Gene-Pharmaco Ontology - Functionality Ontology - Sumi Yoshikawa [email protected] Oct 28 2005...
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Gene-Pharmaco OntologyGene-Pharmaco Ontology- Functionality Ontology -- Functionality Ontology -
Sumi YoshikawaSumi [email protected]@gsc.riken.jp
Oct 28 2005 Oct 28 2005 Workshop on bio-ontologiesWorkshop on bio-ontologies
205 Alfiero Center205 Alfiero Center@University at Buffalo North Campus@University at Buffalo North Campus
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Drug-GO-DiseaseDrug-GO-Disease
GO:Function
GO
FunctionFunction
ProcessProcess
Drug Disease
How ? How ?
Indication, adverse reactions etc.How ?
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TopicsTopics
Relations between molecular function anRelations between molecular function and processd process Determinant of “functionality” (functioning Determinant of “functionality” (functioning power) power) Integration of pharmacokinetics and pharIntegration of pharmacokinetics and pharmacodynamics in the context of relations omacodynamics in the context of relations of functionalityf functionality Drug-GO relations employing functionality Drug-GO relations employing functionality relations and disease-GO relationsrelations and disease-GO relations
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Why Ontology ? Why Ontology ?
図を入れる
Simulation Result Interpretation
Data Input for Simulation
Link with Public Resources / Mining
Drug Interaction Knowledge BaseInference System
Human intelligible
Risk Communication
Drug InteractionSimulation
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Why Biologists Talk about Function Why Biologists Talk about Function ??
Hypothesis driven approachHypothesis driven approach
Encountering withEncountering with “interesting Phenomenon” “interesting Phenomenon” eg. resistance to multiple drugseg. resistance to multiple drugs
ComparisonComparison with resistant patient (cell) and with resistant patient (cell) and sensitive patient (cell)sensitive patient (cell)
Identification of new molecule Identification of new molecule whichwhich was found was found only or much higher extentonly or much higher extent in resistant in resistant patient (cell)patient (cell)
The molecule was first called “multi-drug resistant protein”. The molecule was first called “multi-drug resistant protein”. Multi-drug resistance was regarded as its Multi-drug resistance was regarded as its functionfunction..
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Why Biologists Talk about Function Why Biologists Talk about Function ??
In Genomics era: sequence to function In Genomics era: sequence to function approachapproach
Obtained dozens of Obtained dozens of sequence datasequence data
The Interest is “in which The Interest is “in which biological processbiological process is it is it responsible ? responsible ? = what is the= what is the function function ? ?
Prediction of function from homology Prediction of function from homology search etc. search etc.
How can we verify ? KO etc.How can we verify ? KO etc.
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Gene – Gene Product – GOGene – Gene Product – GOAnnotated GO terms are mainly about the gene product Annotated GO terms are mainly about the gene product
Gene
GO: Molecular FunctionGO: Biological Process GO: Cellular Component
Gene Product (eg. Protein, RNA)
ANNOTATION TO GO TERMS
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Biological Entities Are Multi-functionalBiological Entities Are Multi-functionalOne to many relationshipOne to many relationship::
a gene - gene products a gene - gene products a gene product - functionsa gene product - functionsa gene product - processesa gene product - processes
GO: Process I
Protein A
Protein B Protein C
GO:Function1
GO:Function2
GO:Function3
GO: Process II
GO: Process III
GO: Process IV
Protein D
Gene X’ products
Gene X
Drug
How ?
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Relations between GO: Function Relations between GO: Function and GO: Processand GO: Process
GO:Function
GO
FunctionFunction
ProcessProcess
How ?
How ?
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Function to Process (1)Function to Process (1)
RelationsRelations ExampleExample
Function(ing) Function(ing) enablesenables process process (type 1)(type 1)
Functioning of Transporter Functioning of Transporter activity activity enablesenables transportationtransportation
Functioning of A Enables Process B : Functionality or Functioning of A is necessary for execution of process B.Without functioning of A, execution of process B is incomplete or none.
