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EBI is an Outstation of the European Molecular Biology Laboratory. Management and provision of computational models Camille Laibe Data Management workshop, 19-20th March 2012, Vienna Nature Precedings : doi:10.1038/npre.2012.7013.1 : Posted 22 Mar 2012

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Page 1: Management and provision of computational models · Management and provision of computational models Camille Laibe ... (DOQCS, CellML Model Repository, JWS Online, ...) Provided by

EBI is an Outstation of the European Molecular Biology Laboratory. 

Management and provision of computational models

Camille Laibe

Data Management workshop, 19­20th March 2012, Vienna

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What is BioModels Database?

   BioModels.net team

    Technology part of the Computational Systems Neurobiology group               (Nicolas Le Novère) at EMBL­EBI

Standards: Minimal Information Required In the Annotation of Models (MIRIAM), Minimal Information About a Simulation Experiment (MIASE), Systems Biology Graphical Notation (SBGN), …

Formats: Systems Biology Markup Language (SBML), Simulation Experiment Description Markup Language (SED­ML), ...

Ontologies: Systems Biology Ontology (SBO), Kinetic Simulation Algorithm Ontology (KiSAO), TErminology for the Description of DYnamics (TEDDY), …

Services: BioModels Database, MIRIAM Registry, Identifiers.org, ...

Tools: libSBML, JSBML, SBFC, SBMLeditor, …

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What is BioModels Database?

   Model

    provides a description of a biological system, taking into account the necessary constituents and their relationships

   Quantitative/mathematical/computational model

    describes a system using mathematical concepts and language and allows the study of its dynamic behaviour (for instance: time and/or space) by mean of simulations

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What is BioModels Database?Basic (biochemical) model example

A_Bk3

k1

k2

A+B Ap+B

d[A]/dt = - k1[B][A] + k2[A_B] d[Ap]/dt = + k3[A_B] d[B]/dt = - k1[B][A] + k2[A_B] + k3[A_B] d[A_B]/dt = + k1[B][A] - k2[A_B] - k3[A_B]

t

[x]

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How to build a model?

Tyson et al (1991) PNAS 88(1):7328-32

biological model mathematical model

computational modelsimulation

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What is BioModels Database?

   quantitative / dynamic understanding of biological systems

integration of data from various scales

make clear the current state of knowledge

effective way of highlighting gaps in the knowledge

   prediction of the behaviour of systems under certain conditions

sometimes the only tool available

   design novel experiments

   …

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What is BioModels Database?

   quantitative / dynamic understanding of biological systems

integration of data from various scales

make clear the current state of knowledge

effective way of highlighting gaps in the knowledge

   prediction of the behaviour of systems under certain conditions

sometimes the only tool available

   design novel experiments

   …

Models are significant tools in Systems Biology

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What is BioModels Database?

Number of results returned for “computational model” for a given year on UKPMC

Models availability

1958 1961 1964 1967 1970 1973 1976 1979 1982 1985 1988 1991 1994 1997 2000 2003 2006 2009 20120

200

400

600

800

1000

1200

1400

1600

1800

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Storage and exchange of models

Modellers need to:

   find

   understand

   reuse

   combine

existing models

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Storage and exchange of models

Modellers need to:

   find

   understand

   reuse

   combine

existing models

This requires:

standard formats

Access to published models

reliable models: curated and annotated

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Production pipeline

http://www.ebi.ac.uk/biomodels/

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What is BioModels Database?

   Biochemical models

interactions between molecules in multiple cellular compartments

   Pharmacometrics models

tumor growth and treatment response

   Single­compartment neurons

membrane voltage, current flow, concentrations of various ions intra­ and extracellularly

  Spread of infectious diseases

outbreak of zombie infection

   Ecosystem models

interaction of living organisms in a given environment 

   ...

