1. The PRECeDI project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 645740. VU University Medical Center Preliminary Training 18-20 June 2015, Rome

2. VU-VUMC Section Community Genetics Department of Clinical genetics University Medical Center – 2 UMCs in Amsterdam, one head of Clinical Genetics – EMGO research institute for Health and Care Research Research on societal aspects of large scale genetic/genomics applications (e.g. population screening, cascade testing) Projects: Non invasive prenatal testing, carrier testing for autosomal recessive diseases, pharmacogenomics (Dutch grants); Computer modelling for genomic medicine (ERC grant); Genetic education primary care (EU Erasmus+ grant) Public & Professional Policy Committee Eur Soc Hum Genet

3. Role in the Project – WP 5 WP leader – Martina Cornel 5.1 Task leader – Martina Cornel 5.2 Task leader – Martina Cornel (together with Bartha Knoppers, Mc Gill ) Tasks: 5.1. to make a sociotechnical analysis of the balancing of pros and cons of informing healthy individuals on their genome 5.2. zoom in: to study and improve the current role of pathologists in (1) testing relevant tumors for microsatellite instability or panels of mutations, and (2) organizing that the message reaches the family.

4. Candidate Hosting Researchers: – 1 Early Stage Researcher from Spain (LinkCare) will be hosted at VUMC for 6 months (Month 12-17). – able to conduct interviews with stakeholders, study literature on guidelines on genetic testing and perform socio technical analysis of dynamics between stakeholders – Health scientist/ sociologist / MD from oncogenetic field or cardiogenetic field Sending Researchers: 1 ER 1 month at LinkCare, Spain [Isa Houwink] 3 ER 4-6 months in total at Better Value Healthcare ltd, UK [Hanne Meijers, Carla van El, Olga Damman] 1 Experienced Researcher 2 months at Myriad Genetics Srl [Martina Cornel] 2 ER 6 months in total McGill, Canada [Danielle Timmermans, Nikki Damen] 1 ESR 3 months Mc Gill, Canada [Dalisa van den IJssel]

5. The PRECeDI project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 645740. Integrating Genomics in Health care Service development in oncology and cardiology Martina Cornel, Professor of community genetics & public health genomics PRECeDI Rome 18-20 June 2015

6. Public Health Genomics: definition The responsible and effective translation of genome-based knowledge and technologies into public policy and health services for the benefit of population health genome-based knowledge and technologies=GBIT PACITA report p. 88 (and elsewhere)

7. Learning goals The student can describe the fast scientific developments in genome-based knowledge and technologies The student can discuss what is needed for translation of genomics knowledge into health care

8. 2000: genome sequence published Bill Clinton: We are here to celebrate the completion of the first survey of the entire human genome … With this profound new knowledge, humankind is on the verge of gaining immense, new power to heal. Genome science will have a real impact on all our lives -- and even more, on the lives of our children. It will revolutionize the diagnosis, prevention and treatment of most, if not all, human diseases. Collins FS (Right at photo). Nature 2010 & © AP PHOTO/RON EDMONDS

9. http://www.genome.gov/images/content/cost_per_megabase2.jpg

10. Result of large scale genomic research Shifting focus: From single gene (Mendelian) conditions – cystic fibrosis, Duchenne muscular dystrophy, Huntington’s disease To common, complex conditions – diabetes, cardiovascular disease, schizophrenia

11. Totally Genetic Totally Environmental Struck by lightning Motor vehicle accident Duchenne muscular dystrophy Cystic fibrosis Heart disease Cancer Schizophrenia Diabetes Obesity Asthma Rheumatoid arthritis PKU Alzheimers Fragile X Autism TB Meningococcus Multiple sclerosis Gene or environment?

12. Understanding the cause of disease Genome wide association studies (GWAS) – Common disorders – SNPs that contribute little to the risk Array and sequencing techniques – Rare disorders (rare variants of common disorders) – Panels to analyse several genes at once Information technologies (high throughput) – Faster and cheaper analysis

13. Extending scope of testing? Will shifting research lead to shifting health care? –From reproductive tests to predictive testing Clinical genetics for infants with MR/MCA, but increasingly oncogenetics & cardiogenetics? –From reproductive decision making to personal risk reduction –From rare monogenic to common complex diseases Monogenic subtypes –From families to large (sections of) healthy populations Screening

14. Learning goals The student can describe the fast scientific developments in genome-based knowledge and technologies The student can discuss what is needed for translation of genomics knowledge into health care – From bench to bedside – Phases of translation (Khoury) – Stakeholders (Rigter) – Guidelines (PPPC)

15. Genetics: “bench” or “bedside”? Science and/or health care? On the left: Watson and Crick describe the structure of DNA Above: clinical geneticist explains the consequences to patients http://education-portal.com/academy/lesson/james-watson- contributions-double-helix-quiz.html#lesson http://www.umcutrecht.nl/subsite/erfelijkheid/erfelijkheidsv oorlichting/Wanneer_erfelijkheidsonderzoek.htm

16. Translation needed Libraries cannot be built fast enough to keep up with modern scientific output. But moving this knowledge off the shelves and into practice.. requires translation. Lenfant NEJM 2005;349:868 www.st-hughs.ox.ac.uk/library

17. “Lost in translation” in Lenfant 2005 … the last and perhaps most important segment, … taking the findings of clinical investigations and translating them into the practice of medicine at the community level. 1981 benefits of beta-blockers for patients who were recovering from myocardial infarction 1996 beta-blockers were being prescribed for only 62.5 percent of patients who had had a myocardial infarction

18. “Lost in translation” in Lenfant 2005 Late 1980s … benefits of cholesterol lowering in patients with coronary heart disease 1999: only half to three quarters of patients who have had a myocardial infarction are even being screened for elevated serum cholesterol levels, much less being prescribed cholesterol- lowering regimens

19. Phases in translational research The continuum of translation research in human genetics: types of research Khoury M et al. Genet Med. 2007;9:665-74.

