1. The Potential of the Digital Anatomist Foundational Model for “Unifying” Biomedical Ontologies Cornelius Rosse M.D., D.Sc. Structural Informatics Group University of Washington Digital Human: Towards a Unified Ontology for Biomedical Modeling and Simulation

2. Role of structure in biomedical concept representation Manifestations of health and disease are conceptualized as attributes of anatomical structures.Manifestations of health and disease are conceptualized as attributes of anatomical structures. Motivation in Structural Informatics Research

3. Role of structure in biomedical concept representation Manifestations of health and disease are conceptualized as attributes of anatomical structures.Manifestations of health and disease are conceptualized as attributes of anatomical structures. Logical and comprehensive representation of anatomical knowledge providesLogical and comprehensive representation of anatomical knowledge provides a foundation for other types of biomedical information. Motivation in Structural Informatics Research

4. Hypothesis Correlation (“unification”) of diverse biomedical ontologies is best accomplished by mapping structural attributes of anatomical entities. Digital Human: Towards a Unified Ontology for Biomedical Modeling and Simulation

5. What is the Foundational Model? What kind of information does it represent? How does it represent it? How can it support organ modeling and simulation? Agenda of talk

6. What is the Foundational Model (FM)? The Digital Anatomist Foundational Model is a symbolic model of the physical organization of the human body; declares the principles for including concepts and relationships that are implicitly assumed when knowledge of anatomy is applied in different contexts; explicitly defines concepts and relationships necessary and sufficient for consistently modeling the structure of the human body.

7. where: Ao= Anatomy ontology ASA= Anatomical Structural Abstraction ATA= Anatomical Transformation Abstraction Mk= Metaknowledge (principles, rules, axioms) where: Ao= Anatomy ontology ASA= Anatomical Structural Abstraction ATA= Anatomical Transformation Abstraction Mk= Metaknowledge (principles, rules, axioms) What is the Foundational Model (FM)? Fm = (Ao, ASA, ATA, Mk) High Level Scheme

8. Ln Location network On Orientation network Cn Connectivity network CTMn Containment network AJn Adjacency network QCn Qualitative Coordinate network CTn Continuity network ATn Attachment network SYn Synaptic Connectivity network FM = (Ao, ASA, ATA, Mk) Do Dimensional ontology Bn Boundary network Pn Part of network SAn Spatial Association network ASA Anatomical Structural Abstraction

9. FM = (Ao, ASA, ATA, Mk) A1A1 Immediate Ancestor D1D1 Immediate Descendant  Pt Phenotype Change PC 1 S1S1  Pt Phenotype Change Immediate precursor Immediate successor POTDSt Post-ovulatory Time Developmental Stage DStrDSpDP Developmental Structure Developmental Space Developmental Process DevO Developmental Ontology DL Developmental Lineage ATA Anatomical Transformation Abstraction PTr Phenotypic Transformation Rn Regulatory networks DTP Developmental Time Parameter TAgScTgGfGf GrGr Prop Transforming Agent Source of TAg Target of TAg Gene facilitated Gene repressed Propagation of TAg  Pt Phenotype Change

10. Implementation of High Level Scheme Principled Modeling = Foundational Principles + Explicit Definitions and Knowledge modeling environment: Protégé-2000

11. Foundational Principles Assertions that provide the basis for reasoning and action Unified context principle Definition principle Constitutive principle Organizational unit principle Unified context principle Definition principle Constitutive principle Organizational unit principle Principled Modeling

12. Explicit Definitions Purpose of FM definitions: Specify the essence of anatomical entities in terms of two sets of structural attributes: those of their genus differentia differentia Provide the rationale for an inheritance hierarchy in a structural context Principled Modeling

13. Foundational Principles Assertions that provide the basis for reasoning and action Unified context principle Definition principle Constitutive principle Organizational unit principle Unified context principle Definition principle Constitutive principle Organizational unit principle Principled Modeling

14. What is the Foundational Model? What kind of information does it represent? How does it represent it? How can it support organ modeling and simulation? Agenda of talk

15. Anatomy ontology: Kinds of anatomical concepts Adapted from Bloom & Fawcett: 1994 12th ed Chapman & Hall Chapman & Hall

16. Principled Modeling Fm = (Ao, ASA, ATA, Mk) Ao : taxonomic classification based on explicit definition of concepts, inheritance of definitional structural attributes; consistent with foundational principles.

