1 What an Ontology is For Barry Smith University at Buffalo Common Anatomy Reference Ontology Workshop

2  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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4 where in the cell ? what kind of process ? we need semantic annotation of data what kind of biological end ?

5 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?

6 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

7 for science science 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 core low hanging fruit

FMA Pleural Cavity Pleural Cavity Interlobar recess Interlobar recess Mesothelium of Pleura Mesothelium of Pleura Pleura(Wall of Sac) Pleura(Wall of Sac) Visceral Pleura Visceral Pleura Pleural Sac Parietal Pleura Parietal Pleura Anatomical Space Organ Cavity Organ Cavity Serous Sac Cavity Serous Sac Cavity Anatomical Structure Anatomical Structure Organ Serous Sac Mediastinal Pleura Mediastinal Pleura Tissue Organ Part Organ Subdivision Organ Subdivision Organ Component Organ Component Organ Cavity Subdivision Organ Cavity Subdivision Serous Sac Cavity Subdivision Serous Sac Cavity Subdivision part_of is_a Foundational Model of Anatomy

9 for science where 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

10 what makes GO so wildly successful ?

11 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

12 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

13 Five bangs for your GO buck cross-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)

14 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

15 a shared portal for (so far) 58 ontologies (low regimentation) First step (2003)

16 Second step (2004) Second step (2004) reform efforts initiated, e.g. linking GO to other OBO ontologies to ensure orthogonality id: CL: name: osteoblast def: "A bone-forming cell which secretes an extracellular matrix. Hydroxyapatite crystals are then deposited into the matrix to form bone." is_a: CL: relationship: develops_from CL: relationship: develops_from CL: 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.

17 The OBO Foundry Third step (2006)

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19 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 Foundry The OBO Foundry

20 A prospective standard designed 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.

21 undergoing rigorous reform new GO Gene Ontology ChEBI Chemical Ontology CL Cell Ontology FMA Foundational Model of Anatomy PaTO Phenotype Quality Ontology SO Sequence Ontology CARO Common Anatomy Reference Ontology CTO Clinical Trial Ontology FuGO Functional Genomics Investigation Ontology PrO Protein Ontology RnaO RNA Ontology RO Relation Ontology The OBO Foundry

22 new GO Gene Ontology ChEBI Chemical Ontology CL Cell Ontology FMA Foundational Model of Anatomy PaTO Phenotype Quality Ontology SO Sequence Ontology CARO Common Anatomy Reference Ontology CTO Clinical Trial Ontology FuGO Functional Genomics Investigation Ontology PrO Protein Ontology RnaO RNA Ontology RO Relation Ontology The OBO Foundry to be absorbed in new Ontology of Biomedical Investigations (OBI)

OntologyScopeURLCustodians 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 entitiesebi.ac.uk/chebi Paula 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 analysis fugo.sf.netFuGO Working Group Gene Ontology (GO) cellular components, molecular functions, biological processes 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.netKaren Eilbeck

24 RELATION TO TIME GRANULARITY CONTINUANTOCCURRENT INDEPENDENTDEPENDENT ORGAN AND ORGANISM Organism (NCBI Taxonomy?) Anatomical Entity (FMA, CARO) Organ Function (FMP, CPRO) Phenotypic Quality (PaTO) Biological Process (GO) CELL AND CELLULAR COMPONENT Cell (CL) Cellular Component (FMA, GO) Cellular Function (GO) MOLECULE Molecule (ChEBI, SO, RnaO, PrO) Molecular Function (GO) Molecular Process (GO)

25 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 The OBO Foundry

26  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 The OBO Foundry

27 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. The OBO Foundry

28 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 The OBO Foundry

29  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

30  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 The OBO Foundry

31  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 The OBO Foundry

32 Foundational is_a part_of Spatial located_in contained_in adjacent_to Temporal transformation_of derives_from preceded_by Participation has_participant has_agent OBO Relation Ontology The OBO Foundry

33 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 The OBO Foundry BUT NOT EVERYONE NEEDS TO JOIN

34  CREDIT for high quality ontology development work  KUDOS for early adopters of high quality ontologies / terminologies e.g. in reporting clinical trial results GOALS The OBO Foundry

35  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 The OBO Foundry

36 A dichotomy universals (types, kinds, classes) vs. instances (particulars, individuals)

37 A515287DC3300 Dust Collector Fan B521683Gilmer Belt C521682Motor Drive Belt Catalog vs. inventory

38 An ontology is a representation of universals

39 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 substance universals animal instances frog leaf class

41 rule of single inheritance no diamonds: C is_a 2 B is_a 1 A

42 problems with multiple inheritance B C is_a 1 is_a 2 A ‘is_a’ no longer univocal

43 ‘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

44 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.

45 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

46 What single inheritance brings Coherent hierarchies Modularity Statistical representativeness Jointly exhaustive pairwise disjoint classification Coherent methodology for definitions

47 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.

48 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

49 Canonical ontologies

50 The FMA is a canonical representation of 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.

51 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.

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

53 The core of the OBO Foundry consists of canonical ontologies (pathoanatomy, pathophysiology will come later)

54 Three canonical ontologies CARO + Ontology of Functions + Ontology of Developmental Processes (part of GO Biological Process ontology?)

