Principles of (Biomedical) Ontology Design

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Principles of Principles of (Biomedical) Ontology (Biomedical) Ontology

DesignDesign

Barry SmithBarry SmithDepartment of Philosophy, University at Department of Philosophy, University at

BuffaloBuffaloNational Center for Biomedical Ontology National Center for Biomedical Ontology

(http://ncbo.us)(http://ncbo.us)

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A methodology for building A methodology for building and evaluating ontologiesand evaluating ontologies

applied thus far in the biomedical domain applied thus far in the biomedical domain to:to:– FMAFMA– GO + other OBO OntologiesGO + other OBO Ontologies– NCI ThesaurusNCI Thesaurus– UMLS Semantic NetworkUMLS Semantic Network– FuGOFuGO– SNOMEDSNOMED– ICF (International Classification of Functioning, ICF (International Classification of Functioning,

Disability and Health)Disability and Health)– BirnLex, RadioLex, NeuronamesBirnLex, RadioLex, Neuronames– ISO Terminology StandardsISO Terminology Standards– HL7-RIMHL7-RIM

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Some ExamplesSome Examples

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Foundational Model of Foundational Model of Anatomy Anatomy

(FMA)(FMA)ProPro

Clear statement of scope: Clear statement of scope: structural structural human human anatomy, at all levels of granularity, from the anatomy, at all levels of granularity, from the whole organism to the biological macromolecule. whole organism to the biological macromolecule. Powerful treatment of definitionsPowerful treatment of definitionsSingle inheritance Single inheritance is_a is_a hierarchyhierarchy

ConConSome unfortunate artifacts in the ontology Some unfortunate artifacts in the ontology deriving from its specific computer deriving from its specific computer representation (Protégé)representation (Protégé)

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Pleural Cavity

Interlobar recess

Mesothelium of Pleura

Pleura(Wall of Sac)

VisceralPleura

Pleural Sac

Parietal Pleura

Anatomical Space

OrganCavity

Serous SacCavity

AnatomicalStructure

Organ

Serous Sac

MediastinalPleura

Tissue

Organ Part

Organ Subdivision

Organ Component

Organ CavitySubdivision

Serous SacCavity

Subdivision

part_

of

is_a

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FMA FMA follows formal rules follows formal rules for Aristotelian definitionsfor Aristotelian definitions

When When A is_a B, A is_a B, the definition of ‘the definition of ‘A A ’ takes ’ takes the form:the form:

an A an A =Def=Def. a B which C s.... a B which C s...

a human being a human being =Def. =Def. an animal which is an animal which is rationalrational

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ExamplesExamplesCellCell =Def. an =Def. an anatomical structure anatomical structure

which which consists ofconsists of cytoplasmcytoplasm surrounded bysurrounded by a a plasma plasma membranemembrane

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The FMA regimentationThe FMA regimentationbrings the advantage that circular brings the advantage that circular

definitions are avoideddefinitions are avoidedeach definition reflects the position in the each definition reflects the position in the

hierarchy to which a defined term hierarchy to which a defined term belongs belongs

the position of a term within the hierarchy the position of a term within the hierarchy enriches its own definition by enriches its own definition by incorporating automatically the incorporating automatically the definitions of all the terms above it.definitions of all the terms above it.

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The entire information content of the The entire information content of the FMA’s term hierarchy can be FMA’s term hierarchy can be translated very cleanly into a translated very cleanly into a computer representationcomputer representation

But the definitions encapsulate this But the definitions encapsulate this information in a modular form which information in a modular form which is of maximal advantage to human is of maximal advantage to human beingsbeings

The FMA regimentationThe FMA regimentation

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The FMA regimentation The FMA regimentation ensures intelligibility of ensures intelligibility of

definitionsdefinitionsThe terms used in a definition should The terms used in a definition should be simpler (more intelligible) than the be simpler (more intelligible) than the term to be defined; otherwise the term to be defined; otherwise the definition provides no assistance definition provides no assistance – to human understandingto human understanding– to machine processingto machine processing

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FMAFMAorganized in a graph-theoretical organized in a graph-theoretical structure involving two sorts of links or structure involving two sorts of links or edges: edges:

is-ais-a (= (= is a subtype of is a subtype of ))((pleural sac pleural sac is-a is-a serous sacserous sac) )

part-of part-of ((cervical vertebra cervical vertebra part-of part-of vertebral vertebral columncolumn))

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Pleural Cavity

Interlobar recess

Mesothelium of Pleura

Pleura(Wall of Sac)

VisceralPleura

Pleural Sac

Parietal Pleura

Anatomical Space

OrganCavity

Serous SacCavity

AnatomicalStructure

Organ

Serous Sac

MediastinalPleura

Tissue

Organ Part

Organ Subdivision

Organ Component

Organ CavitySubdivision

Serous SacCavity

Subdivision

part_

of

is_a

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at every level of at every level of granularitygranularity

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The FMA is a Structural The FMA is a Structural AnatomyAnatomy

Plasma membranePlasma membrane =Def =Def. a. a cell part cell part that that surroundssurrounds the the cytoplasmcytoplasm

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The Gene OntologyThe Gene Ontology

ProProOpen SourceOpen SourceCross-SpeciesCross-SpeciesImpressive annotation resourceImpressive annotation resourceImpressive policies for maintenanceImpressive policies for maintenanceHas recognized the need for reformHas recognized the need for reform

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ConConPoor formal architecture (Mk I.) Poor formal architecture (Mk I.) Poor support for automatic reasoning Poor support for automatic reasoning

and error-checkingand error-checkingNo cross-ontology relationsNo cross-ontology relationsNot (yet) transgranularNot (yet) transgranular

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GO:0019836 hemolysis of red GO:0019836 hemolysis of red blood cellsblood cells

=Def. The processes by which an =Def. The processes by which an organism effects hemolysis ...organism effects hemolysis ...

XX = =Def. Def. the the Y Y of of XX

This sort of definition is worse than This sort of definition is worse than circularcircular

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Gene Ontology now adopting Gene Ontology now adopting structured definitions built out of structured definitions built out of

genusgenus and and differentiaedifferentiae

Species =Def Genus + Differentiae

neuron cell differentiation =Defdifferentiation by which a cell acquires features of a neuron

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National Cancer Institute National Cancer Institute Thesaurus (NCIT)Thesaurus (NCIT)

ProProNCIT is open sourceNCIT is open sourceNCIT has broad coverageNCIT has broad coverageNCIT has some formal structure (OWL-DL)NCIT has some formal structure (OWL-DL)NCIT has realized the errors of its waysNCIT has realized the errors of its ways

ConConFull of errors (many inherited from UMLS)Full of errors (many inherited from UMLS)Bad realization of formal structureBad realization of formal structure

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Goals of NCITGoals of NCIT

to make use of current terminology to make use of current terminology best practices to relate relevant best practices to relate relevant concepts to one another in a formal concepts to one another in a formal structure, e.g. to support automatic structure, e.g. to support automatic reasoning;reasoning;

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Formal DefinitionsFormal Definitionsof 37,261 nodes, 33,720 remain of 37,261 nodes, 33,720 remain formally undefinedformally undefinedThus only a small portion of the NCIT Thus only a small portion of the NCIT ontology can be used for purposes of ontology can be used for purposes of automatic classification and error-automatic classification and error-checkingchecking

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Verbal DefinitionsVerbal DefinitionsAbout half the NCIT terms are assigned About half the NCIT terms are assigned

verbal definitions for human useverbal definitions for human useUnfortunately some are assigned more Unfortunately some are assigned more

than onethan one

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Disease ProgressionDisease ProgressionDefinition1Definition1

Cancer that continues to grow or Cancer that continues to grow or spread. spread.

Definition2Definition2 Increase in the size of a tumor or Increase in the size of a tumor or spread of cancer in the body. spread of cancer in the body.

Definition3Definition3 The worsening of a disease over time. The worsening of a disease over time.

