BFO and Disease Barry Smith Milan, September 4, 2009 1

BFO and Disease

Barry Smith

Milan, September 4, 2009

1

BFO

A simple top-level ontology to support information integration in scientific research

No abstracta

Nothing propositional

No overlap with domain ontologies (for society, for information, …) – built by populating downwards

2

Blinding Flash of the Obvious

Continuant Occurrent(Process, Event)

IndependentContinuant

DependentContinuant

http://ifomis.uni-saarland.de/bfo/3

DOLCE taxonomy

QQuality

PQPhysicalQuality

AQAbstractQuality

TQTemporalQuality

PDPerdurant

EVEvent

STVStative

ACHAchievement

ACCAccomplishment

STState

PROProcess

PTParticular

RRegion

PRPhysicalRegion

ARAbstractRegion

TRTemporalRegion

TTimeInterval

SSpaceRegion

ABAbstract

SetFact…

… … …

TLTemporalLocation

SLSpatialLocation

… … …

ASOAgentive Social Object

NASONon-agentive Social Object

SCSociety

MOBMental Object

SOBSocial Object

FFeature

POBPhysicalObject

NPOBNon-physicalObject

PEDPhysicalEndurant

NPEDNon-physicalEndurant

EDEndurant

SAGSocial Agent

APOAgentive Physical Object

NAPONon-agentive Physical Object

…

ASArbitrarySum

MAmount ofMatter

… … … …

DOLCE taxonomy

QQuality

PQPhysicalQuality

AQAbstractQuality

TQTemporalQuality

PDPerdurant

EVEvent

STVStative

ACHAchievement

ACCAccomplishment

STState

PROProcess

PTParticular

RRegion

PRPhysicalRegion

ARAbstractRegion

TRTemporalRegion

TTimeInterval

SSpaceRegion

ABAbstract

SetFact…

… … …

TLTemporalLocation

SLSpatialLocation

… … …

ASOAgentive Social Object

NASONon-agentive Social Object

SCSociety

MOBMental Object

SOBSocial Object

FFeature

POBPhysicalObject

NPOBNon-physicalObject

PEDPhysicalEndurant

NPEDNon-physicalEndurant

EDEndurant

SAGSocial Agent

APOAgentive Physical Object

NAPONon-agentive Physical Object

…

ASArbitrarySum

MAmount ofMatter

… … … …

Example: The Cell Ontology

Benefits of coordination

No need to reinvent the wheel

Can profit from lessons learned through mistakes made by others

Can more easily reuse what is made by others

Can more easily inspect and criticize results of others’ work (PATO)

Leads to innovations (e.g. Mireot) in strategies for combining ontologies

7

Users of BFO

NCI BiomedGT

SNOMED CT

Ontology for General Medical Science (OGMS)

ACGT Clinical Genomics Trials on Cancer – Master Ontology / Formbuilder (Case Report Forms for Cancer Clinical Trials)

8

Users of BFO

MediCognos / Microsoft Healthvault

Cleveland Clinic Semantic Database in Cardiothoracic Surgery

Major Histocompatibility Complex (MHC) Ontology (NIAID)

Neuroscience Information Framework Standard (NIFSTD) and Constituent Ontologies

9

Users of BFO

Interdisciplinary Prostate Ontology (IPO)

Nanoparticle Ontology (NPO): Ontology for Cancer Nanotechnology Research

Neural Electromagnetic Ontologies (NEMO)

ChemAxiom – Ontology for Chemistry

Ontology for Risks Against Patient Safety (RAPS/REMINE) (EU FP7)

IDO Infectious Disease Ontology (NIAID)

10

IDO Consortium

• MITRE, Mount Sinai, UTSouthwestern – Influenza

• IMBB/VectorBase – Vector borne diseases (A. gambiae, A. aegypti, I. scapularis, C. pipiens, P. humanus)

• Colorado State University – Dengue Fever

• Duke University – Tuberculosis, Staph. aureus

• Case Western Reserve – Infective Endocarditis

• University of Michigan – Brucilosis

11

RELATION TO TIME

GRANULARITY

CONTINUANT OCCURRENT

INDEPENDENT DEPENDENT

ORGAN ANDORGANISM

Organism(NCBI

Taxonomy)

Anatomical Entity(FMA, CARO)

OrganFunction

(FMP, CPRO) Phenotypic

Quality(PaTO)

