1 what an ontology is for barry smith university at buffalo common anatomy reference ontology...

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What an Ontology is ForBarry SmithUniversity at Buffalohttp://ontology.buffalo.edu/smith

Common Anatomy Reference Ontology Workshop

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how do we know what data we have ?

how do I know what data you have ?

how do we know what data we don’t have ?

how do we make different sorts of data combinable ?

we are accumulating huge amounts of data

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where in the cell ?

what kind of process ?

we need semantic annotation of data

what kind of biological end ?

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Semantic Web, Moby, wikis, UMLS, etc.

let a million flowers (weeds) bloom

and create integration via post hoc mappings

how create broad-coverage semantic annotation systems for biomedicine?

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for science

develop high quality annotation resources in a collaborative, community effort

create an evolutionary path towards improvement

on the basis of common prospective standards

based on science

an alternative

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for sciencescience works out from a validated core, and strives to isolate and resolve inconsistencies as it extends outwards

we need to create a validated core including ontologies corresponding to the basic biomedical sciences in this corelow hanging fruit

FMA

Pleural Cavity

Pleural Cavity

Interlobar recess

Interlobar recess

Mesothelium of Pleura


Pleura(Wall of Sac)

Pleura(Wall of Sac)

VisceralPleura

VisceralPleura

Pleural SacPleural Sac

Parietal Pleura

Parietal Pleura

Anatomical SpaceAnatomical Space

OrganCavityOrganCavity

Serous SacCavity

Serous SacCavity

AnatomicalStructure

AnatomicalStructure

OrganOrgan

Serous SacSerous Sac

MediastinalPleura

MediastinalPleura

TissueTissue

Organ PartOrgan Part

Organ Subdivision

Organ Subdivision

Organ Component

Organ Component

Organ CavitySubdivision


Serous SacCavity

Subdivision

Serous SacCavity

Subdivision

part

_of

is_a

Foundational Model of Anatomy

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for sciencewhere do we find scientifically validated information linking gene products and other entities represented in biochemical databases to semantically meaningful terms pertaining to disease, anatomy, development, histology in different model organisms?

but we need more

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what makes GO so wildly successful ?

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science base: trained experts curating peer-reviewed literature

create an evolving set of standardized descriptions used to annotate the entities represented in the major biochemical databases

and thereby to integrate these databases

The methodology of annotations

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this leads to improvements and extensions of the ontology

which in turn leads to better annotations

which leads to further improvement in the quality and reach of both future annotations and the ontology itself

RESULT: a slowly growing computer-interpretable map of biological reality within which major databases are automatically integrated in semantically searchable form

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Five bangs for your GO buckcross-species database integration

cross-granularity database integration

through links to the things which are of biomedical relevance

semantic searchability links people to software

human curated science base creates de facto gold standard (benchmark for comparison)

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but now

need to create a de jure standard:

improve the quality of the GO

establish common rules governing best practices for creating ontologies and for using these in annotations

apply these rules to create a complete suite of orthogonal interoperable biomedical reference ontologies

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a shared portal for (so far) 58 ontologies (low regimentation)

http://obo.sourceforge.net

First step (2003)First step (2003)

http://obo.sourceforge.net/

http://obo.sourceforge.net/

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Second step (2004)Second step (2004)reform efforts initiated, e.g. linking GO to other

OBO ontologies to ensure orthogonality

id: CL:0000062name: osteoblastdef: "A bone-forming cell which secretes an extracellular matrix. Hydroxyapatite crystals are then deposited into the matrix to form bone." is_a: CL:0000055relationship: develops_from CL:0000008relationship: develops_from CL:0000375

GO

Cell type

New Definition

+

=Osteoblast differentiation: Processes whereby an osteoprogenitor cell or a cranial neural crest cell acquires the specialized features of an osteoblast, a bone-forming cell which secretes extracellular matrix.

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The OBO FoundryThe OBO Foundryhttp://obofoundry.org/http://obofoundry.org/

Third step (2006)Third step (2006)

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a family of interoperable gold standard biomedical reference ontologies to serve the annotation of inter alia

scientific literature model organism databases clinical trial data

The OBO FoundryThe OBO Foundry

The OBO FoundryThe OBO Foundry http://obofoundry.org/http://obofoundry.org/

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A prospective standarddesigned to guarantee interoperability of ontologies from the very start (contrast to: post hoc mapping)

12 initial candidate OBO ontologies – focused primarily on basic science domains

several being constructed ab initio by influential consortia who have the authority to impose their use on large parts of the relevant communities.

