title: Comparison of different IRT-PAP protocols to screen newborns for cystic fibrosis in three central European populations.
abstract: BACKGROUND
  In recent years different IRT/PAP protocols have been evaluated, but the individual performance remains unclear. To optimize the IRT/PAP strategy we compared protocols from three regional CF newborn screening centers (Heidelberg, Dresden, and Prague).
  
  
  METHODS
  We evaluated the effect of elevating the IRT-cut-off from 50 to 65 μg/l (~97.5th to ~99.0th percentile), the need of a failsafe protocol (FS, IRT ≥ 99.9th percentile) and the relative performance using either two IRT-dependent PAP-cut-offs or one PAP-cut-off.
  
  
  RESULTS
  Elevation of the IRT cut-off to 65 μg/l (~99.0th percentile) increased the PPV significantly (Dresden: 0.065 vs. 0.080, p < 0.0001, Prague: 0.052 vs. 0.074, p < 0.0001) without reducing sensitivity. All three IRT/PAP protocols showed a trend towards a higher sensitivity with FS than without and when using one PAP-cut-off instead of two IRT-dependent PAP-cut-offs.
  
  
  CONCLUSIONS
  For best performance we suggest an IRT/PAP protocol with an IRT-cut-off close to the 99.0th percentile, FS, and a single PAP-cut-off.
authors.affiliation: Division of Paediatric Pulmonology & Allergy and Cystic Fibrosis Center, Department of Paediatrics III, Children's Hospital, University of Heidelberg, Im Neuenheimer Feld 430, D-69120 Heidelberg, Germany; Translational Lung Research Centre Heidelberg (TLRC), Member of the German Center for Lung Research (DZL), Im Neuenheimer Feld 350, D-69120 Heidelberg, Germany. Electronic address: olaf.sommerburg@med.uni-heidelberg.de.
authors.forename: Olaf
authors.initials: O
authors.lastname: Sommerburg
authors.affiliation: Department of Biology and Medical Genetics, University Hospital Motol and 2nd Faculty of Medicine, Charles University, V Uvalu 84, Prague 5, CZ 150 06, Czech Republic.
authors.forename: Veronika
authors.initials: V
authors.lastname: Krulisova
authors.affiliation: Pediatric Department, University Hospital of Dresden, Fetscherstr. 74, D-01307 Dresden, Germany.
authors.forename: Jutta
authors.initials: J
authors.lastname: Hammermann
authors.affiliation: 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.
authors.forename: Martin
authors.initials: M
authors.lastname: Lindner
authors.affiliation: Division of Paediatric Pulmonology & Allergy and Cystic Fibrosis Center, Department of Paediatrics III, Children's Hospital, University of Heidelberg, Im Neuenheimer Feld 430, D-69120 Heidelberg, Germany; Translational Lung Research Centre Heidelberg (TLRC), Member of the German Center for Lung Research (DZL), Im Neuenheimer Feld 350, D-69120 Heidelberg, Germany.
authors.forename: Mirjam
authors.initials: M
authors.lastname: Stahl
authors.affiliation: Division of Paediatric Pulmonology & Allergy and Cystic Fibrosis Center, Department of Paediatrics III, Children's Hospital, University of Heidelberg, Im Neuenheimer Feld 430, D-69120 Heidelberg, Germany; Translational Lung Research Centre Heidelberg (TLRC), Member of the German Center for Lung Research (DZL), Im Neuenheimer Feld 350, D-69120 Heidelberg, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Muckenthaler
authors.affiliation: 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.
authors.forename: Dirk
authors.initials: D
authors.lastname: Kohlmueller
authors.affiliation: Division of Paediatric Pulmonology & Allergy and Cystic Fibrosis Center, Department of Paediatrics III, Children's Hospital, University of Heidelberg, Im Neuenheimer Feld 430, D-69120 Heidelberg, Germany.
authors.forename: Margit
authors.initials: M
authors.lastname: Happich
authors.affiliation: Division of Paediatric Pulmonology & Allergy and Cystic Fibrosis Center, Department of Paediatrics III, Children's Hospital, University of Heidelberg, Im Neuenheimer Feld 430, D-69120 Heidelberg, Germany.
