1. BIRN Ontologies Ontology Task Force

2. Topics Building the BIRNLex Structure of BIRNLex BIRN anatomy Next steps

3. The Ontology Task Force: Cross Test Beds  Carol Bean (co-chair), NIH-NCRR  Maryann Martone (co-chair), BIRN CC  Amarnath Gupta, BIRN CC  Bill Bug, Mouse BIRN  Christine Fennema-Notestine, Morph BIRN  Jessica Turner, FBIRN Jeff Grethe, BIRN CC Daniel Rubin, NCBO David Kennedy, Morph BIRN Provide a dynamic knowledge infrastructure to support integration and analysis of BIRN federated data sets, one which is conducive to accepting novel data from researchers to include in this analysis Identify and assess existing ontologies and terminologies for summarizing, comparing, merging, and mining datasets. Relevant subject domains include clinical assessments, assays, demographics, cognitive task descriptions, neuroanatomy, imaging parameters/data provenance in general, and derived (fMRI) data Identify the resources needed to achieve the ontological objectives of individual test-beds and of the BIRN overall. May include finding other funding sources, making connections with industry and other consortia facing similar issues, and planning a strategy to acquire the necessary resources

4. Ontology efforts: July 2005-March 2006 Created “Bonfire”: a collation of BIRN knowledge sources, e.g., UMLS and Neuronames –Held workshop in January 2006 for 3 test beds –Each database concept was mapped to unique identifier Very useful for “semantic concordance”, i.e., Purkinje cell = Purkinje neuron –If no entity existed, added entity; assigned unique ID and marked as “uncurated” Have added ~150 terms to Bonfire –Problems: UMLS too inconsistent in relationships and semantic types most terms lack definitions Can’t assign attributes to entities Too complicated for most domain scientists: BIRNLex Started development of BIRN ontology “best practices” Evaluated existing ontology/terminology efforts –Neuronames –BAMS: Brain Architecture Management System –Mammalian Phenotype Database –BIRN Lex –PATO –Psych Info –FUGO Made contact with other major groups working on ontologies to ensure that our efforts would be synergistic with other groups

5. Ontology Task Force Workshop with NCBO National Center for Biomedical Ontologies (NCBO), NCBC, Mark Musen, P. I. –Daniel Rubin from NCBO participates in OTF calls Carol Bean arranged for OTF to attend workshop in March 2006 –Suzanna Lewis, Barry Smith, Michael Ashburner, Mark Musen, Daniel Rubin Educated us on efforts underway at NCBO and vice versa Provided their view on ontology “best practices” and what were examples of good ontologies Evaluated BIRN’s current efforts

6. Conclusions from “Fact Finding” Well structured ontologies promote integration across ontologies –NCBO has established the ontology foundary http://obofoundary.org for hosting good ontologieshttp://obofoundary.org Problems in current ontologies: –Mix their metaphors: structure and function –Multiple parents Definitions: In a well structure ontology, the human readable definition and the machine processable definition should be the same –Humans: Define according to Aristotle: A is a B which has C Recommended reference ontologies: Foundational Model of Anatomy for Structure; Functional Genomics Ontology (FuGO) for experimental process; PATO for phenotype

7. Use of Foundational Ontologies National Center for Biomedical Ontologies Mark Musen, PI Stanford University Facilitates alignment with other ontologies across scales and modalities Structure not function (kept them rigorously separate) Adopted framework proposed by Barry Smith and colleagues for biological ontologies (Rosse et al., 2005, AMIA proceedings) Utilizes basic structure of the Foundational Model of Anatomy –Regional part –Constitutional part –Systemmic part Imports existing ontologies where possible, e.g., cell type ontology, Gene ontology cell components Open Biomedical Ontologies Biological Entity Biological Continuant Biological Occurrent Dependent Continuant Independent Continuant

8. Animal model of Parkinson’s disease Animal models of Alzheimer’s disease Alpha synuclein overexpressor Alpha synuclein overexpressor Alzheimer’s disease aggregate Is it or isn’t it?

