Biomedical Ontologies: The State of the Art

Barry Smith and Werner Ceusters

MIE, Sarajevo, August 30

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Part 1: Barry SmithOntologies are Representations of What is General in Reality

Part 2: Werner CeustersReferent Tracking: Pinning Ontologies to Instances in Reality

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Uses of ‘ontology’ in PubMed abstracts

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By far the most successful: GO (Gene Ontology)

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You’re interested in which genes control heart muscle development

17,536 results

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Selected Gene Tree: pearson lw n3d ...Branch color classification:Set_LW_n3d_5p_...

Colored by: Copy of Copy of C5_RMA (Defa...Gene List: all genes (14010)

attacked

time

control

Puparial adhesionMolting cyclehemocyanin

Defense responseImmune responseResponse to stimulusToll regulated genesJAK-STAT regulated genes

Immune responseToll regulated genes

Amino acid catabolismLipid metobolism

Peptidase activityProtein catabloismImmune response

Selected Gene Tree: pearson lw n3d ...Branch color classification:Set_LW_n3d_5p_...

Colored by: Copy of Copy of C5_RMA (Defa...Gene List: all genes (14010)

Microarray datashows changed expression ofthousands of genes.

How will you spot the patterns?

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You’re interested in which of your hospital’s patient data is relevant to understanding how genes control heart muscle development

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Lab / pathology dataEHR dataClinical trial dataFamily history data Medical imagingMicroarray dataModel organism dataFlow cytometryMass specGenotype / SNP data

How will you spot the patterns?How will you find the data you need?

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One strategy for bringing order into this huge conglomeration of data is through the

use of Common Data Elements

• Discipline-specific (cancer, NIAID, …)• Do not solve the problems of balkanization

(data siloes)• Do not evolve gracefully as knowledge

advances• Support data cumulation, but do not readily

support data integration and computation

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An ontology is not a terminology

Existing term lists and CDEs

• built to serve specific data-processing

• in ad hoc ways

Ontologies

• designed from the start to ensure integratability and reusability of data

• by incorporating a common logical structure

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How does theGene Ontology work?

with thanks to Jane Lomax, Gene Ontology Consortium

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GO provides a controlled system of representations 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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Definitions

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Gene products involved in cardiac muscle development in humans 15

GO provides answers to three types of questions

for each gene product• in what parts of the cell has it been identified?• exercising what types of molecular functions?• with what types of biological processes?

when is a particular gene product involved • in the course of normal development?• in the process leading to abnormality

with what functions is the gene product associated in other biological processes?

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Some pain-related terms in GO

GO:0048265 response to pain

GO:0019233 sensory perception of pain

GO:0048266 behavioral response to pain

GO:0019234 sensory perception of fast pain

GO:0019235 sensory perception of slow pain

GO:0051930 regulation of sensory perception of pain

GO:0050967 detection of electrical stimulus during sensory perception of pain

GO:0050968 detection of chemical stimulus involved in sensory perception of pain

GO:0050966 detection of mechanical stimulus involved in sensory perception of pain

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GO:0050968 detection of chemical stimulus involved in sensory perception of pain

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GO provides a tool for algorithmic reasoning

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Hierarchical view representing relations between represented types 20

GO allows a new kind of biological research, based on analysis and comparison of the massive quantities of annotations linking GO terms to gene products

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One standard method

Sjöblöm T, et al. analyzed13,023 genes in 11 breast and 11 colorectal cancers

using functional information captured by GO for given gene product types

identified 189 as being mutated at significant frequency and thus as providing targets for diagnostic and therapeutic intervention.

Science. 2006 Oct 13;314(5797):268-74.

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Uses of GO in studies of:• Biomedical discovery acceleration, with applications to

craniofacial development. PMID: 19325874• Persistent changes in spinal cord gene expression after

recovery from inflammatory hyperalgesia: a preliminary study on pain memory. PMID: 18366630

• Spinal cord transcriptional profile analysis reveals protein trafficking and RNA processing as prominent processes regulated by tactile allodynia. PMID: 17069981

• Immune system involvement in abdominal aortic aneurisms (PMID 17634102)

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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

experimental results reported in 52,000 scientific journal articles manually annoted by expert biologists using GO

ontologies provide the basis for capturing biological theories in computable form

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GO is amazingly successful in overcoming problems of balkanization

but it covers only generic biological entities of three sorts:

– cellular components

– molecular functions

– biological processes

and it does not provide representations of diseases, symptoms, …

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Extending 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

