This document summarizes discussions from the 6th Genomic Medicine Colloquium hosted by the National Human Genome Research Institute. The colloquium brought together 50 international genomic medicine leaders from 25 countries to discuss opportunities for collaboration. Key areas of discussion included establishing standards for genomic data storage, implementing global pharmacogenomic screening programs, developing genomic medicine policy, and creating an international genomic medicine collaborative.

1. Teri Manolio
Director, Office for Population Genomics,
National Human Genome Institute (NHGRI),
USA
Perspective from a Global Leader

2. Applying Genomics to Clinical Care: The Global Genomic Medicine Collaborative (G2MC)
National Human Genome Research Institute
National Institutes of Health
U.S. Department of Health and Human Services
U.S. Department of Health and Human Services National Institutes of Health National Human Genome Research Institute
Teri Manolio, M.D., Ph.D.
EuroBioForum Personalised Medicine 2014
September 22, 2014

3. Sunrise in Washington DC
http://iqdc.com/pics/sunrise.jpg

4. Discovery Research
Clinical
Validation
Clinical Implementation
Assess genotype- phenotype associations
Assess outcomes after using genetics to direct therapy
Develop processes for performing genetic testing and using results in care
•Identify persons at increased risk of disease based on their genetic variants
•Assess impact on health outcomes and care utilization of reporting genomic findings
•Develop clinical informatics systems for reporting genomic results and decision support
•Find all variants related to given phenotype or disease
•Identify causes of rare or undiagnosed diseases
•Educate clinicians and patients in clinical use of genomic results
•Characterize variation in genes known to be related to disease or treatment response
•Validate drug targets and develop improved therapeutic agents
•Define and disseminate information on actionable clinical variants and relevant evidence base
Spectrum of Disease-Related Genomics Research

5. NHGRI Genomic Medicine Meetings
http://www.genome.gov/27549225 or google “NHGRI Genomic Medicine”

6. Genomic Medicine Colloquium, June 2011
GM II: Forming Collaborations, Dec 2011
GM III: Stakeholders, May 2012
GM IV: Physician Education, Jan 2013
GM V: Federal Strategies, May 2013
GM VI: Global Leaders, Jan 2014
GM VII: Genomic CDS, Oct 2-3, 2014

8. 50 International Genomic Medicine Leaders 25 Countries
Courtesy,G Ginsburg, Duke U

9. Global Leaders International Attendees
•Canada (CIHR, GenomeCan)
•UK (MRC, WT, Genom Engl)
•Belgium (U Brux, U Leuven)
•Estonia (Eston Genom Ctr)
•France (INSERM)
•Greece (U Patras)
•Luxembourg (Ctr Syst Biomed)
•Sweden (Swed Res Council)
•European Commission
•Israel (Hadassah U, Clalit Med)
•Kuwait (Kuwait U)
•Saudi Arabia (Pr Salman Ctr)
•Tunisia (Tunis U)
•India (Min Sci Tech, Natl Inst Biomed Genomics)
•Sri Lanka (U Colombo)
•China (Chinese Acad Med Sci)
•Japan (U Tokyo, Ctr Integ Med, Min Science)
•Korea (NIH Kor, Seoul Natl U)
•Singapore (National U)
•Thailand (Mahidol U, Min Hlth)
•Australia (MRC)
•New Zealand (Natl Hlth Cmte)

10. Objectives of GMVI: Global Leaders in Genomic Medicine
•Identify areas of active translation and implementation
•Prioritize common barriers to implementation in healthcare
•Frame a policy agenda to advance the field
•Highlight nations with unique capabilities
•Discuss opportunities for international collaborations

11. Plethora of Genomics Implementation Efforts
•UK: Genomics England to sequence 100K whole genomes and link to NHS medical record
•Japan: Implementation of Genomic Medicine Project including genomic prediction of drug response, efficacy and cost-effectiveness studies
•Estonia: proposed project for personal medicine
•Thailand: PGx card identifying risk for top ten SJS-TEN drugs, clinical exomes and genomes