Biological Process

(GO)CELL AND CELLULAR

COMPONENT

Cell(CL)

Cellular Compone

nt(FMA, GO)

Cellular Function

(GO)

MOLECULEMolecule

(ChEBI, SO,RnaO, PrO)

Molecular Function(GO)

Molecular Process

(GO)

The Open Biomedical Ontologies (OBO) Foundry12

Initial Candidate Members– GO Gene Ontology– CL Cell Ontology– SO Sequence Ontology– ChEBI Chemical Ontology – PATO Phenotype (Quality) Ontology– FMA Foundational Model of Anatomy– ChEBI Chemical Entities of Biological Interest – CARO Common Anatomy Reference Ontology – PRO Protein Ontology

The OBO Foundry

13

Under development – Disease Ontology– Infectious Disease Ontology– Mammalian Phenotype Ontology – Plant Trait Ontology– Environment Ontology– Ontology for Biomedical Investigations– Behavior Ontology– RNA Ontology  

The OBO Foundry

14

RELATION TO TIME

GRANULARITY

CONTINUANT OCCURRENT

INDEPENDENT DEPENDENT

COMPLEX OF ORGANISMS

Family, Community,

Deme, Population OrganFunction

(FMP, CPRO)

Population

Phenotype

Population Process

ORGAN ANDORGANISM

Organism(NCBI

Taxonomy)

(FMA, CARO)

Phenotypic Quality(PaTO)

Biological Process

(GO)CELL AND CELLULAR

COMPONENT

Cell(CL)

Cell Com-

ponent(FMA, GO)

Cellular Function

(GO)

MOLECULEMolecule

(ChEBI, SO,RnaO, PrO)

Molecular Function(GO)

Molecular Process

(GO)

E N

V I R

O N

M E

N T

15

CONTINUANT OCCURRENT

INDEPENDENT DEPENDENT

ORGAN ANDORGANISM

Organism(NCBI

Taxonomy)

Anatomical Entity

(FMA, CARO)

OrganFunction

(FMP, CPRO) Phenotypic

Quality(PaTO)

Organism-Level Process

(GO)

CELL AND CELLULAR

COMPONENT

Cell(CL)

Cellular Compone

nt(FMA, GO)

Cellular Function

(GO)

Cellular Process

(GO)

MOLECULEMolecule

(ChEBI, SO,RNAO, PRO)

Molecular Function(GO)

Molecular Process

(GO)

rationale of OBO Foundry coverage (homesteading principle)

GRANULARITY

RELATION TO TIME

16

OBO Foundry organized in terms of Basic Formal Ontology

Each Foundry ontology can be seen as an extension of a single upper level ontology (BFO)

17

BFO and the 3 Gene Ontologies (GO)

Continuant Occurrent

IndependentContinuant

DependentContinuant

cell component

biological process

molecular function

Kumar A., Smith B, Borgelt C. Dependence relationships between Gene Ontology terms based on TIGR gene product annotations. CompuTerm 2004, 31-38.

Bada M, Hunter L. Enrichment of OBO Ontologies. J Biomed Inform. 2006 Jul 26

18

Continuant

IndependentContinuant

DependentContinuant

..... .....

Non-realizableDependentContinuant(quality)

Realizable DependentContinuant(function, role, disposition)

19

Realizable dependent continuants

plan

function

role

disposition

capability

tendency

continuants

20

Their realizations

execution

expression

exercise

realization

application

course

occurrents

21

Continuant

IndependentContinuant

DependentContinuant

..... .....

Non-realizableDependentContinuant(quality)

Realizable DependentContinuant(function, role, disposition)

22

realization depends_on realizable

Continuant Occurrent

IndependentContinuant

bearer

DependentContinuant

disposition

.... ..... .......23

Process of realization

Specific Dependenceon the instance level

a depends_on b =def. a is necessarily such that if b ceases to exist than a ceases to exist

on the type level

A specifically_depends_on B =def. for every instance a of A, there is some instance b of B such that a depends_on b.

