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http://dx.doi.org/10.1007/s10545-012-9484-z

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Metadata of the article that will be visualized in OnlineFirst

1 Article Title NEWBORN screening programmes in Europe; arguments and

efforts regarding harmonization. Part 2 – From screeninglaboratory results to treatment, and follow-up, and qualityassurance

2 Article Sub- Title

3 Article Copyright -Year

SSIEM and Springer 2012(This will be the copyright line in the final PDF)

4 Journal Name Journal of Inherited Metabolic Disease

5

Corresponding

Author

Family Name Burgard

6 Particle

7 Given Name Peter

8 Suffix

9 Organization University Hospital - Heidelberg (DE)

10 Division Department of Paediatrics

11 Address Im Neuenheimer Feld 430, Heidelberg 69120,Germany

12 e-mail peter.burgard@med.uni-heidelberg.de

13

Author

Family Name Rupp

14 Particle

15 Given Name Kathrin

16 Suffix

17 Organization University Hospital - Heidelberg (DE)

18 Division Department of Paediatrics

19 Address Im Neuenheimer Feld 430, Heidelberg 69120,Germany

20 e-mail

21

Author

Family Name Lindner

22 Particle

23 Given Name Martin

24 Suffix

25 Organization University Hospital - Heidelberg (DE)

26 Division Department of Paediatrics

27 Address Im Neuenheimer Feld 430, Heidelberg 69120,Germany

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28 e-mail

29

Author

Family Name Haege

30 Particle

31 Given Name Gisela

32 Suffix

33 Organization University Hospital - Heidelberg (DE)

34 Division Department of Paediatrics

35 Address Im Neuenheimer Feld 430, Heidelberg 69120,Germany

36 e-mail

37

Author

Family Name Rigter

38 Particle

39 Given Name Tessel

40 Suffix

41 Organization VU University Medical Center - Amsterdam (NL)

42 Division Clinical Genetics/EMGO Institute

43 Address Amsterdam , Netherlands

44 e-mail

45

Author

Family Name Weinreich

46 Particle

47 Given Name Stephanie S.

48 Suffix

49 Organization VU University Medical Center - Amsterdam (NL)

50 Division Clinical Genetics/EMGO Institute

51 Address Amsterdam , Netherlands

52 e-mail

53

Author

Family Name Loeber

54 Particle

55 Given Name J. Gerard

56 Suffix

57 Organization National Institute for Public Health (RIVM)

58 Division

59 Address Bilthoven (NL) , Netherlands

60 e-mail

61

Author

Family Name Taruscio

62 Particle

63 Given Name Domenica

64 Suffix

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65 Organization National Institute for Health - Rome (IT)

66 Division

67 Address Rome , Italy

68 e-mail

69

Author

Family Name Vittozzi

70 Particle

71 Given Name Luciano

72 Suffix

73 Organization National Institute for Health - Rome (IT)

74 Division

75 Address Rome , Italy

76 e-mail

77

Author

Family Name Cornel

78 Particle

79 Given Name Martina C.

80 Suffix

81 Organization VU University Medical Center - Amsterdam (NL)

82 Division Clinical Genetics/EMGO Institute

83 Address Amsterdam , Netherlands

84 e-mail

85

Author

Family Name Hoffmann

86 Particle

87 Given Name Georg F.

88 Suffix

89 Organization University Hospital - Heidelberg (DE)

90 Division Department of Paediatrics

91 Address Im Neuenheimer Feld 430, Heidelberg 69120,Germany

92 e-mail

93

Schedule

Received 7 December 2011

94 Revised 13 March 2012

95 Accepted 28 March 2012

96 Abstract In a surv ey conducted in 2010/2011 data f rom the 28 EU member states,f our EU candidate states (Croatia, FYROM, Iceland, Turkey ), threepotential EU candidate states (Bosnia Herzegov ina, Montenegro, Serbia),and two EFTA states (Norway and Switzerland) were collected. The statusand f unction of newborn screening (NBS) programmes were inv estigatedf rom the inf ormation to prospectiv e parents and the public v ia conf irmationof a positiv e screening result up to decisions on treatment. This articlesummarises the results f rom screening laboratory f indings to start of

AUTHOR'S PROOF!

treatment. In addition we asked about the existence of f eedback loopsreporting the conclusions of conf irmation of screening results to thescreening laboratory and communication of long-term outcome todiagnostic units and possibly existing central registries. Parallel to thedescription of actual practices of where, how and by whom the dif f erentsteps of the programmes are executed, we also asked f or the existence ofguidelines or directiv es regulating the screening programmes, material tosupport inf ormation of parents about diagnoses and treatment and trainingf acilities f or prof essionals inv olv ed in the programmes. This surv ey giv esa f irst comprehensiv e ov erv iew of the steps f ollowing a positiv e screeningresult in European NBS programmes. The 37 data sets rev eal substantialv ariation of national screening panels, but also a lot of similarities. Analy sisacross all countries rev ealed that actual practice is of ten organised but notregulated by guidelines. Material to inf orm patients is av ailable more of tenf or explaining treatment (69 %) than explaining the necessity ofconf irmatory diagnostics (41 %). Training of prof essionals is rarelyregulated by a guideline (2 %), but is of f ered f or paediatricians (40 %) anddieticians (29 %) and only rarely f or other prof essions (e.g. geneticists,clinical nurse specialists, psy chologists). Registry -based ev aluation oflong-term outcome is as y et almost nonexistent (3 %).

97 Keywordsseparated by ' - '

98 Foot noteinformation

Communicated by : Rodney Pollitt

Presented at the Annual Sy mposium of the SSIEM, Genev a, Switzerland,August 30 – September 2, 2011.

The online v ersion of this article (doi:10.1007/s10545-012-9484-z) containssupplementary material, which is av ailable to authorised users.

