SBML, SBML Packages, SED-ML, COMBINE Archive, and more
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SBML, SBML Packages, SED-ML, COMBINE Archive, and more is a presentation about standards for representing computational models in systems biology. It introduces SBML (Systems Biology Markup Language) as a format for exchanging models of biological processes between software tools. It describes extensions to SBML called packages that add new modeling constructs. It also briefly mentions related standards like SED-ML and COMBINE Archive.
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SBML, SBML Packages, SED-ML, COMBINE Archive, and more
- 1. SBML, SBML Packages, SED-ML, COMBINE Archive, and more Michael Hucka, Ph.D. on behalf of many people NIH MSM Satellite Meeting, Sep. 10, 2015, Bethesda, MD, USA Email: mhucka@caltech.edu Twitter: @mhucka
- 2. Outline SBML introduction SBML Level 3 and Level 3 packages Annotations SED-ML COMBINE Archive format
- 3. What is SBML, and why might you care?
- 4. ABC-SysBio CellNetAnalyzer Karyote* PaVESy SBW: Auto Layout acslXtreme CellNOpt KEGGconverter PAYAO sbw: javasim ALC Cellware KEGGtranslator PET sbw: stochastic simulator AMIGO CLEML Kineticon PhysioLab Modeler SCIpath Antimony CL-SBML Kinsolver PINT SED-ML Web Tools APMonitor COBRA libAnnotationSBML PK-Sim / MoBi semanticSBML Arcadia CompuCell3D libRoadRunner PNK SensSB Asmparts ConsensusPathDB libSBML PottersWheel SGMP Athena COPASI libSBMLSim PRISM Sigmoid* AutoSBW CRdata libStruct ProcessDB SIGNALIGN AVIS CycSim MASS Toolbox ProMoT SignaLink BALSA CySBML MatCont PROTON SigPath BASIS Cytoscape MathSBML pybrn SigTran BetaWB Cyto-Sim Medicel PyDSTool SIMBA Bifurcation Discovery Tool DBSolve MEMOSys PySB SimBiology BiGG DEDiscover MesoRD PySCeS Simpathica BiNoM Dizzy Meta-All RANGE SimPheny* BiNoM Cytoscape Plugin DOTcvpSB Metaboflux RAVEN Simulate3D Bio Sketch Pad E-CELL MetaCrop Reactome Simulation Core Library BioBayes ecellJ MetaFluxNet ReMatch Simulation Tool BIOCHAM EPE Metannogen RMBNToolbox SimWiz BioCharon ESS Metatool roadRunner SloppyCell BioCyc Facile MetExplore RSBML SmartCell BioGRID FAME MetNetMaker SABIO-RK Snoopy Biological Networks FASIMU MIRIAM Resources Saint SOSlib BioMet Toolbox FBASBW MMT2 SBFC SPDBS BioModels Database FERN modelMaGe SBML Harvester SRS BioModels Importer FluxBalance ModeRator SBML Layout STEPS BioNessie Fluxor Modesto SBML Reaction Finder StochKit BioNetGen Genetdes Moleculizer SBML Translators StochPy BioPARKIN Genetic Network Analyzer MonaLisa SBML2APM StochSim BioPathwise Gepasi Monod SBML2BioPax STOCKS BioPAX2SBML Gillespie2 MOOSE SBML2LaTeX SurreyFBA BioRica GINsim MuVal (Multi-valued logic) SBML2NEURON SyBiL BioSens GNAT Narrator SBML2Octave SYCAMORE BioSPICE Dashboard GNU MCSim nemo SBML2SMW SynBioSS BioSpreadsheet GRENDEL NetBuilder' SBML2TikZ Systrip BioSyS HSMB NetPath SBML2XPP TERANODE Suite BioTapestry HybridSBML NetPro SBMLEditor The Cell Collective BioUML iBioSim Odefy SBML-PET-MPI Tide BoolNet IBRENA Omix SBMLR TinkerCell braincirc Insilico Discovery ONDEX SBML-SAT Trelis BRENDA insilicoIDE optflux SBML-shorthand UTKornTools BSTLab iPathways Oscill8 SBMLSim VANTED ByoDyn JACOBIAN PANTHER Pathway SBMLsqueezer Vcell CADLIVE Jacobian Viewer PathArt sbmltidy WebCell Cain Jarnac Pathway Access SBMLToolbox WinSCAMP CARMEN JarnacLite Pathway Analyser SBMM assistant Wolfram SystemModeler Cell Illustrator JDesigner Pathway Builder SBO xCellerator CellDesigner JigCell Pathway Solver SBSI Xholon Cellerator JSBML Pathway Tools SBToolbox2 XPPAUT CellMC JSim PathwayLab sbtranslate CellML2SBML JWS Online PATIKAweb SBW Many software tools for modeling and simulation are available
- 5. https://www.behance.net/gallery/d/7465033 Research often involves the use of more than one tool
- 6. Need flexible way to exchange results between tools (and researchers)
- 8. Format for representing models of biological processes • Data structures + principles + serialization to XML • (Mostly) Declarative, not procedural—not a scripting language (Mostly) neutral with respect to modeling framework • E.g., ODE, stochastic systems, etc. Does not store experimental data, or simulation descriptions • But software may write their own metadata (annotations) in SBML For software to read/write, not humans SBML = Systems Biology Markup Language
- 9. SBML is a file format based on XML
- 10. SBML is a file format based on XML Don’t work with it directly! Let software do it.