17. Representation of Anatomical Entities

18. Representation of Anatomical Entities

19. Representation of Anatomical Entities

20. Representation of Anatomical Entities

21. Representation of Anatomical Entities

22. Representation of Anatomical Entities

23. Representation of Anatomical Entities

24. What is the Foundational Model? What kind of information does it represent? How does it represent it? How can it support organ modeling and simulation? Agenda of talk

25. Anatomical Entity

26. Biological entity, which forms the whole or a part of, or is an attribute of, the structural organization of a biological organism.

27. Anatomical Entity Physical Anatomical Entity Physical Anatomical Entity -is a- Conceptual Anatomical Entity Conceptual Anatomical Entity

28. Physical Anatomical Entity Physical Anatomical Entity -is a- Conceptual Anatomical Entity Conceptual Anatomical Entity Material Physical Anatomical Entity Material Physical Anatomical Entity Non-material Physical Anatomical Entity Non-material Physical Anatomical Entity

29. Physical Anatomical Entity Physical Anatomical Entity Material Physical Anatomical Entity Material Physical Anatomical Entity -is a- Non-material Physical Anatomical Entity Non-material Physical Anatomical Entity Conceptual Anatomical Entity Conceptual Anatomical Entity Anatomical Point Anatomical Point Anatomical Line Anatomical Line Anatomical Surface Anatomical Surface Anatomical Space Anatomical Space

30. Anatomical Entity Physical Anatomical Entity Physical Anatomical Entity Material Physical Anatomical Entity Material Physical Anatomical Entity -is a- Non-material Physical Anatomical Entity Non-material Physical Anatomical Entity Conceptual Anatomical Entity Conceptual Anatomical Entity Anatomical Structure Anatomical Structure Body Substance Body Substance

31. Anatomical Entity Physical Anatomical Entity Physical Anatomical Entity Material Physical Anatomical Entity Material Physical Anatomical Entity -is a- Non-material Physical Anatomical Entity Non-material Physical Anatomical Entity Conceptual Anatomical Entity Conceptual Anatomical Entity Anatomical Structure Anatomical Structure Body Substance Body Substance Body Part Body Part Human Body Human Body Organ System Organ System Organ Cell Organ Part Organ Part Tissue Organ component Organ subdivision

32. Anatomical Structure Anatomical Structure Biological Macromolecule Biological Macromolecule Acellular Anatomical Structure Acellular Anatomical Structure Cell Cell Part

33. Implementation of FM in Protégé 2000

34. Implementation of FM in Protégé 2000 Material physical anatomical entity which has inherent 3D shape; is generated by coordinated expression of the organism's own structural genes.

35. Implementation of FM in Protégé 2000 Anatomical structure that consists of cytoplasm surrounded by a plasma membrane, with or without the cell nucleus.

36. Experiments in Cell Classification

38. Somatic cell which has intercellular junctions with homologous cells.

39. Experiments in Cell Classification

40. Somatic cell which has adhesion sites with extracellular matrix components.

41. Experiments in Cell Classification

42. Frame of Cell

43. FM = (Ao, ASA, ATA, Mk) ASA Anatomical Structural Abstraction

44. FM = (Ao, ASA, ATA, Mk) Do Dimensional ontology Bn Boundary network Pn Part of network SAn Spatial Association network ASA Anatomical Structural Abstraction

45. Ln Location network On Orientation network Cn Connectivity network FM = (Ao, ASA, ATA, Mk) Do Dimensional ontology Bn Boundary network Pn Part of network SAn Spatial Association network ASA Anatomical Structural Abstraction

