1 part iii.the obo foundry project: towards scientific standards and principles-based coordination...
Post on 24-Jan-2016
216 views
TRANSCRIPT
1
Part III. The OBO Foundry Project:
Towards Scientific Standards and Principles-Based Coordination in Biomedical Ontology Development
2
High quality shared ontologies build communities
NIH, FDA trend to consolidate ontology-based standards for the communication and processing of biomedical data.
caBIG / NECTAR / BIRN / BRIDG ...
3
http://obo.sourceforge.net
4
http://www.geneontology.org/
5
6
7
8
The Methodology of Annotations
GO employs scientific curators, who use experimental observations reported in the biomedical literature to link gene products with GO terms in annotations.
This gene product exercises this function, in this part of the cell, leading to these biological processes
9
The Methodology of Annotations
This process of annotating literature leads to improvements and extensions of the ontology, which in turn leads to better annotations
This institutes a virtuous cycle of improvement in the quality and reach of both future annotations and the ontology itself.
Annotations + ontology taken together yield a slowly growing computer-interpretable map of biological reality.
RECALL: Alignment of GO and Cell ontologies will permit the generation of consistent and complete
definitions
id: CL:0000062name: osteoblastdef: "A bone-forming cell which secretes an extracellular matrix. Hydroxyapatite crystals are then deposited into the matrix to form bone." [MESH:A.11.329.629]is_a: CL:0000055relationship: develops_from CL:0000008relationship: develops_from CL:0000375
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.
11
The OBO The OBO FoundryFoundry
12
A subset of OBO ontologies, whose developers have agreed in advance to accept a common set of principles designed to ensure
intelligibility to biologists (curators, annotators, users)
formal robustness
stability
compatibility
interoperability
support for logic-based reasoning
The OBO FoundryThe OBO Foundry
13
Custodians
• Michael Ashburner (Cambridge)• Suzanna Lewis (Berkeley)• Barry Smith (Buffalo/Saarbrücken)
The OBO FoundryThe OBO Foundry
14
A collaborative experiment
participants have agreed in advance to a growing set of principles specifying best practices in ontology development
designed to guarantee interoperability of ontologies from the very start
The OBO FoundryThe OBO Foundry
15
The developers of each ontology commit to its maintenance in light of scientific advance, and to soliciting community feedback for its improvement. They commit to working with other Foundry members to ensure that, for any particular domain, there is community convergence on a single reference ontology.
The OBO FoundryThe OBO Foundry
16
Initial Candidate Members of the OBO Foundry
GO Gene Ontology
CL Cell Ontology
SO Sequence Ontology
ChEBI Chemical Ontology
PATO Phenotype (Quality) Ontology
FuGO Functional Genomics Investigation Ontology
FMA Foundational Model of Anatomy
RO Relation Ontology
The OBO FoundryThe OBO Foundry
17
Under development Disease Ontology
Mammalian Phenotype Ontology
OBO-UBO / Ontology of Biomedical Reality
Organism (Species) Ontology
Plant Trait Ontology
Protein Ontology
RnaO RNA Ontology
NCI Thesaurus ????
The OBO FoundryThe OBO Foundry
18
Considered for development
Environment OntologyBehavior OntologyBiomedical Image OntologyClinical Trial Ontology
The OBO FoundryThe OBO Foundry
19
CRITERIA
The OBO FoundryThe OBO FoundryThe OBO FoundryThe OBO Foundry
The ontology is open and available to be used by all.
The developers of the ontology agree in advance to collaborate with developers of other OBO Foundry ontology where domains overlap.
The ontology is in, or can be instantiated in, a common formal language.
20
The ontology possesses a unique identifier space within OBO.
The ontology provider has procedures for identifying distinct successive versions.
The ontology includes textual definitions for all terms.
CRITERIA
The OBO FoundryThe OBO Foundry
21
The ontology has a clearly specified and clearly delineated content.
The ontology is well-documented.
The ontology has a plurality of independent users.
