OREMP: Ontology Reasoning Engine for Molecular Pathways

In collaboration with:
Department of Mathematics and Computer Science, University of Catania, Catania, CT, 95125, Italy.
Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.
Harvard Medical School, Boston, MA, 02115, USA.

The information about molecular processes is expanding continuously and the descriptions are shared in the form of computable pathways. Biomedical ontologies are being created to provide a semantic context for the molecular species and reactions that they contain. Current advances in both topics suggest an information integration cycle based on shared knowledge-bases, but because of different languages (i.e., the data formats) spoken by the data sources and different abstraction levels, there is a lack of an overall frame capable of identifying overlaps and duplications.
One can envision searchable biological resources, such as the Gene Ontology (GO), UniProt, ChEBI, KEGG, Reactome and BioPortal, defining the biological context of the pathways in a machine-readable format. Substantial effort has been devoted to the creation of ontological resources which are publicly available, but there are semantic obstacles that inhibit their combined use. On the other hand, it is desirable to inform databases of runnable pathways, such as the BioModels.net collection, the CellML repository and even specialist repositories, with the information contained in the curated molecular ontologies in a manner that can be used easily. Some syntactic conversions are available among pathway data-formats, and the state of the art for adjudication of the discrepancies between two SBML models is SemanticSBML, which exploits machine-readable information and the user input to create a merged SBML model. Unfortunately, in the context of large-scale composite biological pathways, the merged-model approach is undesirable because it destroys the original component models and interrupts the curation process. For more than two SBML files, the tool must be run repeatedly with user-input, subjecting it to increasing human error, and suggesting that the order in which the models are aligned matters. An alternative approach based on the use of ontologies discerns when and on which topics models are a relevant part of the large-scale context. Where bio-ontologies are concerned, the state of the art is represented by BioPortal which provides uniform access to most of the biomedical ontologies through a single user-interface and advanced tools to query over biomedical data resources. As a matter of fact, there is still a large chasm between today’s functionality and the true ability to use ontological data to inform molecular pathways. Additionally, there is a lack of strategies for the database and ontology integration of quantitative biological sources written in different standards (e.g., SBML and CellML).
What is described here is a system that creates extended ontologies out of different biochemical information sources and provides path duplication detection, sharing, integration, and knowledge discovery over heterogeneous resources. This cross-format system, I called OREMP (Ontology Reasoning Engine for Molecular Pathways) exports the extended ontologies in OWL2 format; the latter can be fed to Protege, where the information can be then browsed and edited at different levels of abstraction. This framework is currently employed in the Cytosolve@MIT project.

Papers:

