A summary of various COMBINE standardization activities
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Invited presentation given at the Whole-Cell Modeling Summer School, held in Rostock, Germany, March 2015. https://sites.google.com/site/vwwholecellsummerschool/important-dates/programm
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A summary of various COMBINE standardization activities
- 1. A summary of various COMBINE standardization activities Michael Hucka, Ph.D. Department of Computing and Mathematical Sciences California Institute of Technology Pasadena, CA, USA Whole-cell modeling summer school, Rostock, Germany, March 2015
- 2. The need for standards
- 5. 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 available today
- 6. https://www.behance.net/gallery/d/7465033 Modeling often entails the use of more than one tool
- 7. Different tools different interfaces & languages
- 8. Developing standards is not easy Need bring together people with diverse set of knowledge & skills • Scientific needs • Technical implementation skills • Practical experience Need manage multiple phases • Creation • Evolution • Support
- 9. Developing standards is not easy Need bring together people with diverse set of knowledge & skills • Scientific needs • Technical implementation skills • Practical experience Need manage multiple phases • Creation • Evolution • Support } This is just for the specification of the standards, to say nothing of the necessary software and other infrastructure!
- 10. Very recent example of how doing a poor job can be costly Claim: published FBA results are incorrect. Reality: poor file format led to misinterpretation.
- 11. Where does COMBINE fit in?
- 12. Realizations about the state of affairs in late-2000’s • Many efforts overlapped, but lacked coordination • Efforts were inventing their own processes from scratch • Many individual meetings meant more travel for many people • Limited and fragile funding didn’t support solid, coherent base COMBINE = Computational Modeling in Biology Network • Coordinate meetings • Coordinate standards development • Develop common procedures & tools • Provide a recognized voice Motivations for the creation of COMBINE
- 13. Standardization efforts represented in COMBINE today BioPAX Qualifiers GPML COMBINE Standards Associated Standardization Efforts Related Standardization Efforts COMBINE Archive MAMO
- 14. COMBINE formats cover many areas – from Nicolas Le Novère
- 15. Example of practical infrastructure provided by COMBINE Common URI scheme for specification documents ! ! ! ! ! ! E.g.: http://identifiers.org/combine.specifications/sbgn.er.level-1.version-1 • Resolves to a page that lists where the specification can be found - Actual document can be stored anywhere • Hierarchical structure
- 16. SBML in (slightly) more depth
- 17. Background context: formal models {
- 18. Communication of models in the olden days… Describe the models and equations in a paper, and you’re done, right? Problems: • Errors in printing • Missing information • Dependencies on implementation • Outright errors • Can be a huge effort to recreate Solution: use a standard electronic format
- 20. 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
- 21. SBML is a file format based on XML
- 22. SBML is a file format based on XML Software shields you from working with this directly
- 23. 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 Models can further include: • Other constants & variables • Discontinuous events Core SBML concepts are fairly simple • Unit definitions • Annotations • Other, explicit math na1 A nb1 B+ nc1 C f1(...) na2 A nd2 D+ ne1 E f2(...) ... nc3 C nf3 F f3(...) + ng3 G
- 24. Core SBML constructs support many types of models ! ODE (e.g., cell differentiation) Conductance-based (e.g., Hodgin-Huxley) Typically do not use SBML “reaction” construct, but instead use “rate rules” construct Neural (e.g., spiking neurons) Typically use “events” for discontinuous changes Pharmacokinetic/dynamics “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
- 25. Community-based development process Defines process for • Proposing changes and additions to SBML and SBML packages • Developing specifications • Voting • The roles of editors ! Small changes forthcoming in package requirements and procedures
- 26. Frank Bergmann Andreas Dräger Michael Hucka Brett Olivier Sven Sahle DagmarWaltemath SBML Editors Stefan Hoops Sarah Keating Nicolas Le Novère Chris Myers James Schaff Lucian Smith DarrenWilkinson PastCurrent (chair)
