BioUML

1
BioUML
Fedor Kolpakov Institute of Systems
Biology(spin-off of DevelopmentOnTheEdge.com)La
boratory of Bioinformatics,Design Technological
Institute of Digital TechniquesNovosibirsk,
Russia
2
Agenda

• Part 1 overview of BioUML workbench
• Cafe break
• Part 2 new concepts and possibilities(versions
  0.8.0 0.8.3)
• Further development
• Questions and discussion

3
Part 1 overview of BioUML workbench

• Overview
• Main concepts
• Meta model
• Architecture overview
• Diagram types
• Database module concepts
• Full text search
• Graph search
• Simulation engine
• BioUML server
• BMOND/Biopath database

• Live demonstration
• Installation of BioUML workbench
• Creating and simulating simple model
• SBML - Biomodels module
• BioPAX import
• BMOND database web interface
• JavaScript shell

4
Part 2 new concepts and possibilities

• Overview
• Reconstruction as solitaire game
• Levels of biological information
• BioHub concept
• Composite database module
• Composite diagram
• Experiment concept
• Graphic notation editor
• Microarray data analysis

• Live demonstration
• Loading database modules from server
• Text search
• Graph search
• Creating of composite database module
• Creating of composite diagram
• Experiment
• Graphic notation editor
• Microarray data analysis

5
Useful resources

• http//www.biouml.org/demo
• Flash movies that demonstrates how to work with
  BioUML workbench
• http//www.biouml.org/user/help/index.html
• http//www.biouml.org/download/0.7.8/manual.doc
• Useguide, gt200 pages
• HTML version
• MS Word document
• http//bmond.biouml.org
• Examples of pathway annotation
• BMOND Biological Models aNd Diagrams database

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Part 1Overview of BioUML workbench
7
Main BioUML concepts and ideas

• Visual modeling
• Meta model problem domain neutral level of
  abstraction that describes system as
  compartmentalized graph
• Diagram type concept formally defines graphical
  notation and provides its incorporation into
  BioUML workbench.
• Automated code generation for model simulation.
• Database module concept - allows developer to
  incorporate databases on biological pathways into
  BioUML workbench taking into account database
  peculiarities.
• Plug-in based architecture (Eclipse platform
  runtime from IBM company).

8
Biological databases
Data search and retrieving
Formal description of structure of biological
system
Visual modeling
Automated code generation for model simulation of
model behavior
MATLAB code
Java code
code
Simulating using MATLAB. JMatLink allows to
BioUML workbench to start MATLAB and retrieve
simulations results
Java simulation plug-in. Contains ODE solvers
ported from odeToJava and methods for hybrid
models support.
9
Meta model
10
Example system from two chemical reactions
-
k1A
-
k2B
k1A
K2B
A
B
C
R1
R2
100
0
0
k1 - reaction rate for R1 k2 reaction rate for
R2
Corresponding mathematical model
11
Meta-model example of formal description of
system from two chemical reactions
-
k1A
-
k2B
k1A
k2B
A
B
C
R1
R2
100
0
0
Description of system
ID R1
ID B
ID R2
ID C
ID A
A
-
gtB
CC ..
B
-
gtC
CC ..
CC ..
components in the
...
...
...
...
...
database
//
//
//
//
//
System structure is
R1
R2
described as a graph
C
A
B
Mathematical model
-
k2B
k2B
0
k1A
100
-
k1A
0
of the system
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• Suggested approach can be applied for modeling
  biological systems using
• Systems of ordinary differential equations
• Systems of algebra-differential equations
• State and transition diagrams
• Hybrid models
• Boolean and logical networks
• Petri nets
• Markov chains
• Stochastic models
• Cellular automates
• Some limitations
• Spatial models
• PDE

13
BioUML architecture
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Plug-in based architecture
A plug-in is the smallest unit of BioUML
workbench function that can be developed and
delivered separately into BioUML workbench. A
plug-in is described in an XML manifest file,
called plugin.xml. The parsed contents of plug-in
manifest files are made available
programmatically through a plug-in registry API
provided by Eclipse runtime. -
extension points are well-defined function points
in the system where other plug-ins can contribute
functionality. - extension is a
specific contribution to an extension point.
Plug-ins can define their own extension points,
so that other plug-ins can integrate tightly with
them.

