Transcript BFO_and_Disease - Buffalo Ontology Site

BFO, SNOMED and Disease
Barry Smith
IHTSDO, Bethesda, October 8 , 2009
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with acknowledgements to
NLM: 1R21LM009824-01A1
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infectious agent
is_a navigational concept
with acknowledgements to
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NLM: 1R21LM009824-01A1
infectious agent
is_a navigational concept
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with acknowledgements to
NLM: 1R21LM009824-01A1
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with acknowledgements to
NLM: 1R21LM009824-01A1
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with acknowledgements to
NLM: 1R21LM009824-01A1
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with acknowledgements to
NLM: 1R21LM009824-01A1
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with acknowledgements to NLM: 1R21LM009824-01A1
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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
44132006
Abscess (disorder)
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
Independent
Continuant
Occurrent
(Process, Event)
Dependent
Continuant
http://ifomis.uni-saarland.de/bfo/
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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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The OBO Foundry
–
–
–
–
–
–
–
–
–
–
–
–
–
–
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
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RELATION
TO TIME
CONTINUANT
INDEPENDENT
OCCURRENT
DEPENDENT
GRANULARITY
ORGAN AND
ORGANISM
Organism
(NCBI
Taxonomy)
CELL AND
CELLULAR
COMPONENT
Cell
(CL)
MOLECULE
Anatomical
Organ
Entity
Function
(FMA,
(FMP, CPRO) Phenotypic
CARO)
Quality
(PaTO)
Cellular
Cellular
Component Function
(FMA, GO)
(GO)
Molecule
(ChEBI, SO,
RnaO, PrO)
Molecular Function
(GO)
Biological
Process
(GO)
Molecular Process
(GO)
The Open Biomedical Ontologies (OBO) Foundry
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RELATION
TO TIME
CONTINUANT
INDEPENDENT
GRANULARITY
ORGAN AND
ORGANISM
CELL AND
CELLULAR
COMPONENT
MOLECULE
Family, Community,
Deme, Population
Organism
(FMA,
(NCBI
CARO)
Taxonomy)
Cell
(CL)
Cell Component
(FMA,
GO)
Molecule
(ChEBI, SO,
RnaO, PrO)
DEPENDENT
ENVIRONMENT
COMPLEX OF
ORGANISMS
OCCURRENT
Organ
Function
(FMP,
CPRO)
Population
Phenotype
Population
Process
Phenotypic
Quality
(PaTO)
Biological
Process
(GO)
Cellular
Function
(GO)
Molecular Function
(GO)
Molecular
Process
(GO)
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RELATION TO
TIME
GRANULARITY
INDEPENDENT
ORGAN AND
ORGANISM
Organism
(NCBI
Taxonomy)
CELL AND
CELLULAR
COMPONENT
Cell
(CL)
MOLECULE
CONTINUANT
DEPENDENT
Anatomical
Organ
Entity
Function
(FMA,
(FMP, CPRO) Phenotypic
CARO)
Quality
(PaTO)
Cellular
Cellular
Component Function
(FMA, GO)
(GO)
Molecule
(ChEBI, SO,
RNAO, PRO)
OCCURRENT
Molecular Function
(GO)
Organism-Level
Process
(GO)
Cellular Process
(GO)
Molecular
Process
(GO)
rationale of OBO Foundry coverage
(homesteading principle)
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BFO and the 3 Gene Ontologies (GO)
Continuant
Occurrent
biological process
Independent
Continuant
cell component
Dependent
Continuant
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
Independent
Continuant
Dependent
Continuant
Non-realizable
Dependent
Continuant
(quality)
Realizable
Dependent
Continuant
(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
Independent
Continuant
Dependent
Continuant
Non-realizable
Dependent
Continuant
(quality)
Realizable
Dependent
Continuant
(function, role,
disposition)
..... .....
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realization depends_on realizable
Continuant
Independent
Continuant
Dependent
Continuant
bearer
disposition
Occurrent
Process of
realization
.... ..... .......
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Specific Dependence
on 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
Continuant
Independent
Continuant
Dependent
Continuant
thing
quality
Occurrent
process, event
temperature depends
on 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 universal red
instantiates
the particular case
of redness (of a
particular fly eye)
the universal eye
instantiates
an instance of an
depends_on
eye (in a particular
fly)
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color
is_a
red
instantiates
the particular case
of redness (of a
particular fly eye)
anatomical structure
is_a
eye
instantiates
an instance of an
depends on
eye (in a particular
fly)
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depends_on
Continuant
Occurrent
process
Independent
Continuant
Dependent
Continuant
thing
quality
temperature depends
on bearer
.... ..... .......
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Specifically Dependent Continuants
Specifically
Dependent
Continuant
if the bearer ceases to
exist, then its quality,
function, role ceases
to exist
the color of my skin
Quality,
Pattern
Realizable
Dependent
Continuant
the function of my
heart to pump blood
my weight
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Generically Dependent Continuants
if one bearer ceases to
exist, then the entity can
survive, because there
are other bearers
Generically
Dependent
Continuant
(copyability)
the pdf file on my laptop
the DNA (sequence) in
this chromosome
Information
Object
Gene
Sequence
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Continuant
Independent
Continuant
Quality
Role
Occurrent
Specifically
Dependent
Continuant
Realizable
Generically
Dependent
Continuant
Information
Artifact
Disposition
Function
Functioning
Sequence…
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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.
2.
3.
4.
of people (patients, carriers, …)
of diseases (cases, instances, problems, …)
of courses of disease (symptoms, treatments…)
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 continuant
objects
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.
produces
etiological process
bears
disorder
realized_in
disposition
pathological process
produces
diagnosis
interpretive process
produces
signs & symptoms
used_in
abnormal bodily features
recognized_as
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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: baldness
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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 - phenobarbitolinduced 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
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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
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 64
disorder (transient disease course).
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
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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.69