The Translational Medicine Ontology provides terminology that bridges diverse areas of translational medicine including hypothesis management, discovery research, drug development and formulation, clinical research, and clinical practice. Designed primarily from use cases, the ontology consists of essential terms that are mapped to other ontologies. It serves as a global schema for data integration while simultaneously facilitating the formulation of complex queries across heterogeneous sources. We demonstrate the utility of the ontology through question answering over a prototype knowledge base composed of sample patient data integrated with linked open data. This work forms a basis for the development of a computational platform for managing information relevant to personalized medicine.

1. The Translational Medicine Ontology: driving personalized medicine by bridging the gap from bedside to bench 1 Bio-ontologies 2010:July 9, 2010 Michel Dumontier on behalf of the HCLS TMO Subgroup Carleton University, Ottawa, Canada

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3. HCLS TMO subgroup BosseAndersson, AstraZeneca, Lund, Sweden Colin Batchelor, Royal Society of Chemistry, Cambridge, UK Christine Denney, Eli Lilly, Indianapolis, IN, USA Christopher Domarew, Warrington Hospital, Warrington, UK AnjaJentzsch, FreieUniversitat, Berlin, Germany Joanne Luciano, Predictive Medicine Inc., Belmont, MA, USA Elgar Pichler, W3C HCLSIG Eric Prud'hommeaux, W3C, Cambridge, MA, USA Patricia L. Whetzel, Stanford University, Stanford, CA, USA Olivier Bodenreider, National Library of Medicine, Bethesda, MD, USA Tim Clark, Harvard Medical School, Cambridge, MA, USA , Lee Harland, Pfizer, Sandwich, UK VipulKashyap, Cigna, Hartford, CT, USA Peter Kos, Harvard Medical School, Cambridge, MA, USA Julia Kozlovsky, AstraZeneca, Waltham, MA, USA James McGurk, Daiichi Sankyo, NJ, USA ChimezieOgbuji Cleveland Clinic, Cleveland,OH, USA Matthias Samwald, Digital Enterprise Research Institute, Galway, Ireland Lynn Schriml, University of Maryland, Institute for Genome Sciences Peter J. Tonellato, Harvard Medical School, Cambridge, MA, USA Jun Zhao, University of Oxford, Oxford, UK. Susie StephensJohnson & Johnson Pharmaceutical Research & Development L.L.C., Radnor, PA, USA. Bio-ontologies 2010:July 9, 2010 3

4. Goals of the W3C HCLSIG Advance the state of the art in knowledge discovery for health care and the life sciences Investigate approaches to facilitate the integration of patient care, clinical research and basic life science research Provide effective demonstrations of using Semantic Web technologies for knowledge representation, data integration, data visualization and question answering Bio-ontologies 2010:July 9, 2010 4

5. Personalized Medicine The ability to offer The Right Drug To The Right Patient For The Right Disease At The Right Time With The Right Dosage Genetic and metabolic data will allow drugs to be tailored to patient subgroups 5 Bio-ontologies 2010:July 9, 2010

6. “If it were not for the great variability among individuals, medicine might as well be a science and not an art” Sir William Osler, 1892 6 Bio-ontologies 2010:July 9, 2010

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10. The Semantic Web is the new global web of knowledge 10 Bio-ontologies 2010:July 9, 2010 It is about standards for publishing, sharing and querying knowledge drawn from diverse sources It makes possible the answering sophisticated questions using background knowledge

11. A growing web of linked data 11 Bio-ontologies 2010:July 9, 2010

12. Bio-ontologies 2010:July 9, 2010 How do we query across these linked data? 12

13. Formal Ontology as a Strategy 13 Bio-ontologies 2010:July 9, 2010

14. Problem Statement Growing number of biomedical terminologies Over 200 listed at NCBO bioportal Ontologies are a formal specification of a conceptualization Not all are well formulated, nor properly formalized OBO Foundry to create a reference set of ontologies, but the task is enormous, until then, we need working solutions Increasing amounts of linked data Conceptualization is haphazard not formulated using formal ontologies Relations and types are not grounded to shared conceptualization. ontologies applied to linked data will be useful to integrate and provide support for queries Bio-ontologies 2010:July 9, 2010 14