• Plug-in
• plugin.xml
• Java jar files

• Plug-in
• plugin.xml
• Java jar files

• Plug-in
• plugin.xml
• etc.

Eclipse platform runtime
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• Formal description and modeling of biological
  systems require coordinated efforts of different
  group of researchers
• programmers - they should provide computer tools
  for this task.
• problem domain experts - they should specify what
  and how should be described.
• experimenters and annotators - they should
  describe corresponding data following to these
  rules.
• mathematicians - they should provide methods for
  models analysis and simulations.
• BioUML architecture separates these tasks so they
  can be effectively solved by corresponding group
  of researchers and provides simple contract how
  these groups and corresponding software parts
  should communicate.

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Diagram types
18
Diagram type concept

• Diagram type defines
•   types of biological components and their
  interactions that can be shown on the diagram
•   diagram view builder - it is used to generate
  view for each diagram element taking into account
  problem domain peculiarities
• semantic controller - provides semantic
  integrity of the diagram during its editing
• filters hide or highlight diagram elements
  according to some selection criteria.

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Reconstruction and formal description of
biological systems using different diagram types
Formality, details
Semi-structureddata
1. Semantic network
2. Pathway diagram(semantic network gene
network or metabolic pathway)
Structured data(reactions and its components)
4. Gene network
3. Metabolic pathway
Kinetic data(kinetic laws, constants, initial
values
5. Pathway simulation (mathematical model)
20
Graphic notation

21
Stimulus activating NF-kappaB(semantic network,
ontology)
22
NF-kappaB family (semantic network, ontology)
23
Function of human DNA methyltransferases
(pathway diagram)
24
The biosynthesis of catecholamines(metabolic
pathway)
25
Cell cycle model of mammalian G1/S transition
control with E2F feedback loops(pathway
simulation diagram)
26
DGR0356 NF-kB model (Hoffmann et al., 2002)
27
NF-kB dynamics in nucleus and cytoplasm before
and after TNF-alpha stimulation (Hoffmann et al.,
2002)
28
Regulation of caspase-3 activation and
degradation (Stucki and Simon, 2005 )
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Database module concept

• The database module concept allows to developer
  define new diagram types and incorporate other
  databases on biological pathways into BioUML
  framework.
• The database module defines mapping of database
  content into diagram elements and diagram types
  that can be used with the database.
• Module also provides query engine that can be
  used by BioUML workbench to find interactiong
  components of the system.

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BioUML database modules

• BioUML standard module
• Databases
• EBI databases Ensembl, UniProt, ChEBI,
  GeneOntology
• Biopath/BMOND (http//biopath.biouml.org)
• KEGG/Ligand (http//www.kegg.com)
• TRANSPATH (http//www.biobase.de)
• GeneNet (http//wwwmgs.bionet.nsc.ru)
• Formats
• SBML Systems Biology Markup Language, level 1,
  2 (http// www.sbml.org)
• CellML Cell Markup Language (http//www.cellml.o
  rg)
• BioPax Biological Pathways Exchange
  (http//www.biopax.org)
• PSI-MI
• OBO
• GXL - Graph eXchange Language (http//www.gupro.de
  /GXL)

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KEGG pathway
36
CellML model
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SBML model
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Full text search
39
User interface for full text search 1) pop-up
menu 2) menu buttons for selected entity 3)
full text search pane.
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Full text search (uses Lucene engine)
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Graph search
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Graph search engine
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Simulation engine
46
Biological databases
Data search and retrieving
Formal description of structure of biological
system
Visual modeling
Automated code generation for model simulation of
model behavior
MATLAB code
Java code
code
Simulating using MATLAB. JMatLink allows to
BioUML workbench to start MATLAB and retrieve
simulations results
Java simulation plug-in. Contains ODE solvers
ported from odeToJava and methods for hybrid
models support.
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• script for 'CellCycle_1991Gol' model simulation
• constants declaration
• global Reaction1_vi Reaction2_kd Reaction4_K1
  Reaction4_Kc Reaction4_VM1 Reaction5_K3
  Reaction5_VM3 Reaction6_K2 Reaction6_V2
  Reaction7_K4 Reaction7_V4
• Reaction1_vi 0.023
• Reaction2_kd 0.00333
• Reaction4_K1 0.1
• Reaction4_Kc 0.3
• Reaction4_VM1 0.5
• Reaction5_K3 0.1
• Reaction5_VM3 0.2
• Reaction6_K2 0.1
• Reaction6_V2 0.167
• Reaction7_K4 0.1
• Reaction7_V4 0.1
• Model rate variables and their initial values
• y
• y(1) 0.0 y(1) -
  cytoplasm.C