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1212Enabling Place
ThreeThree components for molecular i components for molecular interaction: eg. Drug X, inside celll nteraction: eg. Drug X, inside celll ((triggertrigger), biomolecule Y – trans m), biomolecule Y – trans membrane (embrane (situated objectsituated object), drug X ), drug X outside cell (outside cell (outputoutput) ) are participanare participants ofts of mol. interaction of X&Y mol. interaction of X&YDrug X-inside cell, biomolecule Y Drug X-inside cell, biomolecule Y - membrane - membrane are enabling participaare enabling participants ofnts of mol. interaction of X&Y mol. interaction of X&Ydrug X outside cell drug X outside cell is a resultant pis a resultant participant ofarticipant of mol. interaction XY = mol. interaction XY = emergence of drug X is resultant pemergence of drug X is resultant phenomenon of mol. Interaction of henomenon of mol. Interaction of X&YX&Y
Molecular Interaction as ProcessMolecular Interaction as ProcessModel in Drug Interaction Ontology (DIO)Model in Drug Interaction Ontology (DIO)
Drug X, inside cell
Drug X, outside cell
Biomolecule Y
(Transporter)
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Molecular Interaction and PathwayMolecular Interaction and PathwayTriadic relations of molecules are pathway Triadic relations of molecules are pathway (process) building blocks. Emergence of resultant (process) building blocks. Emergence of resultant participant participant triggerstriggers next molecular interactions. next molecular interactions.
Process 1 Process 2
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Function to Process (2)Function to Process (2)RelationsRelations ExampleExample
Functioning Functioning enablesenables process process (type2)(type2)
Functioning of Functioning of Thymidilate synthaThymidilate synthase activityse activity enablesenables dTMP biosyntdTMP biosynthesishesis (one of other enablers)(one of other enablers)
Thymidilate synthaseThymidilate synthase activityactivity enaenablesbles Pyrimidine biosynthesisPyrimidine biosynthesis (one o(one of other enablers)f other enablers)
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Thymidylate synthase
dTMP
dUMP
dUDP
UDP
UMP
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Function to Process (2)Function to Process (2)RelationsRelations ExampleExample
Functioning Functioning enablesenables process process (type2)(type2)
Functioning of Functioning of Thymidilate synthaThymidilate synthase activityse activity enablesenables dTMP biosyntdTMP biosynthesishesis (one of other enablers)(one of other enablers)
Thymidilate synthaseThymidilate synthase activityactivity enaenablesbles Pyrimidine biosynthesisPyrimidine biosynthesis (one o(one of other enablers)f other enablers)
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Function to Process (3)Function to Process (3)RelationsRelations ExampleExampleFunctioning Functioning enablesenables process process (type3)(type3)
Functioning of Functioning of Thymidilate synthaThymidilate synthase activityse activity enables enables DNA replicatioDNA replicationn
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Process to ProcessProcess to Process
RelationsRelations ExampleExample
Process Process enablesenables process (type 2)process (type 2)
dTMP biosynthesisdTMP biosynthesis enablesenables nucleotide biosynthesisnucleotide biosynthesis ( sub process)( sub process)
Process Process enablesenables process (type 3)process (type 3)
nucleotide biosynthesisnucleotide biosynthesis enablesenables DNA replicationDNA replication
(linked process)(linked process)
Process A Enables Process B : Execution of process A is necessary for execution of process B.
Without execution of A, execution of process B is incomplete or none.
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Mini Summary:Mini Summary: Relations to Process Relations to ProcessProcess - process relations (non is_a relation)Process - process relations (non is_a relation)
Enables as participant(type 2)
Enables as participant
Enables as (participant of) Linked Process (type3)
Enables as participant relation (type 1 one-to-one)
“enables” could be included in larger context:
Influence / affects on ….