46. Ln Location network On Orientation network Cn Connectivity network CTMn Containment network AJn Adjacency network QCn Qualitative Coordinate network FM = (Ao, ASA, ATA, Mk) Do Dimensional ontology Bn Boundary network Pn Part of network SAn Spatial Association network ASA Anatomical Structural Abstraction

47. Ln Location network On Orientation network Cn Connectivity network CTMn Containment network AJn Adjacency network QCn Qualitative Coordinate network CTn Continuity network ATn Attachment network CCn Cell Connectivity network FM = (Ao, ASA, ATA, Mk) Do Dimensional ontology Bn Boundary network Pn Part of network SAn Spatial Association network ASA Anatomical Structural Abstraction

48. Right Ventricle Cardiac Chamber Cardiac Chamber Organ Subdivision Organ Subdivision Organ Part Anatomical Structure Anatomy Ontology -is a- Polyhedron Volume (3-D) Dimensional Ontology Dimensional Ontology ASA = ( Do, Pn, Bn, SAn )

49. Right Ventricle Cardiac Chamber Cardiac Chamber Organ Subdivision Organ Subdivision Organ Part Anatomical Structure Anatomy Ontology -is a- Polyhedron Volume (3-D) Dimensional Ontology Dimensional Ontology Sternocostal Surface Sternocostal Surface Diaphragmatic Surface Diaphragmatic Surface bounded by boundary of Anatomical Surface Anatomical Surface Surface (2-D) bounded by Right Coronary Sulcus Right Coronary Sulcus Anterior Interventricular Sulcus Anterior Interventricular Sulcus Line (1-D) bounded by Coronary Sulcus Coronary Sulcus Inferior margin of heart Inferior margin of heart Apex Boundary Network -is a- Posterior IV Sulcus Posterior IV Sulcus Crux of heart Anatomical Landmark Anatomical Landmark Point (1-D) -is a- ASA = ( Do, Bn, Pn, SAn )

50. Right Ventricle Cardiac Chamber Cardiac Chamber Organ Subdivision Organ Subdivision Organ Part Anatomical Structure Anatomy Ontology -is a- Polyhedron Volume (3-D) Dimensional Ontology Dimensional Ontology Sternocostal Surface Sternocostal Surface Diaphragmatic Surface Diaphragmatic Surface bounded by boundary of Anatomical Surface Anatomical Surface Surface (2-D) bounded by Right Coronary Sulcus Right Coronary Sulcus Anterior Interventricular Sulcus Anterior Interventricular Sulcus Line (1-D) bounded by Coronary Sulcus Coronary Sulcus Inferior margin of heart Inferior margin of heart Apex Boundary Network -is a- Posterior IV Sulcus Posterior IV Sulcus Crux of heart Anatomical Landmark Anatomical Landmark Point (1-D) -is a- Part-of Network Part-of Network HeartHeart super- object super- object Inflow part of RV of RV Inflow part of RV of RV Infundibulum Wall of RV Cavity of RV subobject -is a- has Cavity of infund. infund. Cavity of infund. infund. Cavity of infl.part infl.part ASA = ( Do, Bn, Pn, SAn )

51. Right Ventricle Cardiac Chamber Cardiac Chamber Organ Subdivision Organ Subdivision Organ Part Anatomical Structure Anatomy Ontology -is a- Polyhedron Volume (3-D) Dimensional Ontology Dimensional Ontology Sternocostal Surface Sternocostal Surface Diaphragmatic Surface Diaphragmatic Surface bounded by boundary of Anatomical Surface Anatomical Surface Surface (2-D) bounded by Right Coronary Sulcus Right Coronary Sulcus Anterior Interventricular Sulcus Anterior Interventricular Sulcus Line (1-D) bounded by Coronary Sulcus Coronary Sulcus Inferior margin of heart Inferior margin of heart Apex Boundary Network -is a- Posterior IV Sulcus Posterior IV Sulcus Crux of heart Anatomical Landmark Anatomical Landmark Point (1-D) -is a- Part-of Network Part-of Network HeartHeart super- object super- object Inflow part of RV of RV Inflow part of RV of RV Infundibulum Wall of RV Cavity of RV subobject -is a- has Cavity of infund. infund. Cavity of infund. infund. Cavity of infl.part infl.part has adjacency adjacency anterioranteriorinferiorinferior to left Left ventricle ventricle Pericardial sac sacPericardial has adjacency adjacency DiaphragmDiaphragm inferiorinferior Spatial Association Network SAn ) ASA = ( Do, Bn, Pn, SAn )