Electronic supplementary material

ESM 1(DOC 279 kb)

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1

23 SSIEM SYMPOSIUM 2011

4 NEWBORN screening programmes in Europe;5 arguments and efforts regarding harmonization.6 Part 2 – From screening laboratory results to treatment,7 and follow-up, and quality assurance

8 Peter Burgard & Kathrin Rupp & Martin Lindner &

9 Gisela Haege & Tessel Rigter & Stephanie S. Weinreich &

10 J. Gerard Loeber & Domenica Taruscio &

11 Luciano Vittozzi & Martina C. Cornel &12 Georg F. Hoffmann

13 Received: 7 December 2011 /Revised: 13 March 2012 /Accepted: 28 March 201214 # SSIEM and Springer 2012

15

16 Abstract In a survey conducted in 2010/2011 data from the17 28 EU member states, four EU candidate states (Croatia,18 FYROM, Iceland, Turkey), three potential EU candidate19 states (Bosnia Herzegovina, Montenegro, Serbia), and two20 EFTA states (Norway and Switzerland) were collected. The21 status and function of newborn screening (NBS) pro-

22grammes were investigated from the information to prospec-23tive parents and the public via confirmation of a positive24screening result up to decisions on treatment. This article25summarises the results from screening laboratory findings to26start of treatment. In addition we asked about the existence27of feedback loops reporting the conclusions of confirmation28of screening results to the screening laboratory and commu-29nication of long-term outcome to diagnostic units and pos-30sibly existing central registries. Parallel to the description of31actual practices of where, how and by whom the different32steps of the programmes are executed, we also asked for the33existence of guidelines or directives regulating the screening34programmes, material to support information of parents35about diagnoses and treatment and training facilities for36professionals involved in the programmes. This survey37gives a first comprehensive overview of the steps following38a positive screening result in European NBS programmes.39The 37 data sets reveal substantial variation of national40screening panels, but also a lot of similarities. Analysis41across all countries revealed that actual practice is often42organised but not regulated by guidelines. Material to in-43form patients is available more often for explaining treat-44ment (69 %) than explaining the necessity of confirmatory45diagnostics (41 %). Training of professionals is rarely reg-46ulated by a guideline (2 %), but is offered for paediatricians47(40 %) and dieticians (29 %) and only rarely for other48professions (e.g. geneticists, clinical nurse specialists,49psychologists). Registry-based evaluation of long-term50outcome is as yet almost nonexistent (3 %). 51

Communicated by: Rodney Pollitt

Presented at the Annual Symposium of the SSIEM, Geneva,Switzerland, August 30 – September 2, 2011.

Electronic supplementary material The online version of this article(doi:10.1007/s10545-012-9484-z) contains supplementary material,which is available to authorised users.

P. Burgard (*) :K. Rupp :M. Lindner :G. Haege :G. F. HoffmannDepartment of Paediatrics, University Hospital - Heidelberg (DE),Im Neuenheimer Feld 430,69120 Heidelberg, Germanye-mail: peter.burgard@med.uni-heidelberg.de

T. Rigter : S. S. Weinreich :M. C. CornelClinical Genetics/EMGO Institute,VU University Medical Center - Amsterdam (NL),Amsterdam, Netherlands

J. G. LoeberNational Institute for Public Health (RIVM),Bilthoven (NL), Netherlands

D. Taruscio : L. VittozziNational Institute for Health - Rome (IT),Rome, Italy

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52 Introduction

53 The survey for the evaluation of regulations and practices of54 population newborn (neonatal) screening (NBS) for rare55 disorders in Member States of the European Union, as well56 as candidate, potential candidate and EFTA countries,57 originates from the actions launched by the European58 Commission within the EU Programme of Community59 Action in Public Health. The EU Council Recommendation60 for an Action in the Field of Rare Diseases (European61 Commission 2009) foresees the adoption of national plans62 and strategies for rare diseases within 2013, and establishes63 the lines for the cooperation and coordination among64 Member States in order to better utilise national resources65 and expertise as well as reducing inequalities in the access to66 high quality care. The aim of the survey was to describe67 current practices and existing regulations (guidelines and68 directives) of NBS in all European States.69 In a first step, a model for a complete NBS programme70 was developed based on pertinent literature (e.g. Wilson and71 Jungner 1968; Raffle and Gray 2007; see Fig. 1). This72 model has five structural modules: (A) the legal basis and73 general provisions, (B) information to the public and pro-74 spective parents, (C) blood sampling and informed consent;75 (D) laboratory testing and blood spot storage, and (E)76 confirmation and communication of diagnosis, and treat-77 ment. Across all modules, guidelines, programme evalua-78 tion and epidemiology, training of professionals and79 resources and costs were investigated. The modules are

80functionally interconnected by flow of information, samples81and people.82Although the modules are arranged in a logical sequence,83this does not necessarily represent the factual establishment84and development of a programme, for example screening85can start even before legislation or guidelines come into86practice.87Results of module B to D are reported in a separate88publication (Loeber et. al. this issue). In this article we focus89on the results of module E, covering the domains informa-90tion and communication of the laboratory screening to91parents, practices of confirmation of diagnosis, treatment92and monitoring of long-term outcome, epidemiological93evaluation, quality assurance, empowerment of patients94and training of professionals.

95Material and methods

96For a more comprehensive description of the survey proce-97dures the reader is referred to the accompanying paper by98Loeber et al. (this issue). For module E a questionnaire was99developed covering current practice and its regulation by100directives (defined as legally binding standardization by101state and/or health authorities) and/or by guidelines102(defined as information intended to advise how something103should be done).104The questionnaire was cross-reviewed within the project105and by external reviewers suggested by the Society of the

Q1 Fig. 1 Five modules of a NBSprogramme

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106 Study for Inborn Errors of Metabolism (SSIEM; Jim107 Bonham, Philip Mayne), and converted to a web-based108 instrument. In each country respondents nominated by dif-109 ferent European professional societies (Society for the Study110 of Inborn Errors of Metabolism (SSIEM), European Society111 for Paediatric Endocrinology (ESPE), and European Cystic112 Fibrosis Society (ECFS )) were asked to report national data113 by remote data entry for all disorders (metabolic, endocri-114 nologic, and cystic fibrosis) screened for in their country.115 Respondents for haematological disorders were recommen-116 ded by colleagues contacted for other disorders. The survey117 started in August 2010 and was closed on January 14th, 2011,118 with all data referring to the situation on September 1st, 2010.119 Extensive reports of the project can be downloaded at http://120 www.iss.it/cnmr/prog/cont.php?id01621&lang01&tipo064.