CRITERIA
The OBO FoundryThe OBO Foundry
22
The ontology uses relations which are unambiguously defined following the pattern of definitions laid down in the OBO Relation Ontology.*
*Genome Biology 2005, 6:R46
CRITERIA
The OBO FoundryThe OBO Foundry
23
CRITERIA
Further criteria will be added over time in order to bring about a gradual improvement in the quality of the ontologies in the Foundry
The OBO FoundryThe OBO FoundryThe OBO FoundryThe OBO Foundry
24
Goal
Alignment of OBO Foundry ontologies through a common system of formally defined relations
to enable reasoning both within and across ontologies
The OBO FoundryThe OBO Foundry
25
A reference ontology
is analogous to a scientific theory; it seeks to optimize representational adequacy to its subject matter to the maximal degree that is compatible with the constraints of computational usefulness.
The OBO FoundryThe OBO Foundry
26
An application ontology
is comparable to an engineering artifact such as a software tool. It is constructed for a specific practical purpose.
Examples:
National Cancer Institute Thesaurus
FuGO Functional Genomics Investigation Ontology
The OBO FoundryThe OBO Foundry
27
Reference Ontology vs. Application Ontology
Currently, application ontologies are often built afresh for each new task; commonly introducing not only idiosyncrasies of format or logic, but also simplifications or distortions of their subject-matters.
To solve this problem application ontology development should take place always against the background of a formally robust reference ontology framework
The OBO FoundryThe OBO Foundry
28
Reference Ontologies promote re-usability of data
if dataschemas are formulated using terms drawn from a reference ontology used by others, then the data will be to this degree more accessible to others
The OBO FoundryThe OBO Foundry
29
Advantages of the methodology of shared coherently defined ontologies• promotes quality assurance (better coding)• guarantees automatic reasoning across
ontologies and across data at different granularities
• makes links between ontologies explicit• yields direct connection to temporally indexed
instance data
The OBO FoundryThe OBO Foundry
30
Advantages of the methodology of shared coherently defined ontologies
We know that high-quality ontologies can help in creating better mappings e.g. between human and model organism phenotypes
S Zhang, O Bodenreider, “Alignment of Multiple Ontologies of Anatomy: Deriving Indirect Mappings from Direct Mappings to a Reference Ontology”, AMIA 2005
The OBO FoundryThe OBO Foundry
31
Reference Ontologies
are already being used to create technology to aid literature search
http://www.gopubmed.org/
The OBO FoundryThe OBO Foundry
32
Goal:
to create a family of gold standard reference ontologies upon which terminologies developed for specific applications can draw
The OBO FoundryThe OBO Foundry
33
Goal:
to introduce the scientific method into ontology development:– all Foundry ontologies must be constantly updated
in light of scientific advance– all Foundry ontology developers must work with all
other Foundry ontology developers in a spirit of scientific collaboration
The OBO FoundryThe OBO Foundry
34
Goal:
to replace the current policy of ad hoc creation of new database schemas by each clinical research group by providing reference ontologies in terms of which database schemas can be defined
The OBO FoundryThe OBO Foundry
35
Goal:
to introduce some of the features of scientific peer review into biomedical ontology development
The OBO FoundryThe OBO Foundry
36
Goal:
to create controlled vocabularies for use by clinical trial banks, clinical guidelines bodies, scientific journals, ...
The OBO FoundryThe OBO Foundry
37
Goal:
to create an evolving map-like representation of the entire domain of biological reality
The OBO FoundryThe OBO Foundry
GO’s three ontologies
molecular function
cellular component
biological process
cell (types)
molecular function
(GO)
species
molecular process
cellular anatom
y
anatomy(fly, fish,
human...)
cellularphysiology
organism-levelphysiology
ChEBI,Sequence,
RNA ...
cell (types)
molecular function
(GO)
species
molecular process
cellular anatom
y
anatomy(fly, fish,
human...)
cellularphysiology
organism-levelphysiology
ChEBI,Sequence,
RNA ...
granular levels
cell (types)
molecular function
(GO)
species
molecular process
cellular anatom
y
anatomy(fly, fish, human...)
