COMPUTATIONAL ANALYSIS, VISUALIZATION AND TEXT MINING OF METABOLIC NETWORKS by XINJIAN QI Submitted in partial fulfillment of the requirements For the degree of Doctor of Philosophy Dissertation Advisor: Dr. Gültekin Özsoyoğlu Department of Electrical Engineering and Computer Science CASE WESTERN RESERVE UNIVERSITY January, 2014 CASE WESTERN RESERVE UNIVERSITY SCHOOL OF GRADUATE STUDIES We hereby approve the thesis/dissertation of ____Xinjian Qi____________________________________________ candidate for the Doctor of Philosophy___degree *. (signed) __Dr. Gültekin Özsoyoğlu__________________________ (chair of the committee) __________Dr. Andy Podgurski______________________________ __________Dr. M. Cenk Cavusoğlu__________________________ __________Dr. Nicola Lai___________________________________ __________Dr. Z. Meral Özsoyoğlu__________________________ ___________________________________________________________ (date) _____June 24, 2013____ *We also certify that written approval has been obtained for any proprietary material contained therein. Table of Contents Table of Contents ................................................................................................................ 1 List of Tables ...................................................................................................................... 6 List of Figures ..................................................................................................................... 7 Acknowledgements ........................................................................................................... 10 Abstract ............................................................................................................................. 12 Introduction ....................................................................................................................... 14 1.1 Computational Interpretation of Metabolomics Measurements: Steady-State Metabolic Network Dynamics Analysis ....................................................................... 15 1.2 Performing Gene Lethality Testing with SMDA ............................................... 17 1.3 Visualization Tools for PathCase Systems......................................................... 19 1.4 Locating Basic Bio-Entities in Genome-Scale Reconstructed Metabolic Networks ....................................................................................................................... 22 1.5 Thesis Organization............................................................................................ 24 Computational Interpretation of Metabolomics Measurements: Steady-State Metabolic Network Dynamics Analysis ............................................................................................ 25 2.1 Introduction ........................................................................................................ 25 2.2 Condition-Based Modeling ................................................................................ 33 2.2.1 Assumptions and Terminology ................................................................... 33 2.2.2 Metabolite Pool Label Identifiers ............................................................... 36 1 2.2.3 Metabolite Label Condition Characterization ............................................. 38 2.2.4 Trigger Values and Activation Condition Sets for Reactions, Transport Processes, or Pathways ............................................................................................. 39 2.2.5 Biochemistry-Based Rules .......................................................................... 43 2.3 Active/Inactive Graph Generation And Expansion ............................................ 45 2.3.1 Initial GAI Generation ................................................................................. 46 2.3.2 GAI Graph Expansion .................................................................................. 48 2.3.3 Merging GAI Graphs ................................................................................... 56 2.3.4 Algorithm Sketch ........................................................................................ 58 2.4 Experimental Evaluation .................................................................................... 59 2.4.1 Experimental Setting ................................................................................... 59 2.4.2 Experimental Results .................................................................................. 61 2.5 Related Work: Metabolic Network Analysis Techniques .................................. 63 2.6 Conclusions ........................................................................................................ 66 Performing Gene Lethality Testing with SMDA .............................................................. 67 3.1 Introduction ........................................................................................................ 67 3.2 Summary of SMDA Algorithm .......................................................................... 70 3.2.1 SMDA Terminology ................................................................................... 70 3.2.2 Algorithm Flow ........................................................................................... 72 3.2.3 Conflicts ...................................................................................................... 74 2 3.3 Existing Gene Lethality Techniques and SMDA ............................................... 75 3.4 Revising SMDA For Gene Lethality Testing ..................................................... 80 3.5 Experimental Evaluation .................................................................................... 83 3.5.1 Experimental Setting ................................................................................... 83 3.5.2 Gene Lethality Test Results ........................................................................ 86 3.5.3 Gene Non-Lethality Test Results ................................................................ 90 3.6 Conclusions ........................................................................................................ 91 Visualization Tools for PathCase Systems ....................................................................... 92 4.1 Introduction ............................................................................................................ 92 4.2 Visualization Tool for PathCase-SB System ..................................................... 94 4.3 Visualization Tools for other PathCase Systems ............................................... 98 4.3.1 PathCase-MAW and PathCase-MAW Editor ............................................. 98 4.3.2 PathCase-SMDA ......................................................................................... 99 4.3.3 PathCase-RCMN and PathCase-Recon .................................................... 101 4.3.4 PathCase-MQL ......................................................................................... 103 4.4 General Framework .......................................................................................... 106 4.5 Visualization Tool for iPad Applications ......................................................... 108 4.6 Conclusions ...................................................................................................... 109 Locating Basic Bio-Entities in Genome-Scale Reconstructed Metabolic Networks ...... 110 5.1 Introduction ...................................................................................................... 110 3 5.1.1 Entity Identification .................................................................................. 111 5.1.2 Similarity Score ........................................................................................ 112 5.2 Metabolite Identification .................................................................................. 114 5.2.1 Exact Match via Metabolite Id/Synonyms ................................................ 116 5.2.2 Approximate Name Matching................................................................... 117 5.2.3 Filtering Metabolite Match Candidates .................................................... 125 5.3 Reaction Identification .......................................................................................... 129 5.3.1 Reaction Name Matching ......................................................................... 130 5.3.2 Reaction Property Matching ..................................................................... 131 5.3.3 Reaction Compound Matching ................................................................. 132 5.3.4 Reaction Similarity Score ......................................................................... 134 5.4 Experimental Evaluation .................................................................................. 135 5.4.1 Metabolite Identification Results .............................................................. 136 5.4.2 Reaction Identification Results ................................................................. 144 5.5 Conclusion ........................................................................................................ 150 Conclusions and Future Work ........................................................................................ 152 6.1 Future work ...................................................................................................... 153 6.1.1 SMDA ......................................................................................................