basic building blocks for biomedical ontologies

Basic Building Blocks for Biomedical Ontologies

Barry Smith

Problems with UMLS-style approaches

• let a million ontologies bloom, each one close to the terminological habits of its authors

• in concordance with the “not invented here” syndrome

• then map these ontologies, and use these mappings to integrate your different pots of data

Mappings are hardThey create an N2 problem; are fragile, and expensive to

maintainNeed new authorities to maintain(one for each pair of

mapped ontologies), yielding new risk of forking – who will police the mappings?

The goal should be to minimize the need for mappings, by avoiding redundancy in the first place – one ontology for each domain

Invest resources in disjoint ontology modules which work well together – reduce need for mappings to minimum possible

Why should you care?

• you need to create systems for data mining and text processing which will yield useful digitally coded output

• if the codes you use are constantly in need of ad hoc repair huge, resources will be wasted

• serious investment in annotation will be defeated from the start

• relevant data will not be found, because it will be lost in multiple semantic cemeteries

How to do it right?• how create an incremental, evolutionary process,

where what is good survives, and what is bad fails• where the number of ontologies needing to be

used together is small – integration = addition• where these ontologies are stable• by creating a scenario in which people will find it

profitable to reuse ontologies, terminologies and coding systems which have been tried and tested

Reasons why GO has been successful

It is a system for prospective standardization built with coherent top level but with content contributed and monitored by domain specialists

Based on community consensusUpdated every nightClear versioning principles ensure backwards

compatibility; prior annotations do not lose their value

Initially low-tech to encourage users, with movement to more powerful formal approaches (including OWL-DL – though still proceeding caution)

GO has learned the lessons of successful cooperation

• Clear documentation• The terms chosen are already familiar• Fully open source (allows thorough testing in

manifold combinations with other ontologies)• Subjected to considerable third-party critique• Tracker for user input and help desk with rapid

turnaround

GO has been amazingly successful in overcoming the data balkanization

problembut it covers only generic biological entities of three sorts:

– cellular components– molecular functions– biological processes

no diseases, symptoms, disease biomarkers, protein interactions, experimental processes …

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

MOLECULEMolecule

(ChEBI, SO,RnaO, PrO)

Molecular Function(GO)

Molecular Process

OBO (Open Biomedical Ontology) Foundry proposal(Gene Ontology in yellow) 14

RELATION TO TIME

GRANULARITY

ORGAN ANDORGANISM

Organism(NCBI

Taxonomy)

OrganFunction

Quality(PaTO)

Biological Process

COMPONENT

Cell(CL)

Cellular Compone

nt(FMA, GO)

Cellular Function

MOLECULEMolecule

Molecular Process

Environment Ontology

RELATION TO TIME

GRANULARITY

COMPLEX OFORGANISMS

Family, Community, Deme, Population

OrganFunction

(FMP, CPRO)

Population Phenotype

PopulationProcess

ORGAN ANDORGANISM

Organism(NCBI

Taxonomy)

Anatomical Entity(FMA, CARO) Phenotypic

Quality(PaTO)

Biological Process

COMPONENT

Cell(CL)

Cellular Componen

t(FMA, GO)

Cellular Function

MOLECULEMolecule

Molecular Process

Population-level ontologies 16

Developers commit to working to ensure that, for each domain, there is community convergence on a single ontology

and agree in advance to collaborate with developers of ontologies in adjacent domains.

http://obofoundry.org

The OBO Foundry: a step-by-step, evidence-based approach to

expanding the GO

OBO Foundry Principles

Common governance (coordinating editors)

Common training

Common architecture:

• simple shared top level ontology (BFO)

• shared Relation Ontology: www.obofoundry.org/ro

Open Biomedical Ontologies Foundry

Seeks to create high quality, validated terminology modules across all of the life sciences which will be

• one ontology for each domain, so no need for mappings

• close to language use of experts

• evidence-based

• incorporate a strategy for motivating potential developers and users

• revisable as science advances

Principles

http://obofoundry.org/wiki/index.php/OBO_FoundryPrinciples

ORGAN ANDORGANISM

Organism(NCBI

Taxonomy)

Anatomical Entity

(FMA, CARO)

OrganFunction

Quality(PaTO)

Organism-Level Process

CELL AND CELLULAR

COMPONENT

Cell(CL)

Cellular Compone

nt(FMA, GO)

