prioritization
以網路為基礎之疾病基因排序
指導教授: 蘇豐文
Soo, Von-Wun
口試委員: 陳朝欽
Chen, Chaur-Chin
賴尚宏
Lai, Shang-Hong
蔡宗翰
Tsai, Tzong-Han
許聞廉
Hsu, Wen-Lian
洪炯宗
Horng, Jorng-Tzong
蘇豐文
Soo, Von-Wun
學位類別: 博士
Doctor
系所名稱: 電機資訊學院 - 資訊系統與應用研究所
Institute of Information Systems and Applications
論文出版年: 2012
畢業學年度: 100
語文別: 中文
論文頁數: 109
中文關鍵詞: 基因排序最短路徑微陣列數據蛋白質相互作用網絡前列腺癌
外文關鍵詞: Gene Prioritization, Shortest Paths, Microarray Data, Protein Interaction Network, Prostate Cancer
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  • Many biological processes, at any level of organization from cellular to ecosystem, can be modeled as a complex network. In ecosystems, the objects in the network are the organisms involved in the model and the relationships are how the organisms interact with each other. At the cellular level, objects range from genes to metabolites and the relationship represent the interactions between them. In recent years, we have witnessed an explosion of available biological data that started with the Human Genome Project, and then it matured with the birth of a new field of study called systems biology. In this field, available data is integrated and viewed from the systems perspective. A vast amount of data has become publicly available, and a significant amount of it can be modeled using networks. A subfield of systems biology, network biology takes special interest in the biological network models. Network biology helps the biomedical community to unravel the mysteries of life, and also of diseases.
    Identification of diseases is a long time research subject, in this thesis we will present a method for disease gene identification using biological networks approach. The approach is based on protein interaction networks and microarray expression data. It integrates techniques like random walk with restarts with filtering purposes, shortest paths analysis for the core of the prioritization, and topological features of the network to help identify key genes. The contribution of this thesis is an integrated method for disease gene prioritization, that was tested using the prostate cancer as domain, obtaining the best performance for the top 50 rank compared to other state of the art methods.


    1 Introduction 1 2 Background 4 2.1 Graph Theory . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 2.1.1 Vertex Invariants . . . . . . . . . . . . . . . . . . . . . . . . 5 2.1.2 Network Invariants . . . . . . . . . . . . . . . . . . . . . . . 12 2.2 Biology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 2.2.1 Biological Networks Overview . . . . . . . . . . . . . . . . . 14 2.2.2 Available Bioinformatics Databases . . . . . . . . . . . . . . 17 2.2.3 BioDB . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 2.2.4 Disease Gene Prioritization Problem and Previous Research 19 3 Computing the All Pairs Shortest Paths on Biconnected Graphs 26 3.1 All Pairs Shortest Path Problem . . . . . . . . . . . . . . . . . . . . 27 3.2 Articulation Points and Single Vertices . . . . . . . . . . . . . . . . 27 3.3 Previous and Related Work . . . . . . . . . . . . . . . . . . . . . . 28 3.4 Method Description . . . . . . . . . . . . . . . . . . . . . . . . . . . 28 3.4.1 Input Assumptions . . . . . . . . . . . . . . . . . . . . . . . 29 3.4.2 Input Preparation . . . . . . . . . . . . . . . . . . . . . . . . 29 3.4.3 Preprocessing . . . . . . . . . . . . . . . . . . . . . . . . . . 30 3.4.4 Compute APSP . . . . . . . . . . . . . . . . . . . . . . . . . 32 3.4.5 Fold Distance Matrix . . . . . . . . . . . . . . . . . . . . . . 32 3.4.6 Expand Singles . . . . . . . . . . . . . . . . . . . . . . . . . 33 3.5 KC-APSP Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 3.6 KC-APSP Remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . 39 4 Software Tools Used and Developed 50 4.1 Third Party Libraries . . . . . . . . . . . . . . . . . . . . . . . . . . 50 4.2 Developed Library . . . . . . . . . . . . . . . . . . . . . . . . . . . 52 4.3 BioNetXplorer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53 4.3.1 Modules . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53 4.4 GP-MIDAS-VXEF Application . . . . . . . . . . . . . . . . . . . . 60 4.4.1 GP-MIDAS-VXEF Modules . . . . . . . . . . . . . . . . . . 60 4.5 Remarks on the Application Software . . . . . . . . . . . . . . . . . 62 5 Disease Gene Prioritization 64 5.1 GP-MIDAS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65 5.1.1 Setting up the Weights of the Network . . . . . . . . . . . . 65 5.1.2 Shortest paths analysis . . . . . . . . . . . . . . . . . . . . . 67 5.2 GP-MIDAS-XEF . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68 5.2.1 Filtering Non-Relevant Interactions from PPI . . . . . . . . 68 5.2.2 Extending the Score of Genes . . . . . . . . . . . . . . . . . 73 5.3 GP-MIDAS-VXEF . . . . . . . . . . . . . . . . . . . . . . . . . . . 74 5.3.1 Voting Strategy . . . . . . . . . . . . . . . . . . . . . . . . . 75 5.3.2 Final Biological Boosting . . . . . . . . . . . . . . . . . . . . 76 6 Experimental Results 78 6.1 Materials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78 6.2 Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80 6.2.1 Results Comparing Prostate Cancer and Normal Samples . . 83 6.2.2 Results Comparing Prostate Cancer and Lymph Node Metastasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85 7 Discussion and Conclusions 88 7.1 Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88 7.2 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89 Reference 90 Appendix 104

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