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CancerCancera a processprocess (of getting better or worse) (of getting better or worse)

an an objectobject (which can grow and spread) (which can grow and spread)

occurrent vs. continuantoccurrent vs. continuant

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DiseaseDiseaseDefinition1Definition1

A disease is any abnormal A disease is any abnormal conditioncondition of the body or mind that causes of the body or mind that causes discomfort, dysfunction, or distress discomfort, dysfunction, or distress to the person affected or those in to the person affected or those in contact with the person. ...contact with the person. ...

Definition2Definition2 A definite pathologic A definite pathologic processprocess with a with a characteristic set of signs and characteristic set of signs and symptoms. ...symptoms. ...

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Confuses definitions with Confuses definitions with descriptionsdescriptions

TuberculosisTuberculosis =Def. =Def.A chronic, recurrent infection caused by the bacterium A chronic, recurrent infection caused by the bacterium Mycobacterium tuberculosis. Tuberculosis (TB) may affect Mycobacterium tuberculosis. Tuberculosis (TB) may affect almost any tissue or organ of the body with the lungs being almost any tissue or organ of the body with the lungs being the most common site of infection. The clinical stages of TB the most common site of infection. The clinical stages of TB are primary or initial infection, latent or dormant infection, are primary or initial infection, latent or dormant infection, and recrudescent or adult-type TB. Ninety to 95% of primary and recrudescent or adult-type TB. Ninety to 95% of primary TB infections may go unrecognized. Histopathologically, TB infections may go unrecognized. Histopathologically, tissue lesions consist of granulomas which usually undergo tissue lesions consist of granulomas which usually undergo central caseation necrosis. Local symptoms of TB vary central caseation necrosis. Local symptoms of TB vary according to the part affected; acute symptoms include according to the part affected; acute symptoms include hectic fever, sweats, and emaciation; serious complications hectic fever, sweats, and emaciation; serious complications include granulomatous erosion of pulmonary bronchi include granulomatous erosion of pulmonary bronchi associated with hemoptysis. If untreated, progressive TB associated with hemoptysis. If untreated, progressive TB may be associated with a high degree of mortality. This may be associated with a high degree of mortality. This infection is frequently observed in immunocompromised infection is frequently observed in immunocompromised individuals with AIDS or a history of illicit IV drug use.individuals with AIDS or a history of illicit IV drug use.

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Confuses definitions with Confuses definitions with descriptionsdescriptions

TuberculosisTuberculosis =Def. =Def.A chronic, recurrent infection caused by the bacterium A chronic, recurrent infection caused by the bacterium Mycobacterium tuberculosis. Mycobacterium tuberculosis. Tuberculosis (TB) may affect Tuberculosis (TB) may affect almost any tissue or organ of the body with the lungs being almost any tissue or organ of the body with the lungs being the most common site of infection. The clinical stages of TB the most common site of infection. The clinical stages of TB are primary or initial infection, latent or dormant infection, are primary or initial infection, latent or dormant infection, and recrudescent or adult-type TB. Ninety to 95% of primary and recrudescent or adult-type TB. Ninety to 95% of primary TB infections may go unrecognized. Histopathologically, TB infections may go unrecognized. Histopathologically, tissue lesions consist of granulomas which usually undergo tissue lesions consist of granulomas which usually undergo central caseation necrosis. Local symptoms of TB vary central caseation necrosis. Local symptoms of TB vary according to the part affected; acute symptoms include according to the part affected; acute symptoms include hectic fever, sweats, and emaciation; serious complications hectic fever, sweats, and emaciation; serious complications include granulomatous erosion of pulmonary bronchi include granulomatous erosion of pulmonary bronchi associated with hemoptysis. If untreated, progressive TB associated with hemoptysis. If untreated, progressive TB may be associated with a high degree of mortality. This may be associated with a high degree of mortality. This infection is frequently observed in immunocompromised infection is frequently observed in immunocompromised individuals with AIDS or a history of illicit IV drug use.individuals with AIDS or a history of illicit IV drug use.

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A better definitionA better definitionTuberculosisTuberculosis Definition:Definition:A chronic, recurrent infection caused A chronic, recurrent infection caused

by the bacterium Mycobacterium by the bacterium Mycobacterium tuberculosis. tuberculosis.

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DuratecDuratec, , LactobutyrinLactobutyrin, , StilbeneStilbene AldehydeAldehyde

are classified by the NCIT as are classified by the NCIT as Unclassified Drugs and ChemicalsUnclassified Drugs and Chemicals

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NCIT recognizes threeNCIT recognizes three disjoint classes of plantsdisjoint classes of plants

Vascular PlantVascular PlantNon-vascular PlantNon-vascular PlantOther PlantOther Plant

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and three kinds of cellsand three kinds of cells

Abnormal CellAbnormal Cell is a top-level class (thus is a top-level class (thus not subsumed by not subsumed by CellCell ) )

Normal CellNormal Cell is a subclass of is a subclass of MicroanatomyMicroanatomy. .

Cell Cell is a subclass of is a subclass of Other Anatomic Other Anatomic Concept Concept (so that cells themselves are (so that cells themselves are concepts) concepts)

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NCIT as now constituted NCIT as now constituted will block automatic will block automatic

reasoningreasoning

Neither Neither Normal CellsNormal Cells nor nor Abnormal Abnormal CellsCells are are CellsCells within the context of within the context of the NCIT the NCIT

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UMLS Semantic UMLS Semantic NetworkNetwork

Alexa McCray, “An upper level Alexa McCray, “An upper level ontology for the biomedical ontology for the biomedical domain”. domain”. Comp Functional Comp Functional Genomics Genomics 2003; 4: 80-84.2003; 4: 80-84.

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UMLS Semantic UMLS Semantic NetworkNetwork

ProsProsBroad coverage; no multiple inheritanceBroad coverage; no multiple inheritanceConsConsIncoherent use of ‘conceptual entities’ Incoherent use of ‘conceptual entities’ (e.g. the digestive system as a(e.g. the digestive system as a

conceptual part conceptual part of the organism)of the organism)

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UMLS Semantic NetworkUMLS Semantic Network

Edges in the graph represent merely Edges in the graph represent merely “possible significant relations” :“possible significant relations” :– Bacterium Bacterium causes causes Experimental Model Experimental Model

of Diseaseof Disease– Experimental Model of Disease Experimental Model of Disease affectsaffects

FungusFungus– Experimental model of diseaseExperimental model of disease is_a is_a

Pathologic FunctionPathologic Function

3636a hodgepodge of ‘concepts’

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location_oflocation_of

Tissue Tissue location_oflocation_of Mental or Mental or Behavioral DysfunctionBehavioral Dysfunction

Fungus Fungus location_oflocation_of VitaminVitamin

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Fungus Fungus location_oflocation_of VitaminVitamin

Every instance of fungus is located in Every instance of fungus is located in some vitamin?some vitamin?

Every instance of fungus is located in Every instance of fungus is located in every vitamin?every vitamin?

Some instances of fungus are located Some instances of fungus are located in some vitamins?in some vitamins?

Some instances of vitamin have Some instances of vitamin have instances of fungi located in them?instances of fungi located in them?

3939what are the nodes in this graph?

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A is_a B A is_a B =Def. =Def. A A is narrower in meaning than is narrower in meaning than BB

A disrupts BA disrupts BA contained_in BA contained_in B

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Drug Delivery Device contains Drug Delivery Device contains Clinical Drug Clinical Drug

Drug Delivery Device Drug Delivery Device narrower_in_meaning_than narrower_in_meaning_than Manufactured ObjectManufactured Object

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General Ontological Overview

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Good ontologies require:Good ontologies require:Consistent use of terms, supported Consistent use of terms, supported by logically coherent (non-circular) by logically coherent (non-circular) definitions, in equivalent human-definitions, in equivalent human-readable and computable formatsreadable and computable formats

Coherent shared treatment of Coherent shared treatment of relations to allow cascading relations to allow cascading inference both within and between inference both within and between ontologiesontologies

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Three fundamental Three fundamental dichotomiesdichotomies

continuants vs. occurrentscontinuants vs. occurrents dependent vs. independent dependent vs. independent types vs. instancestypes vs. instances

ONTOLOGIES AREONTOLOGIES AREREPRESENTATIONS OF REPRESENTATIONS OF

TYPESTYPES

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ONTOLOGIES AREONTOLOGIES AREREPRESENTATIONS OF REPRESENTATIONS OF

TYPESTYPES

aka kinds, universals, aka kinds, universals, categories, species, genera, categories, species, genera,

......