Cellular Function

Cellular Process

MOLECULEMolecule

Molecular Process

OBO Foundry coverage

GRANULARITY

RELATION TO TIME

ORTHOGONALITY

modularity ensures • annotations can be additive• division of labor amongst domain experts• high value of training in any given module• lessons learned in one module can benefit

work on other modules• incentivization of those responsible for

individual modules

Benefits of coordination

• Can more easily reuse what is made by others• Can more easily inspect and criticize what is

made by others• Leads to innovations (e.g. Mireot strategy for

importing terms into ontologies)

RELATION TO TIME

GRANULARITY

ORGAN ANDORGANISM

Organism(NCBI

Taxonomy)

OrganFunction

Quality(PaTO)

Biological Process

(GO)XAO ZFA

CELL AND CELLULAR

COMPONENT

Cell(CL)

Cellular Compone

nt(FMA, GO)

Cellular Function

MOLECULEMolecule (SO, RnaO)

Molecular Process

(GO)ChEBI PRO

Current Foundry members in yellow24

Foundry ontologies currently under review

Plant Ontology (PO)Ontology for Biomedical Investigations (OBI)Ontology for General Medical Science (OBMS)Infectious Disease Ontology (IDO)

Anatomy Ontology(FMA*, CARO)

Environment

Ontology(EnvO)

Infectious Disease

Ontology(IDO*)

Biological Process

Ontology (GO*)

Cell Ontology

CellularComponentOntology

(FMA*, GO*) Phenotypic Quality

Ontology(PaTO)

Subcellular Anatomy Ontology (SAO)Sequence Ontology

(SO*) Molecular Function

(GO*)Protein Ontology(PRO*) OBO Foundry Modular Organization

top level

mid-level

domain level

Information Artifact Ontology

Ontology for Biomedical Investigations

Ontology of General Medical Science

(OGMS)

Basic Formal Ontology (BFO)

The Ontology for Biomedical Investigations

hfp://purl.org/obo/OBI_0000225

Purpose of OBI

To provide a resource for the unambiguous description of the components of biomedical investigations such as the design, protocols and instrumentation, material, data and types of analysis and statistical tools applied to the data

NOT designed to model biology

OBI Collaborating CommunitiesCrop sciences Generation Challenge Programme (GCP),Environmental genomics MGED RSBI Group, www.mged.org/Workgroups/rsbiGenomic Standards Consortium (GSC),

www.genomics.ceh.ac.uk/genomecatalogueHUPO Proteomics Standards Initiative (PSI), psidev.sourceforge.netImmunology Database and Analysis Portal, www.immport.orgImmune Epitope Database and Analysis Resource (IEDB),

http://www.immuneepitope.org/home.doInternational Society for Analytical Cytology, http://www.isac-net.org/Metabolomics Standards Initiative (MSI), Neurogenetics, Biomedical Informatics Research Network (BIRN),Nutrigenomics MGED RSBI Group, www.mged.org/Workgroups/rsbiPolymorphismToxicogenomics MGED RSBI Group, www.mged.org/Workgroups/rsbiTranscriptomics MGED Ontology Group

Ontology for General Medical Science

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

(OBO) http://purl.obolibrary.org/obo/ogms.obo

(OWL) http://purl.obolibrary.org/obo/ogms.owl

OGMS-based initiatives

Vital Signs Ontology (VSO) (Welch Allyn)

EHR / Demographics Ontology

Infectious Disease Ontology

Mental Health Ontology

Emotion Ontology

Ontology for General Medical Science

Jobst Landgrebe (then Co-Chair of the HL7 Vocabulary Group):

“the best ontology effort in the whole biomedical domain by far”

EXPERIMENTAL ARTIFACTS Ontology for Biomedical Investigations (OBI)

CLINICAL MEDICINE Ontology of General Medical Science (OGMS)

INFORMATION ARTIFACTS Information Artifact Ontology (IAO)

How to keep clear about the distinction• processes of observation,

• results of such processes (measurement data)

• the entities observed

How is the OBO Foundry organized?

• Top-Level: Basic Formal Ontology (BFO)• Mid-Level: IAO, OBI, OGMS ...• Domain-Level: Foundry Bio-Ontologies

Anatomy Ontology(FMA*, CARO)

Environment

Ontology(EnvO)

Infectious Disease

Ontology(IDO*)

Biological Process

Ontology (GO*)

Cell Ontology

CellularComponentOntology

(FMA*, GO*) Phenotypic Quality

Ontology(PaTO)

Subcellular Anatomy Ontology (SAO)Sequence Ontology

(SO*) Molecular Function

(GO*)Protein Ontology(PRO*) OBO Foundry Modular Organization

top level

mid-level

domain level

Information Artifact Ontology

Ontology of General Medical Science

(OGMS)

Basic Formal Ontology (BFO)

