1. Creating Metabolic Network Models using Text Mining and Expert Knowledge J.A. Dickerson, D. Berleant, Z. Cox, W. Qi, and E. Wurtele Iowa State University

2. 22 April 2003© 2003, SNU BioIntelligence Lab, http://bi.snu.ac.kr/2 Outline Introduction to the Gene Expression Toolkit Graphical Network Models PathBinder Fuzzy Cognitive Map (FCM) Modeling Tool Example Conclusions and Future Work

3. 22 April 2003© 2003, SNU BioIntelligence Lab, http://bi.snu.ac.kr/3 Gene Expression Toolkit PathBinder: Automatic document processing system that automates the process of pulling relationships from publications. ChipView: Explanatory models synthesized by clustering techniques together with a genetic algorithm-based data mining tool FCModeler: Predictive models summarize known regulatory relationships in fuzzy cognitive maps (FCMs).

4. 22 April 2003© 2003, SNU BioIntelligence Lab, http://bi.snu.ac.kr/4 Gene Expression Toolkit Components

5. 22 April 2003© 2003, SNU BioIntelligence Lab, http://bi.snu.ac.kr/5 Metabolic Networks Metabolic networks form the basis for the net accumulation of biomolecules in organisms. Regulatory networks modulate the action of metabolic networks, leading to physiological and morphological changes. Modeling tool represents the interactions within and between these networks – Nodes represent specific biochemicals such as proteins, RNA, and small molecules, or stimuli, such as light, heat, or nutrients. – Links- interactions between nodes

6. 22 April 2003© 2003, SNU BioIntelligence Lab, http://bi.snu.ac.kr/6 Link Types Conversion link (black arrow), a node is converted into another node, and used up in the process. Regulatory link (green and red arrows), node activates or deactivates another node, not used up. Catalytic link (blue arrows) an enzyme that enables a chemical conversion and not used up in the process.

7. 22 April 2003© 2003, SNU BioIntelligence Lab, http://bi.snu.ac.kr/7 What is PathBinder? PathBinder extracts node-node interactions from MEDLINE The processing unit is single sentences: abstracts are parsed into individual sentences, which in turn are searched for the presence of a pair of node names and an interaction-related Verb.

8. 22 April 2003© 2003, SNU BioIntelligence Lab, http://bi.snu.ac.kr/8 Features of PathBinder Users can select one or more protein name from a list of protein names. The query can contain one or more “starting terms,” and use words like “And” and “Or” to connect them.

9. 22 April 2003© 2003, SNU BioIntelligence Lab, http://bi.snu.ac.kr/9 Program Operation Processing steps –user input –document pre-processing –find synonyms –synonym extraction –document retrieval –sentences extraction –multi- display

10. 22 April 2003© 2003, SNU BioIntelligence Lab, http://bi.snu.ac.kr/10 Format of synonym list & sentence index

11. 22 April 2003© 2003, SNU BioIntelligence Lab, http://bi.snu.ac.kr/11 FCModeler Goals Capture the intuitions of biologists and provide a modeling framework for assessing large amounts of information Goals of this work: –Model the data matrix as a fuzzy cognitive map and explore ways to combine the information from different FCMs. –Locate and visualize closely coupled subgraphs or signal transduction modules. –Develop simulation tools for modeling intervention in the network (e.g. what happens when a node is shut off) and search for critical paths and control points in the network.

12. 22 April 2003© 2003, SNU BioIntelligence Lab, http://bi.snu.ac.kr/12 Fuzzy Cognitive Maps Fuzzy Cognitive Maps to show interactions between different variables –Fuzzy signed digraphs represent causal flow between objects or concepts –Constructed using expert knowledge or neural learning

13. 22 April 2003© 2003, SNU BioIntelligence Lab, http://bi.snu.ac.kr/13 Simple Fuzzy Cognitive Maps Graph edges are {-1,0,1}. Used when the direction of causality is agreed on, but not its degree Concepts either occur or do not occur Can test out hypotheses Concepts are usually summed then thresholded to get the next state

14. 22 April 2003© 2003, SNU BioIntelligence Lab, http://bi.snu.ac.kr/14 Nested FCMs If more information is known about the links between concepts, then more detailed functional links can combine information –Differential equations –Fuzzy approximators

15. 22 April 2003© 2003, SNU BioIntelligence Lab, http://bi.snu.ac.kr/15 FCM Combination Can combine FCMs additively

16. 22 April 2003© 2003, SNU BioIntelligence Lab, http://bi.snu.ac.kr/16 Gibberellin Example Create metabolic map of system using expert knowledge PathBinder literature search for new relationships Add relationships to metabolic map Check implications of the additions

17. 22 April 2003© 2003, SNU BioIntelligence Lab, http://bi.snu.ac.kr/17 Initial Metabolic Network

18. 22 April 2003© 2003, SNU BioIntelligence Lab, http://bi.snu.ac.kr/18 PathBinder Results Query: Find sentences containing (either gibberellin, gibberellins, or GA) AND (either SPY, SPY-4, SPY-5, or SPY-7) Sentence :”Here we describe detailed studies of the effects of two of these suppressors, spy-7 and gar2-1, on several different GA-responsive growth processes (seed germination, vegetative growth, stem elongation, chlorophyll accumulation, and flowering) and on the in plant amounts of active and inactive GA species.” Source: UI - 99214450 Peng J, Richards DE, Moritz T, Cano-Delgado A, Harberd NP, Plant Physiol 1999 Apr;119(4):1199-208.

19. 22 April 2003© 2003, SNU BioIntelligence Lab, http://bi.snu.ac.kr/19 Updated Metabolic Network

20. 22 April 2003© 2003, SNU BioIntelligence Lab, http://bi.snu.ac.kr/20 Conclusions Integration of FCModeler with PathBinder allows biologists to gather and combine information from –Literature databases –Their expert knowledge –Public databases of mRNA results This gives a more complete picture of the metabolism