- 11. The process is central • Literally called“reaction”(not necessarily biochemical) • Participants are pools of entities of the same kind (“species”) • Species are located in containers (“compartments”) - Core SBML assumes well-mixed compartments (but see Level 3) Models can further include: • Discontinuous events • Explicitly-written math Core SBML concepts are fairly simple • Unit definitions • Annotations • Other constants & variables na1 A nb1 B+ nc1 C f1(...) na2 A nd2 D+ ne1 E f2(...) ... nc3 C nf3 F f3(...) + ng3 G
- 12. Core SBML constructs support many types of models Typical ODE models (e.g., cell differentiation) Conductance-based models (e.g., Hodgin-Huxley) Typically do not use SBML “reaction” construct, but instead use “rate rules” construct Neural models (e.g., spiking neurons) Typically use “events” for discontinuous changes Pharmacokinetic/dynamics models “Species”arenotrequiredtobebiochemicalentities Infectious diseases BioModels Database model #MODEL1008060001 BioModels Database model #BIOMD0000000451 BioModels Database model #BIOMD0000000020 BioModels Database model #BIOMD0000000127 BioModels Database model #BIOMD0000000234 Example of model type Example model List originally by Nicolas Le Novére
- 13. Many examples of SBML and software resources are available Accepted by dozens of journals * 100’s of software tools available today • 280+ listed in SBML Software Guide † 1000’s of models available • ... in public databases, e.g., BioModels Database, Reactome • ... as supplementary data to papers • ... in private repositories * http://sbml.org/Documents/Publications_known_to_accept_submissions_in_SBML_format † http://sbml.org/SBML_Software_Guide http://sbml.org
- 14. libSBML • Written in portable C++ - Linux, Mac, Windows • APIs for C, C++, C#, Java, JavaScript, MATLAB, Octave, Perl, PHP, Python, Ruby • Reads, writes, validates SBML • Many other features: e.g., unit checking & conversion JSBML • Pure Java • API very similar to libSBML, but more Java-ish • Reads,writes,manipulatesSBML • Additional Java-relevant APIs such as listeners API libraries for supporting SBML Both are free, open-source under LGPL http://sbml.org/Software/libSBML http://sbml.org/Software/JSBML
- 15. Related effort: CellML Feature SBML CellML Overall scope Core: algebraic, ODE, DAE, DDE, stochastic. Level3: rule-based, constraint-based, qualitative, PDE. algebraic, ODE, DAE. Built-in constructs Numerous; constructs add predefined semantics Few; models use components & pure math Math features Subset of“content”MathML Full“content”MathML Events Yes No Time delays Yes No Units Yes Yes Compartments Yes Yes via nested components Annotations 1) Subset of RDF 2) Explicit SBO term attributes Full RDF User-defined functions Yes In principle, via MathML lambda statements Modularity Yes (in Level 3) – model structure-oriented Yes – math-oriented Extensible syntax Yes (in Level 3) No
- 16. SBML Level 3 and Level 3 packages
- 17. Level 3 packagesadd constructs on top of SBML Level 3 Core
- 18. Level 3 package What it supports Hierarchicalmodelcomposition Models composed from other models/parts ✔ Flux balance constraints Constraint-based (a.k.a. steady-state) models ✔ Qualitative models Petri net, Boolean, and similar model types ✔ Graph layout Storing layouts of network diagrams ✔ Arrays Arrays of components 🕒 Distributions Statistical distributions of values 🕒 Groups Grouping elements for conceptual purposes 🕒 Multicomponent/state species Rule-based descriptions of entities with features 🕒 Spatial Nonhomogeneous spatial models 🕒 Dynamic structures Creation/destruction of entities during simulation 🕒 Graph rendering Storing graphical symbols used in Layout diagrams 🕒 Annotations Richer annotation syntax ! Status
- 19. Level 3 package What it supports Hierarchicalmodelcomposition Models composed from other models/parts ✔ Flux balance constraints Constraint-based (a.k.a. steady-state) models ✔ Qualitative models Petri net, Boolean, and similar model types ✔ Graph layout Storing layouts of network diagrams ✔ Arrays Arrays of components 🕒 Distributions Statistical distributions of values 🕒 Groups Grouping elements for conceptual purposes 🕒 Multicomponent/state species Rule-based descriptions of entities with features 🕒 Spatial Nonhomogeneous spatial models 🕒 Dynamic structures Creation/destruction of entities during simulation 🕒 Graph rendering Storing graphical symbols used in Layout diagrams 🕒 Annotations Richer annotation syntax ! Status Implementations being tested Implementations being tested Implementations being tested Implementations being tested Implementations being tested
