1. Towards Interoperability of Biomedical Ontologies Workshop on Biological Upper Ontologies BioTop and Chemistry Ontology Stefan Schulz, Elena Beisswanger, Holger Stenzhorn Freiburg University, Jena University, Saarland University Germany Dagstuhl Seminar 0713227-30 March 2007

2. Organization of the Session 1.Holger Stenzhorn: Overview of BioTop 2.Elena Beisswanger: Interfacing Ontologies 3.Stefan Schulz: Is BFO fit for BioTop and OBO?

3. Outline (1)  Situation: Many different bio-ontologies exist, covering related or even overlapping subdomains of (molecular) biology / biomedicine  Challenge: How to interlink ontologies and how to enable interoperability?

4. Outline (2)  Our solution: BioTop, an integrative top level for biomedical domain ontologies with BFO as its top layer  Not only integration and interlinkage but also cleansing / 'ontologicalization' of the OBOs by mapping to strict upper level

5. Upper Ontology / Top Ontology Domain Upper Ontology / Top Domain Ontology Domain Ontology OBO (Gene Ontology, Sequence Ontology, Cell Ontology, Mouse Anatomy, ChEBI, …) Ontological Layers

6. Upper Ontology / Top Ontology Domain Upper Ontology / Top Domain Ontology Domain Ontology Transcription DNA-dependent transcription antisense RNA transcription mRNA transcription rRNA transcription tRNA transcription … (from Gene Ontology) OBO (Gene Ontology, Sequence Ontology, Cell Ontology, Mouse Anatomy, ChEBI, …) Ontological Layers

7. Upper Ontology / Top Ontology Domain Upper Ontology / Top Domain Ontology Domain Ontology DOLCE BFO OBO (Gene Ontology, Sequence Ontology, Cell Ontology, Mouse Anatomy, ChEBI, …) Ontological Layers

8. Upper Ontology / Top Ontology Domain Upper Ontology / Top Domain Ontology Domain Ontology DOLCE BFO Entity Continuant Dependent Continuant Realizable Entity Function Role Independent Continuant Object Object Aggregate Occurrent (from BFO) OBO (Gene Ontology, Sequence Ontology, Cell Ontology, Mouse Anatomy, ChEBI, …) Ontological Layers

9. Domain Upper Ontology / Top Domain Ontology Upper Ontology / Top Ontology Domain Ontology DOLCE BFO OBO (Gene Ontology, Sequence Ontology, Cell Ontology, Mouse Anatomy, ChEBI, …) Ontological Layers

10. Upper Ontology / Top Ontology Domain Upper Ontology / Top Domain Ontology Domain Ontology DOLCE BFO OBO (Gene Ontology, Sequence Ontology, Cell Ontology, Mouse Anatomy, ChEBI, …) Ontological Layers

11. Upper Ontology / Top Ontology Domain Upper Ontology / Top Domain Ontology Domain Ontology DOLCE BFO Biology Domain: Organism Body Part Cell Cell Component Tissue Protein Nucleic Acid DNA RNA Biological Function Biological Process OBO (Gene Ontology, Sequence Ontology, Cell Ontology, Mouse Anatomy, ChEBI, …) Ontological Layers

12. Upper Ontology / Top Ontology Domain Upper Ontology / Top Domain Ontology Domain Ontology Simple Bio Upper Ontology GFO-Bio DOLCE BFO GENIA OBO (Gene Ontology, Sequence Ontology, Cell Ontology, Mouse Anatomy, ChEBI, …) Ontological Layers

13. Upper Ontology / Top Ontology Domain Upper Ontology / Top Domain Ontology Domain Ontology Simple Bio Upper Ontology GFO-Bio GENIA DOLCE BFO Ontological Layers BioTop OBO (Gene Ontology, Sequence Ontology, Cell Ontology, Mouse Anatomy, ChEBI, …)

14. BioTop Overview (1)  Covers fundamental classes and relations in the biomedical domain (with relations taken from RO but also extending the RO)  Provides verbal and formal definitions (OWL-DL class restrictions, domain/range restrictions)

15. BioTop Overview (2)  BFO as top level (might be other upper ontology, e.g. DOLCE)  BioTop design principles: single hierarchy (pre-inferred ontology), (full) definitions, defined relations, disjoint partitions

16. Development  Implemented in OWL-DL to allow for the use of reasoners to check consistency and classify the ontology  Developed using Protégé as editor and Pellet and Fact++ as reasoners  Using BFO and RO top-level classes and relations via OWL import facility

17. Ontology Facts  Class number  Total classes: 242  Primitive classes: 100  Defined classes: 142  Class restriction number  Total restrictions: 325  Existential restrictions : 194  Universal restrictions: 122

18. Ontology Classification Idea  Actual complex ontology structure „hidden“ in flat structure via restrictions  Need to employ an OWL-DL reasoner to classify the asserted version of the ontology  The inferred version has the proper stucture (e.g. structure the flat list of 'Aggregates')

19. Ontology – Before Classification

20. Ontology – After Classification

21. Further Information  Website: www.ifomis.org/biotop  Mailing list: biotop@googlegroups.combiotop@googlegroups.com  Comments are always highly appreciated!