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Molecules, cell components , Molecules, cell components , organisms organisms are independent are independent continuants which continuants which have have functionsfunctions

FunctionsFunctions are dependent continuants are dependent continuants which which become realized become realized through special through special sorts of processes we call functioningssorts of processes we call functionings

ProcessesProcesses (occurrents) include: (occurrents) include: functionings, side-effects, stochastic functionings, side-effects, stochastic processesprocesses

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Continuants (aka endurants)Continuants (aka endurants)– have continuous existence in timehave continuous existence in time– preserve their identity through changepreserve their identity through change– exist exist in totoin toto whenever they exist at all whenever they exist at all

Occurrents (aka processes)Occurrents (aka processes)– have temporal partshave temporal parts– unfold themselves in successive unfold themselves in successive

phasesphases– exist only in their phasesexist only in their phases

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YouYou are a continuant are a continuantYour Your lifelife is an occurrent is an occurrent

YouYou are 3-dimensional are 3-dimensionalYour Your lifelife is 4-dimensional is 4-dimensional

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Dependent entitiesDependent entities

require independent continuants as require independent continuants as their bearerstheir bearers

There is no grin without a catThere is no grin without a cat

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Dependent vs. independent Dependent vs. independent continuantscontinuants

Independent continuants (organisms, Independent continuants (organisms, cells, molecules, environments)cells, molecules, environments)

Dependent continuants (qualities, Dependent continuants (qualities, shapes, roles, propensities, shapes, roles, propensities, functionsfunctions))

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All occurrents are All occurrents are dependent entitiesdependent entities

They are dependent on those They are dependent on those independent continuants which are independent continuants which are their participants (agents, patients, their participants (agents, patients, media ...)media ...)

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Top-Level OntologyTop-Level Ontology

ContinuantOccurrent

(always dependent on one or more

independent continuants)

IndependentContinuant

DependentContinuant

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= A representation of top-level = A representation of top-level typestypes

Continuant Occurrent


DependentContinuant

cell component

biological process

molecular function

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DependentContinuant Functioning Side-Effect,

Stochastic Process, ...

Function

5555




DependentContinuant Functioning Side-Effect,

Stochastic Process, ...

Function

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DependentContinuant

Quality Function Spatial Region

Functioning Side-Effect, Stochastic Process, ...

instances (in space and time)

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Smith B, Ceusters W, Kumar A, Rosse C. On Carcinomas and Other Pathological Entities, Comp Functional Genomics, Apr. 2006

http://ontology.buffalo.edu/bio/ISMB/ISMB_Bio-ontologies.pdf

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everything here is an independent continuant

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Functions, etc.Functions, etc.

Some dependent continuants Some dependent continuants are are realizablerealizable

expression of a geneexpression of a geneapplication of a therapyapplication of a therapycourse of a diseasecourse of a diseaseexecution of an algorithmexecution of an algorithmrealization of a protocolrealization of a protocol

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Functions vs Functions vs FunctioningsFunctionings

the function of your heart = to pump the function of your heart = to pump blood in your bodyblood in your bodythis function is this function is realizedrealized in processes in processes of pumping blood of pumping blood not all functions are not all functions are realized realized (consider the function of this (consider the function of this sperm ...)sperm ...)

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The OBO FoundryThe OBO Foundry

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High quality shared High quality shared ontologies ontologies

build communitiesbuild communitiesGeneral trend on the part of NIH, FDA General trend on the part of NIH, FDA and other bodies to consolidate and other bodies to consolidate ontology-based standards for the ontology-based standards for the communication and processing of communication and processing of biomedical data. biomedical data.

caBIG / NECTAR / BIRN / BRIDG / OBO caBIG / NECTAR / BIRN / BRIDG / OBO ......

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Responses to this trendResponses to this trend

Old style: UMLS (Unified Medical Old style: UMLS (Unified Medical Language System) – rooted in Language System) – rooted in faithfulness to the ways language is faithfulness to the ways language is used by different medical used by different medical communitiescommunities

New style: OBO Foundry – pre-emptive New style: OBO Foundry – pre-emptive regimentation of language, structure regimentation of language, structure and formatand format

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Two strategies for creating Two strategies for creating terminologies and database terminologies and database

schemasschemas Ad hoc creation by each clinical or research Ad hoc creation by each clinical or research

communitycommunityvs.vs.Pre-established reference ontologies upon Pre-established reference ontologies upon which specific local applications can drawwhich specific local applications can draw

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We know that high-quality We know that high-quality ontologies can helpontologies can help

in creating better mappings between in creating better mappings between human and model organism human and model organism phenotypesphenotypes

S Zhang, O Bodenreider, “Alignment of S Zhang, O Bodenreider, “Alignment of Multiple Ontologies of Anatomy: Deriving Multiple Ontologies of Anatomy: Deriving Indirect Mappings from Direct Mappings to Indirect Mappings from Direct Mappings to a Reference Ontology”, AMIA 2005a Reference Ontology”, AMIA 2005

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The solutionThe OBO FoundryThe OBO Foundry

http://ontology.buffalo.edu/obofoundry

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Goals: Goals: to create the conditions for a step-to create the conditions for a step-by-step evolution towards robust by-step evolution towards robust gold standardgold standard reference ontologies in reference ontologies in the biomedical domainthe biomedical domainto introduce some of the features of to introduce some of the features of scientific peer reviewscientific peer review into biomedical into biomedical ontology developmentontology development


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Goal:Goal:to create controlled vocabularies for to create controlled vocabularies for use by clinical trial banks, clinical use by clinical trial banks, clinical guidelines bodies, scientific guidelines bodies, scientific journals, ...journals, ...


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OBO FoundryOBO Foundry

A subset of OBO ontologies whose developers A subset of OBO ontologies whose developers agree in advance to accept a common set of agree in advance to accept a common set of principles designed to assure principles designed to assure – intelligibility to biologist curators, annotators, usersintelligibility to biologist curators, annotators, users– formal robustness formal robustness – stabilitystability– compatibilitycompatibility– interoperability interoperability – support for logic-based reasoningsupport for logic-based reasoning


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OBO FoundryOBO Foundry– OBO-UBO / Ontology of Biomedical RealityOBO-UBO / Ontology of Biomedical Reality– OBO Relation OntologyOBO Relation Ontology– Gene OntologyGene Ontology– Sequence OntologySequence Ontology– RNA OntologyRNA Ontology– PATO Phenotype OntologyPATO Phenotype Ontology– FuGO Functional Genomics Investigation FuGO Functional Genomics Investigation

OntologyOntology– Mk. II NCI ThesaurusMk. II NCI Thesaurus– FMA (?)FMA (?)


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A reference ontologyA reference ontology

is analogous to a scientific theory; it is analogous to a scientific theory; it seeks to optimize representational seeks to optimize representational adequacy to its subject matter to the adequacy to its subject matter to the maximal degree that is compatible maximal degree that is compatible with the constraints of computational with the constraints of computational usefulness. usefulness.

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An application ontologyAn application ontologyis comparable to an engineering artifact is comparable to an engineering artifact such as a software tool. It is constructed such as a software tool. It is constructed for a specific practical purpose.for a specific practical purpose.