24

depends_on

Continuant Occurrent

process, eventIndependentContinuant

thing

DependentContinuant

quality

.... ..... .......temperature dependson bearer

25

Specifically dependent continuants

• the quality of whiteness of this cheese

• your role as lecturer

• the disposition of this patient to experience diarrhea

26

the particular case of redness (of a particular fly eye)

the universal red

instantiates

an instance of an eye (in a particular fly)

the universal eye

instantiates

depends_on

27

the particular case of redness (of a particular fly eye)

red

instantiates

an instance of an eye (in a particular fly)

eye

instantiates

depends on

color anatomical structure

is_a is_a

28

depends_on

Continuant Occurrent

process

IndependentContinuant

thing

DependentContinuant

quality

.... ..... .......temperature dependson bearer

29

Specifically Dependent Continuants

SpecificallyDependentContinuant

Quality, Pattern

Realizable Dependent Continuant

if the bearer ceases to exist, then its quality, function, role ceases to exist

the color of my skin

the function of my heart to pump blood

my weight30

Generically Dependent Continuants

GenericallyDependentContinuant

Information Object

Gene Sequence

if one bearer ceases to exist, then the entity can survive, because there are other bearers

(copyability)

the pdf file on my laptop

the DNA (sequence) in this chromosome 31

Four distinct classificatory tasks

1. of people (patients, carriers, …)

2. of diseases (cases, instances, problems, …)

3. of courses of disease (symptoms, treatments…)

4. of representations (records, observations, data, diagnoses…)

ICD confuses 1. & 2.

HL7, most standard terminologies, confuse 2. and 4

32

Four distinct BFO categories

1. person (patient, carrier, …) – independent continuant

2. disease (case, instance, problem, …) – specifically dependent continuant

3. course of disease (symptom, treatment…)– occurrent

4. representation (record, datum, diagnosis…)– generically dependent continuant

33

Four distinct BFO categories

1. people (patients, carriers, …) – independent continuants

2. disease (case, instance, problem, condition …) – disposition

3. course of disease (symptom, episode, outbreak …)– realization of dispositions

4. representations (records, data, diagnoses…)– generically dependent continuants

34

Disposition

Internally-Grounded Realizable Entity

A disposition is

a realizable entity which is such that, if it ceases to exist, then its bearer is physically changed,

whose realization occurs, in virtue of the bearer’s physical make-up, when this bearer is in some special physical circumstances

35

Disorder

1. person

– independent continuantobjects

fiat object part

object aggregate

36

Disorder

A fiat object part of an organism which serves as the bearer of a disposition of a certain sort

This fiat object may have no determinate boundaries

(compare: Downtown Santa Barbara)

37

Where does Mount Everest begin and end?Cf. Barry Smith and David M. Mark, “Do Mountains Exist?”, Environment and Planning B, 30, 2003.

38

Big Picture (with thanks to Richard Scheuermann)

39

A disease is a disposition rooted in a

physical disorder in the organism and

realized in pathological processes.

etiological process

produces

disorder

bears

disposition

realized_in

pathological process

produces

abnormal bodily features

recognized_as

signs & symptomsinterpretive process

produces

diagnosis

used_in40

Elucidation of Primitive Terms ‘bodily feature’ - an abbreviation for a physical

component, a bodily quality, or a bodily process. disposition - an attribute describing the propensity to

initiate certain specific sorts of processes when certain conditions are satisfied.

clinically abnormal - some bodily feature that (1) is not part of the life plan for an organism of the relevant

type (unlike aging or pregnancy), (2) is causally linked to an elevated risk either of pain or other

feelings of illness, or of death or dysfunction, and (3) is such that the elevated risk exceeds a certain threshold

level.*

*Compare: baldness41

Definitions - Foundational Terms

Disorder =def. – A causally linked combination of physical components that is clinically abnormal.

Pathological Process =def. – A bodily process that is a manifestation of a disorder and is clinically abnormal.

Disease =def. – A disposition (i) to undergo pathological processes that (ii) exists in an organism because of one or more disorders in that organism.

42

Dispositions and Predispositions

All diseases are dispositions; not all dispositions are diseases. A predisposition is a disposition. Predisposition to Disease of Type X =def. – A disposition in an

organism that constitutes an increased risk of the organism’s subsequently developing the disease X.

HNPCC is caused by a disorder (mutation) in a DNA mismatch repair gene that disposes to the acquisition of additional mutations from

defective DNA repair processes, and thus is a predisposition to the development of colon cancer.