49
Function to calculate dy/dt for the model

• function dy CellCycle_1991Gol_dy(t, y)
• Calculates dy/dt for 'CellCycle_1991Gol' model.
• constants declaration
• global Reaction1_vi Reaction2_kd Reaction4_K1
  Reaction4_Kc Reaction4_VM1 Reaction5_K3
  Reaction5_VM3 Reaction6_K2 Reaction6_V2
  Reaction7_K4 Reaction7_V4
• write rules to calculate some eqution
  parameters
• rateOfReaction1 Reaction1_vi
• rateOfReaction4 ((1 - y(3))Reaction4_VM1y(1))/
  ((1 Reaction4_K1 - y(3))(Reaction4_Kc
  y(1)))
• rateOfReaction5 (Reaction5_VM3(1 -
  y(4))y(3))/(1 Reaction5_K3 - y(4))
• rateOfReaction6 (y(3)Reaction6_V2)/(Reaction6_K
  2 y(3))
• rateOfReaction7 (Reaction7_V4y(4))/(Reaction7_K
  4 y(4))
• rateOfReaction2 y(1)Reaction2_kd
• calculates dy/dt for 'CellCycle-1991Gol.xml'
  model
• dy rateOfReaction1 - rateOfReaction2
• - rateOfReaction1 - rateOfReaction4 -
  rateOfReaction5 rateOfReaction6
  rateOfReaction7 rateOfReaction2
• rateOfReaction4 - rateOfReaction6

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Results of SBML semantic tests
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BioModels comparison BioUML simulation results
with other simulatorshttp//www.biouml.org/_biom
odels/
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Simulators comparison criteria

• Passed CSV file was generated by simulator
• interval criteria
• no difference - 0.999 min lt x lt 1.001 max
  or
• x lt ZERO and max lt
  ZERO
• small difference 0.5 min lt x lt 1.5 max
• significant difference - otherwise
• median criteria
• no difference - abs((x median)/median) lt
  0.01 or
• x lt ZERO and median lt
  ZERO
• small difference - abs((x median)/median) lt
  0.5
• significant difference otherwise
• x variable value provided by compared simulator
• min, max, median calculated from values
  provided by other simulators with which the
  specified simulator is being compared.
• Implementation note if result file was not
  generated by BioUML, then other simulators can be
  compared one to each other.

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BioUML Enterprise EditionBioUML server
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BioUML EE architecture
BioUML workbench
Web browser
Client side
Database module
Servlet container Tomcat
Server side
BioUML servlet
BeanExplorerEnterprise Edition
JDBC DB module
Lucene full text search engine
JDBC
MySQL database
59
BMOND Biological MOdels aNd Diagrams
database(former name Biopath)
60
BMOND system architecture
BioUML workbench
Web browser
Biopath module
Client side
Servlet container Tomcat
Server side
BeanExplorerEnterprise Edition
JDBC
BiopathMySQL database
61
Figure 4. G1/S entry model (Kel et al., 2000)
described using BioUML technology.
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BMOND web interfacelive demonstrationhttp//bmon
d.biouml.org

• Interface overview
• View diagrams
• View diagram components
• List of diagram components
• Categories (classification)
• Filter
• Dynamic columns
• Web forms for components editing

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Part 2New concepts and possibilities
65
Part 2 new concepts and possibilities

• Overview
• Reconstruction as solitaire game
• Levels of biological information
• BioHub concept
• Composite database module
• Composite diagram
• Experiment concept
• Graphic notation editor
• Microarray data analysis

• Live demonstration
• Loading database modules from server
• Text search
• Graph search
• Creating of composite database module
• Creating of composite diagram
• Experiment
• Graphic notation editor
• Microarray data analysis

66
Metaphor biological systems reconstruction as
solitaire (patience) game
Desk BioUML editor Solitaire biological
pathway Cards biological objects(genes,
proteins, lipids, etc.) Pack of cards
different biological databases
67
Levels of biological information