12. Belgian Medical Genomics Initiative A national plan for exomes
12
To create the best possible framework for exome sequencing in a clinical context
Courtesy M Abramowicz, Hôpital Erasme, Université Libre de Bruxelles

13. 1st degree family history of breast cancer reported in
Israeli National Mammo Program
11.4
17.2
9.6
14.2
4.8
8
3.2
6.8
0
2
4
6
8
10
12
14
16
18
%
Jews (n=812100) Christian Arabs (n=14363) Moslem Arabs (n=61068) Druze (n=7136)
Mammo no cancer (n=1,008,421)
Mammo with cancer (n=39,895)
OR=1.62
(1.57-1.67)
OR=1.55
(1.18-2.03)
OR=1.71
(1.38-2.11)
OR=2.22
(1.11-4.41)
Courtesy G Rennert, Clalit Health Services, Haifa

14. Courtesy R Balling, Luxembourg Centre for Systems Biomedicine.

15. The EuroPGx project
McLeod et al., in preparation, 2014; Dalabira et al., in preparation (2014)
 European populations display significant differences in >130 pharmacogenomic biomarkers each.
 Replication of these findings in larger population samples to establish common grounds for pharmacogenomic testing in developing countries.
Courtesy G Patrinos, U Patras.

16. www.hgucolombo.org
Only Medical Genetics Center in Sri Lanka Provide Clinical /Diagnostic Genetic Services, Provide Undergraduate and Postgraduate Training, and Conduct Research by it self and in collaboration with academic and the private sector both nationally and internationally Serving a Population of 20.1 Million People
Courtesy V Dissanyake,
U Colombo
Bench to Bedside in a Developing Country: Sri Lanka

17. Singapore: Stromal Corneal Dystrophies and TGFBI Testing
•Inherited disorders leading to loss of corneal transparency.
•TGFBI mutations underlie the majority of stromal corneal dystrophies.
Screening of family members
Disease Diagnosis
Treatment Selection for Patients
TGFBI Testing
Clinical Utility
Courtesy P Tan, Duke-Natl U Singapore

18. Approved at the Estonian Government Research and Development Council on 17.12.2013. - Health care - Educating health care professionals - Educating the patients - Further development of eHealth including decision support systems
- Research and Development - Sequencing 5,000 individuals, Estonian Chip and analysis software - International collaboration
- Commercialization - Business agreements - IPR
Proposed Estonian Program for Personal Medicine
Courtesy A Metspalu, U Tartu

19. Estonian Program: Research and Development
Courtesy A Metspalu, U Tartu
PILOT PROJECT - Sequence 5,000 – assay SNV up to 0.1% - Estonian chip – ca 0.7 – 1.0 million SNVs - Pilot with 50,000 gene donors from the Estonian Biobank during one year using PCP, eHealth database, and decision support software MAIN PROJECT
-Offer to everyone 35-65 years old as a disease risk and drug response prediction test (75-80% will accept)
-Estimate ca 500,000 people in the database with EMR, genotypes, samples and longitudinal prescription data This system could be used as a additional “instrument” for physicians in diagnosing, treating and preventing disease, but also for research.

20. Virtuous Cycle of Clinical Decision Support
Measure
Guideline
CDS
Practice
Registry
http://www2.eerp.usp.br/Nepien/DisponibilizarArquivos/tomada_de_decis%C3%A3o.pdf
Courtesy A Metspalu, U Tartu

21. Evidence Generating Medicine
•The next step beyond evidence-based medicine
•The systematic incorporation of research and quality improvement considerations into the organization and practice of healthcare
•To advance biomedical science and thereby improve the health of individuals and populations.
Courtesy A Metspalu, U Tartu

22. Partly supported by
Genomic Medicine in Thailand
Courtesy W Chantratita, Ramathibodi Hospital

23. High Incidence of SJS/TEN in Thailand
Courtesy W Chantratita, Ramathibodi Hospital

24. Carbamazepine: SJS/TEN B*1502
Carbamazepine and SJS/TEN: Allele Frequency of HLA-B*15:02
Courtesy W Chantratita, Ramathibodi Hospital