9. Strict rules for developing taxonomies Behavioral Paradigm –Oddball paradigm Auditory oddball paradigm Visual oddball paradigm Telencephalon –Has regional part: Amygdala Working memory paradigm –Serial item recognition task –Radial maze Limbic system –Has systemic part: Amygdala

10. Why Aristotle? A is a B which has C –Defines class structure –Defines properties Electron microscope is a type of microscope which uses electrons to form an image –Microscope Electron microscope –Has property »Image formation

11. Foundational Model of Anatomy Regional part Constitutional part Systemic part Head regional part Head proper Face Head constitutional part Skin Muscle Skull

12. Core domain: Neuroanatomy What is the hippocampus? Biological Reality DataTechnique Annotator

13. DataTechnique AnalysisAnnotator Biological Entity FUGO OBI PATO

14. Unnamed Entities Each biological entity is an unnamed class –Preferred label e.g., Biomaterial_Class_1 –Preferred label = amygdala –Alternative label = amygdaloid complex –Unique identifier = 000000

15. Structure of BIRNLex Bill Bug

16. The state of Neuroanatomy in BIRN Assessed the usage of anatomical terms in each atlas used by BIRN Inconsistency in application of terms Resolution of technique was not considered Create standard “atomic” definitions for core brain parts Create a volumetric hierarchy Provides a basis for accounting for resolution Structure not function no arguments about whether the amygdala exists functionally No arguments about whether the fornix is functionally part of the hypothalamus Imported Neuronames hierarchy for volummetric relations among brain parts e.g., hippocampal formation has part Mostly gray matter = dentate gyrus, hippocampus Mostly white matter = alveus Develop consistent application rules: “My hippocampus” = dentate gyrus + hippocampus”

17. Rock Hyrax brainLlama brain Can we develop a core high level anatomy that can span species?

18. Atomic Anatomy Modular approach for describing location in the brain Based on structure of the adult brain –Resolution ~ equivalent to MRI-based segmentations (~35 structures) –Entities have to have clear definitions Definitions will be structural with boundaries and subparts specified –Only those areas that have non-controversial correspondences will be identified Mouse fornix = Human fornix (Yes!) M1 = Area 4 (No!) –Strip function from the mix Amygdala is just the name of the area, not a statement about its function

19. A Man Walks into the Drycleaners… Man: I’d like to drop off some shirts for drycleaning Cleaner: That’s fine, sir. Man: When will they be ready Cleaner: 3 days, sir Man: 3 days! But the name of the shop is “60 Minute Cleaners” Cleaner: That’s just the name of the shop, sir.

20. Amygdala What is the amygdala –Mostly gray matter structure Where is the amygdala? –Regional part of telencephalon consisting of a non-laminar nucleus lying anterior to the hippocampal formation in the temporal lobe and anterior to the temporal horn of the lateral ventricle in some species. Bona fide boundaries Fiat boundaries What are its parts? –Basal lateral complex –Cortical amygdala –Central amygdala What does the amygdala do?

21. How low can we go?

22. Cerebral ventricle Neuronames: ventricles of the brain: lateral ventricle, third ventricle, fourth ventricle Mouse BIRN: ventricular system: lateral ventricle, third ventricle, fourth ventricle, cerebral aqueduct Morph BIRN: ventricle: lateral ventricle, third ventricle, fourth ventricle BIRNLex: Cerebral ventricle: Does anyone object to including the cerebral aqueduct in our definition of the cerebral ventricle

23. Cerebral Peduncle Wikipedia: The cerebral peduncle, by most classifications, is everything in the mesencephalon except the tectum. The region includes the midbrain tegmentum, crus cerebri, substantia nigra and pretectum. mesencephalonmidbrain tegmentum crus cerebrisubstantia nigrapretectum Brain Info BAMS