Examples: Examples: NCITNCIT

FuGO Functional Genomics Investigation FuGO Functional Genomics Investigation OntologyOntology

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Reference Ontology vs. Reference Ontology vs. Application OntologyApplication Ontology

Currently application ontologies are often Currently application ontologies are often built afresh for each new task; commonly built afresh for each new task; commonly introducing not only idiosyncrasies of format introducing not only idiosyncrasies of format or logic, but also simplifications or or logic, but also simplifications or distortions of their subject-matters. distortions of their subject-matters. To solve this problem application ontology To solve this problem application ontology development shoud take place always development shoud take place always against the background of a formally robust against the background of a formally robust reference ontology frameworkreference ontology framework

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CRITERIACRITERIA

http://ontology.buffalo.edu/obofoundryhttp://ontology.buffalo.edu/obofoundry


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The ontology isThe ontology is open open and available to be used by and available to be used by all.all.

The developers of the ontology agree in advance The developers of the ontology agree in advance to to collaborate collaborate with developers of other OBO with developers of other OBO Foundry ontology where domains overlap.Foundry ontology where domains overlap.

The ontology is in, or can be instantiated in, a The ontology is in, or can be instantiated in, a common formal languagecommon formal language..

The ontology possesses a The ontology possesses a unique identifier unique identifier space space within OBO. within OBO.

The ontology provider has procedures for The ontology provider has procedures for identifying distinct successive identifying distinct successive versionsversions. .

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The ontology has a clearly specified and The ontology has a clearly specified and clearly clearly delineated content.delineated content.

The ontology includes The ontology includes textual definitionstextual definitions for all for all terms. terms.

The ontology is The ontology is well-documented.well-documented.The ontology has a plurality of The ontology has a plurality of independent independent

usersusers..The ontology uses relations which are The ontology uses relations which are

unambiguously defined following the unambiguously defined following the pattern of definitions laid down in the pattern of definitions laid down in the OBO OBO Relation OntologyRelation Ontology..

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CRITERIACRITERIA

Further criteria will be added over Further criteria will be added over time in order to bring about a time in order to bring about a gradual improvement in the quality gradual improvement in the quality of the ontologies in the Foundryof the ontologies in the Foundry


7878

Advantages of the Advantages of the methodology of shared methodology of shared

coherently defined coherently defined definitionsdefinitions

promotes quality assurance (better promotes quality assurance (better coding)coding)

guarantees automatic reasoning guarantees automatic reasoning across ontologies and across data at across ontologies and across data at different granularitiesdifferent granularities

yields direct connection to temporally yields direct connection to temporally indexed instance dataindexed instance data

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Rules for Good Rules for Good OntologiesOntologies

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A basic distinctionA basic distinctiontype vs. instancetype vs. instance

science text vs. clinical documentscience text vs. clinical document

‘‘man’man’ vs. ‘Michael’vs. ‘Michael’

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Instances are not Instances are not represented in an represented in an

ontologyontologyFor ontology, it is the scientific For ontology, it is the scientific generalizations that are importantgeneralizations that are important

(but instances must still be taken (but instances must still be taken into account)into account)

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A A 515287 515287 DC3300 Dust Collector DC3300 Dust Collector FanFan

B B 521683 521683 Gilmer BeltGilmer BeltC C 521682 521682 Motor Drive BeltMotor Drive Belt

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Ontology Types Ontology Types InstancesInstances

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Ontology = Ontology = A Representation of TypesA Representation of Types

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Each node of an ontology consists of:

• preferred term (aka term)

• term identifier (TUI, aka CUI)

• synonyms

• definition, glosses, comments

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Nodes in an ontology are connected by relations:

primarily: is_a (= is subtype of) and part_of

designed to support search, reasoning and annotation

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siamese

mammal

cat

organism

substancetypestypes

animal

instances

frog

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Motivation: To capture Motivation: To capture realityreality

Inferences and decisions we make are Inferences and decisions we make are based upon what we know of reality.based upon what we know of reality.

An ontology is a computable An ontology is a computable representation of biological reality, representation of biological reality, which is designed to enable a which is designed to enable a computer to reason over the data we computer to reason over the data we collect about this reality in (some of) collect about this reality in (some of) the ways that we do.the ways that we do.

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ConceptsConcepts

Biomedical ontology integration will never Biomedical ontology integration will never be achieved through integration of be achieved through integration of meanings or conceptsmeanings or concepts

The problem is precisely that different The problem is precisely that different user communities use user communities use different concepts different concepts

Concepts are in your head and will change Concepts are in your head and will change as your understanding changesas your understanding changes

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ConceptsConcepts

Ontologies represent Ontologies represent typestypes: not : not concepts, meanings, ideas ...concepts, meanings, ideas ...

Types exist, with their instances, in Types exist, with their instances, in objective realityobjective reality

– – including types of image, of imaging including types of image, of imaging process, of brain region, of clinical process, of brain region, of clinical procedure, etc.procedure, etc.

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Rules on typesRules on typesDon’t confuse types with wordsDon’t confuse types with wordsDon’t confuse types with conceptsDon’t confuse types with conceptsDon’t confuse types with ways of Don’t confuse types with ways of

getting to know typesgetting to know typesDon’t confuse types with ways of Don’t confuse types with ways of

talking about typestalking about typesDon’t confuses types with data about Don’t confuses types with data about

typestypes

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Some other simple rules for Some other simple rules for high quality ontologieshigh quality ontologies

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Univocity Univocity

Terms should have the same meanings Terms should have the same meanings on every occasion of use.on every occasion of use.

They should refer to the same kinds of They should refer to the same kinds of entities in realityentities in reality

Basic ontological relations such as Basic ontological relations such as is_a is_a and and part_ofpart_of should be used in the should be used in the same way by all ontologiessame way by all ontologies

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PositivityPositivity

Complements of types are not Complements of types are not themselves types. themselves types.

Hence terms such as Hence terms such as non-mammalnon-mammal non-membranenon-membrane other metalworker in New Zealandother metalworker in New Zealand

do not designate types in realitydo not designate types in reality

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Ontology of types Ontology of types logic of logic of termsterms

There are no conjunctive and disjunctive There are no conjunctive and disjunctive types: types:

anatomic structure, system, or anatomic structure, system, or substancesubstance

musculoskeletal and connective tissue musculoskeletal and connective tissue disorderdisorder

rheumatism, excluding the backrheumatism, excluding the back

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ObjectivityObjectivity

Which types exist in reality is not a Which types exist in reality is not a function of our knowledge.function of our knowledge.

Terms such asTerms such asunknownunknownunclassifiedunclassifiedunlocalizedunlocalizedarthropathies not otherwise specifiedarthropathies not otherwise specified

do not designate types in reality.do not designate types in reality.

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Keep Epistemology Separate Keep Epistemology Separate from Ontologyfrom Ontology

If you want to say that If you want to say that We do not know where We do not know where A’A’ss are locatedare located

do not invent a new class of do not invent a new class of A’s with unknown locationsA’s with unknown locations(A well-constructed ontology should grow (A well-constructed ontology should grow linearly; it should not need to linearly; it should not need to delete delete classes or relations because of classes or relations because of increases increases in in knowledge)knowledge)

9898

Syntactic SeparatenessSyntactic SeparatenessDo not confuse sentences with termsDo not confuse sentences with terms

If you want to sayIf you want to say

I surmise that this is a case of I surmise that this is a case of pneumoniapneumonia

do not invent a new class of do not invent a new class of surmised surmised pneumoniaspneumonias

9999

Single InheritanceSingle Inheritance

No kind in a classificatory No kind in a classificatory hierarchy should have more hierarchy should have more than one than one is_a is_a parent on the parent on the immediate higher levelimmediate higher level

100100

Multiple InheritanceMultiple Inheritance

thingthing

carcar

blue thingblue thing

blue carblue car

is_a is_a

101101


is a source of errorsis a source of errorsencourages lazinessencourages lazinessserves as obstacle to integration with serves as obstacle to integration with

neighboring ontologiesneighboring ontologieshampers use of Aristotelian hampers use of Aristotelian

methodology for defining termsmethodology for defining terms

102102


thingthing

carcar

blue thingblue thing

blue carblue car

is_a1 is_a2

103103

is_ais_a Overloading Overloading

The success of ontology alignment The success of ontology alignment demands that ontological relations demands that ontological relations ((is_a, part_of, ...is_a, part_of, ...) have the same ) have the same meanings in the different ontologies meanings in the different ontologies to be aligned. to be aligned.

