Towards an Ontological Treatment of Disease and Diagnosis

Towards an Ontological Treatment of Disease and Diagnosis

Barry SmithNew York State Center of Excellence in Bioinformatics and Life Sciences

University at Buffalo

http://ontology.buffalo.edu/smith 1

Anders Grimsmo, “Patients, diagnoses and processes in general practice in the Nordic countries. An attempt to

make data from computerised medical records available for comparable statistics”

Scandinavian Journal of Primary Health Care, 2001

“The major obstacle to extracting more epidemiological data from computerised medical records is caused by information in the databases not being uniquely linked to episodes of care.”


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What is to be linked with what?

What is information in the databases about?To answer this question (to assign numbers to discrete entities), we need a good ontology of the care domain, including episodes of care on the one hand and entities on the side of the patient on the other.

http://ontology.buffalo.edu/smith

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and we need to take account of context

– of multiple diseases– of the patient’s style of life– of the patient’s environment– of specific aspects of the presentation


5

we do this by paying attention to natural language

but the more we succeed in this, the more difficult it is to aggregate the data

disease of UMLSitis


New York State Center of Excellence in Bioinformatics & Life Sciences

R T U New York State Center of Excellence in Bioinformatics & Life Sciences

R T U

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R T U

7



R T UOBO Foundry

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http://www.obofoundry.org/

http://www.obofoundry.org/

11with acknowledgements to NLM: 1R21LM009824-01A1

Buffalo Longitudinal Cancer Data

Even with the best of intentions, and even if we just use one coding system, results are not always what they seem

Problem of SNOMEDitis

Why does SNOMED change so much?

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SNOMED CT: Anaplasma marginale (organism)

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infectious agentis_a navigational concept

with acknowledgements to Werner Ceusters NLM: 1R21LM009824-01A1

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infectious agentis_a navigational concept


• Problems with ‘concept’ no real coherence as to what SNOMED is representing

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• No proper hierarchy (of more and less general)

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

• Confusion of ‘disorders’ with ‘morphological abnormalities’

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SNOMED CT

128477000 Abscess (disorder)44132006 Abscess (morphologic abnormality)

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Epistemology and Combinatorial Explosion

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

from Bill Hogan

Epistemology and Combinatorial Explosion

• 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)

from Bill Hogan

An Alternative: Basic Formal Ontology

360 BC: Aristotle’s Metaphysics 1879: Invention of modern logic (Boole,

Frege) 1920: The problem of the Unity of

Science (Logical Positivism) 1940Birth of computing (Turing)


Ontology Timeline

1970: AI, Robotics (J. McCarthy, P. Hayes)

1980: KIF: Knowledge Interchange Format

1990: Description Logics 2000: Semantic Web (OWL), Protégé 2007: National Center for Biomedical

Ontology (NCBO) Bioportal


Uses of ‘ontology’ in PubMed abstracts

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2000 2001 2002 2003 2004 2005 2006 2007 2008 20090

100

200

300

400

500

600

700

800

900

1000

35 37 69

143

283

412

501

618

860900

Biomedical Ontology in PubMed

By far the most successful: GO (Gene Ontology)

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Ontology Timeline

1990: Human Genome Project 1999: The Gene Ontology (GO) – Model

Organism Research 2005: The Open Biomedical Ontologies

(OBO) Foundry 2010: Ontology for General Medical

Science


The GO is a controlled vocabulary for use in annotating data

multi-species, multi-disciplinary, open source

contributing to the cumulativity of scientific results obtained by distinct research communities

compare use of kilograms, meters, seconds … in formulating experimental results

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NIH Mandates for Data Sharing

Organizations such as the NIH now require use of common standards in a way that will ensure that the results obtained through funded research are more easily accessible to external groups. ODR will be created in such a way that its use will address the new NIH mandates. It will designed also to allow information presented in its terms to be usable in satisfying other regulatory purposes—such as submissions to FDA.