24. Cerebral peduncle Internal capsule Corticospinal tract

25. What do we do? Give up? Adopt Neuronames definition ? –change Mouse atlas to “crus cerebri”? –Human crus cerebri = mouse cerebral peduncle

26. Questions so far Telencephalon-diencephalon-mesencephalon- rhombencephalon Does thalamus include epithalamus?epithalamus –Difficult to resolve habenular complex and stria medullaris –Probably don’t want the pineal gland Should the cerebellar peduncles be included as cerebellar white matter? Cerebral peduncle = crus cerebri or not? Hippocampus = we prefer hippocampal formation Do entities like “archicortex”, “archistriatum” serve a purpose? What about neostriatum? What about “limbic lobe”?

27. What should we do? Adopt standard definitions Define a volumetric hierarchy Use BIRNLex or else define existing structures in terms of BIRNLex entities –e.g., QAHippocampus = dentate gyrus + hippocampus proper + alveus + subiculum + fimbria –MBATHippocampus = dentate gyrus + hippocampus proper + alveus –Fsthalamus = thalamus + habenular nuclei + stria medullaris Adopt spatial qualifiers –Overlaps with, coextensive with, contained in –Look to GIS???

28. Where’s the function? No simple mapping between brain structure and function –Most of our structures are artificial, based on boundaries that we can see or easily reveal Remember the extended amygdala? Most biological entities do not fit into “is a” hierarchies Provide formalized way of describing “brain voxels???” to facilitate comparison

29. Next steps Finish the definitions Define the BIRN Core entities Build the ontology –Assign part of’s –Create an ontology for properties of brain regions Important for homology How should the ontology be “served”? Community involvement –BIRN “Wikipedia”? Additional core domains –Phenotype (analysis)

30. BIRN-Lex: What’s next? Image content –Anatomical regions Neuronames (FMA) –Cell components GO Ontology for subcellular anatomy of nervous system –Signal Protein, RNA, DNA –Relationship of the label to the thing –Relationship among these entities Activation Image Analysis –Segmentation Image Processing Image data –Image type –resolution Phenotype (analysis result) –Behavioral –Biochemical –Genetic –Cognitive –Morphometric –“environmental” Instruments –MRI –Microscopes Optical microscope Electron microscope Subject Experimental design Experimental platform Specimen preparation –Fixation –Contrast agent Assay –Behavioral –Cognitive –Biochemical etc

32. Comparing animal models against disease Human holo- prosencephaly Zebrafish shh Zebrafish oep

33. Environment Algorithm Hypothesis Objective Protocol Study Factor Study Report Study Design Dependent Factor Independent Factor Conclusion Publication Correlational StudyDescriptive StudyExperimental Study Function Software Part of Instrument Part of Microscope Microscope Lens Part of MR Scanner Consumable Reagent Physical Datum Instrument Platform Consists of Utilizes Investigator Role Study Object Study Organism Study Population Specimen Study Group Gross DissectionCell Fraction Study Sample Contained In Organ Cell Sample Preparation Is of Type In Vivo Ex Vivo In Vitro Post Mortem Institution Event Time Point Time Interval Unit of Measure Analysis ProtocolPreparation Protocol Cardinal Part of Protocol Consists of CP Immunolabeling Protocol Incubation with Primary Antibody Project Measuring Measurement Observing Observation Setting Parameter Value Specimen Preparation Process Fixing Session Longitudinal StudyTime Independent Study Disease Progression Study Episode Consists of Data Collection Episode Investigation Study Consists of Results In Produced Through Participates In Has Site Located At Participates In Results In Has Review Board Has Protocol Approval Provides Required By Results From Study Protocol Has Experimental Condition Has Informs Has Produced Via Results In Has BIRN Ontology for the Multi-Scale Investigation of Neurological Disorders FuGO Entity FuGO/BIRN Conflict BONFIRE Entity “Is A” Relation “Modifies Relation” Relation Applies to Entity Relation Applies to Entity and Narrower Legend Study Group Session Consists of Investigation Study Consists of Participates In Results In