- 20. SBMLLevel3package:HierarchicalModelComposition(“comp”) Defines syntax for composing models from other models (or fragments) Developed by Lucian Smith, Mike Hucka, Stefan Hoops, Chris Myers, Andrew Finney, Martin Ginkel, Ion Moraru, Wolfram Liebermeister Species ... Compartments ... Parameters ... Reactions ... Model“A” Core SBML Species ... Compartments ... Parameters ... Reactions ... Model“A” With hierarchical model composition Species ... Compartments ... Parameters ... Reactions ... Model“B” Species ... Compartments ... Parameters ... Reactions ... Model“C”
- 21. The‘comp’package supports multiple arrangements Species ... Compartments ... Parameters ... Reactions ... Model“A” Species ... Compartments ... Parameters ... Reactions ... Model“B” Separate files (possibly in databases) Species ... Compartments ... Parameters ... Reactions ... Model“C” Model“C” Model“D” Species ... Compartments ... Parameters ... Reactions ... Model“D” Model“B” Substitutions and deletions of entities can be defined
- 22. Results can be“flattened”to plain SBML Level 3 Core Allows tools to read L3 +‘comp’models as if they were just plain L3 Algorithm is implemented in libSBML Species ... Compartments ... Parameters ... Reactions ... Model“A” Species ... Compartments ... Parameters ... Reactions ... Model“B” Species ... Compartments ... Parameters ... Reactions ... Model“C” Model“C” Model“D” Species ... Compartments ... Parameters ... Reactions ... Model“D” Model“B” Species ... Compartments ... Parameters ... Reactions ... Model“A” SBML Level 3 CoreOriginal SBML Level 3 Core + SBML‘comp’
- 23. Define syntax for constraint-based (e.g., flux-balance analysis) models • E.g. problem: optimize a specific property subject to constraints on reaction fluxes and other parameters Developed by Brett Olivier and Frank Bergmann, with considerable community discussion and feedback for Version 2. • Version 2 is essentially final Implemented in libSBML, JSBML; supported in CMBPy, FAME, SBW; converters available to/from CORBA Toolbox SBML Level 3 package: Flux Balance Constraints (“fbc”) http://sbml.org/Documents/Specifications/SBML_Level_3/Packages/fbc
- 24. SBMLLevel3package:Multistate&Multicomponentspecies Core SBML lacks support for structured entities and pattern rules • Different states of molecular entities must be different entities/species SBML Level 3 effort for“multi”aims to add support for structures & patterns • First proposals were by Finney, Blinov, Faeder, Hlavacek, Le Novère • Revived by F. Zhang from Simmune group (Meier-Schellersheim et al.) • Aspects of new effort: species types, binding sites, complexes, rules http://sbml.org/Documents/Specifications/SBML_Level_3/Packages/multi
- 25. SBML Level 3 package: Spatial Processes (“spatial”) Main components: • Definition of coordinate systems • Definition of patches of spatial geometries, called domains • Mapping of SBML compartments, species, & parameters to domains • Definition of molecular transport mechanisms (advection, diffusion, boundary conditions) • Mapping of molecular transport mechanisms to domains Developed mostly by Jim Schaff & Anu Lakshminarayana (VCell), with recent input and involvement from Devin Sullivan (U. Pittsburgh) • Beta implementation for libSBML available today http://sbml.org/Documents/Specifications/SBML_Level_3/Packages/spatial
- 26. Virtual Cell Draftimplementationsavailableinseveraltoolsalready SBML Level 3 Spatial package draft specification COPASI MCell and CellBlender
