Five years of experience with biochemical cystic fibrosis newborn screening based on IRT/PAP in Germany.
BACKGROUND
Evidence from recent studies suggests that IRT/PAP protocols may be successfully used as a purely biochemical newborn screening (NBS) for cystic fibrosis (CF) that does not require genetic screening. However, the experience with the performance of different IRT/PAP protocols remains limited. In this study, we evaluated the performance of IRT/PAP-based CF-NBS used in two German regions between 2008 and 2013 in a large cohort.


METHODS
In both regions slightly different IRT/PAP protocols were used to screen newborns for CF. In contrast to the original IRT/PAP protocol published by Sarles et al., both German protocols contained an IRT-dependent safety net strategy (CF-NBS positive, if IRT≥99.9th percentile). Positive rating of the screening result led to confirmatory diagnostics using sweat chloride testing and clinical assessment.


RESULTS
A total of 328,181 newborns were tested with IRT/PAP in Germany within 5 years. 639 of these newborns (0.19%) were tested positive, and 60 infants were diagnosed with CF leading to a sensitivity of 0.968 and a PPV (positive predictive value) of 0.097. Compared to IRT/DNA protocols, the PPV of IRT/PAP is lower, but PAP used as second tier test has the advantage of a lower detection rate of healthy carriers and CF patients with equivocal results.


CONCLUSIONS
Our results obtained in a large cohort of ∼330,000 newborns support the use of a purely biochemical IRT/PAP protocol as an acceptable alternative when genetic CF-NBS has to be avoided.
Division of Pediatric Pulmonology & Allergy and Cystic Fibrosis Center, Department of Pediatrics III, University of Heidelberg, Im Neuenheimer Feld 430, D-69120, Heidelberg, Germany.|Translational Lung Research Center TLRC, Member of the German Center for Lung Research (DZL), Im Neuenheimer Feld 350, D-69120, Heidelberg, Germany.
Olaf
O
Sommerburg
Pediatric Department, University Hospital of Dresden, Fetscherstr. 74, D-01307, Dresden, Germany.
Jutta
J
Hammermann
Department of Paediatrics, Children's Hospital, University of Frankfurt, Haus 32 A, Theodor-Stern-Kai 7, D-60590, Frankfurt, Germany.
Martin
M
Lindner
Division of Pediatric Pulmonology & Allergy and Cystic Fibrosis Center, Department of Pediatrics III, University of Heidelberg, Im Neuenheimer Feld 430, D-69120, Heidelberg, Germany.|Translational Lung Research Center TLRC, Member of the German Center for Lung Research (DZL), Im Neuenheimer Feld 350, D-69120, Heidelberg, Germany.
Mirjam
M
Stahl
Division of Pediatric Pulmonology & Allergy and Cystic Fibrosis Center, Department of Pediatrics III, University of Heidelberg, Im Neuenheimer Feld 430, D-69120, Heidelberg, Germany.|Translational Lung Research Center TLRC, Member of the German Center for Lung Research (DZL), Im Neuenheimer Feld 350, D-69120, Heidelberg, Germany.
Martina
M
Muckenthaler
Division of Metabolic Diseases and Newborn Screening Center, Department of Paediatrics I, Children's Hospital, University of Heidelberg, Im Neuenheimer Feld 430, D-69120, Heidelberg, Germany.
Dirk
D
Kohlmueller
Division of Pediatric Pulmonology & Allergy and Cystic Fibrosis Center, Department of Pediatrics III, University of Heidelberg, Im Neuenheimer Feld 430, D-69120, Heidelberg, Germany.
Margit
M
Happich
Division of Pediatric Pulmonology & Allergy and Cystic Fibrosis Center, Department of Pediatrics III, University of Heidelberg, Im Neuenheimer Feld 430, D-69120, Heidelberg, Germany.
Andreas E
AE
Kulozik
Institut of Clinical Chemistry and Laboratory Medicine, University Hospital of Dresden, Fetscherstr. 74, D-01307 Dresden, Germany.
Marina
M
Stopsack
Pediatric Department, University Hospital of Dresden, Fetscherstr. 74, D-01307, Dresden, Germany.
Manfred
M
Gahr
Translational Lung Research Center TLRC, Member of the German Center for Lung Research (DZL), Im Neuenheimer Feld 350, D-69120, Heidelberg, Germany.|Division of Metabolic Diseases and Newborn Screening Center, Department of Paediatrics I, Children's Hospital, University of Heidelberg, Im Neuenheimer Feld 430, D-69120, Heidelberg, Germany.
Georg F
GF
Hoffmann
Division of Pediatric Pulmonology & Allergy and Cystic Fibrosis Center, Department of Pediatrics III, University of Heidelberg, Im Neuenheimer Feld 430, D-69120, Heidelberg, Germany.|Translational Lung Research Center TLRC, Member of the German Center for Lung Research (DZL), Im Neuenheimer Feld 350, D-69120, Heidelberg, Germany.|Department of Translational Pulmonology, University of Heidelberg, Im Neuenheimer Feld 350, D-69120, Heidelberg, Germany.
Marcus A
MA
Mall
D000951:Antigens, Neoplasm / Q000097:blood*; D015415:Biomarkers / Q000097:blood; D014408:Biomarkers, Tumor / Q000097:blood*; D015331:Cohort Studies; D003550:Cystic Fibrosis / Q000097:blood* / Q000175:diagnosis; D005260:Female; D005858:Germany; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D037181:Lectins, C-Type / Q000097:blood*; D008297:Male; D015997:Neonatal Screening / Q000379:methods*; D000073718:Pancreatitis-Associated Proteins; D012680:Sensitivity and Specificity; D014362:Trypsinogen / Q000097:blood*
D000951:Antigens, Neoplasm; D015415:Biomarkers; D014408:Biomarkers, Tumor; D037181:Lectins, C-Type; D000073718:Pancreatitis-Associated Proteins; C000612141:REG3A protein, human; D014362:Trypsinogen
Cystic fibrosis; biochemical screening; immunoreactive trypsinogen; newborn screening; pancreatitis associated protein