authors.forename: Andreas E
authors.initials: AE
authors.lastname: Kulozik
authors.affiliation: Department of Pediatrics, University Hospital Kralovske Vinohrady and 3rd Faculty of Medicine, Charles University, Srobarova 50, Prague 10, CZ 100 34, Czech Republic.
authors.forename: Felix
authors.initials: F
authors.lastname: Votava
authors.affiliation: Department of Biology and Medical Genetics, University Hospital Motol and 2nd Faculty of Medicine, Charles University, V Uvalu 84, Prague 5, CZ 150 06, Czech Republic.
authors.forename: Miroslava
authors.initials: M
authors.lastname: Balascakova
authors.affiliation: Department of Pediatrics, University Hospital Motol and 2nd Faculty of Medicine, Charles University, V Uvalu 84, Prague 5, CZ 100 06, Czech Republic.
authors.forename: Veronika
authors.initials: V
authors.lastname: Skalicka
authors.affiliation: Institute of Clinical Chemistry and Laboratory Medicine, University Hospital of Dresden, Fetscherstr. 74, D-01307 Dresden, Germany.
authors.forename: Marina
authors.initials: M
authors.lastname: Stopsack
authors.affiliation: Pediatric Department, University Hospital of Dresden, Fetscherstr. 74, D-01307 Dresden, Germany.
authors.forename: Manfred
authors.initials: M
authors.lastname: Gahr
authors.affiliation: Department of Biology and Medical Genetics, University Hospital Motol and 2nd Faculty of Medicine, Charles University, V Uvalu 84, Prague 5, CZ 150 06, Czech Republic.
authors.forename: Milan
authors.initials: M
authors.lastname: Macek
authors.affiliation: Division of Paediatric Pulmonology & Allergy and Cystic Fibrosis Center, Department of Paediatrics III, Children's Hospital, University of Heidelberg, Im Neuenheimer Feld 430, D-69120 Heidelberg, Germany; Translational Lung Research Centre Heidelberg (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.
authors.forename: Marcus A
authors.initials: MA
authors.lastname: Mall
authors.affiliation: Translational Lung Research Centre Heidelberg (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.
authors.forename: Georg F
authors.initials: GF
authors.lastname: Hoffmann
mesh_terms: D000951:Antigens, Neoplasm / Q000032:analysis / Q000097:blood* / Q000235:genetics; D014408:Biomarkers, Tumor / Q000032:analysis / Q000097:blood* / Q000235:genetics; D002624:Chemistry, Clinical / Q000379:methods / Q000592:standards; D003550:Cystic Fibrosis / Q000097:blood / Q000175:diagnosis* / Q000235:genetics; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics; D059788:Dried Blood Spot Testing / Q000379:methods* / Q000592:standards; D005060:Europe; D005820:Genetic Testing / Q000379:methods / Q000592:standards; D006801:Humans; D007231:Infant, Newborn; D037181:Lectins, C-Type / Q000032:analysis / Q000097:blood* / Q000235:genetics; D015997:Neonatal Screening / Q000379:methods* / Q000592:standards; D000073718:Pancreatitis-Associated Proteins; D011446:Prospective Studies; D012189:Retrospective Studies; D012680:Sensitivity and Specificity; D014362:Trypsinogen / Q000032:analysis / Q000097:blood* / Q000235:genetics
chemical_list: D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; C505032:CFTR protein, human; D037181:Lectins, C-Type; D000073718:Pancreatitis-Associated Proteins; C000612141:REG3A protein, human; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D014362:Trypsinogen
keywords: Biochemical screening; CF; CFNBS; Cystic fibrosis; DBS; FS; IRT; Immunoreactive trypsinogen; MI; NBS; Newborn screening; PAP; PI; PS; Pancreatitis associated protein; cystic fibrosis; cystic fibrosis newborn screening; dried blot spot; failsafe strategy; immunoreactive trypsinogen; meconium ileus; newborn screening; pancreatic insufficient; pancreatic sufficient; pancreatitis associated protein