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undergoing rigorous reform

new

GO Gene OntologyChEBI Chemical Ontology CL Cell OntologyFMA Foundational Model of AnatomyPaTO Phenotype Quality OntologySO Sequence Ontology

CARO Common Anatomy Reference Ontology CTO Clinical Trial OntologyFuGO Functional Genomics Investigation OntologyPrO Protein Ontology RnaO RNA Ontology RO Relation Ontology


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new

GO Gene OntologyChEBI Chemical Ontology CL Cell OntologyFMA Foundational Model of AnatomyPaTO Phenotype Quality OntologySO Sequence Ontology

CARO Common Anatomy Reference Ontology CTO Clinical Trial OntologyFuGO Functional Genomics Investigation OntologyPrO Protein Ontology RnaO RNA Ontology RO Relation Ontology


to be absorbed in new Ontology of Biomedical Investigations (OBI)

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.orgGene 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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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)

MOLECULE Molecule

(ChEBI, SO,RnaO, PrO)

Molecular Function(GO)

Molecular Process

(GO)

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all OBO Foundry developers have agreed to a common set of evolving principles reflecting best practice in ontology development designed to ensure

tight connection to the biomedical basic sciences

compatibility

interoperability, common relations

formal robustness

support for logic-based reasoning


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The ontology is OPEN and available to be used by all.

The ontology is in, or can be instantiated in, a COMMON FORMAL LANGUAGE.

The developers of the ontology agree in advance to COLLABORATE with developers of other OBO Foundry ontology where domains overlap.

PRINCIPLES


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PRINCIPLES UPDATE: The developers of each ontology

commit to its maintenance in light of scientific advance, and to soliciting community feedback for its improvement.

ORTHOGONALITY: They commit to working with other Foundry members to ensure that, for any particular domain, there is community convergence on a single controlled vocabulary.


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for science

if we annotate a database or body of literature with one high-quality biomedical ontology, we should be able to add annotations from a second such ontology without conflicts

science aims for consistency

because science aims for correctness

orthogonality of ontologies implies additivity of annotations


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IDENTIFIERS: The ontology possesses a unique identifier space within OBO.

VERSIONING: The ontology provider has procedures for identifying distinct successive versions to ensure BACKWARDS COMPATIBITY with annotation resources already in common use

The ontology includes TEXTUAL DEFINITIONS and where possible equivalent formal definitions of its terms.

PRINCIPLES

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CLEARLY BOUNDED: The ontology has a clearly specified and clearly delineated content.

DOCUMENTATION: The ontology is well-documented.

USERS: The ontology has a plurality of independent users.

PRINCIPLES


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COMMON ARCHITECTURE: The ontology uses relations which are unambiguously defined following the pattern of definitions laid down in the OBO Relation Ontology.*

* Smith et al., Genome Biology 2005, 6:R46

PRINCIPLES


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Foundational is_apart_of

Spatial located_incontained_inadjacent_to

Temporal transformation_ofderives_frompreceded_by

Participation has_participanthas_agent

OBO Relation Ontology


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Further principles will be added over time in light of lessons learned

The Foundry is not seeking to serve as a check on flexibility or creativity

IT WILL GET HARDER


BUT NOT EVERYONE NEEDS TO JOIN

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CREDIT for high quality ontology development work

KUDOS for early adopters of high quality ontologies / terminologies e.g. in reporting clinical trial results

GOALS


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to introduce some of the features of SCIENTIFIC PEER REVIEW into biomedical ontology development

to providing a FRAMEWORK OF RULES to counteract the current policy of ad hoc creation

if data-schemas are formulated using a single ontology system in widespread use this supports DATA REUSABILITY

GOALS


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A dichotomy

universals (types, kinds, classes) vs.

instances (particulars, individuals)

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A 515287 DC3300 Dust Collector Fan