cellularphysiology
organism-levelphysiology
ChEBI,Sequence,
RNA ...
normal(functionings)
pathophysiology(disease)
pathoanatomy(fly, fish, human ...)
pathological(malfunctionings)
cell (types)
molecular function
(GO)
species
molecular process
cellular anatom
y(GO)
anatomy(fly, fish, human...)
cellularphysiology
organism-levelphysiology
ChEBI,Sequence,
RNA ...
pathophysiology(disease)
pathoanatomy(fly, fish, human ...)
cell (types)
molecular function
(GO)
species
molecular process
cellular anatom
y
anatomy(fly, fish, human...)
cellularphysiology
organism-levelphysiology
ChEBI,Sequence,
RNA ...
pathophysiology(disease)
pathoanatomy(fly, fish, human ...)
phenotype
cell (types)
molecular function
(GO)
species
molecular process
cellular anatom
y
anatomy(fly, fish, human...)
cellularphysiology
organism-levelphysiology
ChEBI,Sequence,
RNA ...
pathophysiology(disease)
pathoanatomy(fly, fish, human ...)
phenotype
investigation(FuGO)
46
Judith Blake:
“The use of bio-ontologies … ensures consistency of data curation, supports extensive data integration, and enables robust exchange of information between heterogeneous informatics systems. ..
ontologies … formally define relationships between the concepts.”
47
"Gene Ontology: Tool for the Unification of Biology"
an ontology "comprises a set of well-defined terms with well-defined relationships"
(Ashburner et al., 2000, p. 27)
48
Low Hanging Fruit
Ontologies should include only those relational assertions which hold universally (= have the ALL-SOME form)
Often, order will matter here:
We can include
adult transformation_of child
but not
child transforms_into adult
49
The Gene Ontology
50
GO’s three ontologies
molecular functions
cellular components
biological processes
51
When a gene is identified
three types of questions need to be addressed:
1. Where is it located in the cell?
2. What functions does it have on the molecular level?
3. To what biological processes do these functions contribute?
52
Three granularities:
Cellular (for components)
Molecular (for functions)
Organ + organism (for processes)
53
GO has cells
but it does not include terms for molecules or organisms within any of its three ontologies
except e.g. GO:0018995 host
=Def. Any organism in which another organism spends part or all of its life cycle
54
Are the relations between functions and processes a matter of granularity?
Molecular activities are the ‘building blocks’ of biological processes ?
But they are not allowed to be represented in GO as parts of biological processes
55
GO’s three ontologies
molecular functions
cellular components
biological processes
56
What does “function” mean?
an entity has a biological function if and only if it is part of an organism and has a disposition to act reliably in such a way as to contribute to the organism’s survival
the function is this disposition
57
Improved version
an entity has a biological function if and only if it is part of an organism and has a disposition to act reliably in such a way as to contribute to the organism’s realization of the canonical life plan for an organism of that type
58
This canonical life plan might include
canonical embryological development
canonical growth
canonical reproduction
canonical aging
canonical death
59
The function of the heart is to pump blood
Not every activity (process) in an organism is the exercise of a function – there are
mal functionings
side-effects (heart beating)
accidents (external interference)
background stochastic activity
60
Kidney
61
Nephron
62
Functional Segments
63
Functions
64
FunctionsThis is a screwdriver
This is a good screwdriver
This is a broken screwdriver
This is a heart
This is a healthy heart
This is an unhealthy heart
65
Functions are associated with certain characteristic process shapes
Screwdriver: rotates and simultaneously moves forward simultaneously transferring torque from hand and arm to screw
Heart: performs a contracting movement inwards and an expanding movement outwards
66
Not functioning at allleads to death, modulo
internal factors:
plasticity
redundancy (2 kidneys)
criticality of the system involved
external factors:
prosthesis (dialysis machines, oxygen tent)
special environments
assistance from other organisms
67
What clinical medicine is for
to eliminate malfunctioning by fixing broken body parts
(or to prevent the appearance of malfunctioning by intervening e.g. at the molecular level)
68
Hypothesis: there are no ‘bad’ functionsIt is not the function of an oncogene to cause cancer
Oncogenes were in every case proto-oncogenes with functions of their own
They become oncogenes because of bad (non-prototypical) environments
69
Is there an exception for molecular functions?