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) Foundry27

Ontology Scope URL Custodians

Cell Ontology (CL)

cell types from prokaryotes to mammals

obo.sourceforge.net/cgi-

bin/detail.cgi?cell

Jonathan Bard, Michael Ashburner, Oliver Hofman

Chemical Entities of Bio-

logical Interest (ChEBI)

molecular entities ebi.ac.uk/chebiPaula Dematos,Rafael Alcantara

Common Anatomy Refer-

ence Ontology (CARO)

anatomical structures in human and model

organisms(under development)

Melissa Haendel, Terry Hayamizu, Cornelius

Rosse, David Sutherland,

Foundational Model of Anatomy (FMA)

structure of the human body

fma.biostr.washington.

edu

JLV Mejino Jr.,Cornelius Rosse

Functional Genomics Investigation

Ontology (FuGO)

design, protocol, data instrumentation, and

analysisfugo.sf.net FuGO Working Group

Gene Ontology (GO)

cellular components, molecular functions, biological processes

www.geneontology.org

Gene Ontology Consortium

Phenotypic Quality Ontology

(PaTO)

qualities of anatomical structures

obo.sourceforge.net/cgi

-bin/ detail.cgi?attribute_and_value

Michael Ashburner, Suzanna

Lewis, Georgios Gkoutos

Protein Ontology (PrO)

protein types and modifications

(under development)Protein Ontology

Consortium

Relation Ontology (RO)

relationsobo.sf.net/

relationshipBarry Smith, Chris

Mungall

RNA Ontology(RnaO)

three-dimensional RNA structures

(under development) RNA Ontology Consortium

Sequence Ontology(SO)

properties and features of nucleic sequences

song.sf.net Karen Eilbeck

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OBO Foundry

recognized by NIH as framework to address mandates for re-usability of data collected through Federally funded research

see NIH PAR-07-425: Data Ontologies for Biomedical Research (R01)

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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

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Under development – Disease Ontology– Infectious Disease Ontology– Mammalian Phenotype Ontology – Plant Trait Ontology– Environment Ontology– Ontology for Biomedical Investigations– Behavior Ontology– RNA Ontology  – RO Relation 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) Foundry32

OBO Foundry is organized in terms of Basic Formal Ontology

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

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Basic Formal Ontology (BFO)

Continuant Occurrent(Process, Event)

IndependentContinuant

DependentContinuant

http://ifomis.uni-saarland.de/bfo/34

Fundamental Dichotomy• Continuants preserve their identity through

change

vs.

• Occurrents (aka processes)

– have temporal parts

– unfold themselves in successive phases

– exist only in their phases

– have all their parts of necessity

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Ontology and Referent Tracking

Continuant Occurrent

process, eventIndependentContinuant

thing

DependentContinuant

quality

.... ..... .......

types

instances 36

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

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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

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The Gene Ontology (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

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Users of BFO

GO / OBO Foundry

NCI BiomedGT

SNOMED CT

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

Ontology for Risks Against Patient Safety (RAPS) (EU)

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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)

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IDO Infectious Disease Ontology

• 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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Users of BFO

Interdisciplinary Prostate Ontology (IPO)

Nanoparticle Ontology (NPO): Ontology for Cancer Nanotechnology Research

Neural Electromagnetic Ontologies (NEMO): Ontology-based Tools for Representation and Integration of Event-related Brain Potentials

Ontology for General Medical Science

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depends_on

Continuant Occurrent

process, eventIndependentContinuant

thing

DependentContinuant

quality

.... ..... .......quality 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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depends_on

Continuant Occurrent

process

IndependentContinuant

thing

DependentContinuant

quality

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

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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

IndependentContinuant

DependentContinuant

..... .....

Non-realizableDependentContinuant(quality)

Realizable DependentContinuant(function, role, disposition)

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realization depends_on disposition

Continuant Occurrent

IndependentContinuant

bearer

DependentContinuant

disposition

.... ..... .......50

Process of realization

Dependence

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

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Specifically Dependent Continuants

SpecificallyDependentContinuant

Quality, Pattern

Realizable Dependent Continuant

if any bearer ceases to exist, then the quality or function ceases to exist

the color of my skin

the function of my heart to pump blood

my weight52

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 53

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. diseases (cases, instances, problems, …) – dispositions

3. courses of disease (symptoms, treatments…)– realizations of dispositions

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

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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

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 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

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 representation of 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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