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Enablers and ParticipantEnablers and ParticipantEnablers and Participants of process BEnablers and Participants of process B
(some) Linked process(eg. Process A)
Participants of BEnablers of B
Participants of (some) Linked process(eg. Participants ofProcess A)
Resultant continuant participant(output continuant participant)
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Influence on what ?Influence on what ?
Efficiency of Process: Efficiency of Process:
Relative increase or decrease of Relative increase or decrease of resultant phenomenaresultant phenomena
Quality of Process: Quality of Process:
If the process occurs or notIf the process occurs or not
Erroneous resultant phenomena Erroneous resultant phenomena (erroneous output)(erroneous output)
Termination at mid stream Termination at mid stream
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Process to FunctionProcess to Function
Process A Enables Functioning of B :
its meaning is :
Execution of process A is necessary for functioning of B.
Without execution of A, functioning of B is incomplete or none.
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What is functioningWhat is functioning ??What would influence on functioning ? What would influence on functioning ?
And how ?And how ?
Generalization of this question would apply to ontoGeneralization of this question would apply to onto
logy of drug action. logy of drug action.
Because effect of drug is achieved through modifiBecause effect of drug is achieved through modification of functioning (functionality) of biomoleculecation of functioning (functionality) of biomolecule
s.s.
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What would possibly influence on What would possibly influence on efficiency of functioning ?efficiency of functioning ?
Gene expression
Maturation/Activation
LocatingMigration
ExcretionDegradation
Execution
Meta LevelRegulation
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Analogy : Key’s functionAnalogy : Key’s function
EmbodimentMaturation(Activation) Locating Execution
Elimination/DegradationMeta Level
Regulation
Not applicable to inanimate system
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Determinant on Functionality of Gene ProductDeterminant on Functionality of Gene ProductFunctionality is influenced by
Functionality of participantExternal Influencers
enabling placeenabling place
Effect on Functioning
Functionality of participant
trigger participanttrigger participant
situated participantsituated participant
transient participanttransient participant
Functionality of participantExternal Influencers
Functionality of participantExternal Influencers
Functionality of participantExternal Influencers
Functionality of participantExternal Influencers
Gene Expression
Maturation
Locating
Elimination
Meta levelRegulation
Effect onExternal
Influencers
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Influence on Functioning / ProcessInfluence on Functioning / Process
A affects BA affects B
Upward direction(positive direction)
Non +/- modulation
Enables
Downward direction(negative direction)
Non-Enables
increase
decrease
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Determinant on Functionality of DrugDeterminant on Functionality of DrugFunctionality is influenced by
Functionality of Drug
enabling placeenabling place
trigger participanttrigger participant
situated participantsituated participant
transient participanttransient participant
Functionality of participantExternal Influencers
Functionality of participantExternal Influencers
Functionality of participantExternal Influencers
Functionality of participantExternal Influencers
Functionality of participantExternal Influencers
Pharmaco-Dynamics
(Effect on Functioning
Pharmaco-Kinetics
(Effect onExternal
Influencers)
Absorption(Embodiment)
Metabolism(Maturation)
Distribution(Locating)
Excretion(Elimination)
Meta levelRegulation
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Determinant on Functionality of DrugDeterminant on Functionality of DrugFunctionality (functioning efficiency /quality) is influenced by
Drug Affecting Process
enabling placeenabling place
trigger participanttrigger participant
situated participantsituated participant
transient participanttransient participantPharmaco-Dynamics
(Effect on Functioning
PK
Functionality of participantExternal Influencers
