COMBINE standards & tools: Getting model management right

Prof. Dr. Dagmar Waltemath
Medical Informatics Laboratory
University Medicine Greifswald
dagmarwaltemath
COMBINE standards & tools
Getting [sysmed] model
management right
Computational Systems Biology for Complex Human Disease
December 10, 2020 | Wellcome Advanced Courses | slideshare

COMBINE coordinates standards
developments in systems biology.
Editorial boards
Specifications
Software tool support
Mailing lists
Annual meetings
2
https://co.mbine.org/

3
Who is behind COMBINE?
BioPAX
(GD Bader)
SBOL Visual
(T Gorochowski)
SBML
(S Keating)
SBOL & chair
(C Myers)
CellML
(D Nickerson)
SED-ML
(M König)
NeuroML
(P Gleeson)
M Golebiewski
Semantics, med inf & vice-chair
(D Waltemath)
10th COMBINE Forum (2019)
SBGN
(F Schreiber)

4
Systems medicine
transformed from purely
paper-based reporting
… to reproducible and
standardized
experiments…
…with rich
tool support.

What are the benefits?
https://pixabay.com/images/id-92566/

6
You can retrieve and verify
reproducible virtual studies.
Looking for
more COVID-
19 models
https://www.ebi.ac.uk/biomodels/covid-19 (EOSC OVID-19 fast track funding)

Example model: https://www.ebi.ac.uk/biomodels/BIOMD0000000144
Simulation by MathSBML Original Simulation, COPASI, SED-ML Web Tools
Scharm & Waltemath (2016) A fully featured COMBINE archive of a simulation study on syncytial mitotic cycles in
Drosophila embryos. F1000Research 5:2421. https://doi.org/10.12688/f1000research.9379.1
You can retrieve and verify
7
Select Download Reuse

8
You can build & simulate your
models using different tools.
Screenshot: Frank Bergmann, Bruce E. Shapiro and Michael Hucka. SBML Software Matrix.
http://sbml.org/SBML_Software_Guide/SBML_Software_Matrix (accessed 2020-11-12)
http://ginsim.org/

9
You can share your studies
with partners and beyond.
https://cat.bio.informatik.uni-
rostock.de/#archive/ff486cd9-2a01-419f-a7dd-
d240cd430c49
COVID-19 disease maps on FAIRDOMHub
https://fairdomhub.org/projects/190
Wolstencroft et al (2017) FAIRDOMHub: a repository and collaboration environment for sharing systems biology research.
NAR 45(D1) 10.1093/nar/gkw1032

10
You can generate (and publish)
https://cat.bio.informatik.uni-rostock.de/
https://sysbioapps.spdns.org/SED-ML_Web_Tools/

11
You can generate (and publish)
https://www.ebi.ac.uk/biomodels/
http://bigg.ucsd.edu/ http://www.opensourcebrain.org/
https://jjj.bio.vu.nl/

12
You get support for managing &
modifying your models. (biased)
Reproduce a simulation Detect differences Understand model evolution
http://sed-ml.org/ https://github.com/SemsProject/BiVeS https://most.bio.informatik.uni-rostock.de/
https://yomost.bio.informatik.uni-rostock.de/
F Bergmann D Nickerson M Scharm T GebhardtV Touré

13
You get support for managing &
modifying your models. (biased)
Bundle all files in one archive Retrieve models efficiently Link models and other data
https://github.com/MaSyMoShttps://combinearchive.org/ https://covidgraph.org/
Wolfgang
Müller
Ron
Henkel
Mariam
Nassar
Martin
Peters
Henkel et al (2015) Combining computational models, semantic annotations and simulation experiments in
a graph database. Oxford DATABASE
2 experiments,
3 model versions,
changes, meta-data
Martin
Preusse
Lea
Gütebier

14
You can build tool chains to
check & automate analyses.
Cardiac Electrophysiology Web Lab, Oxford
M2CAT, SEMS
WebCAT, SEMS
JWS Online, Stellenbosch, SA SED-ML Web Tools, BIOQUANT

15
Fig.: M2CAT, Scharm & Waltemath (2015) BTW http://www.btw-
2015.de/res/proceedings/Workshops/DMS/Scharm-Extracting_reproducible_sim.pdf
You can build tool chains to
check & automate analyses.

What‘s in a shareable
archive?

17
Scharm & Waltemath (2016) A fully featured COMBINE archive of a simulation study on syncytial mitotic cycles in
Drosophila embryos. F1000Research 5
Biosimulation studies comprise
of heterogenous data items.
Original
publication
Visualisation Model encoding Simulation encoding
COMBINE
Archive

How long did it take to
build this infrastructure?