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Model submissionN

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Support for deposition

   From authors prior to publication

     Supported (listed in instructions for authors) by > 300 journals, including:

● Molecular Systems Biology● All PLoS journals● All BioMedCentral journals● …

   Submitted by curators

implemented from literature

imported from journal supplementary materials

exchanged with other repositories

                   (DOQCS, CellML Model Repository, JWS Online, ...)

   Provided by other people curating models out of interest

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CurationN

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MIRIAM

The Minimum Information Required In the Annotation of a Model

http://biomodels.net/miriam/

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MIRIAM STANDARDMIRIAM Guidelines

set of guidelines for the curation and annotation of quantitative models

about encoding and annotation

applicable to any structured model format

cf. Nicolas Le Novère et al. Minimum Information Requested in the Annotation of biochemical Models (MIRIAM). Nature Biotechnology, 2005

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MIRIAM Compliance

Models must (among other things):

be encoded in a public machine­readable format

be clearly linked to a single publication

reflect the structure of the biological processes described in the reference paper (list of reactions, ...)

be instantiable in a simulation (possess initial conditions, ...)

be able to reproduce the results given in the reference paper

contain creator’s contact details

annotated: each model constituent must be unambiguously identified

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AnnotationN

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Support for deposition

   Curated branch

    MIRIAM compliant models

   Non­curated branch

    valid SBML but not curated or annotated

not MIRIAM compliant models

cannot reproduce published results

different model structure

non kinetic model (FBA, stoichiometric maps, ...)

MIRIAM compliant models

models contain kinetic that we cannot curate up to now

work in progress, will be moved to curated branch in the near future

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Why are annotations important?

Annotations, and generally metadata, are essential for:

    understanding data

    reusing data

    comparing data

    integrating data

    converting data

    providing efficient search strategies

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Why are annotations important?

Annotations, and generally metadata, are essential for:

    understanding data

    reusing data

    comparing data

    integrating data

    converting data

    providing efficient search strategies

    ...

 → true for any kind of data!

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Identifiers for annotations

   Unique and unambiguous

     an identifier must never be assigned to two different objects

   Perennial

     the identifier is constant and its lifetime is permanent

   Standards compliant

     must conform on existing standards, such as URI

   Resolvable

     identifiers must be able to be transformed into locations of online resources storing the object or information about the object

   Free of use

     everybody should be able to use and create identifiers, freely and at no cost

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Towards globally unique identifiers

Entity identifierNamespace

provided by the data collection

unique within the data collection

format defined by the data collection

from a shared list of namespaces

Identifies a data collection

Identifies a data entry within the data collection

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Provision of URIs for annotations

   MIRIAM Registry

catalogue of data collections and their associated namespace

provides perennial identifiers for annotation and cross­referencing purposes

   

Activation of MAPKK activity: GO:0000186 in Gene Ontology

Human calmodulin: P62158 in UniProt

Alcohol dehydrogenase: 1.1.1.1 in Enzyme Nomenclature

urn:miriam:uniprot:P62158

urn:miriam:ec-code:1.1.1.1

urn:miriam:obo.go:GO%3A0000186

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Provision of URIs for annotations

   MIRIAM Registry

catalogue of data collections and their associated namespace

provides perennial identifiers for annotation and cross­referencing purposes

   Identifiers.org

● built on the information stored in the Registry● provides directly resolvable URIs

Activation of MAPKK activity: GO:0000186 in Gene Ontology

Human calmodulin: P62158 in UniProt

Alcohol dehydrogenase: 1.1.1.1 in Enzyme Nomenclature

http://identifiers.org/obo.go/GO:0000186

http://identifiers.org/ec-code/1.1.1.1

http://identifiers.org/uniprot/P62158

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Current BioModels.net Qualifiers

   bqmodel:is

   bqmodel:isDerivedFrom

   bqmodel:isDescribedBy

   bqbiol:is

   bqbiol:isDescribedBy

   bqbiol:hasPart

   bqbiol:hasProperty

   bqbiol:isPartOf 

http://biomodels.net/qualifiers/

   bqbiol:isPropertyOf

   bqbiol:isVersionOf

   bqbiol:hasVersion

   bqbiol:isHomologTo

   bqbiol:isDescribedBy

   bqbiol:encodes

   bqbiol:isEncodedBy

   bqbiol:occursIn

   [...]