B 521683 Gilmer Belt

C 521682 Motor Drive Belt

Catalog vs. inventory

38An ontology is a representation of universals

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An ontology is a representation of universals

We learn about universals by looking at scientific texts – which describe what is general in reality

siamese

mammal

cat

organism

substanceuniversals

animal

instances

frogleaf class

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rule of single inheritance

no diamonds:

C

is_a2

B

is_a1

A

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problems with multiple inheritance B C

is_a1 is_a2

A

‘is_a’ no longer univocal

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‘is_a’ is pressed into service to mean a variety of different things

shortfalls from single inheritance are often clues to incorrect entry of terms and relations

the resulting ambiguities make the rules for correct entry difficult to communicate to human curators

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is_a overloading

serves as obstacle to integration with neighboring ontologies

The success of ontology alignment depends crucially on the degree to which basic ontological relations such as is_a and part_of can be relied on as having the same meanings in the different ontologies to be aligned.

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What single inheritance costs

In some respects harder to build ontologies

harder to use ontologies to find terms

Solutions: normalization, GUIs

Recommendation: if building from scratch use single inheritance

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What single inheritance brings

Coherent hierarchies

Modularity

Statistical representativeness

Jointly exhaustive pairwise disjoint classification

Coherent methodology for definitions

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Aristotelian definitions

When A is_a B, the definition of ‘A’ has the form:

an A =def. a B which ...

a human being =def. an animal which is rational

Each definition reflects the position in the hierarchy to which a defined term belongs.

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FMA Examples

Cell =def. an anatomical structure which consists of cytoplasm surrounded by a plasma membrane with or without a cell nucleus

Plasma membrane =def. a cell part that surrounds the cytoplasm

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Canonical ontologies

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The FMA is a canonical representationof types and relations between types deduced from the qualitative observations of the normal human body, which have been refined and sanctioned by successive generations of anatomists and presented in textbooks and atlases of structural anatomy.

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The GO is a canonical representation

“The Gene Ontology is a computational representation of the ways in which gene products normally function in the biological realm”

Nucl. Acids Res. 2006: 34.

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The Gene Ontology

is a canonical ontology – it represents only what is normal in the realm of molecular functioning

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The core of the OBO Foundry consists of canonical ontologies

(pathoanatomy, pathophysiology will come later)

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Three canonical ontologies

CARO

+ Ontology of Functions

+ Ontology of Developmental Processes (part of GO Biological Process ontology?)

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A second fundamental dichotomy

• universals vs. instances

• continuants vs. occurrents

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Continuants (aka endurants)

– have continuous existence in time

– preserve their identity through change

Occurrents (aka processes)

– have temporal parts

– unfold themselves in successive phases

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You are a continuant

Your life is an occurrent

You are 3-dimensional

Your life is 4-dimensional

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A third fundamental dichotomy

• types vs. instances

• continuants vs. occurrents

• dependent vs. independent

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Dependent entities

require independent continuants as their bearers

There is no grin without a cat

There is no quality without a bearer

There is no disease without an organism

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All occurrents are dependent entities

They are dependent on those independent continuants which are their participants (agents, patients, media ...)

There is no run without a runner

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Dependent vs. independent continuants

Independent continuants (organisms, cells, molecules, environments)

Dependent continuants (qualities, shapes, roles, propensities, functions)

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Top-Level Ontology

ContinuantOccurrent

(always dependent on one or more

independent continuants)

IndependentContinuant

DependentContinuant

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Continuant Occurrent


DependentContinuant

cell component

biological process

molecular function

The GO Top-Level Ontology

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Functions vs Functioningsthe function of your heart = to pump blood in your body

this function is realized in processes of pumping blood

not all functions are realized (consider the function of this sperm ...)

not all processes are functionings

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OccurrentContinuant


DependentContinuant(Function)

FunctioningIncidental by-product

Stochasticprocess

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The OBO Relation Ontology

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Part_of as a relation between universals

heart part_of human being ?

human heart part_of human being ?

human testis part_of human being ?

human being has_part human testis ?

