Pathway Database

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Pathway Database

• Carl Schaefer
• February 21, 2003

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Why Spend Effort on Pathways?

• Target as process vs. target as molecule
• In the end, what matters is a hyperactive process
  (e.g. mitosis), not just an over-expressed
  protein
• Phenotype classification
• Higher-level feature than transcript abundance

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Why Spend Effort on a Pathway Database?

• A picture may be worth a thousand words ...
• but a computable representation is even better
• Make assumptions explicit
• Combine sources of data
• KEGG, BioCarta, ...
• Merge data from separate pathways
• E.g. BioCartas Cyclins and Cell Cycle
  Regulation and Cyclin E Destruction Pathway
• Causal framework for quantitative
  simulation/analysis
• ... when the data becomes available

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Basics

• Model a causal network
• Be composable (novel pathways)
• Cope with lack of knowledge
• Promote understanding

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Model A Causal Network

• Graph (nodes edges)
• Distinguish two kinds of nodes (molecules
  processes)
• Allow labels on nodes and edges
• molecule-type (compound, protein, complex, rna)
• molecule-id (...)
• process-type (reaction, binding, modification,
  translocation, transcription, cell process)
• edge-type (input, output, agent, inhibitor)
• activity-state (active, inactive)
• location (extracellular, transmembrane,
  cytoplasm, nucleus)
• reversible (yes, no)

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Composable

• Atomic pathway
• a process node
• immediately adjacent molecules
• the connecting edges
• Join atomic pathways on identical molecules
• ... and maybe on molecule subtype relation

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Pathway ConstructionJoining Atomic Pathways
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Lack of Knowledge

• Hierarchy of label values
• e.g., edge-type ? incoming-edge ? agent
• Hierarchy of molecule ids
• GO id
• Gene product
• Specific protein
• Families of molecules
• Handbook
• E.g. for Raf-1, active-1 means
  phosphorylation at S259

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Promote Understanding

• Hide unwanted detail
• prune common molecules
• encapsulate sub-pathways
• Query by connectedness (cause effect)
• Find patterns

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Omission of Dont Care DetailPruning Common
Compounds
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Query by ConnectednessPredecessors/Successors
atom-id 411 direction forward degree
3 prune common compounds
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Patterns

• Templates for atomic pathways
• process-typemodification
• molecule-typeprotein1edge-typeagent
• molecule-typeprotein2edge-typeinputactivity-
  stateinactive
• molecule-typeprotein2edge-typeoutputactivity
  -stateactive
• Maybe multi-process templates (e.g., a cascade)

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What Do We Need?

• Computation model of pathway interactions
• Persistent data model
• Tools
• data input
• query and analysis
• visualization
• Data, data, data, ...

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What Do We Have?

• Computation model mostly worked out
• Persistent data model mostly worked out
• Tools
• working on data input
• have a query/analysis tool
• joins, prunes, finds predecessors/successors
• produces graph output
• extracts first-order patterns
• using GraphViz to produce SVG diagrams
• Data, data, data ...
• Loaded KEGG into database
• Next 30 BioCarta pathways related to apoptosis,
  cell-cycle regulation and histone deacetylase
  activity