• Main idea for data integration and pathway
  reconstruction - escape information duplication
• - classify components of biological pathways by
  levels
• each next level should refer but do not
  duplicate information from previous levels
• use free EBI databases whenever it is possible.

wiki

• Cyclonet
• leads
• actions
• targets

• LipidNet
• classifications
• lipids
• genes

UbiProtclassificationsE1, E2, E3,
wiki
wiki
Level 3 Problem specific
refers
refers
refers
Level 2 Pathways, models
GeneModels
BMOND
refers
refers
ChEBI
UniProt
Ensembl
GO
Level 1 Catalogs
Biological objects
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Add-on technology
This approach should help us to solve
difficulties with usage of external catalogs when
external catalog does not contain needed entity
(for example gene or substance) or when we would
like to add some information to existing entity
description. Example for BMOND2, gene special
table allow us to add new entity to BMOND2 if
such entity missing in corresponding external
catalog.
Classification
BioUML
Java object
Gene catalog
Ensembl
BeanExplorer
SQL
Synonyms
Web interface
query
Description
Gene
Lucene
add
-
on table
DB references
Document
Literature
references
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BioHub
70
BioHub concept

• BioHUB an approach link information from
  different databases.Main usage
• binding microarray (omics) data to pathway
  diagrams
• graph search
• DBReferences editor
• microarray (omics) data analysis
• Follows to MIRIAM standard
• References to database objects
• Relationships between biological objects
• Simple Java API

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BioHub structure

• Entities
• - DB_ID
• version
• ID
• AC
• species
• description
• key words

• Relations
• DB_ID_1
• DB_version_1
• ID_1
• DB_ID_2
• DB_version_2
• ID_2
• relation
• evidence
• comment

• Databases
• - DB_ID
• name
• description
• URL
• url_patern_ID
• url_patern_AC

• RelationTypes
• relation
• description
• backwardRelation
• comment

• RelationInfo
• DB_ID_1
• DB_ID_2
• relation
• comment

72
Linking with experimental data and results of
analysis
wiki

• LipidNet
• classifications
• lipids
• genes

wiki
wiki

• Cyclonet
• leads
• actions
• targets

UbiProtclassificationsE1, E2, E3,
Level 3 Problem specific
refers
refers
refers
Level 2 Pathways, models
GeneModels
BMOND
refers
refers
ChEBI
UniProt
Ensembl
GO
Level 1 Catalogs
Biological objects
BioHUB
Experimental data, results of analysis
OMICS data
Results of analysis
MSigDB
GeneAtlas,NCI60
73
Linking with external databases
wiki

• Cyclonet
• leads
• actions
• targets

• LipidNet
• classifications
• lipids
• genes

UbiProtclassificationsE1, E2, E3,
wiki
wiki
Level 3 Problem specific
refers
refers
refers
Level 2 Pathways, models
GeneModels
BMOND
refers
refers
ChEBI
UniProt
Ensembl
GO
Level 1 Catalogs
Biological objects

• External databases
• KEGG
• LipidMap, LipidBank
• Reactome,

Experimental data, results of analysis
BioHUB
OMICS data
Results of analysis
MSigDB
GeneAtlas,NCI60
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Coloring diagram according to microarray
data. Each bar corresponds to one value from
corresponding microarray series.
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Coloring diagram according to omics data
76
BioHub usage graph search engine
77
Composite database moduleFlash movie
XML_module.exe
78
Composite database module

• Composite database module is defined formally as
  XML document. It allows
• specify dependencies from other database modules
• specify data types that can be used from
  external database modules
• describe dynamic properties for add-on
  technology
• specify what dynamic properties can be added to
  data types from external modules. This
  information will be stored in local module and
  merged dynamically with information from external
  modules. By this way user can add information to
  external catalogs like Ensembl, UniPropt, etc.
• specify data types used by local module
• specify diagram types used by local module
• specify QueryEngine

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DTD lt!ELEMENT dbModule (jdbcConnection,
properties?, dependencies?, types?)gt lt!ATTLIST
dbModule gt name CDATA
REQUIRED title CDATA
REQUIRED description PCDATA
version CDATA "0.8.0" type
CDATA textSQL
databaseType CDATA databaseVersion
CDATA databaseName CDATA
gt lt!ELEMENT jdbcConnectiongt lt!ATTLIST
jdbcConnectiongt name CDATA
REQUIRED jdbcDriverClass CDATA
REQUIRED jdbcURL CDATA
REQUIRED jdbcUser CDATA
jdbcPassword CDATA gt
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lt!--
--gt lt!-- Properties -
definition of properties for all types of diagram
--gt lt!-- elements used by the graphic notation.
--gt lt!--

