title: Improving the Sensitivity and Positive Predictive Value in a Cystic Fibrosis Newborn Screening Program Using a Repeat Immunoreactive Trypsinogen and Genetic Analysis.
abstract: To evaluate the performance of a new cystic fibrosis (CF) newborn screening algorithm, comprised of immunoreactive trypsinogen (IRT) in first (24-48 hours of life) and second (7-14 days of life) dried blood spot plus DNA on second dried blood spot, over existing algorithms.
  
  
  
  A retrospective review of the IRT/IRT/DNA algorithm implemented in Colorado, Wyoming, and Texas.
  
  
  
  A total of 1 520 079 newborns were screened, 32 557 (2.1%) had abnormal first IRT; 8794 (0.54%) on second. Furthermore, 14 653 mutation analyses were performed; 1391 newborns were referred for diagnostic testing; 274 newborns were diagnosed; and 201/274 (73%) of newborns had 2 mutations on the newborn screening CFTR panel. Sensitivity was 96.2%, compared with sensitivity of 76.1% observed with IRT/IRT (105 ng/mL cut-offs, P < .0001). The ratio of newborns with CF to heterozygote carriers was 1:2.5, and newborns with CF to newborns with CFTR-related metabolic syndrome was 10.8:1. The overall positive predictive value was 20%. The median age of diagnosis was 28, 30, and 39.5 days in the 3 states.
  
  
  
  IRT/IRT/DNA is more sensitive than IRT/IRT because of lower cut-offs (∼97 percentile or 60 ng/mL); higher cut-offs in IRT/IRT programs (>99 percentile, 105 ng/mL) would not achieve sufficient sensitivity. Carrier identification and identification of newborns with CFTR-related metabolic syndrome is less common in IRT/IRT/DNA compared with IRT/DNA. The time to diagnosis is nominally longer, but diagnosis can be achieved in the neonatal period and opportunities to further improve timeliness have been enacted. IRT/IRT/DNA algorithm should be considered by programs with 2 routine screens.
authors.affiliation: Department of Epidemiology, Colorado School of Public Health, University of Colorado Anschutz Medical Campus, Aurora, CO. Electronic address: marci.sontag@ucdenver.edu.
authors.forename: Marci K
authors.initials: MK
authors.lastname: Sontag
authors.affiliation: Laboratory Services Section, Texas Department of State Health Services, Austin, TX; Laboratory Services Division, Colorado Department of Public Health and Environment, Denver, CO.
authors.forename: Rachel
authors.initials: R
authors.lastname: Lee
authors.affiliation: Laboratory Services Division, Colorado Department of Public Health and Environment, Denver, CO.
authors.forename: Daniel
authors.initials: D
authors.lastname: Wright
authors.affiliation: Laboratory Services Section, Texas Department of State Health Services, Austin, TX.
authors.forename: Debra
authors.initials: D
authors.lastname: Freedenberg
authors.affiliation: Department of Pediatrics, Children's Hospital Colorado, University of Colorado School of Medicine, Aurora, CO.
authors.forename: Scott D
authors.initials: SD
authors.lastname: Sagel
mesh_terms: D000465:Algorithms; D015415:Biomarkers / Q000097:blood; D003550:Cystic Fibrosis / Q000097:blood / Q000175:diagnosis* / Q000201:enzymology / Q000235:genetics; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics*; D059788:Dried Blood Spot Testing; D005260:Female; D005500:Follow-Up Studies; D005819:Genetic Markers; D005820:Genetic Testing; D006801:Humans; D007159:Immunologic Tests; D007231:Infant, Newborn; D008297:Male; D009154:Mutation; D015997:Neonatal Screening / Q000379:methods*; D011237:Predictive Value of Tests; D012189:Retrospective Studies; D012680:Sensitivity and Specificity; D014362:Trypsinogen / Q000097:blood*; D014481:United States
chemical_list: D015415:Biomarkers; C505032:CFTR protein, human; D005819:Genetic Markers; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D014362:Trypsinogen
keywords: accuracy; carriers; cystic fibrosis-related metabolic syndrome; neonatal screening