55 A second fundamental dichotomy universals vs. instances continuants vs. occurrents

56 Continuants (aka endurants) –have continuous existence in time –preserve their identity through change Occurrents (aka processes) –have temporal parts –unfold themselves in successive phases

57 You are a continuant Your life is an occurrent You are 3-dimensional Your life is 4-dimensional

58 A third fundamental dichotomy types vs. instances continuants vs. occurrents dependent vs. independent

59 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

60 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

61 Dependent vs. independent continuants Independent continuants (organisms, cells, molecules, environments) Dependent continuants (qualities, shapes, roles, propensities, functions)

62 Top-Level Ontology Continuant Occurrent (always dependent on one or more independent continuants) Independent Continuant Dependent Continuant

63 Continuant Occurrent Independent Continuant Dependent Continuant cell component biological process molecular function The GO Top-Level Ontology

64 Functions vs Functionings the 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

65 Occurrent Continuant Independent Continuant Dependent Continuant ( Function) Functioning Incidental by-product Stochastic process

66 The OBO Relation Ontology

67 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 ?

68 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

69 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 not adult human being has_part human testis

70 Continuants –have continuous existence in time –preserve their identity through change Occurrents (aka processes) –have temporal parts –unfold themselves in successive phases

71 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

72 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 where ‘part_of’ is the instance-level part relation ALL-SOME STRUCTURE

73 part_of (for continuants) A part_of B =def. if an A exists at t then it is part_of some B at t where ‘part_of’ is the instance-level part relation

74 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

75 human testis part_of adult human being but not adult human being has_part human testis

76 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

77 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

78 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

79 OBO Relation Ontology Foundationalis_a part_of Spatiallocated_in contained_in adjacent_to Temporaltransformation_of derives_from preceded_by Participationhas_participant has_agent

80 David Sutherland For 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?

81 For any structure x, I should be able to answer the questions: 1.What type of thing is x? Say: A 2.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

82 David The first 2 questions are important for navigating the ontology The second 2 questions are crucial to grouping curations If 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 Mesothelium of Pleura Mesothelium of Pleura Pleura(Wall of Sac) Pleura(Wall of Sac) Visceral Pleura Visceral Pleura Pleural Sac Parietal Pleura Parietal Pleura Anatomical Space Organ Cavity Organ Cavity Serous Sac Cavity Serous Sac Cavity Anatomical Structure Anatomical Structure Organ Serous Sac Mediastinal Pleura Mediastinal Pleura Tissue Organ Part Organ Subdivision Organ Subdivision Organ Component Organ Component Organ Cavity Subdivision Organ Cavity Subdivision Serous Sac Cavity Subdivision Serous Sac Cavity Subdivision part_of is_a Foundational Model of Anatomy

84 human uterus part_of human being but not human body has_part human uterus

85 Temporal relations

86 c at t 1 C c at t C 1 time same instance transformation_of

87 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

88 C c at t c at t 1 C 1 embryological development

89 C c at t C 1 c 1 at t 1 C' c' at t time instances zygote derives_from ovum sperm derives_from

90 two continuants fuse to form a new continuant C c at t C 1 c 1 at t 1 C' c' at t fusion

91 one initial continuant is replaced by two successor continuants C c at t C 1 c 1 at t 1 C 2 c 1 at t 1 fission

92 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’

93 one continuant detaches itself from an initial continuant, which itself continues to exist C c at t c at t 1 C 1 c 1 at t budding

94 one continuant absorbs a second continuant while itself continuing to exist C c at t c at t 1 C' c' at t capture

95 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

96 Principle of low hanging fruit nucleus adjacent_to cytoplasm but not cytoplasm adjacent_to nucleus

97 Principle of low hanging fruit seminal vesicle adjacent_to urinary bladder but not: urinary bladder adjacent_to seminal vesicle

98 Top-Level Categories in the FMA anatomical entity non-physical anatomical entity physical anatomical entity anatomical relationship body substance material physical anatomical entity anatomical structure non-material physical anatomical entity body space boundary anatomical attribute

99 Fiat vs. bona fide boundaries

100 Layers of the body’s surface kidshealth.org/kid/ body/skin_noSW.html

101 Top-Level Categories in the FMA anatomical entity non-physical anatomical entity physical anatomical entity anatomical relationship body substance material physical anatomical entity anatomical structure non-material physical anatomical entity body space boundary anatomical attribute

102 People/Mintchev/stomach.htm

103 anatomical entity non-physical anatomical entity physical anatomical entity anatomical relationship body substance material physical anatomical entity anatomical structure non-material physical anatomical entity body space boundary anatomical attribute fiat boundary bona fide boundary

104 fiat vs. bona fide boundaries fiat boundary in anatomical space physical boundary

105 People/Mintchev/stomach.htm

106 varieties of fiat boundaries in anatomical structures in body spaces spatial vs. temporal (stages, pathways) in instances in the realm of universals

107 varieties of fiat boundaries in anatomical structures

108 modes of connection –attached_to (muscle to bone) –synapsed_with (nerve to nerve, nerve to muscle) –continuous_with (= share a fiat boundary)

109 a continuous_with b = a and b are continuant instances which share a fiat boundary This relation on the instance level is always symmetric: if x continuous_with y, then y continuous_with x

110 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

111 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

112 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

113 do regions have this indeterminacy?

114 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

115 Problems with mass nouns ‘blood’ ‘menstrual fluid’

116 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 body all of the above in the form of samples OUTSIDE the body a type of tissue, e.g. mesothelial tissue

117 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,...

118 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 (?)

119

120 - CM application (current and future) of Foundry principles in GO stages application aspects of multiple inheritance: pre- and post-coordination