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Annotations in SBMLN

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PublicationN

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32List of models

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33Model browsing via GO terms

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34Model browsing via GO terms

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35Model search

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36Advanced model search

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User interfaceN

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43Curation information

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44Graphical export

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45Online simulation

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46JWS Online

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47Sub­model creation

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48Sub­model creation

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51Sub­model creation

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52Model of the month

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53Report issues

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54Web Services

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Supported formats

XPP-Aut

VCML (Vcell)

Octave

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Converter framework

System Biology Format Converter

generic framework that potentially allows any conversion between two formats

aims to be easily extended

currently supported: conversion from SBML to SBGN­ML, BioPAX Level 2 and Level 3, XPP, Octave, Dot, ...

allows the combination of several existing converters (conversion pipeline)

collaborative project developed in Java

online conversion service: 

http://www.ebi.ac.uk/compneur­srv/converters/ (beta)

http://sourceforge.net/projects/sbfc

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Technologies

Java

Apache Tomcat

Apache HTTP Server

MySQL server

Subversion

Apache Lucene

http://sourceforge.net/projects/biomodels/

http://www.ebi.ac.uk/biomodels-main/develop

SOSlib

Gnuplot

several converters

numerous libraries

Bash scripts

...

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Current development model

   Open source

    GNU General Public License

    sources available from SourceForge.net

   main development and maintenance work done at EMBL­EBI

    (BioModels.net team)

   main instance running at EMBL­EBI (UK)

    and one mirror at Caltech (USA)Nat

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What is BioModels Database?Content evolution

Rel

atio

ns M

odels

Evolution of the content of BioModels Database

04/2005 04/2006 04/2007 04/2008 04/2009 04/2010 04/2011 04/20120

20000

40000

60000

80000

100000

120000

140000

160000

0

100

200

300

400

500

600

700

800

900

1000

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Some examples

Increasing size and complexity of models

   Global reconstruction of the human metabolic network (MODEL6399676120)

    17919 species

   Genome­scale human metabolic modeling (MODEL1105100000)

     25600 species, 4894 reactions

   Global model for the yeast molecular interaction network (MODEL3883569319)

    130325 species, 36265 annotations

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Challenges

   storage infrastructure

suitability of some technologies

performance

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Challenges

   annotation

semi­automatic annotation

Annotation and merging of SBML models with semanticSBML. Krause F, Uhlendorf J., Lubitz T., Schulz M., Klipp E., Liebermeister W.  Bioinformatics (2009)

Saint: a lightweight integration environment for model annotation. Lister, A. L., Pocock, M., Taschuk, M. & Wipat, A.  Bioinformatics (2009)

collaborative annotation

Payao: a community platform for SBML pathway model curation. Matsuoka Y , Ghosh S , Kikuchi N , Kitano H. Bioinformatics (2010)

BioCatalogue: a universal catalogue of web services for the life sciences. Bhagat J, Tanoh F, Nzuobontane E, Laurent T, Orlowski J, Roos M, Wolstencroft K, Aleksejevs S, Stevens R, Pettifer S, Lopez R, Goble CA.  Nucleic Acids Res (2010)

The Pfam protein families database. M. Punta, P.C. Coggill, R.Y. Eberhardt, J. Mistry, J. Tate, C. Boursnell, N. Pang, K. Forslund, G. Ceric, J. Clements, A. Heger, L. Holm, E.L.L. Sonnhammer, S.R. Eddy, A. Bateman, R.D. Finn.  Nucleic Acids Research (2012) 

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Challenges

   display

textual

graphical

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Challenges

   search engines

speed

ranked results

making full use of annotations (e.g. ontologies and classifications)

Ranked Retrieval of Computational Biology Models. Henkel R., Endler L., Le Novère N., Peters A., Waltemath D.  BMC Bioinformatics (2010)

Retrieval, alignment, and clustering of computational models based on semantic annotations. Schulz M., Krause F., Le Novere N., Klipp E., Liebermeister W.  Molecular Systems Biology (2011)

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Challenges

   collaborative model development

model versioning

model comparison

...