121 Results

122 Description of the data set

123 The data set for module E has three dimensions: (1)124 countries, (2) disorders screened for, and (3) questions re-125 lated to the screening programme (subdivided by current126 practice and mode of regulation). Supplementary Table 1127 (identical with Table 2 in Loeber et al. this issue) gives an128 overview of the 40 target countries/regions of the survey, as129 well as the countries’ screening panels (including conditions130 investigated in research programmes). In Belgium NBS is131 organised per legislation, and therefore data were collected132 separately for the Flemish and the French speaking commu-133 nities. As there is reportedly no screening in Albania and no134 response was received from Kosovo (both potential candi-135 date countries for the European Union), these countries were136 excluded from further analysis. Newborn screening for137 Liechtenstein is done in Switzerland, resulting in a total138 number of 37 data sets.139 The number of disorders included in national screening140 panels ranges from one (Finland, FYROM, Montenegro) to141 29 (Austria), with congenital hypothyroidism being the only142 condition screened in all 37 countries and malonic aciduria143 (MMA) only screened for in Iceland.144 Most of the data presented in this article are based on an145 analysis by disorder. In a first step answers related to single146 disorders were averaged across all countries screening for147 this disorder, and in a second step data have been aggregated148 across disorders. For example MSUD is screened for in 12149 countries, 11 countries have answered the question about the150 method of confirmation of a positive screening result, five151 out of 12 countries (42 %) reporting mutation analysis to152 confirm a positive screening result. HPA is screened for in153 33 countries, 32 countries have answered the question about154 the method of confirmation of a positive screening result,

155with 17 out of 33 countries (52 %) reporting mutation156analysis to confirm a positive screening result. Combining157the results for these two disorders would allow the conclu-158sion that on average mutation analysis is used for confirma-159tion of diagnoses in 47 % of the cases MSUD or HPA is160screened for.

161Confirmation of screening results

162As screening does not result in a diagnosis, positive screen-163ing results have to be confirmed or rejected by additional164investigations. Seven questions have been asked in the165domain of confirmative diagnostics (Table 1).166The questions aim at four aspects related to the structure,167process and outcome of the confirmation of diagnoses:168institutions (confirmatory investigations can be executed in169specialised centres, local hospitals, GP/Paediatricians, or170other institutions), methods (results are confirmed by quan-171titative analyses of metabolites/hormones, enzyme activity,172mutation analysis, and other methods), time (age at start and173end of confirmational procedures), and costs (for inpatient174and outpatient care and laboratory analysis).175Feedback of confirmed screening results to the screening176laboratory is particularly important, as it is necessary to im-177prove screening algorithms and cut-off values in the screening178laboratory. Costs and economic efficiency as well as quality of179care and timely management are essential parameters of NBS180programmes (Pandor et al. 2004). As soon after birth as181possible access to specialised clinical diagnostic and treatment182services will be particularly necessary when disorders with a183risk for neonatal decompensation are screened for.184In Europe screening results are almost always confirmed185in specialised centres. However, significant exceptions186among the more frequently screened disorders are biotini-187dase deficiency, galactosaemia, congenital hypothyroidism,188congenital adrenal hyperplasia and MCADD. These disor-189ders are screened in more than ten countries and are con-190firmed and treated in at least 15 % of the cases in local191hospitals. However, it should be noticed that “specialised192centre” is not a well-defined concept. Furthermore, as con-193firmation, follow-up and treatment is different for most

t1:1Table 1 Questions of the domain “Confirmative diagnostics”

t1:21. Is there a directive/guideline where to confirm diagnosis?

t1:32. Where are positive screening results predominantly confirmed?

t1:43. Is there a directive/guideline how to confirm diagnosis?

t1:54. How are positive screening diagnoses actually confirmed?

t1:65. What are the average direct health costs of the different nationalscreening panels?

t1:76. Is there a guideline concerning the age to confirm a suspecteddiagnosis?

t1:87. At what ages is confirmation actually started and terminated?

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194 conditions more specification would be necessary for a195 detailed evaluation.196 Methods of confirmation show a complex pattern across197 the different disorders, possibly also depending on the aims of198 confirmation. For example, in the case of hyperphenylalani-199 naemia (HPA) mutation analysis might be regarded as neces-200 sary to establish the severity of phenylalanine hydroxylase201 (PAH) deficiency and possible tetrahydrobiopterin (BH4) re-202 sponsiveness whereas others may rely on pterine analysis and/203 or a loading test with BH4. Local availability of tests will204 determine the set of analyses applied. In disorders where205 genetic counselling and prenatal diagnosis in further pregnan-206 cies is needed, genetic analysis will be mandatory. On average207 in 61 % of the cases where a disorder is screened for, mutation208 analysis is included as a method to confirm screening results.

209 Process times

210 Twenty-six countries inform prospective parents about NBS211 after birth at time of blood sampling, four of them also212 provide information during the 3rd trimester of pregnancy,213 11 countries reported informing parents any time during214 pregnancy. Across all countries blood sampling is per-215 formed at a median age of 2.8 days (min02.5, max03.5).216 Laboratory screening analysis starts at a median age of217 5.3 days (min04.1, max07.1). Confirmatory diagnostics218 started at a median of 8.5 days (Q2508.3, Q7508.9). Me-219 dian age at end of confirmation was 16.2 days (Q25015.2220 Q75020.1) and treatment starts at a median age of 14.9 days221 (Q25013, Q75016.7). Median age at start of treatment is222 earlier than median age at end of confirmation because223 treatment sometimes is initiated immediately after a positive224 screening lab result in order to avoid early decompensation225 following a risk-minimizing strategy. Overall for 75 % of all226 screened disorders positive screening results are confirmed227 within the first 20 days of life.

228 Costs

229 Table 2 shows costs for confirmation of a single screening230 result. Sum of costs was calculated as (number of days in231 hospital \ast cost per hospital day) + (number of outpatient232 visits \ast cost per visit) + laboratory costs + other costs. It233 should be mentioned that in a strict sense the figures repre-234 sent prices, i.e. amounts of money realised by the provider235 and not the cost of the provider’s activities.236 In order to make data from nations with different gross237 domestic products and/or purchasing power comparable,238 raw data from each respondent were converted to percent239 of Gross Domestic Product (GDP) based on purchasing-240 power-parity (PPP) per capita. Results show that total costs241 show a large variation between disorders as well as between242 countries screening for the same disorder. On average

243confirmation of a screening result costs between 182 €244(UDP) and 3.077 € (GA II).245The large variability within disorders only can be compared246against the background of more detailed information, for247example the methods used to confirm a screening result.248Whether confirmation of a diagnosis is done on an inpatient249or an outpatient basis might depend on the disorder but also on250the geographical situation and medical practises of a country.251One of the pillars of economic analysis of health care252programmes is costs (Drummond et al. 2005). Although253respondents predominantly reported that figures have been254estimated, and source of data often has not been specified,255data could be interpreted as educated guesses and serve as a256basis for more in depth analysis.

