Samwald cshals2013

Semantically Enabling

Genetic Medicine

Facilitating Patient - Guideline Matching

and Pharmacogenetic Clinical Decision

Support

Matthias Samwald

Medical University of Vienna & Vienna University of Technology

W3C Semantic Web for Healthcare and Life Science Interest Group

Drug efficacy and toxicity can vary drastically between patients with different genetic profiles

The drug warfarin is a popular example of clinical pharmacogenomics

Such pharmacogenomic information is becoming available for many other drugs

OWL 2 for pharmacogenomic knowledge

representation and clinical decision support

Allele definitions in the Human Cytochrome P450 Allele Nomenclature Database

Allele definitions in PharmGKB

1 Class: 'human with CYP2C9 *3'

2 EquivalentTo:

3 has some rs1057910_C

4 SubClassOf:

5 has some 'CYP2C9 *3',

6 (has some rs1057910_C) and

7 (has some rs1057911_A) and




11 (has some rs72558188_AGAAATGGAA) and

12 (has some rs72558189_G) and

13 (has some rs9332239_C)

...

Allele definitions in OWL 2

1 Class: 'human with CYP2C9 *18'

2 EquivalentTo:


4 (has some rs1057911_T) and

5 (has some rs72558193_C)

6 SubClassOf:

7 has some 'CYP2C9 *18',










...

Allele definitions in OWL 2

Dosing guideline from an FDA drug label

Dosing guideline from an FDA drug label

1 Class: 'human triggering CDS rule 9'

2 Annotations:

3 CDS_message "0.5-2 mg warfarin per day should be considered

4 as a starting dose range for a patient with this genotype

5 According to the warfarin drug label."

6 EquivalentTo:

7 (has some 'CYP2C9 *1') and

8 (has some 'CYP2C9 *3') and

9 (has exactly 2 rs9923231_T)

(of course, entities in the ontology are mapped to other Semantic Web resources such as Bio2RDF)

Definitions can become quite complex – OWL reasoning helps identify inconsistencies and lacking definitions

Describing an individual patient in OWL

1 Individual: example_patient

2 Types:

3 human,

4 (has some rs1208_A) and (has some rs1208_G),

5 (has some rs8192709_C) and (has some rs8192709_T),


7 has exactly 2 rs10264272_C,

8 has exactly 2 rs9923231_T,


10 (has some ‘CYP2C9 *1’) and (has some ‘CYP2C9 *3’),

11 has exactly 2 ‘CYP2C19 *1’,

12 (has exactly 3 CYP2D6) and (has exactly 2 ‘CYP2D6 *1’)

13 and (has exactly 1 ‘CYP2D6 *2’)

...

heterozygous

SNP variants

homozygous

SNP variants

allelic variants

and CNV

Describing an individual patient in OWL

1 Individual: example_patient

2 Types:

3 human,


5 (has some rs8192709_C) and (has some rs8192709_T),



8 has exactly 2 rs9923231_T,


10 (has some ‘CYP2C9 *1’) and (has some ‘CYP2C9 *3’),

11 has exactly 2 ‘CYP2C19 *1’,

12 (has exactly 3 CYP2D6) and (has exactly 2 CYP2D6_star_1)

13 and (has exactly 1 CYP2D6_star_2)

...

heterozygous

SNP variants

homozygous

SNP variants

allelic variants

"0.5 - 2 mg warfarin per day

should be considered as a

starting dose range for a patient

with this genotype according to

the warfarin drug label."

OWL Reasoner

OWL 2 DL reasoning needs to be fast!!

TrOWL is massively more performant than the HermiT reasoner in

classifying our demo ontology

HermiT TrOWL

Genomic CDS light (2150 classes, 9500 axioms)

3 hours 48 minutes 18 seconds

Genomic CDS (2300 classes, 11000 axioms)

did not terminate within

6 hours

54 seconds

Ontologies have ALCQ expressivity.

http://www.genomic-cds.org/

http://trowl.eu/ (Pan et al.)

http://hermit-reasoner.com/ (Horrocks, Motik et al.)

How can we put this into the hands of doctors and

patients?

A prototype based on 2D barcodes

Making pharmacogenomics easier to understand for doctors and patients

Making core set of pharmacogenomic data available for every patient

Making pharmacogenomic decision support available to every doctor

Providing pharmaceutical manufacturers with a basic set of markers for

patient stratification that can be made cheaply available for large patient

populations through prospective genotyping

Curated set of 380+ markers, 50+ pharmacogenes and rule system:

The Medicine Safety Code prototype

(data on 385 pharmacogenetic markers are encoded in there)

A Medicine Safety Code can be represented as a QR code

Modern mobile devices can successfully decode very compact

Medicine Safety Codes

The MSC provides a simple, barrier-free system for storing and

interpreting personal pharmacogenomic information

(of course, the data from an MSC could also be embedded in an EHR where available)

Clinical decision support messages can be

viewed quickly Within 15 seconds in best-case scenarios

See recent JAMIA paper for more information

Upcoming version will be backed by the ontology and

reasoning system I showed you before

Conclusions

Still at an early stage

(Semantic) Web technologies used for entire contiuum from basic knowledge

representation up to deployment in clinical routine

OWL 2 ontologies and reasoning could help to make pharmacogenomic

knowledge more transparent and error-free

OWL 2 could be established as a shared standard for representing

(pharmaco-)genetic knowledge??

Future work

Partnership with clinics, pharmaceutical companies, genetic testing

providers, payers

Create optimized reasoner for the specific OWL 2 fragment needed for

genomics? (ALCQ with arbitrary cardinalities)

Thanks

W3C collaborators:

Michel Dumontier (Carleton University)

Robert R. Freimuth (Mayo Clinic)

Richard Boyce (University of Pittsburgh)

Robert L. Powers (Predictive Medicine, Inc.)

Joanne S. Luciano (Rensselaer Polytechnic Institute)

Eric Prud’hommeaux (W3C)

M. Scott Marshall (MAASTRO Clinic)

Simon Lin (Marhsfield Clinic)

and others

Documents

Samwald cshals2013