Dräger & Waltemath (2020) Overview: Standards for Modeling in Systems Medicine.
Systems Medicine https://doi.org/10.1016/B978-0-12-816077-0.00001-7
It‘s been a long journey 
Invention of FAIR
19

What does COMBINE
offer today?
m n
the
computational modeling in biology network
http://co.mbine.org/

Standard formats for
model representation
• Standardised
representation of
models
• Export from major
modeling tools
• Available from major
model repositories
• Formats: XML/RDF
+semantic annotations
(RDF)
21Myers et al (2017) A brief history of COMBINE. WSC’17. https://dl.acm.org/doi/abs/10.5555/3242181.3242249

22Fig.: Keating et al (2020) SBML Level 3: an extensible format for the exchange and reuse of biological models.
Molecular Systems Biology, 16(8), p.e9110
What does SBML
cover?
http://co.mbine.org/standards

• Standardised
representation of a
model‘s layout
• Glyphs supported in
major modeling tools
• Conversion into model
code possible
• Formats: XML, Format
for SBOLVis?
Vis

• Standardised
representation of a
model‘s layout
code possible
for SBOLVis?
24
Fig: Touré et al (2018) Quick tips for creating effective and
impactful biological pathways using the Systems Biology
Graphical Notation. PLoS Comput Biol
https://doi.org/10.1371/journal.pcbi.1005740
Myers et al (2017) A brief history of COMBINE. WSC’17. https://dl.acm.org/doi/abs/10.5555/3242181.3242249
graphical representation

• Standardised
representation of a
model‘s layout
code possible
for SBOLVis?
25
Fig: Quinn et al (2015) SBOL Visual: A Graphical Language
for Genetic Designs. PLOS Biol
https://doi.org/10.1371/journal.pbio.1002310
Vis

• Standardised
representation of a
simulation setups
applied to a (set of)
models
• Coverage of main
simulation types
• Export from major
simulation tools
• Formats: XML+RDF
26

• Enrichment of the
„technical“ encoding
with semantic
information
• Enables reuse,
comparibility, search
for virtual models and
components
Standard ontologies for
semantic representation

• Minimum Information
guidelines describe
what information
needs to be
transported during
publication
• If encoding your virtual
experiments in
COMBINE standards,
you‘ll be MI-compliant
Guidelines for good
modeling and simulation

How can I make use of the
COMBINE infrastructure to build
and provide better models?
30

BioModels
• Provides models and
associated files
• Keeps file history
• Description of model
components
• Curation results,
metadata, tagging,
• Detailed curation
https://www.ebi.ac.uk/biomodels/
31
Reuse published studies
whenever possible.

Screenshot (2020-11-10): https://www.ebi.ac.uk/biomodels/BIOMD0000000144#Overview
Reuse published studies
whenever possible.
32

33
Use standards whenever
possible.
Overview of standards & accessing latest specifications via JIB or the COMBINE website.

34
Fig.: Schreiber et al (2020) Specifications of standards in systems and synthetic biology: status and
developments in 2020. Journal of integrative bioinformatics, 17(2-3). https://doi.org/10.1515/jib-2018-0013
Use standards whenever
possible.

38
12/11/14 © 2009 UNIVERSITÄT ROSTOCK | Fakultät für Informatik und Elektrotechnik
https://fairdomhub.org/
Manage your data to avoid
errors and information loss.

Draw meaningful networks.
40
Mol Syst Biol, Volume: 3, Issue: 1, First published:
31 July 2007, DOI: (10.1038/msb4100171)
Touré et al (2018) Quick tips for creating effective and impactful biological pathways using the Systems
Biology Graphical Notation. PLoS Comput Biol 14(2): e1005740. https://doi.org/10.1371/journal.pcbi.1005740

Screenshot (2020-11-10): https://sbgn.github.io/ https://sbgn.github.io/software_support
41
Draw meaningful networks.

Semantically enrich your model.
1. Use technical standards to encode semantic annotations, e.g. RDF, identifiers.org URIs and
BioModels.net qualifiers
2. Store annotations in a separate file: normalize the format in which annotations are stored
3. Develop a software library for support of semantic annotation standards
4. Develop standards-compliant software, promote consistency in annotation practices
5. Document which knowledge resources should be used for annotation and why: publicly
available documentation, e.g. Curation guidelines for a collaborative development of the
COVID-19 Disease Map
6. Establish a repository of reusable annotations: reduce the time required for annotation and
promote inter-annotator consistency
7. Ensure high-quality semantic annotations through training and quality control processes:
specific, complete and consistent annotations, e.g. https://www.ebi.ac.uk/biomodels-
static/jummp-biomodels-help/annotating_models.html
8. Establish and maintain collaborations with knowledge resource developers
42
Neal et al (2019) Harmonizing semantic annotations for computational models in biology, Briefings in
Bioinformatics 20:2, https://doi.org/10.1093/bib/bby087

Archive your results.
https://combinearchive.org/software/
43
Bergmann et al (2014) COMBINE archive and OMEX format: one file to share all information to
reproduce a modeling project. BMC bioinformatics 15:1, https://doi.org/10.1186/s12859-014-0369-z

Check out guidelines and tutorials
for further help.
10 tips for building useful SBGN maps Building fully featured COMBINE archives
44

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Extensive curation leads to higher
quality leads to increased trust.
Easy access access leads to
increased visibility.
Easy executability leads to
increased collaboration.
Better reproducibility
leads to increased reuse.
Remember: Reproducible
studies = better science.

Thank you for your attention!
46
Dagmar Waltemath
Medical Informatics Lab &
Core Unit Research Data Management
University Medicine Greifswald
0000-0002-5886-5563
Mila (now)
SEMS (<2017)
Drawings: Anna Zhukova

COMBINE standards & tools: Getting model management right

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