1. [2011 - Accepted for Publication, article]
   R. Umeton, G. Nicosia, and C. F. Dewey, "OREMPdb: a Semantic Dictionary of Computational Pathway Models," BMC Bioinformatics, p. i, 2011 – Accepted for Publication.
   @ARTICLE{ umeton2011bmcbioinformatics,
  AUTHOR = {Umeton, Renato and Nicosia, Giuseppe and {{Dewey}},
  {C.F}},
  TITLE = {OREMPdb: a Semantic Dictionary of Computational Pathway Models},
  JOURNAL = {BMC Bioinformatics},
  YEAR = {2011 - Accepted for Publication},
  PAGES = {Accepted for Publication},
  URL = {http://www.umeton.com/papers/Umeton-BMC-Bioinf2011.pdf}
}
2. [2011 - Accepted for Publication, article]
   D. Nordsletten, B. Yankama, R. Umeton, S. Ayyadurai, and C. F. Dewey, "Multi-scale Mathematical Modeling to Support Drug Development," IEEE Transactions on Biomedical Engineering, p. i, 2011 – Accepted for Publication.
   @ARTICLE{ umeton2011ieee-tbme,
  AUTHOR = {David Nordsletten and Beracah Yankama and Renato Umeton and Shiva Ayyadurai and {{Dewey}},
  {C.F}},
  TITLE = {Multi-scale Mathematical Modeling to Support Drug Development},
  JOURNAL = {IEEE Transactions on Biomedical Engineering},
  PUBLISHER = {IEEE},
  YEAR = {2011 - Accepted for Publication},
  PAGES = {Accepted for Publication},
  URL = {http://dx.doi.org/10.1109/TBME.2011.2173245}
}
3. [2011, inproceedings]
   R. Umeton, G. Nicosia, and C. F. Dewey, "OREMPdb: a Semantic Dictionary of Runnable Biological Circuits," in Proceedings of the 8th meeting of the Bioinformatics Italian Society (BITS), Pisa, Italy, June 20-22, 2011, pp. 16-18.
   @INPROCEEDINGS{ umeton2011bits,
  AUTHOR = {Renato Umeton and Giuseppe Nicosia and {{Dewey}},
  {C.F}},
  TITLE = {OREMPdb: a Semantic Dictionary of Runnable Biological Circuits},
  booktitle = {Proceedings of the 8th meeting of the Bioinformatics Italian Society (BITS), Pisa, Italy, June 20-22},
  YEAR = {2011},
  PAGES = {16-18},
  URL = {http://www.bits2011.it/parts/download.php?filename=../files/Bits-2011.pdf}
}
4. [2011, inproceedings]
   D. Nordsletten, B. Yankama, R. Umeton, S. Ayyadurai, and C. F. Dewey, "Multi-scale Mathematical Modeling to Support Drug Development," in Proceedings of Biomedical Engineering Society (BMES), Hartford, CT, USA, October 12-15, 2011.
   @INPROCEEDINGS{nordsletten_bmes_2011, TITLE = {Multi-scale Mathematical Modeling to Support Drug Development},
  BOOKTITLE = {Proceedings of Biomedical Engineering Society (BMES), Hartford, CT, USA, October 12-15},
  AUTHOR = {David Nordsletten and Beracah Yankama and Renato Umeton and Shiva Ayyadurai and {{Dewey}},
  {C.F}},
  YEAR = {2011},
  URL = {http://www.umeton.com/papers/Nordsletten-BMES11.pdf}
}
5. [2011, misc]
   A. Koo, C. F. Dewey, D. Nordsletten, B. Yankama, R. Umeton, and S. Ayyadurai, Mapping and Simulating Flow-dependent Signaling Pathways in Endothelial Cells, 2011.
   @MISC{ umeton2011postera,
  AUTHOR = {Koo, Andrew and {{Dewey}},
  {C.F} and Nordsletten, David and Yankama, Beracah and Umeton, Renato and Ayyadurai, Shiva},
  TITLE = {Mapping and Simulating Flow-dependent Signaling Pathways in Endothelial Cells},
  HOWPUBLISHED = {Poster at 19th Annual International Conference on Intelligent Systems for Molecular Biology and 10th European Conference on Computational Biology (ISMB-ECCB), Vienna, Austria, 17-19 July 2011},
  Month = {July},
  YEAR = {2011},
  URL = {https://www.iscb.org/cms_addon/conferences/ismbeccb2011/posterlist.php?cat=X},
  ABSTRACT = {Nitric Oxide (NO) produced by endothelial cells plays multiple roles in vascular stasis including being an anti-oxidant, a mediator of inflammation, and a potent vasodilator. Not surprisingly, NO production is complexly regulated by multiple pathways. In order to understand the rich diversity of responses that have been observed experimentally, it is necessary to account for an ensemble of these pathways acting simultaneously- a systems biology problem. We have assembled four different quantitative molecular pathways appearing in the literature that have been proposed for shear stress-induced NO production. In these pathways, endothelial nitric oxide synthase (eNOS) is activated (a) via calcium influx, (b) via phosphorylation reactions, via enhanced eNOS protein expression through (d) the MAP kinase pathway, and (d) the NFkB pathway. To these we added a fifth pseudo-pathway describing the actual NO production from different calcium-bound or phosphorylated states of eNOS. All five components were combined using Cytosolve, a new computational environment for combining independent pathway calculations to create complexes of simultaneous biological reactions. The integrated model is able to describe the changes in NO concentration with time following the application of fluid shear stress to endothelial cells. The complex time history, arising from interaction between various pathways, is computed. The results agree favorably with experimental data. The complete model can also be used to predict the specific effects on NO production following interventional pharmacological and genetic changes to the cell.}