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two kinds of parthood

1. between instances:

Mary’s heart part_of Mary

this nucleus part_of this cell

2. between universals

human heart part_of human

cell nucleus part_of cell

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Definition of part_of as a relation between universals

A part_of B =Def. all instances of A are instance-level parts of some instance of B

human testis part_of adult human being

but notadult human being has_part human testis

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Continuants

– have continuous existence in time

– preserve their identity through change

Occurrents (aka processes)

– have temporal parts

– unfold themselves in successive phases

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part_of (for processes)

A part_of B =def.

For all x, if x instance_of A then there is some y, y instance_of B and x part_of y

where ‘part_of’ is the instance-level part relation

EVERY A IS PART OF SOME B

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part_of (for continuants)

A part_of B =def.

For all x, t if x instance_of A at t then there is some y, y instance_of B at t and x part_of y at t


ALL-SOME STRUCTURE

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part_of (for continuants)

A part_of B =def.

if an A exists at t then it is part_of some B at t


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has_part (for continuants)

A has_part B =def.

if an A exists at t then there is some B of which

it is a part at t

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human testis part_of adult human being

but not

adult human being has_part human testis

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is_a (for processes)

A is_a B =def

For all x, if x instance_of A then x instance_of B

cell division is_a biological process

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is_a (for continuants)

A is_a B =def

For all x, t if x instance_of A at t then x instance_of B at t

abnormal cell is_a cell

adult human is_a human

but not: adult is_a child

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A part_of B, B part_of C ...

The all-some structure of the definitions in the OBO-RO allows

cascading of inferences

(i) within ontologies

(ii) between ontologies

(iii) between ontologies and EHR repositories of instance-data

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OBO Relation OntologyFoundational is_a

part_of

Spatial located_incontained_inadjacent_to

Temporal transformation_ofderives_frompreceded_by

Participation has_participanthas_agent

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David SutherlandFor any structure x, I should be able to answer

the questions:1. What is x (what type of thing is it)?2. Where is x (what is it part of)?3. What subtypes of x are there?4. What parts does x have?

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For any structure x, I should be able to answer the questions:

1. What type of thing is x? Say: A2. What types of things are As part of ?3. What types of things are As located in ?4. What subtypes of A’s are there?5. What parts do A’s have?

For continuants: located_in = either part_of or contained_in

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DavidThe first 2 questions are important for navigating the

ontology The second 2 questions are crucial to grouping

curationsIf we are looking for phenotypes that effect hands,

we need to be able to deduce that a hand has fingers and so add finger phenotypes to our hand phenotype list.

I think that having 'has_part' relationships in the ontology is key to acheiving this.

FMA

Pleural Cavity

Pleural Cavity

Interlobar recess

Interlobar recess



Pleura(Wall of Sac)

Pleura(Wall of Sac)

VisceralPleura

VisceralPleura

Pleural SacPleural Sac

Parietal Pleura

Parietal Pleura

Anatomical SpaceAnatomical Space

OrganCavityOrganCavity

Serous SacCavity

Serous SacCavity

AnatomicalStructure

AnatomicalStructure

OrganOrgan

Serous SacSerous Sac

MediastinalPleura

MediastinalPleura

TissueTissue

Organ PartOrgan Part

Organ Subdivision

Organ Subdivision

Organ Component

Organ Component



Serous SacCavity

Subdivision

Serous SacCavity

Subdivision

part

_of

is_a

Foundational Model of Anatomy

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human uterus part_of human being

but not

human body has_part human uterus

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Temporal relations

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c at t1

C

c at t

C1

time

same instance

transformation_of

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transformation_of

A transformation_of B =Def.

Every instance of A was at some earlier time an instance of B

adult transformation_of child

heart transformation of heart-precursor

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C

c at t c at t1

C1

embryological development

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C

c at t

C1

c1 at t1

C'

c' at t

time

instances

zygote derives_fromovumsperm

derives_from

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two continuants fuse to form a new continuant C

c at t

C1

c1 at t1

C'

c' at t fusion

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one initial continuant is replaced by two successor continuants

C

c at t

C1

c1 at t1

C2

c1 at t1

fission

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is a relation combining transformation with fusion and fission (extended from the binary cases) what we are seeking in order to capture development

via CARO?

should this relation be called ‘derives_from’ or ‘develops_from’

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one continuant detaches itself from an initial continuant, which itself continues to exist

