SBML, SBML Packages, SED-ML, COMBINE Archive, and more

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: [email protected] Twitter: @mhucka

mailto:[email protected]?subject=About%20your%20presentation

https://twitter.com/%23!/mhucka

Outli

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SBML introduction

SBML Level 3 and Level 3 packages

Annotations

SED-ML

COMBINE Archive format

What is SBML, and why might you care?

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 modelingand simulation are available

https://www.behance.net/gallery/d/7465033

Research often involves the use of more than one tool

Need flexible way to exchange results between tools (and researchers)

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

SBML is a file format based on XML

SBML is a file format based on XML

Don’t work with it directly! Let software do it.

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 Cf1(...)

na2 A nd2 D+ ne1 Ef2(...)

. . .nc3 C nf3 F

f3(...) + ng3 G

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” are not required to be biochemical entities

Infectious diseases BioModels Database model #MODEL1008060001

BioModels Database model #BIOMD0000000451




Example of model type Example model

List originally by Nicolas Le Novére

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

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, manipulates SBML

• 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

Related effort: CellML

Feature SBML CellML

Overall scopeCore: algebraic, ODE, DAE, DDE, stochastic. Level 3: 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 NoTime delays Yes NoUnits Yes YesCompartments Yes Yes via nested components

Annotations 1) Subset of RDF2) 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

SBML Level 3 and Level 3 packages

Level 3 packages add constructs on top of SBML Level 3 Core

Level 3 package What it supportsHierarchical model composition 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

Level 3 package What it supportsHierarchical model composition 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





SBML Level 3 package: Hierarchical Model Composition (“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



Model “A”

With hierarchical model composition



Model “B”



Model “C”

The ‘comp’ package supports multiple arrangements



Model “A”



Model “B”

Separate files (possibly in databases)



Model “C”

Model “C”

Model “D”



Model “D”

Model “B”

Substitutions and deletions of entities can

be defined

Results can be “flattened” to plain SBML Level 3 CoreAllows tools to read L3 + ‘comp’ models as if they were just plain L3

Algorithm is implemented in libSBML



Model “A”



Model “B”



Model “C”

Model “C”

Model “D”



Model “D”

Model “B” Species ...Compartments ...


Model “A”

SBML Level 3 CoreOriginal SBML Level 3 Core + SBML ‘comp’

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

SBML Level 3 package: Multistate & Multicomponent speciesCore 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

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

Virtual Cell

Draft implementations available in several tools already

SBML Level 3 Spatial packagedraft specification

COPASI

MCell and CellBlender

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, Linda Taddeo, Akira Funahashi, Akiya Juraku, Ben Kovitz, Nicolas Rodriguez, Andreas Dräger, Alex Thomas

SBML & JSBML Team:

SBML Editors: Mike Hucka, Frank Bergmann, Andreas Dräger, Sarah Keating, Nicolas Le Novère, Chris Myers, Lucian Smith, Stefan Hoops, Sven Sahle, James Schaff, Dagmar Waltemath, Darren Wilkinson, Brett Olivier

SBML Package authors (so far):

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, Denis Thieffry, Martijn P. van Iersel, Leandro Watanabe, Katja Wengler, Darren Wilkinson, Maciej Swat (EBI), Fengkai Zhang

SBML funding sources over the past 15 years

National Institute of General Medical Sciences (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 and Technology 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)

Annotations

Structured formats provide syntax and only limited semantics


No standard identifiers


Low info content



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


Element in the model

Entity elsewhere (e.g., in a database)

relationship qualifier (optional)

Annotations at their simplest

SBML supports two annotation schemesSBO (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


SBO:0000339


SBO:0000339

“forward bimolecular rate constant, continuous case”


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


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


data resources


data resources

Why might you care?

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

Low info content

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

BioModels Database: example of using the annotations

Resolving resource identifiersMIRIAM Registry supports the creation of globally unique identifiers

• Example MIRIAM identifier:urn:miriam:ec-code:1.1.1.1

• Provides various data about theresource, 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

Summary: why care about standard ways of writing annotations?

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

SED-ML – Simulation Experiment Description Markup Language

Another problem: software can’t read figure legends

?

BIOMD0000000319 in BioModels Database

Decroly & Goldbeter, PNAS, 1982

SED-ML = Simulation Experiment Description MLApplication-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

COMBINE Archive

The problemMultiple 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

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-languagespecific

• 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

Acknowledgments

Huge thanks to everyone in the COMBINE community

Attendees of COMBINE 2013, Paris, France

Attendees of COMBINE 2014, Los Angeles, California, USA

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

http://biomodels.net/biomodels

http://co.mbine.org/documents/archive

http://identifiers.org

http://biomodels.net/miriam

http://www.ebi.ac.uk/miriam/main/

http://sbml.org

http://biomodels.net/sed-ml

http://biomodels.net/sbo

SBML, SBML Packages, SED-ML, COMBINE Archive, and more

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