- 27. Many people contributed to the development of SBML Mike Hucka, Sarah Keating, Frank Bergmann, Lucian Smith, Andrew Finney, Herbert Sauro, Hamid Bolouri, Ben Bornstein, Maria Schilstra, Jo Matthews, Bruce Shapiro, LindaTaddeo, Akira Funahashi, Akiya Juraku, Ben Kovitz, Nicolas Rodriguez, Andreas Dräger, AlexThomas SBML& JSBMLTeam: SBML Editors: Mike Hucka, Frank Bergmann, Andreas Dräger, Sarah Keating, Nicolas Le Novère, Chris Myers, Lucian Smith, Stefan Hoops, Sven Sahle, James Schaff, DagmarWaltemath, DarrenWilkinson, Brett Olivier SBML Package authors(sofar): Duncan Berenguier, Frank Bergmann, Claudine Chaouiya, Andreas Dräger, Andrew Finney, Ralph Gauges, Colin Gillespie, Martin Ginkel,Tomás Helikar, Stefan Hoops, Sarah Keating, Anu Lakshminarayana, Nicolas Le Novère,Wolfram Liebermeister, Martin Meier-Schellerscheim, Stuart Moodie, Ion Moraru, Chris Myers, Aurélien Naldi, Brett Olivier, Ursula Rost, Lucian Smith, Sven Sahle, James Schaff, Devin P. Sullivan, DenisThieffry, Martijn P. van Iersel, LeandroWatanabe, KatjaWengler, Darren Wilkinson, Maciej Swat (EBI), Fengkai Zhang
- 28. SBML funding sources over the past 15 years NationalInstituteofGeneralMedicalSciences(USA) Air Force Office of Scientific Research (USA) BBSRC (UK) Beckman Institute, Caltech (USA) DARPA IPTO Bio-SPICE Bio-Computation Program (USA) Drug Disease Model Resources (EU-EFPIA Innovative Medicine Initiate) ELIXIR (UK) European Molecular Biology Laboratory (EMBL) Google Summer of Code International Joint Research Program of NEDO (Japan) Japanese Ministry of Agriculture Japanese Ministry of Education, Culture, Sports, Science andTechnology JST ERATO Kitano Symbiotic Systems Project (Japan) (to 2003) JST ERATO-SORST Program (Japan) Keio University (Japan) Molecular Sciences Institute (USA) National Science Foundation (USA) STRI, University of Hertfordshire (UK)
- 29. Annotations
- 33. Structuredformatsprovidesyntaxandonlylimitedsemantics Modelers are free to choose names Problems: • No universal agreement • Software can’t recognize arbitrary names Need standard schemes for machine-readable annotations • Entity identities • Mathematical semantics • Links to other data resources • Authorship & pub. info Low info content No standard identifiers
- 34. Element in the model Entity elsewhere (e.g., in a database) relationship qualifier (optional) Annotations at their simplest
- 35. SBML supports two annotation schemes SBO (Systems Biology Ontology) • For mathematical semantics • One SBML object ← one SBO term • Short, compact, tightly coupled but limited scope MIRIAM (Minimum Information Requested In the Annotation of Models) • For any kind of annotation • One SBML object ← multiple MIRIAM annotations • Larger, more free-form, wider scope Both are externalized and independent of SBML
- 36. <sbml ...> ... <listOfCompartments> <compartment id="cell" size="1e-15" /> </listOfCompartments> <listOfSpecies> <species compartment="cell" id="S1" initialAmount="1000" /> <species compartment="cell" id="S2" initialAmount="0" /> <listOfSpecies> <listOfParameters> <parameter id="k" value="0.005" sboTerm="SBO:0000339" /> <listOfParameters> <listOfReactions> <reaction id="r1" reversible="false"> <listOfReactants> <speciesReference species="S1" stoichiometry="2" sboTerm="SBO:0000010" /> </listOfReactants> <listOfProducts> <speciesReference species="S1" stoichiometry="2" sboTerm="SBO:0000011" /> </listOfProducts> <kineticLaw sboTerm="SBO:0000052"> <math> ... <math> ... </sbml>
- 37. <sbml ...> ... <listOfCompartments> <compartment id="cell" size="1e-15" /> </listOfCompartments> <listOfSpecies> <species compartment="cell" id="S1" initialAmount="1000" /> <species compartment="cell" id="S2" initialAmount="0" /> <listOfSpecies> <listOfParameters> <parameter id="k" value="0.005" sboTerm="SBO:0000339" /> <listOfParameters> <listOfReactions> <reaction id="r1" reversible="false"> <listOfReactants> <speciesReference species="S1" stoichiometry="2" sboTerm="SBO:0000010" /> </listOfReactants> <listOfProducts> <speciesReference species="S1" stoichiometry="2" sboTerm="SBO:0000011" /> </listOfProducts> <kineticLaw sboTerm="SBO:0000052"> <math> ... <math> ... </sbml> SBO:0000339
