The Translational Medicine Ontology: Driving personalized medicine by bridging the gap from bedside to benchside

Bio-ontologies 2010:July 9, 2010 1

The Translational Medicine Ontology: driving personalized medicine by bridging the gap from bedside

to bench

Michel Dumontier on behalf of the HCLS TMO Subgroup

Carleton University, Ottawa, Canada

HCLS TMO subgroupBosse Andersson, AstraZeneca, Lund, Sweden

Colin Batchelor, Royal Society of Chemistry, Cambridge, UK

Christine Denney, Eli Lilly, Indianapolis, IN, USA

Christopher Domarew, Warrington Hospital, Warrington, UK

Anja Jentzsch, Freie Universitat, 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

Vipul Kashyap, Cigna, Hartford, CT, USA

Peter Kos, Harvard Medical School, Cambridge, MA, USA

Julia Kozlovsky, AstraZeneca, Waltham, MA, USA

James McGurk, Daiichi Sankyo, NJ, USA

Chimezie Ogbuji 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 Stephens Johnson & Johnson Pharmaceutical Research & Development L.L.C., Radnor, PA, USA.


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


Personalized MedicineThe 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

5Bio-ontologies 2010:July 9, 2010

“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





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The Semantic Web is the new global web of knowledge

Bio-ontologies 2010:July 9, 2010

It is about standards for publishing, sharing and querying knowledge drawn from diverse sources

It makes possible the answeringsophisticated questions using

background knowledge


A growing web of linked data

Bio-ontologies 2010:July 9, 2010

How do we query across these linked data?

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Formal Ontology as a Strategy

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


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


Survey reveals diverse needs and interests


Category User Interest

Research Biologist Target identification, assay development

Bioinformatician Molecular profiling, modeling/simulation, knowledge management

Immunologist Natural defense mechanisms

Cheminformatician Predictive chemistry

Medicinal chemist Drug efficacy

Systems physiologist Tolerance, adverse events

Clinic Clinical trial specialist Trial formulation, recruitment

Clinical decision support Data analysis, trend finding

Primary care physician General, conventional care

Specialty medical provider Specialized treatments

Business Sales & marketing Revenue generation

Strategic/portfolio manager Assessing market opportunities

Project manager Prioritizing resources & activities

Health plan provider Insurance coverage

Preparation

• Generate plausible questions of interest• Generate scenerios

– patient centric– research centric

• chemoinformatics / drug discovery• pharmacogenomics• animal models• integrative informatics• drug therapy development


Ontology• 75 classes out of an initial 90 types spanning material

entities, processes, roles, informational entities

• Distinction among different kinds of material entities– molecular entities vs chemical substances– active ingredients vs pharmaceutical formulations

• Distinction among different kinds of informational entities– medical

• medical history (a list of events & bodily features), diagnostic results

– drug• dosage (specification), toxicity (reports), treatment safety (guidelines)



223 class mappings from 60 TMO classes to 201 target classes over 40 ontologies

Data



Linking Open Drug Data (LODD)

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.


formalizing the Dubois AD diagnostic criteria


# the panel is a textual entitydubois: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 diseasedubois:panel2 iao:is_about diseasome:74.

# the panel is from the articledubois:panel2 ro:part_of <http://bio2rdf.org/pubmed:17616482>.

# the panel is about diagnostic criteriondubois:panel2 iao:is_about tmo:TMO_0068.

#inclusion criteriondubois: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 criteriondubois:16 rdfs:label "Major depression [dubois:16]" ; a tmo:TMO_0070; ro:part_of dubois:panel2; iao:is_about diseasome:74.

QueriesClinic• 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 24http://esw.w3.org/topic/HCLSIG/PharmaOntology/Queries

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


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



Acknowledgements

Health & Medicine

The Translational Medicine Ontology: Driving personalized medicine by bridging the gap from bedside to benchside