15. TMO Approach Undertake extensive user-focused requirements Identify key entities and establish their relations Extend the conceptualization as specified by a foundational ontology Map linked data types to ontology types Develop knowledge base containing ontology + mappings + data Demonstrate query answering over TMO KB Bio-ontologies 2010:July 9, 2010 15

16. Survey reveals diverse needs and interests Bio-ontologies 2010:July 9, 2010 16

17. Preparation Generate plausible questions of interest Generate scenerios patient centric research centric chemoinformatics / drug discovery pharmacogenomics animal models integrative informatics drug therapy development Bio-ontologies 2010:July 9, 2010 17

19. Bio-ontologies 2010:July 9, 2010 19 223 class mappings from 60 TMO classes to 201 target classes over 40 ontologies

20. Data Bio-ontologies 2010:July 9, 2010 20

21. Linking Open Drug Data (LODD) Bio-ontologies 2010:July 9, 2010 21

22. focus: Alzheimer’s Disease (AD) Incurable, degenerative, and terminal disease with few therapeutic options. Influenced by a range of genetic, environmental and other factors. Identification of prognostic biomarkers would significantly impact and guide the diagnosis, prescription, and development of therapeutic agents would significantly impact future practice. Efficient aggregation of relevant information to help understand the pathology would benefit researchers, clinicians, and patients and would also facilitate the development of target compounds to reduce or even prevent the burden of the disease. Bio-ontologies 2010:July 9, 2010 22

23. formalizing the Dubois AD diagnostic criteria Bio-ontologies 2010:July 9, 2010 23 # the panel is a textual entity dubois:panel2 a iao:IAO_0000300 . dubois:panel2 rdfs:label "Alzheimer Disease diagnostic criteria as reported in panel 2 of dubois et al - pubmed:17616482 [dubois:panel2]". # the panel is about alzheimer disease dubois:panel2 iao:is_about diseasome:74. # the panel is from the article dubois:panel2 ro:part_of <http://bio2rdf.org/pubmed:17616482>. # the panel is about diagnostic criterion dubois:panel2 iao:is_about tmo:TMO_0068. #inclusion criterion dubois:10 rdfs:label "Proven AD autosomal dominant mutation within the immediate family [dubois:10]" ; a tmo:TMO_0069; ro:part_of dubois:panel2; iao:is_about diseasome:74. # exclusion criterion dubois:16 rdfs:label "Major depression [dubois:16]" ; a tmo:TMO_0070; ro:part_of dubois:panel2; iao:is_about diseasome:74.

24. Queries Clinic Have any AD patients been treated for other neurological conditions Patient 2 was found to suffer from AD and depression. Clinical Trial Since my patient is suffering from drug-induced side effects for AD treatment, identify an AD clinical trial with a different mechanism of action (MOA) Of the 438 drugs linked to AD trials, only 58 are in active trials and only 2 (Doxorubicin and IL-2) have a documented MOA. 78 AD-associated drugs have an established MOA. Research Which existing marketed drugs might potentially be re-purposed for AD because they are known to modulate genes that are implicated in the disease? 57 compounds or classes of compounds that are used to treat 45 diseases, including AD, hyper/hypotension, diabetes and obesity Bio-ontologies 2010:July 9, 2010 24 http://esw.w3.org/topic/HCLSIG/PharmaOntology/Queries

25. Future Directions Enhancement of ontology to increase coverage Increased formalization of patient records so as to facilitate patient recruitment Formalization of pathway diagrams and the aggregate set of processes they specify Refactoring of linked data more explicit representation of quantities/values Bio-ontologies 2010:July 9, 2010 25

26. The Translational Medicine Ontology Provides a global schema for the integration of linked data sets Establishes accurate mappings to relevant ontologies Demonstrative knowledge base focused around AD Bio-ontologies 2010:July 9, 2010 26

27. Bio-ontologies 2010:July 9, 2010 27 Acknowledgements