25. Name & Family Name Outcome of the PGX assay
PGx Interpretation
8 Jan 2014 High Risk of SJS/TEN from Carbamazepine, according to update information Suggestion: According to update information, this person has HLA-B*1502 which has a high risk to develop a severe skin disorder (SJS/TEN), if he takes carbamazepine or drug structurally similar.
Need more information: please contact our PGx laboratory. Tel 02-200-4330-3…
Signature of molecular clinical pharmacist.
Courtesy W Chantratita

26. Cost Effectiveness Analysis
•Incremental cost-effectiveness ratio of universal HLA- B*15:02 screening estimated at 222,000 THB ($6,660)/ QALY gained for epilepsy pts; 130,000 THB/QALY for neuropathic pain pts
•Test 343 patients to prevent one case of SJS/TEN
Courtesy S Mahasirimongkol, Ministry of Public Health

27. National Academy of Sciences Bldg
2101 Constitution Avenue, NW
Washington, DC

28. Opportunities for International Collaboration
•Bioinformatics/Health IT
•Education
•Evidence Generation
•Pharmacogenomics
•Policy
G2MC

29. Goals of the Global Genomic Medicine Collaborative (G2MC)
An international genomic medicine community hosted by the Institute of Medicine and formed to:
•Serve as nexus, clearinghouse, and knowledge base for GM activities globally
•Develop opportunities for global GM demonstration projects (implementation and outcomes research)
•Capture and disseminate best practices for GM (IT, education, evidence, Pgx, policy) across the global GM community
•Develop a financial model for sustained efforts

30. G2MC Steering Committee Geoff Ginsburg (US), Robyn Ward (Australia)
Marc Abramowicz Belgium Fahd Al-Mulla Kuwait Adam Berger US Steve Bleyl US Wasun Chantratita Thailand Vajira Dissanayake Sri Lanka Thierry Frebourg France Anne Kolbe New Zealand John Wong Singapore
Bruce Korf US Michiaki Kubo Japan Erkki Leego Estonia Teri Manolio US Gert Matthijs Belgium Yaakov Naparstek Israel Irene Norstedt Belgium George P. Patrinos Greece Gad Rennert Israel

31. G2MC Bioinformatics/Health IT Working Group Steve Bleyl (US), Erkki Leego (Estonia)
Goal Adopt (or develop) and implement standards for storing individual, discrete, coded genomic features as transmitted from labs for databases or EHRs Use Case Copy number variant transmitted from lab and stored as discrete features in EHR, containing all pertinent data (patient identifiers, test indication, chromosomal anomalies, actionability, array used) Collaboration with GA4GH Define requirements for a global database of clinically actionable variants

32. G2MC Pharmacogenetics Working Group Wasun Chantratita (Thailand), George Patrinos (Greece)
Goal: implement broad program internationally to eradicate preventable SJS/TEN using PGx assays
•Biorepository for identifying additional markers, modifiers, recurrence risk, non-genetic factors
•Pharmacy practice guidelines for preventing recurrence
•Health economic and cost-effectiveness analyses
•In vitro diagnostic tests for causative drugs
•Clinical trials of treatment

33. G2MC Policy Working Group Anne Kolbe (New Zealand), Yaakov Naparstek (Israel)
Goal: assess and address needs of health technology assessors, regulators, industry, policy writers, funders and decision makers including governments
•Identify major issues facing health and social services sectors in next 5, 10 and 15 years, based on global burden of disease
•Determine genomic/epigenetic applications currently available and those in R&D pipeline (gap analysis)
•Bring fit-for-purpose genomic technologies into routine adoption quickly and efficiently
•Map research and R&D activities and investments, gaps
•Work with industry and regulators to bring technologies into effective use

34. What are the next big questions in genomic medicine implementation?
•Can it be done: accuracy, turnaround (warfarin genotyping) burden
•Is it interpretable:
•Can experts interpret it: VUS, penetrance
•Can clinicians interpret it: education and CDS
•Is it actionable: treatment, family at risk
•Does it cause harm: anxiety, unnecessary procedures, diversion of resources
•Can we learn from it: learning healthcare systems
•Does it work (help patients), does it reduce cost