Functionality of participantExternal Influencers
Functionality of participantExternal Influencers
Functionality of participantExternal Influencers
Functionality of participantExternal Influencers
Embodiment
Maturation
Locating
EliminationMeta levelRegulation
Absorption
Metabolism
Distribution
Excretion
Meta levelRegulation
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Determinant of Drug EfficacyDeterminant of Drug Efficacy
PKAbsorption
Metabolism
Distribution
Excretion
Meta levelRegulation
Drug Affecting ProcessPharmaco-Dynamics(Effect on
FunctioningEmbodiment
Maturation
Locating
Elimination
Meta levelRegulation
Gene Expression
Maturation
Locating
Elimination
Meta levelRegulation
Effect onExternal
Influencers
Effect on Functioning
Functionality of participant
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Gene-Gene Product-Drug-GOGene-Gene Product-Drug-GO
Protein B1
Protein B2 Protein B3
GO:Function1
GO:Function2
GO:Function3
Protein B4
Gene X’ product
Drug A1
A1 A1 affects_affects_GO:Function 2 GO:Function 2 by_modulating_gene_by_modulating_gene_expression_process_ofexpression_process_of Gene X to B2 Gene X to B2
Gene X
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Gene-Gene Product-Drug-GO Gene-Gene Product-Drug-GO [Example][Example]
LDL receptor gene
GO: LDL receptor activity
LDL receptors
cholestyramine
cholestyramine cholestyramine affects_affects_GO: LDL receptor activity (hepaGO: LDL receptor activity (hepatic) tic) by_enhancing_gene_expression_process_oby_enhancing_gene_expression_process_of f LDL receptor gene to hepatic LDL receptorLDL receptor gene to hepatic LDL receptor
Hepatic LDL receptor
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Gene-Gene Product-Drug-GOGene-Gene Product-Drug-GO
Protein B1
Protein B2 Protein B3
GO:Function1
GO:Function2
GO:Function3
Protein B4
Gene X’ product
A2 A2 affects_GOaffects_GO:Function3 :Function3 by_direct_interaction_withby_direct_interaction_with B1, B2, and BB1, B2, and B33..
Drug A2
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Gene-Gene Product-Drug-GO [5]Gene-Gene Product-Drug-GO [5]
Protein B1Protein B2
Protein B3
GO:Function1
GO:Function2
GO:Function3
Protein B4
Gene X’ product
A3 affects_GOA3 affects_GO: Function3 : Function3 by_modulating_activation_process_ofby_modulating_activation_process_of B B3.3.
Drug A3
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QuestionQuestionTask scope :Task scope : looking through “mechanism of drug action” looking through “mechanism of drug action”
GO:Function
GO?
FunctionFunction
ProcessProcess
Drug Disease
Interaction of Functionality
?
Treatment / adverse events etc.
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DiseaseDisease
A definite A definite pathologic processpathologic process with a with a characteristic set of signs and symptoms. characteristic set of signs and symptoms. (mesh) (mesh)
A disease is any A disease is any abnormal condition ofabnormal condition of the the body or mind that causes discomfort, body or mind that causes discomfort, dysfunction, or distress to the person dysfunction, or distress to the person affected or those in contact with the affected or those in contact with the person. (NCI thesaurus)person. (NCI thesaurus)
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Normal State vs. Disease StateNormal State vs. Disease State
Disease Disease statestate is characterized as deviations is characterized as deviations from “normal” from “normal” statestate. . Various phenomena (symptoms etc.) as a Various phenomena (symptoms etc.) as a result of result of altered processesaltered processes & specific & specific process profiles are observed.process profiles are observed.
Standard (normal) state
Disease State
Aggravated State
Alleviated State
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Processes associated with diseaseProcesses associated with disease
Treatment Treatment motivated viewmotivated view Processes in a
current disease State
Processes contributed for emergence of current disease state
Processes for cure / alleviation
Processes for aggravation
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Processes as Treatment TargetProcesses as Treatment Target
Treatment target is not only noticeable Treatment target is not only noticeable processes but also causal, aggravating, processes but also causal, aggravating, alleviating, compensational ones. alleviating, compensational ones.
