Harmony 2011: Formalization of SBML models as OWL ontologies

Formalizing Systems Biology
Models with Biomedical Ontologies
work by:
Robert Hoehndorf, Michel Dumontier,
John H. Gennari, Sarala Wimalaratne,
Bernard de Bono, Dan Cook, George Gkoutos

Cambridge University, Carleton University,
EBI, University of Washington
Harmony @ NYC. April 21,2011

Systems Biology

We create and simulate models to :
gain biological insight into the structure
and function of biochemical networks
reveal capabilities and predict
phenotypes
undertake metabolic
engineering maximize desired product

To do this, we need
to manage our data & knowledge in a
coherent, scalable and machine
understandable manner
use efficient software to execute
simulations

Computational Knowledge Discovery

Terminological resources increasingly being used to
annotate biomolecular models
easier to explore or find models

converting models into formal representations of knowledge
check the annotation consistency
infer knowledge explicit in terminological resources
discover biological implications inherent in the models.

SBML

XML-based representation of biochemical models, their
components (compartments, species, reactions, events),
descriptors (rules, constraints, functions, units)

Consider the following enzymatic reaction:

SBML is an XML-based format

<?xml version="1.0" encoding="UTF-8"?>
<sbml level="2" version="3" xmlns="http://www.sbml.org/sbml/level2/version3">
<model name="EnzymaticReaction">
<listOfUnitDefinitions>
<unitDefinition id="per_second">
<listOfUnits>
<unit kind="second" exponent="-1"/>
</listOfUnits>
</unitDefinition>
<unitDefinition id="litre_per_mole_per_second">
<listOfUnits>
<unit kind="mole" exponent="-1"/>
<unit kind="litre" exponent="1"/>
<unit kind="second" exponent="-1"/>
</listOfUnits>
</unitDefinition>
</listOfUnitDefinitions>
<listOfCompartments>
<compartment id="cytosol" size="1e-14"/>
</listOfCompartments>
<listOfSpecies>
<species compartment="cytosol" id="ES" initialAmount="0" name="ES"/>
<species compartment="cytosol" id="P" initialAmount="0" name="P"/>
<species compartment="cytosol" id="S" initialAmount="1e-20" name="S"/>
<species compartment="cytosol" id="E" initialAmount="5e-21" name="E"/>
</listOfSpecies>

<listOfReactions>
<reaction id="veq">
<listOfReactants>
<speciesReference species="E"/>
<speciesReference species="S"/>
</listOfReactants>
<listOfProducts>
<speciesReference species="ES"/>
</listOfProducts>
<kineticLaw>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<times/>
<ci>cytosol</ci>
<apply>
<minus/>
<apply>
<times/>
<ci>kon</ci>
<ci>E</ci>
<ci>S</ci>
</apply>
<apply>
<times/>
<ci>koff</ci>
<ci>ES</ci>
</apply>
</apply>
</apply>
</math>
<listOfParameters>
<parameter id="kon" value="1000000" units="litre_per_mole_per_second"/>
<parameter id="koff" value="0.2" units="per_second"/>
</listOfParameters>
</kineticLaw>
</reaction>

<reaction id="vcat" reversible="false">
<listOfReactants>
<speciesReference species="ES"/>
</listOfReactants>
<listOfProducts>
<speciesReference species="E"/>
<speciesReference species="P"/>
</listOfProducts>
<kineticLaw>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<times/>
<ci>cytosol</ci>
<ci>kcat</ci>
<ci>ES</ci>
</apply>
</math>
<listOfParameters>
<parameter id="kcat" value="0.1" units="per_second"/>
</listOfParameters>
</kineticLaw>
</reaction>
</listOfReactions>
</model>
</sbml>

SBML specifies what models can have
as attributes

Biomodels are semantically annotated
SBML models
EBI managed
resource
600 + models
available as SBML
269 models are
curated with GO
process, function and
component terms,
and has links to
protein databases.
Possible to browse
by GO terms: http://www.ebi.ac.uk/biomodels-main/

Biomodels are semantically annotated
SBML models
<?xml version="1.0" encoding="UTF-8"?>
<sbml xmlns="http://www.sbml.org/sbml/level2" metaid="metaid_0000001" level="2" version="1">
<model metaid="metaid_0000002" id="Proctor2005_Hsp90" name="Hsp90model_basis510">
<annotation>
<rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#"
xmlns:bqbiol="http://biomodels.net/biology-qualifiers/"
xmlns:bqmodel="http://biomodels.net/model-qualifiers/">
<bqbiol:isVersionOf>
<rdf:Bag>
<rdf:li rdf:resource="urn:miriam:obo.go:GO%3A0051085"/>
</rdf:Bag>
</bqbiol:isVersionOf>
</rdf:RDF>
</annotation>
</model>
</sbml>

GO:0051085 GO:0007569 GO:0009408
chaperone mediated protein cell aging response to heat
folding requiring cofactor

Gene Ontology

nearly 30,000 terms
covers
biological processes
molecular functions
cellular components
terms organized around "is
a" hierarchy
terms further described with
'has part'/'part of'; 'regulates'
and '+ regulates', '-
regulates'