257Information and communication to parents

258Legal and ethical norms require informed consent and some259confirmatory investigations necessitate practical coopera-260tion of parents (e.g. observation of the child or providing261parental blood samples for molecular biological analysis).262This domain was investigated by six questions, four dealing263with regulations and two with actual practice (Table 3).264The predominant first informant of parents about a pos-265itive NBS result is the GP or a paediatrician (80 %), but on266average, in 24 % of the cases a disorder is screened for, the267screening laboratory informs parents. The preponderant268mode of information is a phone call (87 %), but also in26950 % of the cases information is given in person. Parents270mostly already get detailed information during the first271contact (83 %). Paediatricians (97 %), dieticians (69 %)272and geneticists (65 %) are the key persons in teaching273parents about diagnosis and treatment.

274Treatment

275Presymptomatic start of treatment is the ultimate goal of276screening (Wilson and Jungner 1968). In those cases where277disorders with a substantial risk for acute neonatal decom-278pensation are included in a screening panel, age and clinical279status (asymptomatic vs. symptomatic) at start of treatment280become central outcome parameters of a NBS programme.281Structural features of NBS programmes are the type of282treatment units (specialised centres, local hospital or paedia-283tricians/GPs) and professionals involved (paediatricians284specialised in cystic fibrosis, metabolic, endocrinologic or285haematologic disorders, dieticians, psychologists, social286workers, clinical nurse specialists, geneticists).287In Europe patients are treated almost exclusively (mean028895 %; median098 %) in specialised centres. Professions289involved in the treatment are paediatricians (99 %), dieticians290(80%), psychologists (46%), clinical nurse specialists (19%),291geneticists (17 %), and social workers (15 %).

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t2:1 Table 2 Average direct health costs to confirm or reject a positive screening result

t2:2 Disorder1 No. of countriesscreening

No. of replies % Replies Sum of costs € % GDP PPP 20092 % countries reportingcalculated costs

% countries reportingestimated costs

t2:3 Mean SD Mean SD

t2:4 PKU/HPA 33 25 76 1,746 1,947 9.0 6.7 15 52

t2:5 BIO 10 10 100 832 399 3.9 1.9 20 40

t2:6 GALT 10 7 70 1,760 1,406 7.6 5.4 10 60

t2:7 UDP 3 1 33 182 - 0.7 - 33 0

t2:8 CH 37 29 78 601 670 3.5 3.7 19 54

t2:9 CAH 14 11 79 1,555 1,249 8.5 5.2 21 57

t2:10 CF 9 8 89 764 571 4.2 3.0 22 56

t2:11 ARG 4 2 50 2,165 555 8.8 1.2 0 25

t2:12 ASA 6 4 67 1,855 630 9.0 1.0 17 33

t2:13 CIT I 5 3 60 1,855 630 9.0 1.0 20 20

t2:14 CIT II 2 2 100 2,165 555 8.8 1.2 0 50

t2:15 HCI 7 4 57 1,675 1,288 8.0 5.0 14 43

t2:16 HPT I_III 3 1 33 2,720 - 10.1 - 0 0

t2:17 MSUD 12 9 75 3,030 1,517 13.2 4.9 8 58

t2:18 TYR I 7 4 57 2,583 1,648 12.1 5.2 14 43

t2:19 TYR II-III 3 2 67 3,070 1,835 14.4 5.0 33 33

t2:20 CUD 6 4 67 1,855 630 9.0 1.0 17 33

t2:21 CPT I 7 5 71 1,894 553 9.1 0.8 14 43

t2:22 CPT II 7 5 71 1,888 548 9.1 0.8 14 43

t2:23 LCHADD 8 5 63 1,648 637 8.0 1.7 13 38

t2:24 MCADD 13 8 62 1,351 677 6.5 2.8 8 38

t2:25 SCHADD 2 1 50 2,720 - 10.1 - 0 0

t2:26 SCADDD 3 2 67 1,977 742 9.7 0.4 33 0

t2:27 VLCADD 9 6 67 1,570 652 7.8 2.5 11 44

t2:28 DECR 0 0 n.d. n.d. n.d. n.d. n.d. n.d. n.d.