22. Organization of the Session 1.Holger Stenzhorn: Overview of BioTop 2.Elena Beisswanger: Interfacing Ontologies 3.Stefan Schulz: Is BFO fit for BioTop and OBO?

23. Alignment Step  Find “correspondence” and “subclass” relations between domain ontology classes and BioTop classes  Inheritance of class restrictions and taxonomic links (precondition for consistency check)

24. Analysis Step (1)  Find overlaps  Candidate for true duplicates: ChEBI “proteins” and FMA “protein” (Ask ChEBI and FMA experts. If they agree, introduce cross-reference.)  Seeming duplicates: ChEBI “proteins” / FMA “protein” and SO “protein” (Ask SO experts. If they agree, rename SO “protein” as “protein sequence”)

25. Analysis Step (2)  Find inconsistencies  CO “spheroplast” („A cell, usually of bacteria or yeast, which has partially lost its cell wall.“). CO states:  “spheroplast” is-a “procaryotic cell” AND  “spheroplast” is-a “fungal cell” (Replace AND by OR)

26. Analysis Step (3)  Find gaps (e.g. classes and relations mentioned implicitly within the name of another class)  Missing intermediate classes: SO “chromosome structure variation” and SO “mutation affecting gene structure” (Introduce classes “variation” and “mutation”)  Missing relations: FMA “protein” and FMA “protein complex” (Introduce relation “protein complex” has- part “protein”)

27. Correction and Refinement Step  Correction  True duplicates: Introduce cross references  Seeming duplicates: Refine class names  Inconsistencies: Remodel  Refinement (define implicitly mentioned classes explicitly)  Introduce lacking intermediate classes  Add relations within and between ontologies

28. Integration via BioTop  Implicit mentions of protein  GO: molecular function (protein* function)  GO: biological process (process that has a protein* as agent)  GO: cellular component (cellular location of protein*)  Explicit mentions of protein  SO: protein (protein sequence)  ChEBI: proteins (protein molecule)  FMA: protein (protein molecule)  FMA: protein complex  GO: protein transport (... that has a protein as agent)  GO: protein binding (... by protein)  CO: protein secreting cell ...and others *More precise: gene product inheres-in has-agent has-part

29. Preliminary Conclusions (Integration of domain ontologies)  Cross validation between BioTop and domain ontologies  Alignment enforces clarification of actual meaning of domain ontology classes  Alignment motivates to introduce classes and relations explicitly which have previously been mentioned only implicitly (e.g. in class names)  Increase of completeness of the over-all representation of domain knowledge

30. Open Issues for BioTop (1)  Exact meaning of fundamental domain terms  “What is a protein?” „What is a cell?“  Cut-off to domain ontologies  Example: “protein”, “protein complex”, “protein subunit”, “glycoprotein”  Classes referred to in BioTop class definitions need to be in BioTop (Example: protein has-part polypeptide chain has-part amino acid has-part nitrate atom)  How “picky” must we be? (Example: Distinguish between amino acid and amino acid residue?)

31. Cut-off to domain ontologies  Have an overlap of the most upper class levels of the domain ontologies Upper Ontology / Top Ontology Domain Upper Ontology / Top Domain Ontology Domain Ontology overlap Upper Ontology / Top Ontology Domain Upper Ontology / Top Domain Ontology  Select the most important classes from the domain ontologies even if they are deeper down overlap

32. Open Issues for BioTop (2)  BioTop relations (OBO relation ontology not sufficient)  What is the relation linking “gene” to “protein”? (“encodes”)  What is the relation linking “cell” to “organism”? (“originates from”)

33. Open Issues in Alignment  Reasonable candidates for alignment  Top level classes of domain ontologies (but e.g. SO “consequences of mutation” on a higher level than SO “region”)  Selected fundamental classes of domain ontologies  Right place for new / refined classes and relation definitions  BioTop? The OBO and RO?

34. Organization of the Session 1.Holger Stenzhorn: Overview of BioTop 2.Elena Beisswanger: Interfacing Ontologies 3.Stefan Schulz: Is BFO fit for BioTop and OBO?

