bfo, snomed and disease barry smith ihtsdo, bethesda, october 8, 2009 1

BFO, SNOMED and Disease

Barry Smith

IHTSDO, Bethesda, October 8 , 2009

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2with acknowledgements to NLM: 1R21LM009824-01A1

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infectious agentis_a navigational concept

with acknowledgements to NLM: 1R21LM009824-01A1

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infectious agentis_a navigational concept

General comments

Problems with ‘concept’

(no real coherence as to what SNOMED is representing)

Mixing of singulars and plurals

Confusion of disorder (continuants) with etiological and diagnostic processes (occurrents) and information entities (‘findings’)

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Epistemology and Time (from Bill Hogan)

• According to SNOMED-CT User Guide (p. 42):Concepts in [the Clinical Finding] hierarchy represent

the result of a clinical observation, assessment, or judgment, and include both normal and abnormal clinical states.

• So, does a date/time associated with a ‘finding’ refer to:– Date/time that the observation, assessment, or

judgment occurred and thus the result was obtained– Date/time that the entity (that was found) began to

exist– Date/time that entity (that was found) began to

manifest in symptoms, signs, etc.

Epistemology and Combinatorial Explosion (from Bill Hogan)

• Epistaxis/nosebleed– Epistaxis (disorder)– Nosebleed/epistaxis symptom (finding)– On examination - epistaxis (disorder)– Has nosebleeds - epistaxis (disorder)– Evidence of recent epistaxis (finding)

Epistemology and Combinatorial Explosion Explosion (from Bill Hogan)• Rash

– Cutaneous eruption (morphologic abnormality), with synonym Rash

– Eruption of skin (disorder), with synonym Rash– Complaining of a rash (finding)– On examination - a rash (finding)

• Dry skin– Dry skin (finding)– Complaining of dry skin (finding)– On examination - dry skin (finding)– Dry skin dermatitis (disorder)

128477000 Abscess (disorder)

44132006 Abscess (morphologic abnormality)

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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

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Basic Formal Ontology

Continuant Occurrent(Process, Event)

IndependentContinuant

DependentContinuant

http://ifomis.uni-saarland.de/bfo/17

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

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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)

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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

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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)

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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

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– 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– Infectious Disease Ontology– Plant Ontology– Environment Ontology– Ontology for Biomedical Investigations– RNA Ontology

The OBO Foundry

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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) Foundry24

RELATION TO TIME

GRANULARITY



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 Process

(GO)

E N

V I R

O N

M E

N T

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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 Process

(GO)

rationale of OBO Foundry coverage (homesteading principle)

GRANULARITY

RELATION TO TIME

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BFO and the 3 Gene Ontologies (GO)

Continuant Occurrent


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

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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)

either post hoc, as in the case of the GO

or in virtue of creation ab initio via downward population from BFO

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Example: The Cell Ontology

Continuant


DependentContinuant

..... .....

Non-realizableDependentContinuant(quality)

Realizable DependentContinuant(function, role, disposition)

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Realizable dependent continuants

plan

function

role

disposition

capability

tendency

continuants

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Their realizations

execution

expression

exercise

realization

application

course

occurrents

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Continuant


DependentContinuant

..... .....

Non-realizableDependentContinuant(quality)

Realizable DependentContinuant(function, role, disposition)

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realization depends_on realizable



bearer

DependentContinuant

disposition

.... ..... .......34

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.

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depends_on


process, eventIndependentContinuant

thing

DependentContinuant

quality

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

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Specifically dependent continuants

• the quality of whiteness of this cheese

• your role as lecturer

• the disposition of this patient to experience diarrhea

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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

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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

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depends_on


process


thing

DependentContinuant

quality

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

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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 weight41

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 42



SpecificallyDependentContinuant

Quality

Disposition

Functioning

Function

GenericallyDependentContinuant

Realizable

Role

Information Artifact

Sequence…

Realizable dependent continuants

Role: nurse role, pathogen role, food role

Disposition: fragility, virulence, susceptibility, genetic disposition to disease X

Function: to pump (of the heart), to unlock (of the key)

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Role (Externally-Grounded Realizable Entity)

role =def. a realizable entity

• which exists because the bearer is in some special physical, social, or institutional set of circumstances in which the bearer does not have to be, and

• is not such that, if it ceases to exist, then the physical make-up of the bearer is thereby changed.

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Disposition (Internally-Grounded Realizable Entity)

disposition =def.

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

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

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Function (A Disposition Designed or Selected For)

function =def.

a disposition that

exists in virtue of the bearer’s physical make-up,,

and

this physical make-up is something the bearer possesses because it came into being, either through evolution (in the case of natural biological entities) or through intentional design (in the case of artifacts), in order to realize processes of a certain kind.

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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

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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

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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

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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

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Disorder

1. person

– independent continuantobjects

fiat object part

object aggregate

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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)

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

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Big Picture (with thanks to Richard Scheuermann)

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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_in58

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: baldness59

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.

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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.

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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

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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


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

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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


Symptoms - weakness, dizziness Signs - fever



Hypothesis - rule out influenza suggests


Test results - elevated serum antibody titers used_in


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).

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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


Symptoms - anxiety, depression Signs - difficulties in speaking and

swallowing



Hypothesis - rule out Huntington’s suggests


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


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

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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)

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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.

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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.

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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.

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bfo, snomed and disease barry smith ihtsdo, bethesda, october 8, 2009 1

Documents

clinical observation

cancer clinical trials

simple toplevel ontology

rash findingon examination

clinical finding hierarchy

constituent ontologies

information integration

domain ontologies