t2:29 3HMG 5 3 60 1,838 647 8.9 1.00 20 20

t2:30 3MCC 6 3 50 1,838 647 8.9 1.00 17 17

t2:31 GA I 10 7 70 2,890 1,471 13.0 4.8 10 50

t2:32 GA II 6 4 67 3,077 2,218 13.36 7.8 17 33

t2:33 HCSD 6 3 50 2,165 555 8.84 1.2 0 33

t2:34 IVA 9 6 67 2,528 996 11.51 2.9 11 44

t2:35 MMA 1 1 100 2,720 - 10.07 - 0 0

t2:36 MMACBL 7 5 71 2,327 1,015 10.40 2.8 14 43

t2:37 PA 7 5 71 2,327 1,015 8.88 1.0 14 43

t2:38 BKT 3 2 67 1,952 767 9.52 0.6 33 0

t2:39 BTHA 3 3 100 529 395 2.02 1.2 33 33

t2:40 SC 3 3 100 529 395 2.02 1.2 33 33

t2:41 S-S 4 4 100 881 614 3.77 3.0 0 75

1 3HMG 3-Hydroxy-3-methylglutaric aciduria; 3MCC 3-Methylcrotonyl-CoA carboxylase deficiency/3-Methylglutacon aciduria/2-methyl-3-OH-butyric aciduria; ARG Argininemia; ASA Argininosuccinic aciduria; BIO Biotinidase deficiency; BKT Beta-ketothiolase deficiency; BTHA S, beta0-thalassemia; CAH Congenital adrenal hyperplasia; CF Cystic fibrosis; CH Primary congenital hypothyroidism; CITI Citrullinemia type I; CITIICitrullinemia type II; CPT I Carnitin palmitoyltransferase deficiency type I; CPT II Carnitin palmitoyltransferase type II-/Carnitine acylcarnitinetransporter deficiency; CUD Carnitine uptake defect; DECR 2,4-Dienoyl-CoA reductase deficiency; GAI Glutaric acidaemia type I; GAII Glutaricacidaemia type II; GALT Classical galactosaemia; HCI Homocystinuria (CBS deficiency); HCSD Holocarboxylase synthetase deficiency; HPT I,III Hypermethionemia types I, III; IVA Isovaleric acidemia (IVA)/ 2-Methylbutyrylglycinuria; LCHADD Long-chain L-3-hydroxyacyl-CoAdehydrogenase deficiency/Trifunctional protein deficiency; MCADD Medium-chain acyl-CoA dehydrogenase deficiency; MMA Malonic acid-aemia; MMACBL Methylmalonic acidaemia including Cbl A,B, C, D defects; MSUD Maple sirup urine disease; PA Propionic acidaemia; PKU/HPA Phenylketonuria/Hyperphenylalaninaemia; S-S S,S disease (Sickle cell anaemia); SC S,C disease (Sickle – C disease); SCADD Short-chainacyl-CoA dehydrogenase deficiency; SCHADD Medium-short-chain 3-hydroxyacyl-CoA dehydrogenase deficiency; TYRI Tyrosinaemia type I;TYRII-III Tyrosinaemia types II, III; UDP UDP-galactose-4-epimerase deficiency; VLCADD Very long-chain acyl-CoA dehydrogenase deficiency2 GDP PPP 2009 0 Per capita Gross Domestic Product based on purchasing-power-parity (PPP) in International Dollar converted to Euro at thecurrency exchange rate of 01.01.2009; Source: World Economic and Financial Surveys: World Economic Outlook Database. InternationalMonetary Fund. http://www.imf.org/external/pubs/ft/weo/2010/02/weodata/index.aspx. Retrieved on 04.04.2011 n.d. no data

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292 The median of patients presenting asymptomatically at293 the start of treatment is equal to 84 %. Disorders reported to294 have relatively high rates of patients presenting symptomat-295 ically at start of treatment are classical galactosaemia (50 %296 symptomatic cases),β-ketothiolase deficiency (45%), glutaric297 aciduria type II (40 %), long-chain L-3-hydroxyacyl-CoA298 dehydrogenase/trifunctional protein deficiency (33 %), and299 congenital adrenal hyperplasia (32 %) (Fig. 2). It should be300 noted that 67 % of the data are estimated and not calculated.

301 Epidemiological evaluation

302 Feedback of confirmed or rejected diagnoses and parameters303 measured in the process of confirmation to the screening304 laboratory helps to adjust screening algorithms, and feedback305 of results of confirmation to a central registry will allow

306calculation of prevalence data. On average feedback of diagno-307ses is regulated by guidelines in 88% and by a directive in 27%308of cases where a disorder is screened for. Guidelines are applied309on a national level in 68% of the cases a disorder is screened for310whereas only 38% of the directives have a national application.311Confirmed diagnoses are mostly (87 %) fed back to the screen-312ing laboratory and less often to a registry (19 %). Organisation313of feedback is reported to be predominantly “push”, i.e. the314clinical unit of confirmation actively delivers the results to the315screening laboratory. If feedback is given, predominantly not316only the diagnosis but also detailed results are transmitted.

317Monitoring long-term outcome

318Good long-term outcome is the ultimate goal of NBS and its319monitoring is necessary to evaluate the whole programme.

t3:1 Table 3 Questions of the domain “Information and communication to parents”

t3:2 1. Is there a guideline how professionals should inform parents about positive NBS?

t3:3 2. Is there a directive/guideline who should inform parents about the necessity of confirmatory procedures?

t3:4 3. Who actually informs parents on the necessity of confirmatory procedures?

t3:5 4. Is there a guideline how professionals should explain the confirmed diagnosis and its overall implications?

t3:6 5. Is there a guideline concerning the participation of professions to be involved in teaching parents about diagnosis and treatment?

t3:7 6. Which professional groups actually participate in teaching parents?

0 10 20 30 40 50 60

β ThalassaemiaHPA/PKU

Sickle cell anaemia/diseaseBiotinidase D

Tyrosinaemia ITyrosinaemia III

MCADDHomocystinuria

Hypermethionaemia I-IIICarnitine uptake D

GA IASA

ArgininaemiaVLCADDSCHADD

3 HMG CoA Lyase D3 MCCD

Citrullinaemia IICitrullinaemia I

CPT IIMMACHT

MSUDIVA

Holocarboxylase synthetase DCF

UDP-galactose-4-epimerase DMMA cbl D

CPT ISCADD

PACAH

LCHADDGA II

β ketothiolase DClassic Galactosaemia

% symptomatic

Metabolic Endocrinological CF Haematological

Fig. 2 Clinical presentation atthe start of treatment. Forabbreviations see Table 2

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320 Averaged over all disorders data on long-term outcome are321 evaluated in 80 % of the cases. However, the evaluation is322 predominantly done on the level of treatment units and not323 combined with the emphasis of evaluation of screening324 practises. Data are reported in about 40 % of the cases to325 the diagnostic unit but only in 3 % to a registry. A notewor-326 thy exception is cystic fibrosis where three out of nine327 (33 %) countries screening for the disorder report having a328 registry.

329 Quality control and quality assurance

330 Quality control (QC) is defined as a system of routine331 checks to assure that predefined requirements of the332 programme are fulfilled, whereas quality assurance (QA)333 activities include a planned system of review procedures334 conducted by personnel not directly involved in the335 programme. Actual practice of quality control and assurance336 was investigated regarding seven steps of a screening337 programme (see Fig. 3).338 Quality measures were reported more often for QC than339 for QA. Overall activities for systematic assurance of quality340 are lacking in 60 to 90 % of the cases where a disorder is341 screened for. Laboratory diagnostic procedures are nearly342 always quality approved (either by QC of QA alone or by343 both); process steps dealing with information of parents344 show low levels for QC and/or QA.

