Newborn Screening for Cystic Fibrosis in Switzerland - Evaluation after two years

Transcription

1 Newborn Screening for Cystic Fibrosis in Switzerland - Evaluation after two years R. Fingerhut, T. Torresani, S. Gallati, M.H. Schoeni, C. Kuehni, C. Rueeg, M. Baumgartner, J. Barben and the Swiss CF Screening Group

2 NBS for CF in Switzerland - Consequences after Analysis of 4 Months Pilot Study T Torresani et al. JCF (2013) in press Pilot study Final approval of CF-Screening Retrospective analysis J Barben et al. JCF 11 (2012) Application to the health ministry

3 Legal Regulations NBS = Genetic Screening informed consent necessary IRT/DNA protocol approved CF-screening result pos./neg.

4 Cut-off definitions from: Lehmann Handbuch der Medizinischen Informatik

5 99.9th Percentile v

6 Percentiles CF pos. (n=27) Equivocal CF (n=3) CF pos. with meconium ileus and normal IRT >140

7 IRT-Determination with the GSP TM IRT [ng/ml] AD-1 AD-1- MW AD-2 AD-2- MW GSP-1 GSP-1- MW GSP EDTA [mmol/l]

8 [counts] IRT [ng/ml blood] Mean

9 Analyte Intra-Assay CV Inter-Assay CV mean recovery [%] IRT 3.5 (at 31.6 ng/ml; n=12) 5.0 (at 67.6 ng/ml; n=12) 2.7 (at ng/ml; n=12) 6.1 (at 31.6 ng/ml; n=30) 5.8 (at 67.6 ng/ml; n=30) 5.7 (at ng/ml; n=30) 97.8

10 Children with meconium Ileus IRT measurement on the 4 th day of life (NBS card - term) or 15 th day of life (2 nd NBS card - preterm) F508del Screening 3905insT G542X R553X always both tests 99.2 nd percentile ( 50ng/ml ) Screening for 7 CFTR mutations 1 or 2 CFTR mutations <99.2 nd percentile (<50ng/ml ) No CFTR mutation No further tests IRT from 1 st test 60 ng/ml 2 nd NBS card 2 nd IRT measurement No Yes W1282X 99.2 nd percentile ( 50ng/ml ) <99.2 nd percentile (<50ng/ml ) No further tests G>A Diagnostic N1303K Referral to CF centre Sweat test positive, borderline, unclear Additional diagnostic tests: DNA analysis, pancreas elastase, etc. normal Blood taken for Further IRT measurement in screening lab No further tests

11 Procedure in CF centre since 2012 Sweat test Measurement of chloride and conductivity Cl 60 mmol/l Conductivity 80 mmol/l Cl mmol/l Conductivity mmol/l Chloride < 30 mmol/l Conductivity < 50 mmol/l Sweat test not possible DNA analysis 32 CFTR mutations (informed consent!) 2 mutations CF diagnosis 1 mutation total DNA analysis Follow up and further investigations DNA analysis 32 CFTR mutations (informed consent!) 1 mutation total DNA analysis 1 mutation 2 mut. 2 mut. 2 mutations Equivocal CF or CF Information about possible carrier status or atypical CF Information sheet for parents Information to GP about elevated IRT and normal sweat test DNA analysis 32 CFTR mutations, total DNA analysis if needed (informed consent!) CF, equivocal CF, CF carrier or healthy Feedback to the NGS laboratory fill in assessment sheet for data base

12 Summary of the pilot study Parameter Diagnosis of children with CF (compared to earlier years with clinical diagnosis) Care of children with CF in a CF centre Deniers of Guthrie test Recall rate (Percentage of children who required further investigations) Definition of success 15 per year >90% Not elevated to earlier years (<10 per year) assumed < 1% Evalution after two years 56 CF + 9 equivocal CF 100 % (56/56) 2011: 5 / 2012: % (( )/ ) Positive predictive value (PPV) > 20% 29.2 % (49/186) False negatives (without MI) Time to genetic diagnosis Satisfaction of parents with a CF child Satisfaction of parents with positive screening but without CF diagnosis <5% of all CF diagnosis Before NBS: 198 days ( ) Aim: < 60 days >80% are satisfied >70% are satisfied 3.7 % (2/56) 41 days (12-160) 2011: 100% (18/18), 2012: 96% 2011: 86% (25/29), 2012: 86%

13 Results after 2 years Time from birth to CF diagnosis Parameter (days) Mean Median Interquartile range Range Birth genetic diagnosis Birth heel prick test Heel prick test notification of CF centre Notification of CF centre phone call to parents Phone call to parents visit in CF centre Birth visit in CF centre Visit in CF centre genetic diagnosis Duration of genetic analysis

14 Results after two years Children with meconium ileus children with MI 1 without CF 7 with CF children with MI No. IRT Mutation F508del / G>A F508del / F508del F508del / F508del F508del / F508del F508del / F508del 6 88 F508del / F508del F508del / F508del 3 without CF 4 with CF No. IRT Mutation F508del / F508del F508del / N1303K W1282 / R347H F508del/TG11_T5

15 Newborn screening Situation in Switzerland Disease Tested babies Cases Frequency Phenylketonuria (+ Hyperphenylalaninemia) : Galaktosemia : Hypothyroidism : Biotinidase Deficiency Congenital adrenal hyperplesia 37 ( + 13 mild forms) 1 : (1 : ) : MCAD Deficiency : Cystic Fibrosis :2 581

16 Children with meconium Ileus IRT measurement on the 4 th day of life (NBS card - term) or 15 th day of life (2 nd NBS card - preterm) 333 / year Screening always both tests 99.2 nd percentile ( 50ng/ml ) Screening for 7 CFTR mutations 1 or 2 CFTR mutations <99.2 nd percentile (<50ng/ml ) No CFTR mutation No further tests IRT from 1 st test 60 ng/ml 2 nd NBS card 2 nd IRT measurement No Yes 81 / year 99.2 nd percentile ( 50ng/ml ) <99.2 nd percentile (<50ng/ml ) No further tests Diagnostic Referral to CF centre Sweat test positive, borderline, unclear Additional diagnostic tests: DNA analysis, pancreas elastase, etc. normal Blood taken for Further IRT measurement in screening lab No further tests

17 CF-Screening in Switzerland Thanks to the Swiss CF Screening-Group J. Barben P. Eng C. Kühni N. Regamey J. Spalinger T. Torresani S. Gallati A. Möller I. Rochat R. Spinas C. Barrazzone G. Hafen A. Mornand B. Schiller D. Trachsel M. Baumgartner J. Hammer D. Müller M.H. Schöni M. Zanolari C. Casaulta

18 Thanks to the Colleagues from the Screening-Lab: C. Acosta S. Schmidig E. Albertin A. Ciresa L. Berli S. Semenic S. Bächtold T. Rindlisbacher K. Liebezeit S. Stähli G. Richter C. Riemenschnitter Y. Mäder S. Sugierto Molekulare Diagnostik 2013 Zürich