Version control of pathway models using XML patches. Saffrey P, Orton R.  BMC Systems Biology (2009)

Revision history aware repositories of computational models of biological systems. Miller, A.K., Yu, T., Britten, R., Cooling, M.T., Lawson, J., Cowan, D., Garny, A., Halstead, M.D., Hunter, P.J., Nickerson, D.P., Nunns, G., Wimalaratne, S.M., Nielsen, P.M.  BMC Bioinformatics (2011)

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What is BioModels Database?New ways to build models

Schoeberl et al 2002BIOMD0000000019

Hornberg et al 2005MODEL0848279215

Singh et al 2006BIOMD0000000151

Huang et al 2010

Teusink et al 2000BIOMD0000000064

Pritchard et al 2002BIOMD0000000172

Conant et al 2007BIOMD0000000176BIOMD0000000177

Ung et al 2008BIOMD0000000205

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Challenges

   linked (open) data

structured data

URIs

SPARQL endpoints

Bio2RDF: Towards a mashup to build bioinformatics knowledge systems. Belleau F, Nolin MA, Tourigny N, Rigault P, Morissette J.  Journal of Biomedical Informatics (2008)

An infrastructure for ontology­based information systems in biomedicine: RICORDO case study. Wimalaratne SM, Grenon P, Hoehndorf R, Gkoutos GV, de Bono B.  Bioinformatics  (2012)

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Challenges

   data integration, verification by reasoning, querying, ...

OWL

Annotation of SBML models through rule­based semantic integration. Lister AL, Lord P, Pocock M, Wipat A.  J Biomed Semantics (2010)

Integrating systems biology models and biomedical ontologies. Hoehndorf R, Dumontier M, Gennari JH, Wimalaratne S, de Bono B, Cook DL, Gkoutos GV.  BMC Syst Biol  (2011)

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Challenges

   different communities

new formats but similar needs

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What is BioModels Database?Numerous modelling approaches

Biochemistry

PhysiologyNeurobiology

Developmentalbiology, plant biology

Pharmacometrics

ProcessDescriptions(ODE, Monte-Carlo)

State-Transitions, cableApproximation (PDE)

Variable description(ODE, PDE)

PK/PD, statisticalmodels

Cell automataMulti-agents

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New infrastructure requirements

   Features

format independent

full model versioning

ranked search results (making full use of annotations)

private secured access to the pipeline for the models you submitted

collaboration: model sharing and development

standard access for reviewers (before model publication)

   Software

easy deployment and reuse (independent of EBI infrastructure)

easy to extend (usage of plugins)

improved performance (more and larger models)

improved security

customisable theme

...

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JUMMP: JUst a Model Management Platform

https://bitbucket.org/jummp/jummp/

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Technologies

   Groovy

   Grails (Spring, Hibernate, …)

   Spring Security

   Hibernate Search

   Apache ActiveMQ / D­Bus

   jQuery, jQuery UI

   JSBML

   Subversion / Git

   ...

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Development model

   new application focused on security, performance and flexibility

   multiple instances running in various institutes (various projects using the software to run their infrastructure)

   EBI (and its mirrors) remains the location where models are publicly available

   community developed project

initially undertaken by: 

European Bioinformatics Institute (EBI)

German Cancer Research Center (DKFZ)

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JUMMP: acknowledgements

   Jürgen Eils   Martin Gräßlin   Jochen Schramm   Michael Hoehl

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Acknowledgements

[email protected]

   Nicolas Le Novère   Stuart Moodie   Nicolas Rodriguez   Maciej Swat   Yangyang Zhao

   Viji Chelliah   Mihai Glont   Nick Juty   Sarah Keating   Camille Laibe

BioModels.net Team:

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