BFO: the very top

Continuant Occurrent(Process, Event)

IndependentContinuant

DependentContinuant

RELATION TO TIME

GRANULARITY

ORGAN ANDORGANISM

Organism(NCBI

Taxonomy)

OrganFunction

Quality(PaTO)

Biological Process

COMPONENT

Cell(CL)

Cellular Compone

nt(FMA, GO)

Cellular Function

MOLECULEMolecule

Molecular Process

ORGAN ANDORGANISM

Organism(NCBI

Taxonomy)

Anatomical Entity

(FMA, CARO)

OrganFunction

Quality(PaTO)

Organism-Level Process

CELL AND CELLULAR

COMPONENT

Cell(CL)

Cellular Compone

nt(FMA, GO)

Cellular Function

Cellular Process

MOLECULEMolecule

Molecular Process

obofoundry.org

GRANULARITY

RELATION TO TIME

BFO & GO

continuant occurrent

biological processes

independentcontinuant

cellular component

dependentcontinuant

molecular function

Basic Formal Ontology

Continuant Occurrent

process, eventIndependentContinuant

DependentContinuant

quality

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

instances44

Experience with BFO in building ontologies provides

• a community of skilled ontology developers and users (user group has 120 members)

• associated logical tools • documentation for different types of users• a methodology for building conformant

ontologies by starting with BFO and populating downwards

Example: The Cell Ontology

How to build an ontologyimport BFO into ontology editor such as Protégé

work with domain experts to create an initial mid-level classification

find ~50 most commonly used terms corresponding to types in reality

arrange these terms into an informal is_a hierarchy according to this universality principle

A is_a B every instance of A is an instance of B

fill in missing terms to give a complete hierarchy

(leave it to domain experts to populate the lower levels of the hierarchy)

Users of BFOPharmaOntology (W3C HCLS SIG)

MediCognos / Microsoft Healthvault

Cleveland Clinic Semantic Database in Cardiothoracic Surgery

Major Histocompatibility Complex (MHC) Ontology (NIAID)

Neuroscience Information Framework Standard (NIFSTD) and Constituent Ontologies

Interdisciplinary Prostate Ontology (IPO)

Nanoparticle Ontology (NPO): Ontology for Cancer Nanotechnology Research

Neural Electromagnetic Ontologies (NEMO)

ChemAxiom – Ontology for Chemistry

Users of BFOGO Gene Ontology

CL Cell Ontology

SO Sequence Ontology

ChEBI Chemical Ontology

PATO Phenotype (Quality) Ontology

FMA Foundational Model of Anatomy Ontology

ChEBI Chemical Entities of Biological Interest

PRO Protein Ontology

Plant Ontology

Environment Ontology

RNA Ontology

Users of BFOOntology for Risks Against Patient Safety (RAPS/REMINE)

eagle-i an VIVO (NCRR)

IDO Infectious Disease Ontology (NIAID)

National Cancer Institute Biomedical Grid Terminology (BiomedGT)

US Army Biometrics Ontology

US Army Command and Control Ontology

Sleep Domain Ontology

Subcellular Anatomy Ontology (SAO)

Translaftional Medicine On (VO)

Yeast Ontology (yOWL)

Zebrafish Anatomical Ontology (ZAO)

Basic Formal Ontology

dependentcontinuant

organism

Continuants

• continue to exist through time, preserving their identity while undergoing different sorts of changes

• independent continuants – objects, things, ...

• dependent continuants – qualities, attributes, shapes, potentialities ...

Occurrents

• processes, events, happenings– your life– this process of accelerated cell

division

Qualitiestemperatureblood pressuremass...

are continuantsthey exist through time while undergoing changes

Qualitiestemperature / blood pressure /

mass ...are dimensions of variation within the structure of the entitya quality is something which can change while its bearer remains one and the same

A Chart representing how John’s temperature

changes

A Chart representing how John’s temperature

changes

BFO: The Very Top

continuant

dependentcontinuant

quality

occurrent

temperature 62

Blinding Flash of the Obvious

dependentcontinuant

quality

temperature types

instances

organism

John John’s

temperature 63

dependentcontinuant

quality

temperature types

instances

organism

John John’s

temperature 64

temperature types

instances

organism

John John’s

temperature .inheres_in

temperature types

instances

John’s temperature

37ºC37.1º

C37.5º

C37.2º

C37.3º

C37.4º

instantiates at t1

instantiates at t2

instantiates at t3

instantiates at t4

instantiates at t5

instantiates at t6

human types

instances

embryo

fetus adultneonat

einfant child

instantiates at t1

instantiates at t2

instantiates at t3

instantiates at t4

instantiates at t5

instantiates at t6

Temperature subtypesDevelopment-stage

subtypes

are threshold divisions (hence we do not have sharp boundaries, and we have a certain degree of choice, e.g. in how many subtypes to distinguish, though not in their ordering)