345 Training of professionals

346 Across all four groups of disorders, systematic training is347 most often offered to paediatricians (40 %) and dieticians348 (29 %), followed by geneticists (16 %) and clinical nurse

349specialists (14 %). Training for psychologists (8 %) and350social workers (4 %) is rarely offered. Analysis by groups351of disorders revealed that training is most often offered352for cystic fibrosis screening programmes (25 %), fol-353lowed by metabolic (20 %) and endocrine disorders354(17 %). For haemoglobinopathies, training is offered only355for the clinical nurse specialist and the geneticist. Figure 4356summarises the results regarding the different professional357groups involved in the confirmation of diagnosis and358treatment.

359Awareness and support

360Political support for NBS

361Political support for NBS has been reported by all362responding countries. In most countries political support363is represented by public funding of NBS or by a service364of the public health system. In none of the answers was365reference made to international political support. Refer-366ence was made to the national plan for rare diseases by367Bulgaria, which has been stimulated by the EU. It is368possible that the role of the EU was overlooked because369the present survey was focused on collection of national370information.

371Professional societies

372National professional societies dealing with disorders373screened for (societies for human or medical genetics,374general paediatric societies, societies for endocrinology or375metabolic disorders or working groups for newborn screen-376ing) have been reported for 24 of 35 jurisdictions.

0 10 20 30 40 50 60

7. Information about parents' and patients' groups

6. Information of parents about diagnosis and treatment

5. Feedback LTFU to confirmatorydiagnosis unit

4. Feedback confirmed diagnosis to NBS lab

3. Ages at diagnosis and treatment

2. Where diagnostics and treatment are done

1. Laboratory diagnostic procedures

%

QC QA QC & QA

Fig. 3 Mean percentages ofquality control and qualityassurance in seven steps of theprocess of confirmation of apositive screening result.(FTFU 0 long-term follow up)

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377 Patient’/parents’ groups for disorders screened

378 Twenty-eight of the 35 responding jurisdictions have patient379 and/or parent associations for at least some of the screened380 conditions. Examples of these groups are national PKU-381 societies (http://www.espku.org/), societies of patients and/or382 parents with cystic fibrosis (http://www.cfww.org/cfe/) and383 organisations for rare diseases (http://www.eurordis.org/).

384 Involvement of patient organisations in changes385 of screening programmes

386 Eighteen jurisdictions, which have expanded NBS during387 the last five years, have patient advocacy groups specific to388 screened disorders while two have not. In ten out of the 18389 cases patient groups were reported to have been involved in390 the decision to expand NBS. While it is not clear whether391 these were disease-specific advocacy groups, it is notewor-392 thy that in eight cases relevant advocacy groups were not393 involved in the expansion of screening. However, it may be394 the case that the disease-specific advocacy groups became395 active only after NBS was expanded.

396 Empowerment

397 Most screened disorders are not only rare, but also do not fit398 with common concepts of disease and illness. In general,399 elaborated preventive treatment protocols have to be fol-400 lowed by patients who have never had or will have any401 symptoms. Providing parents/caretakers with instructive402 material supplementing and supporting communication aims

403to improve transmission of information, the understanding of404the child’s problem, compliance with recommendations, and405thus the outcome. Treatment of disorders screened for in NBS406programmes is mainly executed by parents, making empow-407erment of parents regarding understanding and execution of408preventive medicine a central issue. Material to support the409first communication of the meaning and consequences of a410positive NBS result was reported to be available less often411(41 %) than material explaining treatment (69 %). Quality of412these materials has not been investigated during the survey,413but there is evidence that parent educational material often414does not meet standards regarding completeness or readability415(Fant et al. 2005).

416Guidelines and directives

417Figure 5 gives an overview on the regulation (by a guideline418or a directive) of different domains. Early steps proximal to419the positive laboratory screening result appear to be better420regulated than later or more distal steps421Overall confirmation of screening results (where, how,422when) is predominantly regulated by guidelines (75 %) and423less often by directives (29 %). The same was found for424information and communication to parents (50 % guidelines425and 37 % directives). Material describing how to inform426parents, associated with guidelines, is available digitally and427in print. Most often material seems to be produced locally,428but then applied on a national basis. Across countries at least429one (and often multiple) guidelines and at least one material430for first communication are available for each disorder431screened for somewhere in Europe.

0 10 20 30 40 50 60

Other

Social worker

Psychologist

Geneticist

Clinical nurse specialist

Dietician

Paediatrician

% countries screening for disorders

Metabolic Endocrinologic CF Haemoglobin

Fig. 4 Training offered toprofessionals

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432 Issues related to treatment (age at start of treatment,433 where to treat, professions to be involved in treatment,) are434 regulated on average in 60 % of the cases a disorder is435 screened for. Epidemiological evaluation is rarely regulated436 by guidelines (15 %) or directives (18 %). However, in437 practice on average evaluation was reported for 84 % of438 the cases a disorder is screened for. The main parameters439 evaluated are prevalence (79 %), subtypes of severity440 (39 %) and ethnic origin (28 %). If evaluation is done,441 it is performed in national registries (42 %) or on the442 level of local databases (50 %). In 8 % data have not443 been reported. Long-term outcome is scarcely monitored444 on the basis of a guideline (21 %) or directive (2 %).445 Feedback of long-term outcome to a registry or units for446 confirmation is scarcely regulated by guidelines (31 %)447 and never by a directive.

448 Correspondence between regulation449 (guidelines and directives) and current practice

450 For many facets of NBS programmes current practice has451 been reported to be organised, however, without being reg-452 ulated by a guideline or directive. Therefore, the relationship453 between current practice and its regulation was analysed for454 the four domains of feedback of diagnoses to the screening455 laboratory or registry, monitoring of long-term outcome,456 feedback of long-term outcome to the diagnostic unit, and457 epidemiological evaluation of the screening programme. For458 each disorder and country four different results were possi-459 ble in each domain: (1) there could be a practice and a460 regulation (guideline or directive), (2) there could be a461 practice without a regulation, (3) there could be a regulation462 without a practice, and (4) there could be neither a practice463 nor a regulation. Data were first averaged for each disorder464 across countries and then across disorders. Table 4 reports465 the results of the analysis.