20. Framework for translational research T1 BRCA mutation is associated with breast cancer T2 Determine the positive predictive value of BRCA mutations, develop guidelines for testing T3 What proportion of women from BRCA families are tested? T4 Does BRCA testing contribute to living longer and healthier? – These steps need to be planned, they do not come automatically

21. How translational is human genomics research?

22. Premature translation??

23. Translation Doesn’t happen automatically – Only small percentage of research budget devoted to translation May come premature – Valorisation=making money/value after investment If you feel a change is needed: look for opportunities and other stakeholders involved

24. People don’t like change We work in a certain structure, culture & practice Dynamics within or outside this constellation may cause instability Opportunity for change! – 2005: cardiac arrest young footballplayer in Sweden Sense of urgency, not only for clinical geneticists but also for cardiologists etc. Rigter, J Community Genet (2014) 5:337–347

25. Learning goals The student can describe the fast scientific developments in genome-based knowledge and technologies The student can discuss what is needed for translation of genomics knowledge into health care – From bench to bedside – Phases of translation (Khoury) – Stakeholders (Rigter) – Guidelines (PPPC)

26. What is needed for responsible translation? Source: PhD thesis Tessel Rigter Ch 8 http://dare.ubvu.vu.nl/handle/1871/51733

27. We need other stakeholders! A new technique in the laboratory A clinical geneticist can explain the test results Who will inform the patient that the test is available? Who will refer? For many fields (cancer, cardiovascular disease, diabetes) too many patients to counsel in genetic centres Collaboration needed, new division of tasks

28. What is needed for responsible translation? Sources: PhD thesis Tessel Rigter Ch 1 http://dare.ubvu.vu.nl/handle/1871/51733http://dare.ubvu.vu.nl/handle/1871/51733 And Achterbergh et al. Health Policy 2007;83:277-286.

29. Scaling up Changes start at a small scale and need deepening, broadening, and scaling up before a full transition is accomplished and a new constellation (with adapted culture, structure, and/or practice) – Maturity Onset Diabetes of the Young (MODY) testing UK – initiative of a consultant diabetologist, a molecular geneticist, and a diabetes specialist nurse – Network of diabetic nurses

30. Rogers technology adoption life cycle Source: wikipedia

31. Hereditary cancer program in Catalonia, Spain Initiated within the Catalan Institute of Oncology by a group of clinicians and geneticists at the Department of Prevention and Cancer Control in 1998 Most referrals come from medical specialists More than 1,000 carriers of highly penetrant cancer predisposing genes have been identified and are under surveillance More than 900 healthy relatives have been withdrawn from intensive surveillance because they had not inherited the pathogenic mutation

32. What determines success? Clinical need Evidence for clinical validity, clinical utility Perceived need – Stakeholder’s priority and awareness (patients, payers, doctors, etc.) – Public priority and awareness Health economic evaluation – Are the benefits outweighing the costs?

33. New constellation? The service is paid for by the Catalan health system Nowadays, similar services are available in other regions in Spain (scaling up) without clear national guidance. Little comparable services are offered for other conditions than cancer because it seems hard to convince other disciplines of the importance of cascade screening. In addition, private companies are increasingly offering testing, which could keep patients and/or family members from utilizing the services offered in regular health care.

34. Learning goals The student can describe the fast scientific developments in genome-based knowledge and technologies The student can discuss what is needed for translation of genomics knowledge into health care – From bench to bedside – Phases of translation (Khoury) – Stakeholders (Rigter) – Guidelines (PPPC)

35. Developing guidelines: example Stakeholder meeting Circulate draft consensus statement to participants Invite comments from other experts / www Finalize Evaluate results Plan, do, check, act in due time.

36. PPPC guidelines Genetic testing in common disorders Direct-to-consumer genetic testing Genetic testing in minors Whole genome sequencing in health care Whole genome sequencing for newborn screening

37. PPPC guidelines Not a ‘law’ But influential (Council of Europe, IVD regulation) Pinpoint relevant issues for policy making in country Provide & clarify argumentation why something is important May help you to contribute to translation!

38. Conclusion Integrating genomics techniques in health care needs you! Phases in translation – Protocol, training, evaluation Other stakeholders involved Scaling up from small initiatives Use a structured approach

39. Where are your stakeholders? Prepare for tomorrow a presentation on YOUR translational challenge (Poster, PPT) Assignment available on paper – Make a list of relevant stakeholders in your PRECeDI research project or field of interest – Where does the dynamics come from in this field? – Where do you see barriers for implementation? – In what stage would you describe your field of interest to be?