104104

Example: Example: is_a is_a is pressed into is pressed into service by the GO to express service by the GO to express

locationlocationis-located-at is-located-at and similar relations and similar relations are expressed by creating special are expressed by creating special compound terms using:compound terms using:site of …site of …… … within …within …… … in …in …extrinsic to …extrinsic to …yielding associated errorsyielding associated errors

105105

e.g. errors with ‘within’e.g. errors with ‘within’lytic vacuole within a protein storage lytic vacuole within a protein storage

vacuolevacuole

lytic vacuole within a protein storage lytic vacuole within a protein storage vacuole vacuole is-a is-a protein storage vacuoleprotein storage vacuole

Compare:Compare:embryo within a uterus embryo within a uterus is-a is-a uterusuterus

106106

similar problems with similar problems with part_ofpart_of

extrinsic to membrane extrinsic to membrane part_of part_of membranemembrane

107107

CompositionalityCompositionality

The meanings of compound terms The meanings of compound terms should be determined should be determined 1. by the meanings of component 1. by the meanings of component termsterms

together withtogether with2. the rules governing syntax2. the rules governing syntax

108108

Why do we need Why do we need rules/standards for good rules/standards for good

ontology?ontology?Ontologies must be intelligible both to humans Ontologies must be intelligible both to humans

(for annotation and curation) and to (for annotation and curation) and to machines (for reasoning and error-checking): machines (for reasoning and error-checking): the lack of rules for classification leads to the lack of rules for classification leads to human error and blocks automatic reasoning human error and blocks automatic reasoning and error-checkingand error-checking

Intuitive rules facilitate training of curators and Intuitive rules facilitate training of curators and annotatorsannotators

Common rules allow alignment with other Common rules allow alignment with other ontologiesontologies

109109

OBO Relation OntologyOBO Relation Ontology

110110

First stepFirst step

Alignment of OBO Foundry ontologies Alignment of OBO Foundry ontologies through a common system of through a common system of formally defined relations in the OBO formally defined relations in the OBO Relation OntologyRelation Ontology

See “Relations in Biomedical See “Relations in Biomedical Ontologies”, Ontologies”, Genome Biology Genome Biology Apr. Apr. 20052005

111111

Judith Blake:Judith Blake:

““The use of bio-ontologies … ensures The use of bio-ontologies … ensures consistency of data curation, consistency of data curation, supports extensive data integration, supports extensive data integration, and enables robust exchange of and enables robust exchange of information between heterogeneous information between heterogeneous informatics systems. .. informatics systems. .. ontologies … formally define ontologies … formally define relationships between the concepts.”relationships between the concepts.”

112112

"Gene Ontology: Tool for "Gene Ontology: Tool for the Unification of Biology"the Unification of Biology"

an ontology "comprises a set of well-an ontology "comprises a set of well-defined terms with well-defined defined terms with well-defined relationships" relationships" (Ashburner (Ashburner et alet al., 2000, p. 27)., 2000, p. 27)

113113

is_a is_a ((sensusensu UMLS) UMLS)A A is_ais_a B = B =defdef

‘‘A A ’ is narrower in meaning than ‘’ is narrower in meaning than ‘B B ’’

grows out of the heritage of grows out of the heritage of dictionariesdictionaries

(which ignore the basic distinction (which ignore the basic distinction between types and instances)between types and instances)

114114

is_ais_a

congenital absent nipple is_a nipplecongenital absent nipple is_a nipplecancer documentation is_a cancercancer documentation is_a cancerdisease prevention is_a diseasedisease prevention is_a diseaseNazism is_a social scienceNazism is_a social science

115115

is_a is_a (sensu logic)(sensu logic)A A is_ais_a B = B =defdef

For all For all x, x, if if x x instance_of instance_of A A then then x x instance_of instance_of BB

cell division cell division is_a is_a biological processbiological process

adult adult is_a is_a child ???child ???

116116

Two kinds of entitiesTwo kinds of entities

occurrents occurrents (processes, events, (processes, events, happenings)happenings)cell division, ovulation, deathcell division, ovulation, death

continuantscontinuants (objects, qualities, ...) (objects, qualities, ...)cell, ovum, organism, temperature of cell, ovum, organism, temperature of organism, ...organism, ...

117117

is_a is_a (for occurrents)(for occurrents)

A A is_ais_a B = B =defdef

For all For all x, x, if if x x instance_of instance_of A A then then x x instance_of instance_of BB

cell division cell division is_a is_a biological processbiological process

118118

is_a (for continuants)is_a (for continuants)

A A is_ais_a B = B =defdef

For all For all x, t x, t if if x x instance_of instance_of A A at at t t then then x x instance_of instance_of B B at at tt

abnormal cell is_a cellabnormal cell is_a celladult human is_a humanadult human is_a humanbut not: but not: adult is_a childadult is_a child

119119

Part_of Part_of as a relation between as a relation between types is more problematic types is more problematic

than is standardly supposedthan is standardly supposed

heart part_of human being ?heart part_of human being ?human heart part_of human being ?human heart part_of human being ?human being has_part human testis ?human being has_part human testis ?human testis part_of human being ?human testis part_of human being ?

120120

two kinds of parthoodtwo kinds of parthood1.1. between instances:between instances:

Mary’s heart Mary’s heart part_of part_of MaryMarythis nucleus this nucleus part_of part_of this cellthis cell

2.2. between typesbetween typeshuman heart part_of humanhuman heart part_of humancell nucleus part_of cellcell nucleus part_of cell

121121

Definition of Definition of part_of part_of as a as a relation between typesrelation between types

A part_of B =A part_of B =Def Def all all instances of instances of A A are instance-level parts ofare instance-level parts of some some instance of instance of BB

ALL–SOME STRUCTUREALL–SOME STRUCTURE

122122

part_of part_of (for occurrents)(for occurrents)A part_of B =A part_of B =DefDef

For all For all x, x, if if x x instance_of instance_of A A then there then there is some is some y, y y, y instance_of instance_of B B and and x x part_of part_of yywhere ‘where ‘part_ofpart_of’ is the instance-level ’ is the instance-level part relationpart relation

123123

part_of part_of (for continuants)(for continuants)A A part_of part_of B =B =def.def.

For all For all x, t x, t if if x x instance_of instance_of A A at at t t then then there is some there is some y, y y, y instance_of instance_of B B at at t t and and x x part_of part_of yy

where ‘where ‘part_ofpart_of’ is the instance-level ’ is the instance-level part relationpart relation

ALL-SOME ALL-SOME STRUCTURE STRUCTURE

124124

How to use the OBO How to use the OBO Relation OntologyRelation Ontology

Ontologies are representations of types and Ontologies are representations of types and of the relations between typesof the relations between types

The The definitions definitions of these relations involve of these relations involve reference to times and instances, but these reference to times and instances, but these references are washed out when we get to references are washed out when we get to the the assertions assertions (edges) in the ontology(edges) in the ontology

But curators should still be aware of the But curators should still be aware of the underlying definitions when formulating underlying definitions when formulating such assertionssuch assertions

125125

part_of part_of (for occurrents)(for occurrents)A part_of B =A part_of B =DefDef

For all For all x, x, if if x x instance_of instance_of A A then there then there is some is some y, y y, y instance_of instance_of B B and and x x part_of part_of yywhere ‘where ‘part_ofpart_of’ is the instance-level ’ is the instance-level part relationpart relation

126126

A part_of BA part_of B, , B part_of C ...B part_of C ...