Molecular level of such processes can be Molecular level of such processes can be called “disease associated pathways called “disease associated pathways (process)” or “(process)” or “disease pathwaysdisease pathways””
Disease pathways include not only distinct Disease pathways include not only distinct disease specific pathways, but also disease specific pathways, but also deregulated normal processes. deregulated normal processes.
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Disease State and Disease State and Medication StateMedication State
Medication specific biological response Medication specific biological response appearsappears
Normal state
Disease State
Medication State
Alleviated State
Medication associated aggravating response
Medication associated alleviating response
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Disease – GO relationDisease – GO relation
Observation based process
In Disease A, Process / Events B is ..
Part of causal process of observed symptom
Disease associationevidence
need treatment
No need treatment
unknown
Alleviationprocess if
Aggravatingprocess if
Participated indisease development
as
Risk events if
Contributed for protection
Contributed as diseaseestablishment
Other deregulation
Increased than normalDecreased than normal
Other deregulation
Increased than normalDecreased than normal
Other deregulation
Increased than normalDecreased than normal
Other modulation
Increased than normalDecreased than normal
Other deregulation
Increased than normalDecreased than normal
Other deregulation
Increased than normalDecreased than normal
Other modulation
Increased than normalDecreased than normal
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ExampleExampleCancer drug 5FU and Colorectal CancerCancer drug 5FU and Colorectal Cancer
GO:Function
GO
FunctionFunction
ProcessProcess
5FU Colorectal Cancer
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Example: 5FUExample: 5FU
Colorectal Cancer
.DPYD
Gene / GPeg. TYMS / Thymidilate
Synthetase
Thymidilate synthetase activity GOFGOF
Nucleotide biosynthesis GOPGOP
DNA replication GOPGOP
affects as participating enabler
Thymidilate synthetase biosynthesis GOPGOP
(functioning) affects as participating enabler
affects as upstream process enabler
Disease association with evidence
Increased than normal
Part of causal process of observed symptom
Increased than normal
Aggravating process if
Participated in disease development
Increased than normal
Increased than normal
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Example: 5FUExample: 5FU
5FU & metabolites
.DPYD
Gene / GPeg. TYMS / Thymidilate
Synthetase
Thymidilate synthetase activity GOFGOF
Nucleotide biosynthesis GOPGOP
DNA replicationGOPGOP
affects as participating enabler
Thymidilate synthetase biosynthesis GOPGOP
(functioning) affects as participating enabler
affects as upstream processdecreases process efficiency by decreasing upstream process*
decreases functionality by direct interaction (inhibit by direct interaction)
decreases process efficiency by direct interaction with one of situated enabling continuant
participant
Inhibits (non-enables) by competing with
(normal) participantsby drug specific pathway that generate erronous analog
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Example: 5FU & CancerExample: 5FU & Cancer
5FU & metabolites
DNA replication GOPGOP
Decrease process efficiency by decreasing upstream process*
Inhibits (non-enables) by competing with normal participants
Disease association with evidence
Increased than normal
Part of causal process of observed symptom
Increased than normal
Colorectal Cancer
Downward effect
includes cancer treatment
effect is against observed symptom,
aggravating effect ..
Aggravating process if
Participated in disease development
Increased than normal
Increased than normal
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Example: Cholestyramine & HyperlExample: Cholestyramine & Hyperlipidemiaipidemia
Cholestyramine (questra
n)
LDL receptor activity
Increase functionalityby
increasing gene expression
(hepatic)
Increased than normal
Hyper Lipidemia
Upward effect is on
alleviation process
(treatment is for
enhancement of alleviation)
Alleviatingprocess if
GOFGOF
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Overall summaryOverall summary
Potentiality of functionality relations as Potentiality of functionality relations as generic one in biomedical domain.generic one in biomedical domain.
Integration of PK and PD by functionality Integration of PK and PD by functionality relations. Schematized PD.relations. Schematized PD.
Merging drug functionalities and disease Merging drug functionalities and disease process by GO as bridgeprocess by GO as bridge
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