466Results show that the most proximal process of commu-467nicating the results of confirmatory investigations to the468NBS laboratory seems to be very well regulated and organ-469ised. In a substantial number of cases, data collection and470evaluation of long-term outcome and other epidemiological471information is in place on a local level only without being472regulated by a guideline. Feedback of long-term outcome to473the diagnostic unit or to a registry was reported even less474frequently but mostly in association with the existence of a475guideline. The limited practice of this transmission of infor-476mation may be attributed to the number of intervening steps477and to the usually long time interval between the two events,478but may also be due to data protection regulations, as in479general it is not allowed to transmit patient data from treat-480ment units to screening laboratories. Overall exchange of481information across different steps of a NBS programme482often is locally organised even if there is no regulation by483a guideline or a directive.

484Summary and discussion

485The 37 data sets reveal substantial variation across national486screening panels, but also many similarities. Confirmation is487done almost always in specialised centres, and in about48875 % of the cases screening results are confirmed within489the first 20 days of life. However, the definition of a490specialised centre has not been elucidated. Although reported491costs for confirmation are predominantly based on respond-492ents’ estimations, the figures can be taken as educated guesses493showing a large variation between disorders as well as for the494same disorder between countries.495The person informing about a positive NBS result is most496often the GP or a paediatrician, but also screening laboratories497can be the first to inform parents. The preponderant mode of498information is a phone call. Parents already get detailed infor-499mation during the first contact, and paediatricians, dieticians

0 10 20 30 40 50 60 70 80 90 100

Training of professionals

Monitoring long-term outcome

Information and communication to parents

Monitoring epidemiological evaluation

Treatment

Confirmative diagnostics

Do

mai

n

%

Fig. 5 Regulation (byguidelines and/or directives) ofdomains of European NBSprogrammes

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500 and geneticists are the key persons in teaching parents about501 diagnosis and treatment. Material to support the first com-502 munication of the meaning and consequences of a positive503 NBS result was reported to be available less often than504 material explaining treatment.505 For most disorders patients present asymptomatically at506 start of treatment, but for some disorders substantial numb-507 ers are confirmed at a symptomatic stage (classical galacto-508 saemia, β-ketothiolase deficiency, glutaric aciduria type II,509 LCHADD, and CAH). Confirmed diagnoses are mostly fed510 back to the screening laboratory and less often to a registry.511 Long-term outcome is usually evaluated, however, the eval-512 uation is predominantly done at the level of treatment units513 and outcomes are rarely reported to a registry.514 Training of professionals involved in confirmation is515 most often offered to paediatricians, but less often to dieti-516 cians, geneticists, clinical nurse specialists, psychologists,517 and social workers.518 Political support for newborn screening by public fund-519 ing of newborn screening or by a service of the public health520 system seems to be present in all countries. Professional521 societies for screened disorders have been reported to exist522 in two thirds of the jurisdictions. Most countries have523 patient and/or parent associations for at least some of the524 screened conditions. Patient advocacy groups exist in about525 half of the countries where newborn screening was recently526 expanded, but these groups were rarely involved in the527 decision to expand newborn screening.528 Guidelines are nearly always available for laboratory529 diagnostic procedures, often for confirmation of screening530 results, but information to parents showed low levels for531 regulation and quality control. Epidemiological evaluation532 is rarely regulated by guidelines or directives, but practiced533 in most of the cases. Long-term outcome is scarcely moni-534 tored on the basis of a regulation.535 Based on the results of the survey, scientific evidence and536 clinical practice, the European Network of Experts on537 Newborn Screening (EUNENBS:), which was set up with538 experts of health authorities of EU member states, relevant539 European learned societies and European parents’/patients’540 associations to prepare a consensus document to support541 discussion for a future policy initiative has formulated 70542 recommendations on how to develop NBS in Europe

543(Cornel et al. 2011). In the following we summarise the544most important recommendations, but the reader is referred545to the original document for more detailed information (http://546www.iss.it/cnmr/prog/cont.php?id01621&lang01&tipo064).

5471. There is a clear need to develop case definitions for all548disorders screened for, including an attempt to achieve549agreement on these case definitions within the EU550to facilitate assessment and international outcome551studies.5522. The decision whether a screening programme should553be performed can be based on a framework of screen-554ing criteria updated from the traditional Wilson and555Jungner (1968) criteria, relating to disease, treatment,556test and cost.5573. The interest of the child should be central in the558assessment of pros and cons.5594. A European NBS body (or the national NBS bodies)560should further elaborate the specifications and the op-561erative application of the screening criteria through562discussion and agreement with the EU national563authorities.5645. The European NBS body (or the national NBS bodies)565should consider other potential advantages, especially566(a) avoiding a diagnostic odyssey and (b) informed567reproductive choice for the next pregnancy(ies) of the568parents, and later for the child, and the provision of569genetic counselling to the family.5706. Health Technology Assessment to evaluate the evi-571dence on the effectiveness of early detection through572newborn screening and treatment should be achievable573in practice. For rare conditions, best level evidence574should be used. Methods need to be developed to both575optimise health benefit and careful evaluation.5767. Universal screening is generally preferable to ethnically577targeted screening. If there are sound reasons (e.g. health578gain) for targeted screening it is important to avoid579stigmatisation.5808. The health system should ensure treatment to all581confirmed cases diagnosed by screening.5829. Systems should be developed in order to support583screening in countries where it would be beneficial584but not affordable for economic and/or social reasons.

t4:1 Table 4 Correspondence of guidelines and actual practice

t4:2 Regulation &practice

No regulationbut practice

Regulation butno practice

No regulation &no practice

t4:3 1. Feedback of final diagnosis to screening labs/registry 94 % 6 % 0 % 0 %

t4:4 2. Monitoring long-term outcome 22 % 60 % 0 % 18 %

t4:5 3. Feedback of long-term outcome to diagnostic unit 27 % 16 % 4 % 53 %

t4:6 4. Epidemiological evaluation of screening programmes 25 % 60 % 1 % 14 %

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585 10. The EU should put in place systems for helping those586 countries where treatment is not yet available for all587 confirmed cases. The target of treatment for all con-588 firmed cases should be achieved without reducing the589 quality of treatment.590 11. Screening methodology should aim to avoid unintended591 findings, such as cases with mild forms and information592 on carrier status, as much as possible.593 12. If unintended results are found (such as carrier status),594 member states need to consider carefully how results595 are communicated. Parents need to be informed596 adequately in a way which is consistent with the indi-597 vidual data protection rights and the right to privacy as598 well as patient rights.599 13. Economic evaluations of NBS programmes are needed.600 Balancing the right to care of all patients needs to take601 rare disorders into account.