C

c at t c at t1

C1

c1 at t

budding

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one continuant absorbs a second continuant while itself continuing to exist

C

c at t

c at t1

C'

c' at t capture

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Principle of low hanging fruit

often one of two reciprocal relations (e.g. part_of and has_part) will hold universally

human testis part_of human body

but not

human body has_part human testis

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nucleus adjacent_to cytoplasm

but not

cytoplasm adjacent_to nucleus

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seminal vesicle adjacent_to urinary bladder

but not:

urinary bladder adjacent_to seminal vesicle

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Top-Level Categories in the FMAanatomical

entity

non-physicalanatomical entity

physicalanatomical entity

anatomical relationship

body substance

material physical anatomical entity

anatomical structure

non-material physical anatomical entity

body space

boundaryanatomical

attribute

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Fiat vs. bona fide boundaries

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Layers of the body’s surface

kidshealth.org/kid/ body/skin_noSW.html

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Top-Level Categories in the FMAanatomical

entity




body substance




body space

boundaryanatomical

attribute

102www.enel.ucalgary.ca/ People/Mintchev/stomach.htm

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anatomicalentity




body substance




body space

boundaryanatomical

attribute

fiat boundarybona fide boundary

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fiat vs. bona fide boundaries

fiat boundary in anatomical space

physical boundary

105www.enel.ucalgary.ca/ People/Mintchev/stomach.htm

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varieties of fiat boundaries

in anatomical structuresin body spaces

spatial vs. temporal (stages, pathways)

in instancesin the realm of universals

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varieties of fiat boundaries

in anatomical structures

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modes of connection

–attached_to (muscle to bone) –synapsed_with (nerve to nerve, nerve

to muscle)–continuous_with (= share a fiat

boundary)

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a continuous_with b= a and b are continuant instances

which share a fiat boundaryThis relation on the instance level is always symmetric:

if x continuous_with y , then y continuous_with x

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continuous_with(relation between universals)

A continuous_with B =Def.

for all x, if x instance-of A then there is some y such that y instance_of B and x continuous_with y

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continuous_with as a relation between universals is not symmetric

Consider lymph node and lymphatic vessel:

– Each lymph node is continuous with some lymphatic vessel, but there are lymphatic vessels (e.g. lymphs and lymphatic trunks) which are not continuous with any lymph nodes

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wherever we have fiat boundaries

there is a certain indeterminacy in the location of the boundary

where does the arm begin?

where does the head begin?

where does abnormal curvature of the spine begin

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do regions have this indeterminacy?

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An ontology is a representation of types

Each term in an ontology should be a singular common noun

Cell, lung, ...

refer to instances in reality by referring to the types which they instantiate

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Problems with mass nouns

‘blood’

‘menstrual fluid’

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Problems with ‘tissue’a specific portion of cells (instance)a specific portion of cells (type)a specific portion of cells of a certain type (instance)a specific portion of cells of a certain type (type)

an arbitrary portion of cells x 4 as above

all of the above IN the bodyall of the above in the form of samples OUTSIDE the bodya type of tissue, e.g. mesothelial tissue

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Brenda Tissue Ontology contains statements like: arm is-a limb (here everything a tissue)

Aukland Anatomy Ontology Classifies tissue into: Connective tissue, Epithelial tissue, Glandular tissue, Muscle tissue, Nervous tissue;

proceeding further down the hierarchy we find not tissues but SimpleTubularGland, SimpleAcinarGland, etc.

EndocrineGland is asserted to have two ‘instances’ EndocrineGland (!), and FollicularEndocrineGland.

ConnectiveTissue has ‘instances’: Left Humerus, Right Tibia, ...

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Recommendation

avoid ‘tissue’ and all count nouns

hypothesis: in every case where one would want to use ‘portion of tissue’ in a scientific anatomy we mean:

maximally connected portion of tissue, and there is already a common noun for a corresponding type (?)

120

- CMapplication (current and future) of Foundry principles in GOstagesapplication aspects of multiple inheritance: pre- and post-coordination

1 what an ontology is for barry smith university at buffalo common anatomy reference ontology...

Documents

alternative slide

comparison slide

science science

huge amounts of data

searchable form slide

semantic annotation

core low hanging fruit

major databases