GO provides answers to three types of questions:

for each gene product (protein ...)

in what parts of the cell has it been identified? Cell Constituent Ontology

exercising what types of molecular functions? Molecular Function Ontology

with what types of biological processes? Biological Process Ontology

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= part_of= subtype_of

Gene Product Associations

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$100 mill. invested in literature curation using GO

over 11 million annotations relating gene products described in the UniProt, Ensembl and other databases to terms in the GO

ontologies provide the basis for capturing biological theories in computable form

in contrast to terminologies and thesauri – which focus on socially diverse uses of language – the GO method focuses on commonly shared results of basic biological science

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A new kind of biological research

based on analysis and comparison of the massive quantities of annotations linking ontology terms to raw data, including genomic data, clinical data, public health data

What 10 years ago took multiple groups of researchers months of data comparison effort, can now be performed in milliseconds

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The GO covers only generic (‘normal’) biological entities of three sorts:

– cellular components– molecular functions– biological processes

It does not provide representations of diseases, symptoms, genetic abnormalities …How to extend the GO methodology to other domains of biology and medicine?

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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

COMPONENTCell(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) Foundry

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all follow the same principles to ensure interoperability

– GO Gene Ontology– ChEBI Chemical Ontology– PRO Protein Ontology– CL Cell Ontology– ...– OGMS Ontology for General Medical

Science

OBO Foundry ontologies

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Basic Formal Ontology: GO at a high level


Basic Formal Ontology (BFO)

A simple top-level ontology to support information integration in scientific researchNo abstractaNothing propositionalClear hierarchyNo overlap with domain ontologiesNo confusion of ontology with epistemologyNo confusion of terms with what terms represent in reality

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Basic Formal Ontology

Continuant Occurrent(Process, Event)

IndependentContinuant

DependentContinuant

http://ifomis.uni-saarland.de/bfo/50

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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Users of BFO

NCI BiomedGT SNOMED CTOntology 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 HealthvaultCleveland Clinic Semantic Database in

Cardiothoracic SurgeryMajor 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 ResearchNeural Electromagnetic Ontologies (NEMO)ChemAxiom – Ontology for ChemistryOntology for Risks Against Patient Safety

(RAPS/REMINE) (EU FP7)IDO Infectious Disease Ontology (NIAID)

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Infectious Disease Ontology 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 – Brucellosis

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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



ORGAN ANDORGANISM

Organism(NCBI

Taxonomy)

Anatomical Entity(FMA, CARO)

OrganFunction


Quality(PaTO)

Biological Process

(GO)CELL AND CELLULAR

COMPONENTCell(CL)

Cellular Compone

nt(FMA, GO)

Cellular Function

(GO)

MOLECULEMolecule

(ChEBI, SO,RnaO, PrO)


Molecular Process

(GO)The Open Biomedical Ontologies (OBO) Foundry

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ORGAN ANDORGANISM

Organism(NCBI

Taxonomy)

Anatomical Entity

(FMA, CARO)

OrganFunction


Quality(PaTO)

Organism-Level Process

(GO)

CELL AND CELLULAR

COMPONENTCell(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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OBO Foundry organized in terms of Basic Formal Ontology

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

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Example: The Cell Ontology

Ontology for General Medical Science BFO-based ontology for clinical medicine



DependentContinuant

Anatomical Component

+Disorder

Pathological Process

+Clinical Encounter

Disease+

Bodily Quality62

Continuant


DependentContinuant

..... .....Quality Disposition

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realization depends_on realizable



bearer

DependentContinuant

disposition

.... ..... .......67

Process of realization

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

the universal red

instantiates

an instance of 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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portion of water

this portion of H20

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portion of ice

portion of liquid water

portion of gas

instantiates at t1

instantiates at t2

instantiates at t3

Phase transitions

human

John (exists continuously)

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embryo fetus adultneonate infant child

instantiates at t1

instantiates at t2

instantiates at t3

instantiates at t4

instantiates at t5

instantiates at t6

in nature, no sharp boundaries here

temperature

John’s temperature (exists continuously)

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37ºC 37.1ºC 37.5ºC37.2ºC 37.3ºC 37.4ºC

instantiates at t1

instantiates at t2

instantiates at t3

instantiates at t4

instantiates at t5

instantiates at t6



coronary heart disease

John’s coronary heart disease (exists continuously)