35. BFO BioTop Entity Continuant Dependent Continuant Realizable Entity Function Role Independent Continuant Object Object Aggregate Occurrent (from BFO) Is BFO fit for OBO and BioTop? Case Study on Anatomical and Chemical Entities

36. BFO: snap Ontology snap:Continuant snap:Independent continuant snap:Objectsnap:FiatObjectPart snap:ObjectAggregate Df: An independent continuant entity that is spatially extended, maximally self- connected and self-contained (the parts of a substance are not separated from each other by spatial gaps), and possesses an internal unity; the identity of substantial objects is independent of that of other entities and can be maintained through time and through loss and gain of parts and qualities. Examples: an organism, a chair, a cell, a lung, an apple. A independent continuant entity that is part of a object but is not demarcated by any physical discontinuities. Examples: upper and lower lobes of the left lung, the dorsal and ventral surfaces of the body, the east side of Copenhagen, the lower right portion of a human torso.

37. Object or FiatObjectPart ? Lung Surface vs. Pleural Space: Bona Fide Boundary Lung Hilus: Entry of Bronchi, veins and arteries. Fiat Boundary

38. Object or FiatObjectPart ? Nearly all seemingly well-delimited parts of biological organisms exhibit somewhere continuous spatial transitions into neighboring anatomical parts, which can be viewed in different ways by different disciplines. They have to be delineated partly by fiat before they can be spoken of in a well defined way. Schulz & Johansson: Continua in Biological Systems. Forthcoming in: The Monist, 2007

39. FiatObjectPart  BFO:“.…not demarcated by any physical discontinuities”.  How is the lung demarcated from the respiratory tract ?  Is there a physical discontinuity between the extrapulmonar and the intrapulmonar segments of tubular structures?  Other examples: Brain, Heart, Kidney, Liver, Hand, Fingernail, Cell Nucleus…  Which anatomical structures are true BFO:objects ?

40. BFO: snap Ontology snap:Continuant snap:Independent continuant snap:Object snap:FiatObjectPart snap:ObjectAggregate Df: An independent continuant entity that is spatially extended, maximally self- connected and self-contained (the parts of a substance are not separated from each other by spatial gaps), and possesses an internal unity; the identity of substantial objects is independent of that of other entities and can be maintained through time and through loss and gain of parts and qualities. Examples: an organism, a chair, a cell, a lung, an apple. Df: A independent continuant entity that is a mereological sum of separate objects. Examples: a heap of stones, a group of commuters on the subway, a collection of bacteria, a flock of geese, the patients in a hospital, a symphony orchestra.

41. An Object E.coli

42. An ObjectAggregate E.coli BFO: “A independent continuant entity that is a mereological sum of separate objects.”

43. An Object E.coli

44. An Object ? E.coli

45. An Object ?? H H H

46. H H H H H H H H H H H H H H

47. H H H H H H H H H H H 0,0001% nuclei 99,9999% empty space “filled” by probability distributions of electrons

48. BFO Critique  Every object appears – under a fine grained view as an aggregate of non connected elementary particles  Whether something is an object or an object aggregate, depends on the granularity of the view  Biologically relevant material continuants span over a huge range of granularity: From populations to atoms  A realist ontology claims to describe the world as it is, not as it is perceived  Granularity should or should not matter in a realist ontology ??

49. An ObjectAggregate E.coli BFO: “A independent continuant entity that is a mereological sum of separate objects.” separate separate ?

50. Seperatedness / Connectedness strength of connection mechanic adhesion electro- static adhesion Hydogen Bridges (surfaces) (chemicals) Van- der- Waals Metallic Non Polar Covalent Polar Covalent Ionic

51. Continuum between Types of Chemical Bonds

53. Seperatedness / Connectedness  Depends on  kinds of surfaces and mechanic adhesion and cohesion forces  types of chemical bonds  strengths of chemical bonds  number of chemical bonds  Is a continuous property, and therefore problematic as a criterion for the upper level distinction of ontological categories

54. Conclusion  Critique of domain level by applying the rigor of an upper level ontology but also…  Critique of the upper level ontology by assessing the appropriateness of upper level categories from the perspective of the domain level Ontology Intergration: Upper Level, Top Domain, Domain has two aspects:

55. BFO BioTop Domain Ontologies Top-down validation: Do domain ontologies comply with upper-level principles? Bottom-up validation: Do upper ontologies provide adequate means for formally and unambiguously describing the domain?

56. Towards Interoperability of Biomedical Ontologies Workshop on Biological Upper Ontologies BioTop and Chemistry Ontology Stefan Schulz, Elena Beisswanger, Holger Stenzhorn Freiburg University, Jena University, Saarland University Germany Dagstuhl Seminar 0713227-30 March 2007