BIRN Ontologies

Ontology Task Force

Topics

• Building the BIRNLex

• Structure of BIRNLex

• BIRN anatomy

• Next steps

The Ontology Task Force: Cross Test Beds

Carol Bean (co-chair), NIH-NCRRMaryann Martone (co-chair), BIRN CCAmarnath Gupta, BIRN CCBill Bug, Mouse BIRNChristine Fennema-Notestine, Morph BIRNJessica 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

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

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

Conclusions from “Fact Finding”

• Well structured ontologies promote integration across ontologies– NCBO has established the ontology foundary http://obofoundary.org

for hosting good ontologies

• 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

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

Animal model of Parkinson’s disease

Animal models ofAlzheimer’s disease

Alpha synuclein overexpressor

Alpha synucleinoverexpressor

Alzheimer’s disease

aggregate

Is it or isn’t it?

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

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

Foundational Model of Anatomy

•Regional part

•Constitutional part

•Systemic part

•Head

•regional part

•Head proper

•Face

•Head

•constitutional part

•Skin

•Muscle

•Skull

Core domain: NeuroanatomyWhat is the hippocampus?

BiologicalReality

Data Technique

Annotator

Data Technique

Analysis Annotator

Biological EntityBiological Entity

FUGO OBI

PATO

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

Structure of BIRNLex

Bill Bug

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”

Putamen

Globus Pallidus

Caudate Nucleus

Thalamus

Ventral Diencephalon

Hippocampus

Cerebral Cortex

Cerebral White Matter

Rock Hyrax brain Llama brain

Can we develop a core high level anatomy that can span species?

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

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.

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?

How low can we go?

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

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.

Brain Info

BAMS

Cerebral peduncle

Internal capsule

Corticospinal tract

What do we do?

• Give up?

• Adopt Neuronames definition ?– change Mouse atlas to “crus cerebri”?– Human crus cerebri = mouse cerebral

peduncle

Questions so far

• Telencephalon-diencephalon-mesencephalon-rhombencephalon

• Does thalamus include 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”?

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???

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

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)

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

Comparing animal models against disease

Human holo-prosencephaly

Zebrafishshh

Zebrafishoep

Environment

Algorithm

Hypothesis

Objective

Protocol

Study Factor

Study Report

Study Design

Dependent Factor Independent Factor

Conclusion

Publication

Correlational Study Descriptive Study Experimental 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 GroupGross Dissection Cell Fraction

Study Sample

Contained In

OrganCell

Sample Preparation

Is of Type

In Vivo

Ex Vivo

In Vitro

Post Mortem

InstitutionEvent

Time Point

Time Interval

Unit of Measure

Analysis Protocol Preparation 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

Consists of

Consists of

Consists of

Consists of

Results In

Produced Through

Participates In

Has

SiteLocated At

Participates In

Results In

Results In

Has

HasReview Board

HasProtocol Approval

Provides

Required By

Results From

Results From

Study Protocol

Has

Experimental Condition

Has

Informs

Has

Produced ViaResults In

Has

BIRN Ontology for the Multi-Scale Investigation of Neurological DisordersBIRN Ontology for the Multi-Scale Investigation of Neurological Disorders

FuGO Entity

FuGO/BIRN Conflict

BONFIRE Entity

“Is A”

Relation

“ModifiesRelation”

RelationApplies to Entity

RelationApplies to Entity and Narrower

LegendLegend

Study Group

Session

Consists of

Investigation

Study

Consists of Consists of

Consists of

Participates In

Results In