Does this apply only to functions on biological levels of granularity
(= levels of granularity coarser than the molecule) ?
If pathology is the deviation from (normal) functioning, does it make sense to talk of a pathological molecule?
(Pathologically functioning molecule vs. pathologically structured molecule)
70
Is there an exception for molecular functions?
A molecular function is a propensity of a gene product instance to perform actions on the molecular level of granularity.
Hypothesis 1: these actions must be reliably such as to contribute to biological processes.
Hypothesis 2: these actions must be reliably such as to contribute to the organism’s realization of the canonical life plan for an organism of that type.
71
The Gene Ontology
is a canonical ontology – it represents only what is normal in the realm of molecular functioning
72
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.
73
The FMA is a canonical representation
It is a computational 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.
74
The importance of pathways (successive causality)
Each stage in the history of a disease presupposes the earlier stages
Therefore need to reason across time, tracking the order of events in time, using relations such as derives_from, transformation_of ...
Need pathway ontologies on every level of granularity
75
The importance of granularity (simultaneous causality)
Networks are continuants
At any given time there are networks existing in the organism at different levels of granularity
Changes in one cause simultaneous changes in all the others
(Compare Boyle’s law: a rise in temperature causes a simultaneous increase in pressure)
76
The Granularity Gulf
most existing data-sources are of fixed, single granularity
many (all?) clinical phenomena cross granularities
Therefore need to reason across time, tracking the order of events in time
77
Good ontologies require:
consistent use of terms, supported by logically coherent (non-circular) definitions, in equivalent human-readable and computable formats
coherent shared treatment of relations to allow cascading inference both within and between ontologies
78
Three fundamental dichotomies
• continuants vs. occurrents
• dependent vs. independent
• types vs. instances
79
ONTOLOGIES AREREPRESENTATIONS OF
TYPES
aka kinds, universals, categories, species,
genera, ...
80
Continuants (aka endurants)have continuous existence in timepreserve their identity through changeexist in toto whenever they exist at all
Occurrents (aka processes)have temporal partsunfold themselves in successive phasesexist only in their phases
81
You are a continuant
Your life is an occurrent
You are 3-dimensional
Your life is 4-dimensional
82
Dependent entities
require independent continuants as their bearers
There is no run without a runner
There is no grin without a cat
83
Dependent vs. independent continuants
Independent continuants (organisms, cells, molecules, environments)
Dependent continuants (qualities, shapes, roles, propensities, functions)
84
All occurrents are dependent entities
They are dependent on those independent continuants which are their participants (agents, patients, media ...)
Top-Level Ontology
ContinuantOccurrent
(always dependent on one or more
independent continuants)
IndependentContinuant
DependentContinuant
= A representation of top-level types
Continuant Occurrent
IndependentContinuant
DependentContinuant
cell component
biological process
molecular function
Top-Level Ontology
Continuant Occurrent
IndependentContinuant
DependentContinuant
Functioning
Side-Effect, Stochastic Process, ...
Function
Top-Level Ontology
Continuant Occurrent
IndependentContinuant
DependentContinuant
Functioning Side-Effect, Stochastic Process, ...
Function
Top-Level Ontology
Continuant Occurrent
IndependentContinuant
DependentContinuant
Quality Function Spatial Region
Functioning Side-Effect, Stochastic Process, ...
instances (in space and time)
90
Smith B, Ceusters W, Kumar A, Rosse C. On Carcinomas and Other Pathological Entities, Comp Functional Genomics, Apr. 2006
91
everything here is an independent continuant
92
Functions, etc.
Some dependent continuants are realizable
expression of a gene
application of a therapy
course of a disease
execution of an algorithm
realization of a protocol
93
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 ...)
94
Concepts
Biomedical ontology integration will never be achieved through integration of meanings or concepts
The problem is precisely that different user communities use different concepts
Concepts are in your head and will change as your understanding changes