--gt lt!-- Possible property types
--gt lt!-- - simple types
boolean, int, double, String
--gt lt!-- - array
--gt lt!-- - composite

--gt lt!--
--gt lt!ELEMENT properties
(property)gt lt!ELEMENT property
(tags?)gt lt!ATTLIST property name
CDATA REQUIRED type
CDATA REQUIRED short-description
CDATA IMPLIED value
CDATA gt lt!ELEMENT tags (tag)gt lt!ELEMENT
taggt lt!ATTLIST tag name CDATA
REQUIRED value CDATA
IMPLIED gt lt!ELEMENT propertyRefgt lt!ATTLIST
propertyRef name CDATA
REQUIRED value CDATA gt
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lt!--
--gt lt!-- Dependencies from
other databases and modules
--gt lt!-- Graphic notations can be defined in the
specialized module --gt lt!--

--gt lt!ELEMENT dependencies
(dbModule, graphicNotation)gt lt!ELEMENT dbModule
(externalType)gt lt!ATTLIST dbModulegt name
CDATA REQUIRED gt lt!ELEMENT
externalType (propertyRef)gt lt!ATTLIST
externalType name CDATA
REQUIRED readOnly CDATA
truefalse gt lt!ELEMENT graphicNotationgt lt!ATTLIST
graphicNotationgt name CDATA
REQUIRED type CDATA
JavaXML class CDATA path
CDATA gt
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lt!--
--gt lt!-- Internal data types
for this module
--gt lt!-- Description of internal type should
provide all information to --gt lt!-- create
corresponding DataCollection
--gt lt!--
--gt lt!ELEMENT
types (internalType)gt lt!ELEMENT internalType
(querySystem, propertyRef)gt lt!ATTLIST
internalTypegt section CDATA
REQUIRED name CDATA
REQUIRED class CDATA
REQUIRED transformer CDATA
REQUIRED gt lt!ELEMENT querySystem
(index)gt lt!ATTLIST querySystemgt class
CDATA REQUIRED luceneIndexes
CDATA gt lt!ELEMENT indexgt lt!ATTLIST indexgt
class CDATA REQUIRED
table CDATA gt
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Editor for composite database module
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Editor for composite database module
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Editor for composite database module
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Editor for composite database module
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Current status

• Implemented
• Database modules (initial version)Ensembl,
  UniProt, ChEBI, GO,IntAct, Reactome, BioModels
• Composite module (external referencies)
• Defined as XML
• Composite module editor
• Selecting and loading modules from server
• In process
• BioHUB
• Protein state concept
• Add-on technology
• BMOND2 redesigned version of BMOND.

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From huge theory to practical output

• Biological data
• integrations
• Practical output
• catalogs (Ensembl, UniProt, CheBI)
• controlled vocabularies, ontologies
• hubs

• Automated language translation
• Practical output
• electronic dictionaries
• spell checkers

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Model composition
90
Composite diagram main concepts
Block types 1) block only mathematical
equations. Used mainly for physiological
models 2) subdiagram other diagram
Connection types 1) directed input ? output.
Transformation function can be used 2)
undirected contact. Indicates that 2 nodes in
mode is the same entity.
Semantic constraints There are semantic
constraints, for example block can have only one
input for each variable. Two inputs are forbidden
for the same variable.
Flat model Before Matlab or Java code generation
composite model is transformed into flat model
and usual genertions routines are used.
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Experiment
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Experiment

• To make a virtual experiment it is frequently
  needed to modify initial model.
• Typical modifications (changes) are
• changing of initial values
• changing of model parameters to imitate
  different conditions or mutations
• deleting of some model elements to imitate
  knock-out mutations
• adding events to imitate external influences on
  the model
• To skip model duplications for each virtual
  experiment we introduce changes concept.