602603 Following an extensive discussion of the results of the604 survey as well as current scientific evidence and clinical605 experience the EUNENBS approved a list of disorders to606 be considered in the gradual expansion of NBS in the607 European Union (Table 5).608 Over 50 disorders can be detected by NBS based on609 blood samples with varying methods, but also with varying

610certainty. It should be stressed that NBS is a comprehensive611programme: it can not be focussed or even reduced to the612part of the screening laboratory. Screening includes confir-613mation of the positive screening result, decision for or614against treatment, choice of appropriate treatment options615(e.g. diet, drugs, behavioural measures or mere observation)616as well as long-term follow-up of patients and evaluation of617outcome (Rembold 1998; Wilcken et al. 2012, see also618Fig. 1). This expanded concept of NBS is not really new,619as it can already be found in the seminal work by Wilson620and Jungner (1968) on principles and practice of screening621for disease.622An important framework to put principles into practice623has recently been published by the US Secretary for Health624and Human Services Advisory Committee on Heritable625Disorders in Newborns and Children (Hinton et al. 2011).626A two axes model of long-term follow-up (LTFU) for new-627born screening has been formulated. Axis one comprises628four components of LTFU (care coordination, evidence-629based treatment, continuous quality improvement, and re-630search), axis two deals with stakeholders after NBS (chil-631dren and families, primary care providers, specialists and632clinical researchers, and national state entities). There are633four central tasks to be done in effective and efficient NBS634follow-up. First, coordination of the different disciplines and

t5:1 Table 5Q2 Disorders suggested by the EUNENBS to be considered in the expansion of NBS in the European Union

t5:2 Group 1a N of countriesscreening

Group 1b Disorders* withlower prevalence, the test isnot too difficult and healthgain is proven

N of countriesscreening

Group 2 N of countriesscreeningt5:3 Disorders1 with a relatively

high prevalence, the test isnot too difficult and healthgain is proven

Candidates disorders1 where screeningis more challenging according to thecriteria by Wilson and Jungner 1968;cost-effectiveness, RCTs

t5:4 HPA 33 MSUD 12 BIO 10

t5:5 CH 37 GAI 10 CMV infection not surveyed

t5:6 CAH 14 GALT 10 CPTII 7

t5:7 CF 9 CACT not surveyed

t5:8 MCAD 13 GAII 6

t5:9 S_S/SC/BTHA2 3-4 3HMG 5

t5:10 HCSD 6

t5:11 HCI 7

t5:12 IVA 9

t5:13 BKT 3

t5:14 LCHAD 8

t5:15 lysosomal storage disorders not surveyed

t5:16 3MCC 6

t5:17 SCIDD not surveyed

t5:18 TYRI & TYRII_III 7-3

t5:19 VLCAD 9

t5:20 Vitamin B12 DEFICIENCY not surveyed

1 For abbreviations see Table 22 in Mediterranean countries and countries with migrant populations

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635 individuals involved in treatment and care. Second, coordi-636 nation of all stakeholders in new knowledge discovery and637 translational research. The third task is information flow638 between professionals and from professionals to patients639 and vice versa. Finally, there should be a structured process640 of quality improvement of care, knowledge and information.641 The suggested solution for these tasks is the concept of a642 medical home for the patient, a focal point for collaboration643 and coordination (van Dyck and Edwards 2006). Basically644 the medical home is a concrete physical entity where the645 patient can address all his/her questions and problems,646 linked with all specialists needed for information, treatment647 and care, i.e. a physical but also a virtual centre for diagno-648 sis, treatment and care.649 These requirements can at least implicitly already be650 identified in an article published by Blumberg more than651 half a century ago (Blumberg 1957) defining the objectives652 of screening programmes by obtaining epidemiological data653 on the nature of the disease, perfecting the screening proce-654 dures for future use, increasing the likelihood of future655 acceptance of other screening programmes, and improving656 the health of those in the screened community. The author657 also formulated four questions to be answered in a screening658 programme: 1. What is the outlook for a person with the659 disease?, 2. Who is going to do the diagnostic follow-up?, 3.660 What facilities exist for treating cases found?, and last but661 not least 4. What mental status accompanies knowledge or662 suspicion of the disease?663 Our survey revealed that there are positive examples of664 NBS programmes that can be used as templates for further665 research and practice. In Europe for each disorder screened666 for there exists at least one guideline for each step of a667 screening programme. Furthermore, detailed outcome stud-668 ies have been published for the Australian (Wilcken et al.669 2009) and German (Lindner et al. 2011) screening panels,670 but also for single disorders (e.g. glutaric aciduria type I;671 Kölker et al. 2006; Heringer et al. 2010). Evidence-based672 guidelines are available for cystic fibrosis (Castellani et al.673 2009), congenital adrenal hyperplasia (Auchus et al. 2010),674 and glutaric aciduria type I (Kölker et al. 2011), and the675 German Working Group for inborn errors of metabolism has676 approved a guideline on how to confirm positive screening677 results (Lindner 2010).678 There is an ongoing discussion about guiding criteria for679 inclusion of single disorders into a screening panel (e.g.680 Petros 2011) and professionals will have to face the ques-681 tions (not only for research purposes but also as they are682 asked by parents) “why are we all doing different things”683 (Pollitt 2007) and “how are we travelling, and where should684 we be going” (Wilcken 2011). We hope that the EU Council685 Recommendation for an Action in the Field of Rare Diseases686 (European Commission 2009) will lead to the establishment687 of lines for the cooperation and coordination among Member

688States in order to better utilise national resources and expertise689as well as reducing inequalities in the access to high quality690care. Continued support of research and other activities to691tackle these challenges will be required.

692693Acknowledgement We thank all respondents for contributing their694data to the survey695This work was funded by the European Union (Contract number6962009 62 06 of the Executive Agency for Health and Consumers) and697by the Dietmar Hopp Foundation, St. Leon -Rot.

698Conflict of interest None.

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811Parents and patient organisations

812 Q3European Society for Phenylketonuria: http://www.espku.org/,813retrieved 22 Nov 2011814 Q4European Organization for Rare Diseases: http://www.eurordis.org/,815retrieved 22 Nov 2011816 Q5Cystic Fibrosis Europe; http://www.cfww.org/cfe/, retrieved 22817Nov 2011

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