1. Practical aspects of implementing neonatal screening programmes EURORDIS conference Dubrovnik, 31 May 2013 Martina C Cornel Professor of Community Genetics & Public Health Genomics Amsterdam, The Netherlands

2. Neonatal screening (heelprick)

3. The challenges of a screening programme

4. Screening is more than a test… Registration of births (date of birth, address, etc) Information/invitation to parents After 48h “screener” visits child (or during hospital stay blood is taken) Dried blood spots are sent to laboratory (-ies) Laboratories test for diseases according to protocol Above certain thresholds referral to pediatrician Protocol for follow-up

5. Screening is more than a test… True positive: infant receives treatment (diet, medication) True positive: infant will visit pediatrician (Expert Centre?) according to follow up protocol Parents of false positive receive information and will be happy (or worried?) All information to NBS-information system to allow evaluation of programme Long term follow-up to evaluate health effects (do screenees live longer and healthier?)

6. Neonatal screening NL 2006-2007 Biotinidase deficiency Cystic fibrosis (conditional; pilot 2008; start 2011) Galactosemia Glutaric aciduria type I HMG-CoA-lyase deficiency Holocarboxylase synthase deficiency Homocystinuria Isovaleric acidemia Long-chain hydroxyacyl CoA dehydrogenase deficiency Maple syrup urine disease MCAD deficiency 3-methylcrotonyl-CoA carboxylase deficiency Sickle cell disease Tyrosinemia type I Very-long-chain acylCoA dehydrogenase deficiency 2006 PKU (1974) Congenital hypothyroidism (1981) Congenital Adrenal Hyperplasia (2001) Medication or diet to avoid mental retardation or sudden death

7. Why more diseases? More treatment available –Early detection: less health damage More tests available (high throughput) –MS/MS Many more promises in the age of genomics: how to proceed?

8. Challenges for NBS Scientific developments demand horizon scanning, health technology assessment and decisions on WHAT TO SCREEN Countries (legislations) need a GOVERNANCE structure to decide what to screen The programme needs to be organized in practice Source of many pictures/data in this talk: Tender NBS 2011: http://www.iss.it/cnmr/prog/cont.php?id=1621&lang=1&tipo=64 executed with Luciano Vitozzi, Gerard Loeber, Georg Hoffmann http://www.iss.it/cnmr/prog/cont.php?id=1621&lang=1&tipo=64

9. Health Technology Assessment How frequent is the disorder –Finland: no PKU (Loeber 2012) Test properties? (Sensitivity, specificity, PPV) –Cystic fibrosis NBS may lead to many referrals of false positives, unless last steps involve DNA testing (Cornel 2012) Is test acceptable in the country? –DNA testing is sensitive issue in France Is health care for this condition available in the country? –USA 2013: start screening for Pompe. Treatment in NL would cost >100.000€/patientyear

10. Diversity in EU (Tender NBS)

11. Number of screening countries per disorder

12. Governance –Attunement between parties Achterbergh et al. Health Policy 2007; 83: 277-286. Andermann et al. Journal of Health Services Research & Policy 2010; 15: 90-97.

13. Who decides? Actors to be involved in NBS decision making include patients’ and parents’ organizations, laboratory scientists, health-care workers and professional organizations, ethical, legal and economic experts, governmental and non-governmental agencies and health-care providers Cornel 2013 EJHG

14. Governance 17 of 35 jurisdictions surveyed reported to have laws or regulations on newborn screening 18 have a body which oversees newborn screening (“steering committee”) 22 have changed NBS program in 2005-2010 –health authorities almost always involved physicians specialized in paediatrics and clinical chemistry in one case (Sweden) –health technology assessors sometimes –patient organisations sometimes

15. 22 jurisdictions (21 countries) expanded their neonatal screening programs in the last 5 years. In 8 of these 22 cases patient groups were involved in the decision to expand neonatal screening. Involvement of patient organisations in changes in NBS programs 2005-2010

16. Transparency: information to parents

17. Website in 19 out of 35 countries where anyone can get information about the newborn screening program 7 out of 35 of the responding jurisdictions do not actively inform prospective parents No country specifically informs prospective parents in the first or second trimester of the pregnancy 13 countries inform prospective parents only after birth at the time of blood sampling 12 out of 35 countries parents are informed at two or even three time points

18. First test positive, more tests needed…

19. Transparency: information to parents Material to support the first communication of the meaning of consequences of a positive NBS result is available in 41% of the countries. Predominantly the material is authored by local heads or directors (68%), but apparently applied on a national level (83%). Printed or digital material on treatment is available in 69% of the countries. Across all disorders printed or digital material is available in 69% of the countries. Authors predominantly are local heads or directors (61%).

20. Informed consent Allow parents NOT to participate? –But it is in the interest of the child… Allow parents NOT to receive information on carrier status information (incidental findings) Use for research Storage

21. Research? In 15 out of 33 countries parents are informed about the fact that bloodspots are retained

22. Information on blood spot retention More than half of countries do not inform parents of blood spot retention This is an easy topic; information should be available in all countries Large variation in length of storage (1 y till >20 y) Striking number of countries with no defined length Variation within countries e.g. Spain and Italy Discussion is needed on storage

23. Informed consent 20 of the 37 responding jurisdictions report to ask for informed consent (or dissent). 17 of them also have the possibility to opt-out. 17 of the 37 report that they do not ask informed consent (or dissent) from parents before the blood sampling –6 out of 17 report that they do have the possibility to opt-out from screening –7 said not to have informed consent (or dissent) nor to allow opting out

24. Quality control in seven steps after result Burgard 2012 JIMD

25. Training, evaluation Training of professionals is rarely regulated by a guideline (2 %), but is offered for paediatricians (40 %) and dieticians (29 %) and only rarely for other professions (e.g. geneticists, clinical nurse specialists, psychologists). Registry-based evaluation of long-term outcome is as yet almost nonexistent (3 %). Burgard 2012

26. Process time blood sampling is performed at a median age of 2.8 days laboratory screening analysis starts at a median age of 5.3 days confirmatory diagnostics started at a median of 8.5 days treatment starts at a median age of 14.9 days median age at end of confirmation was 16.2 days Burgard 2012

27. Newborn screening in Europe: Expert Opinion document 70 opinions, including: 15. The interest of the child should be central ….

28. Conclusion Challenging field, fast changes in most EU countries Huge variety Not all patients with rare diseases profit from optimal NBS programs Collaboration needed –Training –Exchange of experiences, materials, etc Role for patients(organisations)!

29. Thanks !!!

30. Further reading Loeber JG et al. Newborn screening programmes in Europe; arguments and efforts regarding harmonization. Part 1 - From Blood Spot to Screening Result. Journal of Inherited Metabolic Disease 2012;35:603-11. Burgard P et al. Newborn screening programmes in Europe; arguments and efforts regarding harmonization. Part 2 - From screening laboratory results to treatment, and follow- up, and quality assurance. Journal of Inherited Metabolic Disease 2012;35:613-25. Cornel MC et al. A framework to start the debate on neonatal screening policies in the EU - An Expert Opinion Document. Eur J Hum Genet. 2013 doi:10.1038/ejhg.2013.90 EU Tender newborn screening practices: http://www.iss.it/cnmr/prog/cont.php?id=1621&lang=1&tip o=64 http://www.iss.it/cnmr/prog/cont.php?id=1621&lang=1&tip o=64