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Graphic notationformal definition as XML
document
http//www.biouml.org/sbgn.shtml Flash movie
Graphic_Notations_Editor.exe
96
Graphic notation versus graph layout

• allows edit diagram
• allows to create new diagram
• different graphic notations can be applied to the
  same SBML model
• allows formally define SBGN and use it in SBML
  models
• allows to reuse graphic notation by many tools

97
Graphic notation can be defined formally as XML
document

• properties formal definition of properties that
  can be used as properties of nodes and edges (for
  example, title, multimer, etc.). Definition of
  property includes
• name
• type
• short description
• controlled vocabulary (optional)
• node types definition of node includes
• name
• icon
• properties
• view function (JavaScript)
• short description
• edge types definition of edge includes
• name
• icon
• properties
• view function (JavaScript)
• short description
• semantic controller defines rules for semantic
  control of diagram integrity. For this purpose it
  defines following functions
• canAccept (JavaScript)

98
Basic software architecture for rendering of
biological models according to specified graphic
notation and layout information
Diagram
Rendering API JavaScript API for creating
primitives similar with SBML layout extension
Rendering engine

• JavaScript functions
• - build node/edge view
• semantic control

JavaScriptAPI for data access
Model API
Layout API
Notation API
SBML

BioPAX
Layoutinformation
Graphic notation
Initial data
99
Formal definition of graphic notation as XML
document and integration with SBML format
100
Graphic notation editormain concepts

• graphic notation is defined formally as XML
  document
• graphic notation editor provides user friendly
  interface for XML document editing
• SBGN graphic notation (prototype) is implemented
• BioUML workbench allows to create and edit
  diagrams using graphic notation defined as XML
  document
• May be graphic editor will be useful for SBGN
  community for
• improving SBGN specification
• for testing SBGN specification by creating
  different diagrams
• Details
• http//www.biouml.org/sbgn.shtml

101
BioUML workbech Select Data tab to see the tab
with a list with available graphic notations
102
Click right mouse button on selected graphic
notation to open it Graphic Notation Editor
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Graphic Notation Editor Main sections of formal
definition of graphic notation
104
List of specific properties that are used by
graphic notation
Properties editor
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User can click right mouse button on Properties
node to create new property
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Nodes contains list of all node types used by
graphic notation
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• For each node type user can define
• name
• properties
• icon
• view function (JavaScript)

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By clicking right mouse button on Nodes user
can create new node type
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• By the same way user can define edge type
• name
• properties
• icon
• view function (JavaScript)

110
Examples node contains a set of diagrams that
demonstrates usage of graphic notation.
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User can create and edit such diagram.
112

• When user selects some element on the diagram he
  can edit
• object properties
• JavaScript that builds a view for selected
  diagram element

113
Semantic controller node contains list of
JavaScript functions that provide semantic
constraints and semantic integrity of the diagram.
114
Graphic notation defined as XML document can be
used by BioUML workbench to create corresponding
diagram.
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Graphic Notation EditorSBGN examplescreated in
BioUML
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Skins
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Microarray plug-in(alpha version)
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Microarray plug-in

• Import microarray data in tab delimited format
• Show data as a table
• Filter data by different criteria
• Microarray data analysis
• Revealing up/down regulated genes
• Meta-analyses
• Binding with diagram nodes by ID
• Coloring diagrams
• JavaScript functions
• Data manipulation (filter, join, intersect, trim,
  etc.)
• Statistical analysis

127
Microarray plug-in

• Current work
• Powerful user interface for coloring diagrams
• Support of other formats for microarray data and
  results of analyses
• Sophisticated binding algorithm using different
  database references and ID (gene hub)
• Further work
• Server module that will provide access to
  ArrayExpress data

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BioUML workbench. Data tab contains section
Microarray. User can import microarray data in
tab delimited format into this section.
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• Possibility to filter probe sets
• by column values
• selecting only those probe sets that can be
  linked to the specified diagram

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Microarray analysis
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Coloring diagram according to microarray
data. Each bar corresponds to one value from
corresponding microarray series.
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Coloring diagram according to omics data
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Further developmentProtein state
137
BioUML workbench further development

• Protein states
• Complexes
• Improving team work on annotation
• Login, single sign on
• Editing history (what data were modified, whom
  and when)
• Passing of changes from server to client
• Sequence analysis and visualization
• Agent based modeling

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Protein state
139
Modification

• The functions of macromolecular entities (mainly
  proteins) are often determined not only by their
  primary sequences, but by chemical modifications
  they have undergone.
• In BMOND2 unmodified and modified forms of a
  protein refer to the same entity in UniProt
  database
• List of possible modifications is extracted from
  UniProt Feature Table
• BMOND2 modifications table
• allows to describe modifications that are not
  described in UniProt.These modifications are
  automatically added to the protein, referred from
  BMOND2.
• Modification type control vocabulary that
  describes possible modification types (for
  example, phosphorylation, acetylation,
  ubiqutination)
• To take into account protein modifications State
  concept is used.