The The all-some all-some structure of such structure of such definitions allowsdefinitions allows

cascading of inferences (true path cascading of inferences (true path rule)rule)(i) within ontologies(i) within ontologies(ii) between ontologies(ii) between ontologies(iii) between ontologies and (iii) between ontologies and repositories of instance-datarepositories of instance-data

127127

Strengthened true path Strengthened true path rulerule

Whichever Whichever A A you choose, the instance of you choose, the instance of B B of which it is a part will be included of which it is a part will be included in some in some CC, which will include as part , which will include as part also the also the A A with which you beganwith which you began

The same principle applies to the other The same principle applies to the other relations in the OBO-RO:relations in the OBO-RO:

located_atlocated_at, , transfortransformmationation__ofof, , derivderiveed_from, adjacent_d_from, adjacent_ttoo, etc., etc.

128128

Kinds of relationsKinds of relations

Between types:Between types:– is_ais_a, , part_ofpart_of, ..., ...

Between an instance and a typeBetween an instance and a type– this explosion this explosion instance_ofinstance_of the type the type

explosionexplosionBetween instances:Between instances:

– Mary’s heart Mary’s heart part_ofpart_of Mary Mary

129129

In every ontologyIn every ontologysome terms and some relations are some terms and some relations are primitive primitive = they cannot be defined = they cannot be defined (on pain of infinite regress)(on pain of infinite regress)

Examples of primitive relations:Examples of primitive relations:– identityidentity– instantiationinstantiation– (instance-level) (instance-level) part_ofpart_of– (instance-level) (instance-level)

continuous_withcontinuous_with

130130

Fiat and bona fide boundaries

131131

ContinuityAttachmentAdjacency

132132

everything here is an independent continuant

133133

structures vs. formations = bona fide vs. fiat boundaries

134134

Modes of ConnectionModes of Connection

The body is a highly connected The body is a highly connected entity. entity.

Exceptions: cells floating free in Exceptions: cells floating free in blood.blood.

135135

Modes of ConnectionModes of Connection

Modes of connection:Modes of connection:attached_to attached_to (muscle to bone) (muscle to bone) synapsed_with synapsed_with (nerve to nerve, (nerve to nerve, nerve to muscle)nerve to muscle)

continuous_with continuous_with (= share a fiat (= share a fiat boundary)boundary)

136

articular eminencearticular (glenoid)fossa

ANTERIOR

Attachment, location, containment

137

Containment involves relation to a hole or cavity

1: cavity2: tunnel, conduit (artery)3: mouth; a snail’s shell

138

Fiat vs. Bona Fide Boundaries

Fiat boundary Physical boundary

139

Double Hole Structure

Medium (filling the environing hole)

Tenant (occupying the central hole)

Retainer (a boundary of some surrounding structure)

140

head of condyle

neck of condyle

fossa

fiat boundary

THE THE TEMPOROMANDIBULAR TEMPOROMANDIBULAR

JOINTJOINT

141141

continuous_withcontinuous_with(a relation between instances (a relation between instances which share a fiat boundary)which share a fiat boundary)is always symmetric:is always symmetric:

if if x x continuous_with continuous_with y , y , then then y y continuous_with continuous_with xx

142142

continuous_withcontinuous_with(relation between types)(relation between types)

A continuous_with B A continuous_with B =Def. =Def.

for all for all x, x, if if x x instance-of instance-of A A then there then there is some is some y y such that such that y y instance_ofinstance_of B B and and x x continuous_with continuous_with yy

143143

continuous_withcontinuous_with is not always is not always symmetricsymmetric

Consider Consider lymph node lymph node and and lymphatic lymphatic vessel:vessel:

Each lymph node is continuous with Each lymph node is continuous with some lymphatic vessel, but there are some lymphatic vessel, but there are lymphatic vessels (e.g. lymphs and lymphatic vessels (e.g. lymphs and lymphatic trunks) which are not lymphatic trunks) which are not continuous with any lymph nodescontinuous with any lymph nodes

144144

Adjacent_toAdjacent_toas a relation between types as a relation between types

is not symmetricis not symmetricConsiderConsider

seminal vesicle adjacent_to seminal vesicle adjacent_to urinary bladderurinary bladder

Not: Not: urinary bladderurinary bladder adjacent_to adjacent_to seminal vesicleseminal vesicle

145145

instance levelinstance levelthis nucleus is adjacent to this this nucleus is adjacent to this

cytoplasmcytoplasmimplies:implies:

this cytoplasm is adjacent to this this cytoplasm is adjacent to this nucleusnucleus

type leveltype levelnucleus adjacent_to cytoplasmnucleus adjacent_to cytoplasmNot: Not: cytoplasm adjacent_to nucleuscytoplasm adjacent_to nucleus

146146

ApplicationsApplications

Expectations of symmetry e.g. for Expectations of symmetry e.g. for protein-protein interactions may hold protein-protein interactions may hold only at the instance levelonly at the instance level

if if A A interacts with interacts with BB, it does not follow , it does not follow that that B B interacts with interacts with AA

if if A A is expressed simultaneously with is expressed simultaneously with BB, it does not follow that , it does not follow that B B is is expressed simultaneously withexpressed simultaneously with AA

147

c at t1

C c at t

C1

time

same instance

transformation_of

pre-RNA mature RNAadultchild

148148

transformation_oftransformation_ofA transformation_of B A transformation_of B =Def. =Def. Every instance of Every instance of A A was at some was at some earlier time an instance of earlier time an instance of BB

adult transformation_of childadult transformation_of child

149

C c at t c at t1

C1

tumor development

150

C c at t

C1

c1 at t1

C'

c' at t

time

instances

zygote derives_fromovumsperm

derives_from

151

two continuants fuse to form a new continuant

C c at t

C1

c1 at t1

C'

c' at t fusion

152

one initial continuant is replaced by two successor continuants

C c at t

C1 c1 at t1

C2

c1 at t1

fission

153

one continuant detaches itself from an initial continuant, which itself continues to exist

C c at t c at t1

C1

c1 at t

budding

154

one continuant absorbs a second continuant while itself continuing to exist

C c at t

c at t1

C'

c' at t capture

155155

A suite of defined relations A suite of defined relations between typesbetween types

FoundationFoundational al

is_ais_apart_ofpart_of

SpatialSpatial located_inlocated_incontained_incontained_inadjacent_toadjacent_to

TemporalTemporal transformation_oftransformation_ofderives_fromderives_frompreceded_bypreceded_by

ParticipatioParticipation n

has_participanthas_participanthas_agenthas_agent

156156

To be added to the Relation To be added to the Relation OntologyOntology

lacks lacks (between an instance and a (between an instance and a type, e.g. type, e.g. this fly lacks wingsthis fly lacks wings))

dependent_on dependent_on (between a dependent (between a dependent entity and its carrier or bearer)entity and its carrier or bearer)

quality_of quality_of (between a dependent and (between a dependent and an independent continuant)an independent continuant)

functioning_of functioning_of (between a process (between a process and an independent continuant)and an independent continuant)

157157

Low Hanging FruitLow Hanging FruitOntologies should include only those Ontologies should include only those

relational assertions which hold relational assertions which hold universally (= have the ALL-SOME form)universally (= have the ALL-SOME form)

Often, order will matter here:Often, order will matter here:We can includeWe can include

adult transformation_of childadult transformation_of childbut notbut not

child transforms_into adultchild transforms_into adult

158158


159

GO’s three ontologies

molecular functions

cellular components

biological processes

160160

When a gene is When a gene is identifiedidentified

three types of questions need to be three types of questions need to be addressed: addressed:

1. Where is it located in the cell? 1. Where is it located in the cell? 2. What functions does it have on the 2. What functions does it have on the

molecular level? molecular level? 3. To what biological processes do 3. To what biological processes do

these functions contribute? these functions contribute?