- 27. SBML Level 1 SBML Level 2 SBML Level 3 predefined math functions user-defined functions user-defined functions text-string math notation MathML subset MathML subset reserved namespaces for annotations no reserved namespaces for annotations no reserved namespaces for annotations no controlled annotation scheme RDF-based controlled annotation scheme RDF-based controlled annotation scheme no discrete events discrete events discrete events default values defined default values defined no default values monolithic monolithic modular & extensible
- 28. Level 3 packagesadd constructs on top of SBML Level 3 Core
- 29. SBML Level 3 What it Hierarchical model composition Models containing submodels ✔ Flux balance constraints Constraint-based models ✔ Qualitative models Petri net models, Boolean models ✔ Graph layout Diagrams of models ✔ Multicomponent/state species Entities w/ structure; also rule-based models draft Spatial Nonhomogeneous spatial models draft Graph rendering Diagrams of models draft Groups Arbitrary grouping of components draft Arrays Arrays of entities draft Dynamic structures Creation & destruction of components draft Distributions Numerical values as statistical distributions draft Annotations Richer annotation syntax Status
- 30. SBML Level 3‘comp’: Hierarchical Model Composition Species ... Compartments ... Parameters ... Reactions ... Model“A” Core SBML
- 31. SBML Level 3‘comp’: Hierarchical Model Composition 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”
- 32. 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” (Think of libraries of tested models.)
- 33. Results can be“flattened”to plain SBML Level 3 Core Facility implemented in libSBML Allows tools to read L3 +‘comp’models as if they were just plain L3 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’
- 34. Layer on top of SBML Level 3 Core to define syntax for constraint-based (e.g., flux-balance analysis) models Nicknamed‘fbc’ Developed by Brett Olivier and Frank Bergmann SBML Level 3‘fbc’: Flux Balance Constraints
- 35. Layer on top of SBML Level 3 Core to define syntax for constraint-based (e.g., flux-balance analysis) models Nicknamed‘fbc’ Developed by Brett Olivier and Frank Bergmann SBML Level 3‘fbc’: Flux Balance Constraints New version was just agreed upon last week! New draft specification is under development.
- 36. SBML Level 3‘distrib’: Distributions Layer on top of SBML Level 3 Core to provide mechanisms for: 1. Sampling a random value from a probability distribution 2. Describe uncertainty about values of elements Uses UncertML 3.0 for the definition of various distribution functions
- 38. Need to capture the processes applied to models ? BIOMD0000000319 in BioModels Database Decroly & Goldbeter, PNAS, 1982
- 39. Format to capture procedures, algorithms, parameter values • Neutral format for encoding the steps to go from model to output Can be used for • Simulation experiments encoding parametrizations & perturbations • Simulations using more than one model and/or method • Data manipulations to produce plot(s) ! SED-ML = Simulation Experiment Description ML
- 40. Software apps & libraries available for SED-ML Level 1 v.1 Some SED-ML-compatible software today: • libSedML • jlibsedml • SBW Simulation Tool • CellDesigner • Web tools • others http://sedml.org
- 42. Graphical representation of models Today: broad variation in graphical notation used in biological diagrams • Between authors, between journals, even people in same group However, standard notations would offer benefits: • Consistency = easier to read diagrams with less ambiguity • Software support: verification of correctness, translation to math
- 43. SBGN = Systems Biology Graphical Notation Goal: standardize the graphical notation in diagrams of biological processes 3 sublanguages to describe different facets of a model • Process Diagram: causal sequences of processes & their results - A node represents a given state of an entity • Entity Relationship: interactions bet. entities regardless of sequence - A node represents an entity regardless of state • Activity Flow: information flowing from one entity to another - Hybrid — shows flow of activity without state transitions Languages reuse same symbols, but their interpretations are different
- 44. SBGN support today Being used in publications Numerous software tools and databases • API libraries are under development See http://sbgn.org for more Martin et al., Autophagy, Jan. 2013 Reactome Database — http://reactome.org
- 45. Acknowledgments
- 46. Huge thanks to everyone in the COMBINE community Attendees of COMBINE 2013, Paris, France Attendees of COMBINE 2014, Los Angeles, California, USA
- 47. 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) SBML funding sources over the past 14 years