52. ASA of Cell Generic cellSpecialized cell Skeletal muscle fiber

53. Parts of the Cell

58. Frame of Cell

59. Cell-Specific Attributes

61. What is the Foundational Model? What kind of information does it represent? How does it represent it? How can it support organ modeling and simulation? Agenda of talk

62. Organ Modeling Scenario Generic cell Skeletal muscle fiber Satellite cell

63. FM = (Ao, ASA, ATA, Mk) A1A1 Immediate Precursor D1D1 Immediate Descendant  Pt Phenotype Change PC 1 S1S1  Pt Phenotype Change Immediate precursor Immediate successor POTDSt Post-ovulatory Time Developmental Stage DStrDSpDP Developmental Structure Developmental Space Developmental Process DevO Developmental Ontology DL Developmental Lineage ATA Anatomical Transformation Abstraction PTr Phenotypic Transformation Rn Regulatory networks DTP Developmental Time Parameter TAgScTgGfGf GrGr Prop Transforming Agent Source of TAg Target of TAg Gene facilitated Gene expressed Propagation of TAg  Pt Phenotype Change

64. FM = (Ao, ASA, ATA, Mk) DevO Developmental Ontology DL Developmental Lineage ATA Anatomical Transformation Abstraction PTr Phenotypic Transformation Rn Regulatory networks DTP Developmental Time Parameter DStr Developmental Structure DSp Developmental Space DP Developmental Process

65. FM = (Ao, ASA, ATA, Mk) DevO Developmental Ontology DL Developmental Lineage ATA Anatomical Transformation Abstraction PTr Phenotypic Transformation Rn Regulatory networks DTP Developmental Time Parameter POT Postovulatory time DSt Developmental Stage

66. FM = (Ao, ASA, ATA, Mk) DevO Developmental Ontology DL Developmental Lineage ATA Anatomical Transformation Abstraction PTr Phenotypic Transformation Rn Regulatory networks DTP Developmental Time Parameter A1 Immediate Ancestor D1 Immediate Descendant  Pt Phenotype Change PC 1 Immediate Precursor S1S1 Immediate Successor  Pt Phenotype Change

67. FM = (Ao, ASA, ATA, Mk) DevO Developmental Ontology DL Developmental Lineage ATA Anatomical Transformation Abstraction PTr Phenotypic Transformation Rn Regulatory networks DTP Developmental Time Parameter  Pt Phenotype Change Sc TAg Prop Propagation of TAg GrGr GrGr GfGf GfGf Tg Gene repressed Gene facilitated Target of TAg Source of TAg Transforming Agent

68. Myogenic Lineage Muscle-specific cell markers Terminally differentiated cell: Myosin Muscle progenitor cells: Muscle-specific transcription factors: Myf5 Myf5 MyoD MyoD Myogenin Myogenin

69. Myogenic Lineage

71. Gives rise to

72. Myogenic Lineage Gives rise to

73. Myogenic Lineage Blood-borne stem cellEmbryonic stem cell Myogenic stem cell (Satellite cell) Myoblast Myocyte Immature myotube Skeletal muscle fiber Fuses