161161

Three granularities:Three granularities:

Cellular (for components)Cellular (for components)Molecular (for functions)Molecular (for functions)Organ + organism (for processes)Organ + organism (for processes)

162162

GO has cellsGO has cellsbut it does not include terms for but it does not include terms for molecules or organisms within any of molecules or organisms within any of its three ontologiesits three ontologiesexcept e.g. GO:0018995 except e.g. GO:0018995 hosthost=Def. Any organism in which another =Def. Any organism in which another organism spends part or all of its life organism spends part or all of its life cycle cycle

163163

Are the relations between Are the relations between functions and processes a functions and processes a

matter of granularity?matter of granularity?

Molecular activities are the ‘building Molecular activities are the ‘building blocks’ of biological processes ?blocks’ of biological processes ?

But they are not allowed to be But they are not allowed to be represented in GO as represented in GO as parts parts of of biological processesbiological processes

164


molecular functions

cellular components

biological processes

165165

What does “function” mean?What does “function” mean?

an entity has a biological function if an entity has a biological function if and only if it is part of an organism and only if it is part of an organism and has a disposition to act reliably and has a disposition to act reliably in such a way as to contribute to the in such a way as to contribute to the organism’s survivalorganism’s survival

the function is this dispositionthe function is this disposition

166166

Improved versionImproved versionan entity has a biological an entity has a biological function if and only if it is part of function if and only if it is part of an organism and has a an organism and has a disposition to act reliably in such disposition to act reliably in such a way as to contribute to the a way as to contribute to the organism’s realization of the organism’s realization of the canonical life plancanonical life plan for an for an organism of that typeorganism of that type

167167

This canonical life plan This canonical life plan might includemight include

canonical embryological canonical embryological developmentdevelopment

canonical growthcanonical growthcanonical reproductioncanonical reproductioncanonical agingcanonical agingcanonical deathcanonical death

168168

The function of the heart is The function of the heart is to to pump bloodpump blood

Not every activity (process) in an Not every activity (process) in an organism is the exercise of a function organism is the exercise of a function – there are – there are – mal mal functioningsfunctionings– side-effects (heart side-effects (heart beatingbeating))– accidents (external accidents (external

interference)interference)– background stochastic activitybackground stochastic activity

169169

KidneyKidney

170170

Nephron

171171

Functional Segments

172172

Functions

173173

FunctionsFunctionsThis is a screwdriverThis is a screwdriverThis is a good screwdriverThis is a good screwdriverThis is a broken screwdriverThis is a broken screwdriver

This is a heartThis is a heartThis is a healthy heartThis is a healthy heartThis is an unhealthy heartThis is an unhealthy heart

174174

Functions are associated with Functions are associated with certain characteristic certain characteristic process process

shapesshapesScrewdriver: rotates and Screwdriver: rotates and

simultaneously moves forward simultaneously moves forward simultaneously transferring torque simultaneously transferring torque from hand and arm to screw from hand and arm to screw

Heart: performs a contracting Heart: performs a contracting movement inwards and an movement inwards and an expanding movement outwardsexpanding movement outwards

175175

Not functioning at allNot functioning at allleads to leads to death,death, modulomodulo internal factors:internal factors:

plasticity plasticity redundancy (2 kidneys)redundancy (2 kidneys)criticality of the system involvedcriticality of the system involved

external factors:external factors:prosthesis (dialysis machines, oxygen tent)prosthesis (dialysis machines, oxygen tent)special environmentsspecial environmentsassistance from other organismsassistance from other organisms

176176

What clinical medicine is What clinical medicine is forfor

to eliminate malfunctioning by fixing to eliminate malfunctioning by fixing broken body partsbroken body parts(or to prevent the appearance of (or to prevent the appearance of malfunctioning by intervening e.g. at malfunctioning by intervening e.g. at the molecular level)the molecular level)

177177

Hypothesis: there are no Hypothesis: there are no ‘bad’ functions‘bad’ functions

It is not the function of an oncogene It is not the function of an oncogene to cause cancer to cause cancer Oncogenes were in every case proto-Oncogenes were in every case proto-oncogenes with functions of their oncogenes with functions of their ownownThey become oncogenes because of They become oncogenes because of bad (non-prototypical) environmentsbad (non-prototypical) environments

178178

Is there an exception for Is there an exception for molecular functions?molecular functions?

Does this apply only to functions on Does this apply only to functions on biological levels of granularitybiological levels of granularity

(= levels of granularity coarser than (= levels of granularity coarser than the molecule) ?the molecule) ?

If pathology is the deviation from If pathology is the deviation from (normal) functioning, does it make (normal) functioning, does it make sense to talk of a pathological sense to talk of a pathological molecule?molecule?

179179

Is there an exception for Is there an exception for molecular functions?molecular functions?

A molecular function is a propensity of a A molecular function is a propensity of a gene product instance to perform actions on gene product instance to perform actions on the molecular level of granularity. the molecular level of granularity. Hypothesis 1: these actions must be reliably Hypothesis 1: these actions must be reliably such as to contribute to biological such as to contribute to biological processes.processes.Hypothesis 2: these actions must be reliably Hypothesis 2: these actions must be reliably such as to contribute to the organism’s such as to contribute to the organism’s realization of the canonical life planrealization of the canonical life plan for an for an organism of that type.organism of that type.

180180

The Gene OntologyThe Gene Ontologyis a canonical ontology – it represents is a canonical ontology – it represents

only what is normal in the realm of only what is normal in the realm of molecular functioningmolecular functioning

181181

The GO is a canonical The GO is a canonical representationrepresentation

““The Gene Ontology is a The Gene Ontology is a computational representation of the computational representation of the ways in which gene products ways in which gene products normally function in the biological normally function in the biological realm”realm”

Nucl. Acids Res. Nucl. Acids Res. 2006: 34.2006: 34.

182182

The FMA is a canonical The FMA is a canonical representationrepresentation

It is a computational representation It is a computational representation of types and relations between types of types and relations between types deduced from the qualitative deduced from the qualitative observations of the observations of the normal normal human human body, which have been refined and body, which have been refined and sanctioned by successive sanctioned by successive generations of anatomists and generations of anatomists and presented in textbooks and atlases of presented in textbooks and atlases of structural anatomy. structural anatomy.

183183

The importance of The importance of pathways (successive pathways (successive

causality)causality)Each stage in the history of a disease Each stage in the history of a disease

presupposes the earlier stagespresupposes the earlier stagesTherefore need to reason across time, Therefore need to reason across time,

tracking the order of events in time, tracking the order of events in time, using relations such as using relations such as derives_fromderives_from, , transformation_of ...transformation_of ...

Need pathway ontologies on every Need pathway ontologies on every level of granularitylevel of granularity

184184

The importance of The importance of granularity (simultaneous granularity (simultaneous

causality)causality)Networks are continuantsNetworks are continuantsAt any given time there are networks At any given time there are networks

existing in the organism at different levels existing in the organism at different levels of granularityof granularity

Changes in one cause simultaneous changes Changes in one cause simultaneous changes in all the othersin all the others

(Compare Boyle’s law: a rise in temperature (Compare Boyle’s law: a rise in temperature causes a simultaneous increase in causes a simultaneous increase in pressure)pressure)

185185

The Granularity GulfThe Granularity Gulfmost existing data-sources are of most existing data-sources are of

fixed, single granularityfixed, single granularitymany (all?) clinical phenomena many (all?) clinical phenomena

crosscross granularities granularitiesTherefore need to reason across Therefore need to reason across

time, tracking the order of events time, tracking the order of events in timein time

186


molecular function

cellular component

biological processdependent

independent

187


molecular function

cellular component

organism-level

biological process

cellularprocess

188

molecular function

molecule

cellularprocess

cellular component

organism-level

biological process

organism

Normalization of Granular Levels

189

molecule cellular component

molecular function

cellularfunction

organism-level

biological function

organism

molecular process

cellularprocess

organism-level

biological process

190

moleculecellular

component

molecular function

cellularfunction

organism-level

biological function

organism

molecular process

cellularprocess

organism-level

biological process

functioning functioning functioning

191


molecular function

cellularfunction

organism-level

biological function

organism

molecular process

cellularprocess

organism-level

process

functioningsfunctionings functionings

molecularlocation

cellular location

organism-level

location

192192

The GO is a canonical The GO is a canonical representationrepresentation

““The Gene Ontology is a The Gene Ontology is a computational representation of the computational representation of the ways in which gene products ways in which gene products normally function in the biological normally function in the biological realm”realm”

Nucl. Acids Res. Nucl. Acids Res. 2006: 34.2006: 34.