Harmony 2011: Formalization of SBML models as OWL ontologies

Species may be annotated with
UniProt, KEGG, ChEBI terms
<species metaid="metaid_0000038" id="ROS" name="ROS" compartment="
compartment" initialAmount="100" hasOnlySubstanceUnits="true">
<annotation>
<rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#"
xmlns:bqbiol="http://biomodels.net/biology-qualifiers/"
xmlns:bqmodel="http://biomodels.net/model-qualifiers/">
<rdf:Description rdf:about="#metaid_0000038">
<bqbiol:isVersionOf>
<rdf:Bag>
<rdf:li rdf:resource="urn:miriam:obo.chebi:CHEBI%3A26523"/>
</rdf:Bag>
</bqbiol:isVersionOf>
</rdf:Description> CHEBI:26523 reactive
</rdf:RDF>
</annotation> oxygen species
</species>

Chemical Entities of Biological Interest
(ChEBI)
recently refactored to be in line with formal
(reasoning capable) ontology

scope includes chemical entities (atoms,
substances, groups, molecules), roles and
subatomic particles

large numbers of curated molecules

Approach

The idea is to create sophisticated OWL ontologies from
biomolecular models represented using the Systems Biology
Markup Language (SBML).

Features
ontological commitment: terms in a vocabulary become
formally defined classes and relations in an ontology
upper level ontology to distinguish and constrain model
entities the spatio-temporal entities they represent
basic relations are used to describe (constrain) entities in
terms of the attributes and relationships they hold

code: http://code.google.com/p/sbmlharvester/

Conceptualization (SBML)

2 kinds of entities:
in silico: model components
in vivo: the entities represented by a model

An Upper Level Ontology distinguishes
models from the entities they represent

Ontological commitment

Assumption 1: Every model represents a
material entity (Model SubClassOf: represents
some MaterialEntity)
a Model annotated with class C represents
a C that is a subclass of MaterialEntity

Model entities (models and model
components) are distinguished from the
entities they represent

every element E of the SBML language represents a class Rep(E) and we
assert that E subClassOf: represents some Rep(E)


In addition to annotation to physical entities, we note that
annotations include functions and processes


Assumption 1: Every model represents a material
entity (Model SubClassOf: represents some
MaterialEntity)
a Model annotated with class C represents a
C that is a subclass of MaterialEntity or a Thing
that has-function some C or a Thing that has a
function that is realized by only C's

Model annotations are converted into
ontology axioms

model annotation: ontology axioms:
'is' | 'isVersionOf' | 'isVariantOf' subClassOf
* physical entity --------------------> has-part some physical-entity
* molecular function ---------------> has-part some (has-function some function)
* biological process ---------------> has-part some (
has-function some (realized-by only
process))

3. Relations impose additional
constraints, such that inconsistencies
arise when incorrectly used


Assertion:
M SubClassOf: represents some C or represents
some (has-function some C) or represents some
(has-function some (realized-by only C))

C SubClassOf: MaterialEntity
Then:
represents some C is satisfiable
represents some (has-function some
C) and represents some (has-function some
(realized-by only C)) are unsatisfiable


Assertion:

C SubClassOf: Function
Then:
represents some (has-function some C) is
satisfiable
represents some C and represents some (has-
function some (realized-by only C)) are
unsatisfiable


Assertion:

C SubClassOf: Process
Then:
represents some (has-function some (realized-by
only C)) is satisfiable
represents some C and represents some (has-
function some C) are unsatisfiable

SBML2OWL: Implementation

Combine libSBML and OWLAPI
Use libSBML to access model structure
extract MIRIAM annotations in RDF
use Jena RDF API to parse RDF annotations in SBML
models
use OWLAPI to perform conversion of SBML structure
combine with top-level ontology

SBML2OWL: Implementation

Application to BioModels repository yields:
OWL ontology with more than 800,000 axioms
includes all referenced ontologies
GO
ChEBI
Celltype
FMA
PATO

Model verification

After reasoning, we found 27 models to be inconsistent

reasons
1. our representation - functions sometimes found in the place
of physical entities (e.g. entities that secrete insulin). better
to constrain with appropriate relations
2. SBML abused - species used as a measure of time
3. constraints in the ontologies themselves mean that the
annotation is simply not possible

Finding inconsistencies with
axiomatically enhanced ontologies
recent work treats function as process and axioms state that an
ATPase activity (GO:0004002) is a Catalytic activity that has
Water and ATP as input, ADP and phosphate as output and is
a part of an ATP catabolic process.
Tho this, we add:
GO: ATP + Water the only inputs (universal quantification)
ChEBI: Water, ATP, alpha-D-glucose 6-phosphate are all
different (disjointness)
BIOMD0000000176 and BIOMD0000000177 models of
anaerobic glycolysis in yeast.
“ATP” input to “ATPase” reaction, which is annotated with
ATPase activity. The species “ATP”, however, is mis-
annotated with Alpha-D-glucose 6-phosphate (CHEBI:
17665), not with ATP.

Outcomes

The SBML-derived ontologies can be

i) checked for their consistency, thereby uncovering erroneous
curations

ii) infer attributes and relations of the substances,
compartments and reactions beyond what was originally
described in the models

iii) answer sophisticated questions across a model knowledge
base

Current work

Add more of SBML annotations (aka qualifiers) to the
ontology
Specify the role of species in the processes that they
participate in by extracting the roles from the
semantically annotated kinetic expressions
Simultaneously query knowledge and simulation results
currently time course
Increase performance
Fit the transformation into one of the more
computationally efficient OWL2 profiles

Harmony 2011: Formalization of SBML models as OWL ontologies

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Harmony 2011: Formalization of SBML models as OWL ontologies