43

Definitions - Clinical Evaluation Terms

Sign =def. – A bodily feature of a patient that is observed in a physical examination and is deemed by the clinician to be of clinical significance. (Objectively observable features)

Symptom =def. – A experienced bodily feature of a patient that is observed by and observable only by the patient and is of the type that can be hypothesized by a patient to be a realization of a disease. (A restricted family of phenomena including pain, nausea, anger, drowsiness, which are of their nature experienced in the first person)

Symptoms are subjective. But this does not mean that there is no objective fact of the matter whether a given symptom exists

44

Cirrhosis - environmental exposure Etiological process - phenobarbitol-

induced hepatic cell death produces

Disorder - necrotic liver bears

Disposition (disease) - cirrhosis realized_in

Pathological process - abnormal tissue repair with cell proliferation and fibrosis that exceed a certain threshold; hypoxia-induced cell death produces

Abnormal bodily features recognized_as

Symptoms - fatigue, anorexia Signs - jaundice, splenomegaly

Symptoms & Signs used_in

Interpretive process produces

Hypothesis - rule out cirrhosis suggests

Laboratory tests produces

Test results - elevated liver enzymes in serum used_in

Interpretive process produces

Result - diagnosis that patient X has a disorder that bears the disease cirrhosis

45

Influenza - infectious Etiological process - infection of

airway epithelial cells with influenza virus produces

Disorder - viable cells with influenza virus bears

Disposition (disease) - flu realized_in

Pathological process - acute inflammation produces

Abnormal bodily features recognized_as

Symptoms - weakness, dizziness Signs - fever

Symptoms & Signs used_in

Interpretive process produces

Hypothesis - rule out influenza suggests

Laboratory tests produces

Test results - elevated serum antibody titers used_in

Interpretive process produces

Result - diagnosis that patient X has a disorder that bears the disease flu

But the disorder also induces normal physiological processes (immune response) that can results in the elimination of the disorder (transient disease course).

46

Huntington’s Disease - genetic Etiological process - inheritance of

>39 CAG repeats in the HTT gene produces

Disorder - chromosome 4 with abnormal mHTT bears

Disposition (disease) - Huntington’s disease realized_in

Pathological process - accumulation of mHTT protein fragments, abnormal transcription regulation, neuronal cell death in striatum produces

Abnormal bodily features recognized_as

Symptoms - anxiety, depression Signs - difficulties in speaking and

swallowing

Symptoms & Signs used_in

Interpretive process produces

Hypothesis - rule out Huntington’s suggests

Laboratory tests produces

Test results - molecular detection of the HTT gene with >39CAG repeats used_in

Interpretive process produces

Result - diagnosis that patient X has a disorder that bears the disease Huntington’s disease

47

HNPCC - genetic pre-disposition

Etiological process - inheritance of a mutant mismatch repair gene produces

Disorder - chromosome 3 with abnormal hMLH1 bears

Disposition (disease) - Lynch syndrome realized_in

Pathological process - abnormal repair of DNA mismatches produces

Disorder - mutations in proto-oncogenes and tumor suppressor genes with microsatellite repeats (e.g. TGF-beta R2) bears

Disposition (disease) - non-polyposis colon cancer realized in

Symptoms (including pain)

48

Definition: Etiology

Etiological Process =def. – A process in an organism that leads to a subsequent disorder.

Example: toxic chemical exposure resulting in a mutation in the genomic DNA of a cell; infection of a human with a pathogenic virus; inheritance of two defective copies of a metabolic gene

The etiological process creates the physical basis of that disposition to pathological processes which is the disease.

49

Definitions - Diagnosis

Clinical Picture =def. – A representation of a clinical phenotype that is inferred from the combination of laboratory, image and clinical findings about a given patient.

Diagnosis =def. – A conclusion of an interpretive process that has as input a clinical picture of a given patient and as output an assertion to the effect that the patient has a disease of such and such a type.

50

Definitions - Qualities

Manifestation of a Disease =def. – A bodily feature of a patient that is (a) a deviation from clinical normality that exists in virtue of the realization of a disease and (b) is observable.

Observability includes observable through elicitation of response or through the use of special instruments.

Preclinical Manifestation of a Disease =def. – A manifestation of a disease that exists prior to its becoming detectable in a clinical history taking or physical examination.

Clinical Manifestation of a Disease =def. – A manifestation of a disease that is detectable in a clinical history taking or physical examination.

Phenotype =def. – A (combination of) bodily feature(s) of an organism determined by the interaction of its genetic make-up and environment.

Clinical Phenotype =def. – A clinically abnormal phenotype.

51