193


molecular function

cellularfunction

organism-level

biological function

organism

molecular process

cellularprocess

organism-level

process


everything here is typical

194194

The Methodology of The Methodology of AnnotationsAnnotations

Scientific curators use experimental Scientific curators use experimental observations reported in the biomedical observations reported in the biomedical literature to link gene products with GO literature to link gene products with GO terms in terms in annotationsannotations. .

The gene annotations taken together yield a The gene annotations taken together yield a slowly growing computer-interpretable map slowly growing computer-interpretable map of biological reality.of biological reality.

The process of annotating literature also leads The process of annotating literature also leads to improvements and extensions of the to improvements and extensions of the ontology, which institutes a virtuous cycle of ontology, which institutes a virtuous cycle of improvement in the quality and reach of improvement in the quality and reach of both future annotations and the ontology both future annotations and the ontology itself. itself.

195195

When we annotate the When we annotate the record of an experimentrecord of an experiment

we use terms representing we use terms representing types types to capture to capture what we learn about:what we learn about:– this experiment (instance), performed here this experiment (instance), performed here

and now, in this laboratoryand now, in this laboratory– the instances experimented upon the instances experimented upon These instances are typical = they are These instances are typical = they are representatives of types representatives of types – of experiment (described in FuGO)of experiment (described in FuGO)– of gene product molecules, molecular of gene product molecules, molecular

functions, cellular components, biological functions, cellular components, biological processes (described in GO)processes (described in GO)

196196

Experimental recordsExperimental recordsdocument a variety of instances document a variety of instances (particular real-world examples or (particular real-world examples or cases), ranging from instances of cases), ranging from instances of gene products (including individual gene products (including individual molecules) to instances of molecules) to instances of biochemical processes, molecular biochemical processes, molecular functions, and cellular locationsfunctions, and cellular locations

197197

Experimental recordsExperimental recordsprovide evidence that gene products of provide evidence that gene products of given types have molecular functions of given types have molecular functions of given types by documenting occurrences given types by documenting occurrences in the real world that involve in the real world that involve corresponding instances of functioning. corresponding instances of functioning.

They document the existence of real-world They document the existence of real-world molecules that have the potential to molecules that have the potential to execute (carry out, realize, perform) the execute (carry out, realize, perform) the types of molecular functions that are types of molecular functions that are involved in these occurrences. involved in these occurrences.

198198

GlossaryGlossary

Instance: Instance: A particular entity in spatio-A particular entity in spatio-temporal reality. temporal reality.

Type: Type: A general kind instantiated by A general kind instantiated by an open-ended totality of instances an open-ended totality of instances which share certain qualities and which share certain qualities and propensities in common of the sort propensities in common of the sort that can be documented in scientific that can be documented in scientific literatureliterature

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GlossaryGlossaryGene product instance: Gene product instance: A molecule A molecule

thatthat is generated by the expression is generated by the expression of a DNA sequence and which plays of a DNA sequence and which plays some significant role in the biology of some significant role in the biology of the organism. the organism.

Gene product type:Gene product type: A type of gene A type of gene product instance.product instance.

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GlossaryGlossaryBiological process instance (aka Biological process instance (aka

“occurrence”):“occurrence”): A change or A change or complex of changes on the level of complex of changes on the level of granularity of the cell or organism, granularity of the cell or organism, mediated by one or more gene mediated by one or more gene products.products.

Biological process type:Biological process type: A type of A type of biological process instance.biological process instance.

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Cellular component instance: Cellular component instance: A part of a A part of a cell, including cellular structures, cell, including cellular structures, macromolecular complexes and spatial macromolecular complexes and spatial locations identified in relation to the celllocations identified in relation to the cell

Cellular component type:Cellular component type: A type of A type of cellular component. cellular component.

GlossaryGlossary

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Molecular function instance: Molecular function instance: The The propensity of a gene product propensity of a gene product instance to perform actions, such as instance to perform actions, such as catalysis or binding, on the molecular catalysis or binding, on the molecular level of granularity. level of granularity.

Molecular function type: Molecular function type: A type of A type of molecular function instance. molecular function instance.

GlossaryGlossary

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Molecular function execution instance Molecular function execution instance (aka “functioning”): (aka “functioning”): A process instance A process instance on the molecular level of granularity that on the molecular level of granularity that is the result of the action of a gene is the result of the action of a gene product instance.product instance.

Molecular function execution type: Molecular function execution type: A A type of molecular function execution type of molecular function execution instance (aka “a type of functioning”)instance (aka “a type of functioning”)

GlossaryGlossary

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Should ‘activity’ be dropped Should ‘activity’ be dropped from Molecular Function from Molecular Function

terms?terms?Pro:Pro:Functions are never activities (they are Functions are never activities (they are

propensities)propensities)Many functions are never realizedMany functions are never realizedThe current remedy is ugly The current remedy is ugly The current remedy is not universally acceptable The current remedy is not universally acceptable

((structural constituent of bonestructural constituent of bone))Con:Con:Much renaming work would be needed to advance Much renaming work would be needed to advance

clarityclarity

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Should the Molecular Should the Molecular Function ontology be Function ontology be

renamed?renamed?ProProCould keep ‘activity’ Could keep ‘activity’ FunctioningsFunctionings are observable, are observable, functionsfunctions

are not are not The GO is interested precisely in The GO is interested precisely in

functionings (not in side effects, functionings (not in side effects, malfunctionings, accidents, stochastic malfunctionings, accidents, stochastic processes)processes)

The GO is interested in how functionings The GO is interested in how functionings contribute to biological processescontribute to biological processes

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Should the Molecular Should the Molecular Function ontology be Function ontology be

renamed?renamed?Biological science is marked precisely by the Biological science is marked precisely by the

dominance of the functional orientation (cf. dominance of the functional orientation (cf. classifications of functions in neuroscience) classifications of functions in neuroscience)

ConclusionConclusionKeep ‘Molecular Function’, drop ‘activity’; Keep ‘Molecular Function’, drop ‘activity’;

rename terms where necessary; but in such rename terms where necessary; but in such a way as to avoid double counting of both a way as to avoid double counting of both molecular functions and molecular molecular functions and molecular functioningsfunctionings

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What will be the structure What will be the structure of the OBO Foundry?of the OBO Foundry?

208

moleculecellular

component

molecular function

cellularfunction

organism-level

biological function

organism

molecular process

cellularprocess

organism-level

process


molecularlocation

cellular locations

organism-level

locations

209

cell (types)

molecular function

(GO)

species

molecular process

cellular anatom

y

anatomy(fly, fish,

human...)

cellularphysiology

organism-levelphysiology

ChEBI,Sequence,

RNA ...

210

cell (types)

molecular function

(GO)

species

molecular process

cellular anatom

y

anatomy(fly, fish, human...)

cellularphysiology


ChEBI,Sequence,

RNA ...

normal(functionings)

211

pathophysiology(disease)

pathoanatomy(fly, fish, human ...)

pathological(malfunctionings)

212

cell (types)

molecular function

(GO)

species

molecular process

cellular anatom

y(GO)


cellularphysiology


ChEBI,Sequence,

RNA ...



213

cell (types)

molecular function

(GO)

species

molecular process

cellular anatom

y


cellularphysiology


ChEBI,Sequence,

RNA ...



phenotype

214

cell (types)

molecular function

(GO)

species

molecular process

cellular anatom

y


cellularphysiology


ChEBI,Sequence,

RNA ...



phenotype

investigation(FuGO)

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EndEnd

Documents

Principles of (Biomedical) Ontology Design