74. Myogenic Lineage MyosinMyosin

75. Myosin Myf5 Myf5, MyoD Myogenin

76. Myogenic Lineage Myf5 Myf5, MyoD Myogenin Myosin Myosin Myosin Myogenin

77. FM = (Ao, ASA, ATA, Mk) DevO Developmental Ontology DL Developmental Lineage ATA Anatomical Transformation Abstraction PTr Phenotypic Transformation Rn Regulatory networks DTP Developmental Time Parameter  Pt Phenotype Change Sc TAg Prop Propagation of TAg GrGr GrGr GfGf GfGf Tg Gene repressed Gene facilitated Target of TAg Source of TAg Transforming Agent

78. Organ Modeling Scenario Generic cell Skeletal muscle fiber Satellite cell

79. What is the Foundational Model? What kind of information does it represent? How does it represent it? How can it support alignment (“unification”) of ontologies? Agenda of talk

80. Right Ventricle Cardiac Chamber Cardiac Chamber Organ Subdivision Organ Subdivision Organ Part Anatomical Structure Anatomy Ontology -is a- Polyhedron Volume (3-D) Dimensional Ontology Dimensional Ontology Sternocostal Surface Sternocostal Surface Diaphragmatic Surface Diaphragmatic Surface bounded by boundary of Anatomical Surface Anatomical Surface Surface (2-D) bounded by Right Coronary Sulcus Right Coronary Sulcus Anterior Interventricular Sulcus Anterior Interventricular Sulcus Line (1-D) bounded by Coronary Sulcus Coronary Sulcus Inferior margin of heart Inferior margin of heart Apex Boundary Network -is a- Posterior IV Sulcus Posterior IV Sulcus Crux of heart Anatomical Landmark Anatomical Landmark Point (1-D) -is a- Part-of Network Part-of Network HeartHeart super- object super- object Inflow part of RV of RV Inflow part of RV of RV Infundibulum Wall of RV Cavity of RV subobject -is a- has Cavity of infund. infund. Cavity of infund. infund. Cavity of infl.part infl.part has adjacency adjacency anterioranteriorinferiorinferior to left Left ventricle ventricle Pericardial sac sacPericardial has adjacency adjacency DiaphragmDiaphragm inferiorinferior Spatial Association Network SAn ) ASA = ( Do, Bn, Pn, SAn )

81. Myogenic Lineage Myf5 Myf5, MyoD Myogenin Myosin Myosin Myosin Myogenin

82. ASA Anatomical Structural Abstraction Do Dimensional ontology Bn Boundary network Pn Part_of network SAn Spatial Association network Ln Location network On Orientation network Cn Connectivity network CTMn Containment network AJn Adjacency network QCn Qualitative Coordinate network CTn Continuity network ATn Attachment network SYn Synaptic Connectivity network FM = (Ao, ASA, ATA, Mk)

83. What is the Foundational Model? What kind of information does it represent? How does it represent it? How can it support experiment management systems (EMS)? Agenda of talk

84. Digital Anatomist Information System Anatomy Knowledge Sources Image Repository DA Foundational Model

85. Digital Anatomist Information System Anatomy Knowledge Sources Image Repository Network Authoring Programs End-User Programs Servers DA Foundational Model

86. Digital Anatomist Information System Image Repository Network Authoring Programs Servers End User Interfaces Digital Anatomist Atlases Digital Anatomist Atlases Brain Mapper Brain Mapper EMS DA Foundational Model

87. Digital Anatomist Information System Image Repository Network Authoring Programs Servers EMS(n) EMS(1) EMS(2) DB(n) DB(2) DB(1) DA Foundational Model

88. Conclusions Fm = (Ao, ASA, ATA, Mk)

89. Conclusions Fm BODY = {Fm ANATOMICAL_ENTITY }

90. Role of Foundational Model of Anatomy Role of Foundational Model of Anatomy Prototype for symbolic models in other domains e.g., physiology, pathology, cancer therapy Core of biomedical knowledge bases to solve problems in education, research, health care Align (“unify”) diverse biomedical ontologies Align (“unify”) diverse biomedical ontologies "Foundational" because anatomy is fundamental to all biomedical sciences; anatomical concepts encompassed by FM generalize to all biomedical domains. Conclusions