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UniProt Feature Table

• FT CHAIN 1 561 Cytosolic
  purine 5'-nucleotidase.
• FT
  /FTIdPRO_0000064389.
• FT REGION 202 210 Substrate
  binding (Potential).
• FT COMPBIAS 549 561 Asp/Glu-rich
  (acidic).
• FT ACT_SITE 52 52 Nucleophile.
• FT ACT_SITE 54 54 Proton donor.
• FT METAL 52 52 Magnesium.
• FT METAL 54 54 Magnesium (via
  carbonyl oxygen).
• FT METAL 351 351 Magnesium.
• FT BINDING 127 127 Allosteric
  activator 1.
• FT BINDING 154 154 Allosteric
  activator 2.
• FT BINDING 354 354 Allosteric
  activator 2.
• FT BINDING 436 436 Allosteric
  activator 1 via carbonyl
• FT oxygen.
• FT BINDING 453 453 Allosteric
  activator 2.
• FT MOD_RES 527 527 Phosphoserine
  (By similarity).
• FT VARIANT 3 3 T -gt A (in
  dbSNPrs10883841).
• FT
  /FTIdVAR_024244.
• FT VARIANT 136 136 Q -gt R (in
  dbSNPrs12262171).

141
Modification

• position
• amynoacid
• modification type (controlled vocabulary)
• evidenceexperimental, by similarity, predicted
• comment
• Publication reference

142
State concept

• State describes states of all amino acids
  available for modifications
• possible values
• ? unknown, not specified
• any
• - unmodified
• p phoshporylated
• ac acetylated
• from controlled vocabulary
• Protein states are described in BMOND2 states
  table
• Reaction user should specify protein state
• Diagram user should specify protein state

143
State table

• module (database)
• id
• state short name (like TRANSPATH)
• position
• modification

144
SBGN
Mapping BMOND2 -- SBGN modification state
variable state state of macromolecule
145
Complex concept
146
Complex concept

• A complex is s a biochemical entity composed of
  other biochemical entities, whether
  macromolecules, small molecules, multimers, or
  themselves complexes.
• Complex is specified as a set of units
• Complex modifications
• all possible modifications of its units (some of
  them can not occur due to physical interactions
  between units how we can take it into account)
• Complex state
• var.1 list of modifications for its subunits
• var. 2 list of states for its units

147
Complex tables

• Complex
• ID
• title (short name)
• complete name
• species
• synonyms
• comment
• References
• States
• Synonyms
• Structure
• DBReferences
• Publications

• Complex Units
• complexDB
• complexID
• unitDB
• unitID
• multimer

148
SBGN
149
Reaction

• Reaction components
• component identification
• DB
• id
• state
• compartment
• Reaction
• compartment
• Reaction dialog
• specie state
• specie compartment
• reaction compartment

• Tables
• Reaction
• compartment
• Reaction components
• state
• compartment

150
Diagrams

• Macromolecule state
• New diagram element dialog
• Graphic notation
• BioUML
• states right label, one modification
• complexes
• SBGN skin

151
Acknowledgements

• Part of this work was partially supported by
  following grants
• European Committee grant ?037590 Net2Drug
• Siberian Branch of Russian Academy of Sciences
  (interdisciplinary projects ? 46)
• Volkswagen-Stiftung (I/75941),
• INTAS Nr. 03-51-5218
• RFBR Nr. 04-04-49826-?
• Author is grateful to for useful comments,
  discussions and technical support
• Alexander Kel Sergey
  Zhatchenko Software developers
  Annotators Nikita Tolstyh
  Mikhail Puzanov Ruslan Sharipov
  Sergey Lapukhov Ilya Kiselev
  Ivan YevshinAlexander Magdysyuk
  Denis Ryumin Elena
  CheremushkinaVlad Zhvaleev Alexandr
  Koshukov Ekaterina Kalashnikova Vasiliy
  Hudyakov Igor Tyazhev Sergey
  Graschenko Oleg Onegov