- 38. <sbml ...> ... <listOfCompartments> <compartment id="cell" size="1e-15" /> </listOfCompartments> <listOfSpecies> <species compartment="cell" id="S1" initialAmount="1000" /> <species compartment="cell" id="S2" initialAmount="0" /> <listOfSpecies> <listOfParameters> <parameter id="k" value="0.005" sboTerm="SBO:0000339" /> <listOfParameters> <listOfReactions> <reaction id="r1" reversible="false"> <listOfReactants> <speciesReference species="S1" stoichiometry="2" sboTerm="SBO:0000010" /> </listOfReactants> <listOfProducts> <speciesReference species="S1" stoichiometry="2" sboTerm="SBO:0000011" /> </listOfProducts> <kineticLaw sboTerm="SBO:0000052"> <math> ... <math> ... </sbml> SBO:0000339 “forward bimolecular rate constant, continuous case”
- 39. MIRIAM(MinimumInformationRequestedIntheAnnotationofModels) Addresses 2 general areas of annotation needs: MIRIAM is not specific to SBML Requirements for reference correspondence Scheme for encoding annotations Annotations for attributing model creators & sources Annotations for referring to external data resources
- 40. MIRIAM(MinimumInformationRequestedIntheAnnotationofModels) Addresses 2 general areas of annotation needs: MIRIAM is not specific to SBML Requirements for reference correspondence Scheme for encoding annotations Annotations for attributing model creators & sources Annotations for referring to external data resources Annotations for referring to external data resources
- 41. Why might you care? http://www.ebi.ac.uk/chebi Low info content
- 42. Why might you care? http://www.ebi.ac.uk/chebi Low info content Known by different names – do you want to write all of them into your model? salicylic acid
- 43. BioModels Database: example of using the annotations
- 44. Resolving resource identifiers MIRIAM Registry supports the creation of globally unique identifiers • Example MIRIAM identifier: urn:miriam:ec-code:1.1.1.1 • Provides various data about the resource, including alternate servers • Provides web services identifiers.org is layered on top of that and provides resolvable URIs • Can type it in a web browser! • Example identifiers.org URI: http://identifiers.org/ec-code/1.1.1.1
- 45. Summary:whycareaboutstandardwaysofwritingannotations? Structured, machine-readable annotations increase your model’s utility • Allow more precise identification of model components - Understand model structure - Search/discover models - Compare models • Adds a semantic layer—integrates knowledge into the model - Helps recipients understand the underlying biology - Allows for better reuse of models - Supports conversion of models from one form to another
- 47. Another problem: software can’t read figure legends ? BIOMD0000000319 in BioModels Database Decroly & Goldbeter, PNAS, 1982
- 48. SED-ML = Simulation Experiment Description ML Application-independent format •Captures procedures, algorithms, parameter values Can be used for •Simulation experiments encoding parametrizations & perturbations •Simulations using more than one model and/or method •Data manipulations to produce plot(s) http://sedml.org Simulation Model Task Data generators Reports
- 49. COMBINE Archive
- 50. The problem Multiple files usually comprise a single simulation experiment • Model(s) file(s), possibly in multiple formats • Simulation set-up (e.g., in SED-ML format) • Parameter settings data files • Diagrams (e.g., in SBGN format) • Other files… All the files need to be communicated together • Opportunity to lose or mix up files during exchange & sharing
- 51. Open Modeling EXchange format (OMEX) COMBINE Archive format = single file that supports exchange of all information necessary for any modeling and simulation experiment • Not SBML-specific at all • Not programming-language specific • Not domain specific OMEX = file format for COMBINE Archive • ZIP file containing manifest file (in XML form) + other files • Use of ZIP leverages many existing programming libraries http://co.mbine.org/documents/archive
- 52. Acknowledgments
- 53. Huge thanks to everyone in the COMBINE community Attendees of COMBINE 2013, Paris, France Attendees of COMBINE 2014, Los Angeles, California, USA
- 54. BioModels Database http://biomodels.net/biomodels CellML http://cellml.org COMBINE Archive http://co.mbine.org/documents/archive identifiers.org http://identifiers.org MIRIAM http://biomodels.net/miriam MIRIAM Registry http://www.ebi.ac.uk/miriam/main/ SBML http://sbml.org SED-ML http://biomodels.net/sed-ml SBO http://biomodels.net/sbo URLs