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asymptomatic (‘silent’)

infarction

early lesions and small

fibrous plaques

stable angina

surface disruption of

plaque

unstable angina

instantiates at t1

instantiates at t2

instantiates at t3

instantiates at t4

instantiates at t5

time

OGMS

Ontology for General Medical Science

http://code.google.com/p/ogms/

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OGMS: The Big Picture

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Disposition (potentiality)

A disposition isa 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

independent continuantthat is part of an organismthat deviates from the

canonical anatomy of the organism

in a way that gives rise to pathological processes

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Disorder

serves as the bearer of a disposition to pathological processes

A part of the body that typically gets larger over time

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Disease course• the totality of all disease processes

through which a given disease instance is realized .

• multiple disease courses will be associated with the same disorder type, for example in reflection of the presence or absence of pharmaceutical or other interventions, of differences in environmental influence, and so forth.

The Big Picture

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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_in95

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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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


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

Abnormal bodily features recognized_as

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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Dispositions and Predispositions

All diseases are dispositions; not all dispositions are diseases.

A predisposition is a disposition to acquire 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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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



Hypothesis - rule out cirrhosis suggests


Test results - elevated liver enzymes in serum used_in


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

Systemic arterial hypertension

• Etiological process – abnormal reabsorption of NaCl by the kidney– produces

• Disorder – abnormally large scattered molecular aggregate of salt in the blood– bears

• Disposition (disease) - hypertension– realized_in

• Pathological process – exertion of abnormal pressure against arterial wall– produces


• Symptoms - • Signs – elevated blood pressure



Hypothesis - rule out hypertension suggests


Test results - used_in


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

Type 2 Diabetes Mellitus• Etiological process –

– produces• Disorder – abnormal pancreatic beta

cells and abnormal muscle/fat cells– bears

• Disposition (disease) – diabetes mellitus– realized_in

• Pathological processes – diminished insulin production , diminished muscle/fat uptake of glucose– produces


• Symptoms – polydipsia, polyuria, polyphagia, blurred vision

• Signs – elevated blood glucose and hemoglobin A1c



Hypothesis - rule out diabetes mellitus suggests

Laboratory tests – fasting serum blood glucose, oral glucose challenge test, and/or blood hemoglobin A1c produces

Test results - used_in


Result - diagnosis that patient X has a disorder that bears the disease type 2 diabetes mellitus

Type 1 hypersensitivity to penicillin• Etiological process – sensitizing of mast

cells and basophils during exposure to penicillin-class substance– produces

• Disorder – mast cells and basophils with epitope-specific IgE bound to Fc epsilon receptor I– bears

• Disposition (disease) – type I hypersensitivity– realized_in

• Pathological process – type I hypersensitivity reaction– produces


• Symptoms – pruritis, shortness of breath• Signs – rash, urticaria, anaphylaxis



Hypothesis - suggests

Laboratory tests – produces

Test results – occasionally, skin testing used_in


Result - diagnosis that patient X has a disorder that bears the disease type 1 hypersensitivity to penicillin

Next steps in OGMS• classification of distinct types of disease

courses for instances of each disease type – in different typical environments– with and without treatment– with treatment plan that is or is not

realized by the patient– where the disease exists in combination

with other diseases

Next steps in OGMS

• modify the Big Picture to take account of differences between primary care and specialist care

The Big Picture

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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. – An 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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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. 112

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For an ontology to succeed, potential users should be incentivized to use it, it should be populated using the terms that

they need and using definitions that conform to their understanding of these terms

it should be easily correctable in light of new research discoveries

it should enable the data annotated in its terms to be easily integrated with legacy data from related fields

it should be easily extendable to new kinds of data.


A new kind of Electronic Health Recordresting on the use of the same (public domain) ontologies in mapping proprietary EHR vocabularies to yield patient data annotated in consistent ways that support

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integrated care and continuity of care comparison and integration for diagnosis and

meta-analysis secondary uses for research

Towards an Ontological Treatment of Disease and Diagnosis

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