6. [2010, inproceedings]
   R. Umeton, B. Yankama, G. Nicosia, and C. F. Dewey, "A Cross-format Framework for Consistent Information Integration among Molecular Pathways and Ontologies," in Proceedings of 6th World Congress on Biomechanics (WCB), Singapore, August 1-6, Singapore, 2010, pp. 1595-1598.
   @INPROCEEDINGS{ umeton2010wcb,
  AUTHOR = {Umeton, Renato and Yankama, Beracah and Nicosia, Giuseppe and {{Dewey}},
  {C.F}},
  TITLE = {A Cross-format Framework for Consistent Information Integration among Molecular Pathways and Ontologies},
  BOOKTITLE = {Proceedings of 6th World Congress on Biomechanics (WCB), Singapore, August 1-6},
  ADDRESS = {Singapore},
  SERIES = {IFMBE Proceedings},
  EDITOR = {Lim, C. T. and Goh, J. C. H.},
  YEAR = {2010},
  PAGES = {1595--1598},
  VOLUME = {31},
  ISSN = {1680-0737},
  URL = {http://dx.doi.org/10.1007/978-3-642-14515-5_406},
  PUBLISHER = {Springer Berlin Heidelberg},
  ABSTRACT = {The information coming from biomedical ontologies and runnable pathways is expanding continuously: research communities keep this process up and their advances are generally shared by means of dedicated resources published on the web. Having different objectives and different abstraction levels, most of these resources “speak” different languages. Employing an extensible collection of interpreters, we propose a system that abstracts the information from different resources and combines them together into a common meta-format. Preserving the resource independence, we provide an alignment service that can be used for multiple pur- poses. Two recent examples are: 1) The new web application Cytosolve uses an embedded version of this system to provide congruous parallel simulation of multiple models; 2) Using the BioModels.net database, a searchable dictionary of equivalent molecular reaction paths was built. Finally, the enriched knowledge can be exported in OWL and queried by semantically-enabled tools such as Prot\'eg\'e. In this approach, we see a valuable tool to integrate and test information originating from different sources, while preserving the independence of the model curation process.}
}
7. [2010, inproceedings]
   B. Yankama, R. Umeton, S. Ayyadurai, and C. F. Dewey, "Editing and Aligning Complex Molecular Pathways Using 3D Models," in Proceedings of Biomedical Engineering Society (BMES), Austin, TX, USA, October 6-9, 2010.
   @INPROCEEDINGS{yankama_bmes_2010, TITLE = {Editing and Aligning Complex Molecular Pathways Using {3D} Models},
  BOOKTITLE = {Proceedings of Biomedical Engineering Society (BMES), Austin, TX, USA, October 6-9},
  AUTHOR = {Yankama, Beracah and Umeton, Renato and Ayyadurai, Shiva and {{Dewey}},
  {C.F}},
  YEAR = {2010},
  URL = {http://www.umeton.com/papers/Yankama-BMES10.pdf}
}
8. [2010, inproceedings]
   R. Umeton, B. Yankama, G. Nicosia, and C. F. Dewey, "OREMP: Ontology Reasoning Engine for Molecular Pathways," in Proceedings of 1st International Workshop on Ontology Repositories and Editors for the Semantic Web (ORES) – Co-located with 7th Extended Semantic Web Conference (ESWC), Heraklion, Crete, Greece, May 30, 2010, pp. 26-30.
   @INPROCEEDINGS{ umeton2010eswc,
  AUTHOR = {Umeton, Renato and Yankama, Beracah and Nicosia, Giuseppe and {{Dewey}},
  {C.F}},
  TITLE = {OREMP: Ontology Reasoning Engine for Molecular Pathways},
  BOOKTITLE = {Proceedings of 1st International Workshop on Ontology Repositories and Editors for the Semantic Web (ORES) - Co-located with 7th Extended Semantic Web Conference (ESWC), Heraklion, Crete, Greece, May 30},
  YEAR = {2010},
  PAGES = {26--30},
  EDITOR = {D\'Aquin, Mathieu and Castro, Alexander Garcia and Lange, Christoph and Viljanen, Kim},
  VOLUME = {596},
  ISSN = {1613-0073},
  URL = {http://ceur-ws.org/Vol-596/paper-06.pdf},
  PUBLISHER = {CEUR-WS},
  ABSTRACT = {The information about molecular processes is shared continuously in the form of runnable pathway collections and biomedical ontologies provide a semantic context to the majority of those pathways. Recent advances in both fields pave the way for a scalable information integration based on aggregate knowledge repositories, but the lack of overall standard formats impedes this progress. Here we propose a strategy that integrates these resources by means of extended ontologies built on top of a common meta-format. Information sharing, integration and discovery are the primary features provided by the system; additionally, two current field applications of the system are reported.}
}

Source-code:
OREMP Web Application prototype