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Biomedical Ontologies: The State of the Art Barry Smith and Werner Ceusters MIE, Sarajevo, August 30 PowerPoint Presentation
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Biomedical Ontologies: The State of the Art Barry Smith and Werner Ceusters MIE, Sarajevo, August 30. Part 1: Barry Smith Ontologies are Representations of What is General in Reality Part 2: Werner Ceusters Referent Tracking: Pinning Ontologies to Instances in Reality.

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slide1

Biomedical Ontologies:

The State of the Art

Barry Smith and Werner Ceusters

MIE, Sarajevo, August 30

slide2

Part 1: Barry Smith

Ontologies are Representations of What is General in Reality

Part 2: Werner Ceusters

Referent Tracking: Pinning Ontologies to Instances in Reality

slide6

time

Defense response

Immune response

Response to stimulus

Toll regulated genes

JAK-STAT regulated genes

Puparial adhesion

Molting cycle

hemocyanin

Amino acid catabolism

Lipid metobolism

Peptidase activity

Protein catabloism

Immune response

Immune response

Toll regulated genes

control

attacked

Microarray data

shows changed

expression of

thousands of genes.

How will you spot the patterns?

slide7

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

slide8

Lab / pathology data

EHR data

Clinical trial data

Family history data

Medical imaging

Microarray data

Model organism data

Flow cytometry

Mass spec

Genotype / SNP data

How will you spot the patterns?

How will you find the data you need?

slide9
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
an ontology is not a terminology
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
slide11

How does the

Gene Ontology work?

with thanks to

Jane Lomax, Gene Ontology Consortium

go provides a controlled system of representations for use in annotating data
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
go provides answers to three types of questions
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?

some pain related terms in go
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

slide21

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

one standard method
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.

uses of go in studies of
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)
100 mill invested in literature curation using go
$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

go is amazingly successful in overcoming problems of balkanization
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, …

obo foundry
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)

the obo foundry
The OBO Foundry

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 foundry31
The OBO Foundry

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
obo foundry is organized in terms of basic formal ontology
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)

basic formal ontology bfo
Basic Formal Ontology (BFO)

Continuant

Occurrent

(Process, Event)

Independent

Continuant

Dependent

Continuant

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

fundamental dichotomy
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
ontology and referent tracking
Ontology and Referent Tracking

types

Continuant

Occurrent

process, event

Independent

Continuant

thing

Dependent

Continuant

quality

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

instances

slide37

RELATION TO TIME

GRANULARITY

rationale of OBO Foundry coverage (homesteading principle)

the gene ontology go
The Gene Ontology (GO)

Continuant

Occurrent

biological process

Independent

Continuant

Dependent

Continuant

cell component

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

users of bfo
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)

users of bfo41
Users of BFO

MediCognos / Microsoft Healthvault

Cleveland Clinic Semantic Database in Cardiothoracic Surgery

Major Histocompatibility Complex (MHC) Ontology (NIAID)

Neuroscience Information Framework Standard (NIFSTD)

ido infectious disease ontology
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
users of bfo43
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

depends on
depends_on

Continuant

Occurrent

process, event

Independent

Continuant

thing

Dependent

Continuant

quality

quality depends

on bearer

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

specifically dependent continuants
Specifically dependent continuants
  • the quality of whiteness of this cheese
  • your role as lecturer
  • the disposition of this patient to experience diarrhea
depends on46
depends_on

Continuant

Occurrent

process

Independent

Continuant

thing

Dependent

Continuant

quality

temperature depends

on bearer

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

realizable dependent continuants
Realizable dependent continuants

continuants

plan

function

role

disposition

capability

tendency

their realizations
Their realizations

execution

expression

exercise

realization

application

course

occurrents

slide49

Continuant

Independent

Continuant

Dependent

Continuant

Non-realizable

Dependent

Continuant

(quality)

Realizable

Dependent

Continuant

(function, role,

disposition)

..... .....

realization depends on disposition
realization depends_on disposition

Continuant

Occurrent

Independent

Continuant

bearer

Dependent

Continuant

disposition

Process of

realization

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

dependence
Dependence

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

specifically dependent continuants52
Specifically Dependent Continuants

Specifically

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 weight

Quality, Pattern

Realizable

Dependent

Continuant

generically dependent continuants
Generically Dependent Continuants

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

Generically

Dependent

Continuant

Information

Object

Gene

Sequence

four distinct classificatory tasks
Four distinct classificatory tasks

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

four distinct bfo categories
Four distinct BFO categories

person (patient, carrier, …) – independent continuant

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

course of disease (symptom, treatment…)– occurrent

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

four distinct bfo categories56
Four distinct BFO categories

people (patients, carriers, …) – independent continuants

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

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

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

slide58
A disease is a disposition rooted in a

physical disorder in the organism and

realized in pathological processes.

produces

bears

realized_in

etiological process

disorder

disposition

pathological process

produces

diagnosis

interpretive process

signs & symptoms

abnormal bodily features

produces

used_in

recognized_as

elucidation of primitive terms
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

definitions foundational terms
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.
dispositions and predispositions
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.
definitions clinical evaluation terms
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

cirrhosis environmental exposure
Cirrhosis - environmental exposure
  • 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
  • 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
influenza infectious

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

Influenza - infectious
  • 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
  • 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
huntington s disease genetic
Huntington’s Disease - genetic
  • 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
  • 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
hnpcc genetic pre disposition
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)
definition etiology
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.
definitions diagnosis
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.
definitions qualities
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.