35. 50 International Genomic Medicine Leaders
40 US Genomic Leaders and NHGRI Staff

37. Larson, G. The Complete Far Side. 2003.

38. “The prospect of using the genome as a universal diagnostic is upon us today.”
Richard Resnick
Genetically Inherited Diseases NGS Cancer Panels; Targeted PGD/PGS Prenatal Dx based on NGS
Newborn Screening based on NGS MGC: 5Year project plan for 2013-2017
Viral Deep Sequencing to Detect Emerging Drug Resistance (HIV, HBV, HCV) Unknown Pathogen, Emerging and Re emerging infectious Noninvasive Prenatal Diagnosis Using NGS

39. Courtesy R Balling, Luxembourg Centre for Systems Biomedicine.

40. Incidence of SJS/TEN in Thailand, 1984-2013
0
200
400
600
800
1000
1200
1400
1600
1984-1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
2003
2004
2005
2006
2007
2008
2009
2010
2011
2012
2013
ไม่ระบุเพศ
M
F
Unknown
Courtesy W Chantratita, Ramathibodi Hospital

41. •Current capacity for genomic medicine is small for a country the size of Thailand, need training and capacity building
•Thailand is moderate in size with unique genetic diversity and Universal Health Coverage (UHC)
•Any technology proven to be cost effective can be considered in the UHC package
•SJS/TEN PGx study is unique in having direct access to Thai FDA and being incorporated in the pharmacovigilance program
Unique Aspects of Thai Genomic Medicine
Courtesy W Chantratita, Ramathibodi Hospital

42. Top Ideas in Five Key Areas
•IT/bioinformatics
•Define key elements to be stored in EMR
•Identify most robust and generalizable solutions for potential wider adoption
•Global resource for actionable variants
•Education:
•Define workforce needs
•Develop existing/new educational tools that can be widely shared
•Develop region-specific teaching materials, perhaps common templates

43. Five Break-out Groups’ Top Ideas
•Evidence Generation
•Catalog evidence-generating projects
•Identify poolable/extendable projects
•Develop systems to capture evidence; federated network, standardized APIs (e-tools)
•Pharmacogenomics
•Global eradication of SJS/TEN
•PGx card
•Policy
•Share efforts in consent, results reporting
•Study economics, cost-effectiveness

44. Economic Evaluation
• Cost-effectiveness and cost-utility analyses of various genetic-based medical treatments by reducing the incidence of adverse drug reactions, and reciprocally healthcare expenditure at the national level.
Current projects focus on anticoagulation treatment of warfarin (Croatia), acenocoumarol (Serbia, Greece) and clopidogrel (Serbia) and nicotine addiction treatment (Greece).
• Endorsement of the production of the textbook “Economic Evaluation in Genomic Medicine” by Elsevier/Academic Press in early 2015.
Courtesy G Patrinos, U Patras.

45. •Stevens-Johnson syndrome (SJS) is a rare in other countries, but not in Thailand.
•In Thailand, we interviewed many who survived SJS/TEN
–They felt that their bodies were burning and that someone had poured acid into their eyes
–The pain was so extreme that they wish to die, but they could not
•Eradication of SJS/TEN in Thailand is a priority for our Thai medical genomics team
A Fate Worse than Death
Courtesy W Chantratita, Ramathibodi Hospital

46. Courtesy W Chantratita, Ramathibodi Hospital

47. Stevens-Johnson Syndrome, HLA-B*15:02, and Carbamazepine
Chung et al., Nature 2004;428:486.
N Engl J Med. 2011;364:1134-43.
Clin Pharm Therap 2012;92:757-65.
“Clinicians must determine if a patient has ancestry across broad areas of Asia. This requires clinicians to know what ‘Asian ancestry’ means and use a consistent, reliable method to figure out which
patients have this ancestry.”
CAUTION: This patient carries the HLA- B*15:02 allele, a known risk factor for carbamazepine-induced SJS in persons of Asian ancestry…