dependentcontinuant

quality

temperature types

instances

organism

John John’s

temperature

dependentcontinuant

quality

temperature

organism

John John’s

temperature

occurrent

process

course of temperature

changes

John’s temperature history

dependentcontinuant

quality

temperature

organism

John John’s

temperature

occurrent

process

life of an organism

John’s life

BFO: The Very Top

dependentcontinuant

quality disposition

BFO: The Very Top

continuant

dependentcontinuant

qualityfunctionroledisposition

occurrent

disposition- of a glass vase, to shatter if dropped- of a human, to eat - of a banana, to ripen- of John, to lose hair

dispositionif it ceases to exist, then its bearer and/or its immediate surrounding environment is physically changedits realization occurs when its bearer is in some special physical circumstancesits realization is what it is in virtue of the bearer’s physical make-up

dependentcontinuant

function

to seeeye

John’s eye function of John’s eye: to see

occurrent

process

process of seeing

John seeing

OGMSOntology for General Medical

Science

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

New York State Center of Excellence in Bioinformatics & Life Sciences

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

• ontology for the representation of– diseases, signs, symptoms

– clinical processes

– diagnosis, treatment and outcomes

• fundamental idea:– a disease is a disposition rooted in some

(physical) disorder in the organism

Ontology of General Medical Science (OGMS)

New York State Center of Excellence in Bioinformatics & Life Sciences

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

Motivation

• Clarity about:– disease etiology and progression

– disease and the diagnostic process

– phenotype and signs/symptoms

– entities in reality and observations of sucn entities

Physical Disorder

– independent continuantfiat object part

A causally linked combination of physical components of the extended organism that is clinically abnormal.

Clinically abnormal

– (1) not part of the life plan for an organism of the relevant type (unlike aging or pregnancy),

– (2) causally linked to an elevated risk either of pain or other feelings of illness, or of death or dysfunction, and

– (3) such that the elevated risk exceeds a certain threshold level.*

*Compare: baldness93

Big Picture

Pathological Process=def. A bodily process that is a manifestation of a disorder and is clinically abnormal.

Disease =def. – A disposition to undergo pathological processes that exists in an organism because of one or more disorders in that organism.

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, enlarged spleen

Dispositions and Predispositions

All diseases are dispositions; not all dispositions are diseases.

Predisposition to Disease

=def. – A disposition in an organism that constitutes an increased risk of the organism’s subsequently developing some disease.

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)

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

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

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

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

– recognized_as

• Symptoms - headaches, dizziness

• 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• Abnormal bodily features

– recognized_as• 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• Abnormal bodily features

– recognized_as• 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

Disease vs. Disease course

Disease =def. – A disposition to undergo pathological processes that exists in an organism because of one or more disorders in that organism.

Disease course =def. – The aggregate of processes in which a disease disposition is realized.

coronary heart disease

John’s coronary heart disease

disease associated

with asymptomatic

(‘silent’) infarction

disease associated with early

lesions and small fibrous

plaques

stable angina

disease associated

with surface disruption of plaque

unstable angina

instantiates at t1

instantiates at t2

instantiates at t3

instantiates at t4

instantiates at t5

time107

dependentcontinuant

disposition

diseasedisorder

John’s disordered

John’s coronary heart

disease

occurrent

process

course of disease

course of John’s disease

OGMS IDO

Independent Continuant

DisorderInfectious disorder

Dependent Continuant

Disease

Predisposition to disease

Infectious disease

Protective resistance

Occurrent Disease courseInfectious

disease course

Examples of ontology terms

IDO (Infectious Disease Ontology) CoreFollows GO strategy of providing a

canonical ontology of what is involved in every infectious disease – host, pathogen, vector, virulence, vaccine, transmission – accompanied by IDO Extensions for specific diseases, pathogens and vectorsProvides common terminology resources and tested common guidelines for a vast array of different disease communities

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• Cleveland Clinic – Infective Endocarditis• University of Michigan – Brucellosis• Duke University, University at Buffalo – HIV

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

– recognized_as

• Symptoms - weakness, dizziness

• Signs - fever 112

Influenza – disease course

• 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

– recognized_as

• Symptoms - weakness, dizziness

• Signs - fever 113

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

Big Picture

basic building blocks for biomedical ontologies

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