Missed Cystic Fibrosis Newborn Screening Cases due to Immunoreactive Trypsinogen Levels below Program Cutoffs: A National Survey of Risk Factors

Testing immunoreactive trypsinogen (IRT) is the first step in cystic fibrosis (CF) newborn screening. While high IRT is associated with CF, some cases are missed. This survey aimed to find factors associated with missed CF cases due to IRT levels below program cutoffs. Twenty-nine states responded to a U.S-wide survey and 13 supplied program-related data for low IRT false screen negative cases (CFFN) and CF true screen positive cases (CFTP) for analysis. Rates of missed CF cases and odds ratios were derived for each factor in CFFNs, and two CFFN subgroups, IRT above (“high”) and below (“low”) the CFFN median (39 ng/mL) compared to CFTPs for this entire sample set. Factors associated with “high” CFFN subgroup were Black race, higher IRT cutoff, fixed IRT cutoff, genotypes without two known CF-causing variants, and meconium ileus. Factors associated with “low” CFFN subgroup were older age at specimen collection, Saturday birth, hotter season of newborn dried blood spot collection, maximum ≥ 3 days laboratories could be closed, preterm birth, and formula feeding newborns. Lowering IRT cutoffs may reduce “high” IRT CFFNs. Addressing hospital and laboratory factors (like training staff in collection of blood spots, using insulated containers during transport and reducing consecutive days screening laboratories are closed) may reduce “low” IRT CFFNs.

[1]  K. Southern,et al.  Cystic fibrosis newborn screening: the importance of bloodspot sample quality , 2020, Archives of Disease in Childhood.

[2]  D. Peroni,et al.  Clinical and Genotypical Features of False-Negative Patients in 26 Years of Cystic Fibrosis Neonatal Screening in Tuscany, Italy , 2020, Diagnostics.

[3]  Todd W. Allen,et al.  Galactose-1-phosphate uridyltransferase dried blood spot quality control materials for newborn screening tests. , 2015, Clinical biochemistry.

[4]  R. Iles,et al.  Thirty-years of screening for cystic fibrosis in East Anglia , 2012, Archives of Disease in Childhood.

[5]  P. Farrell,et al.  Immunoreactive Trypsinogen (IRT) as a Biomarker for Cystic Fibrosis: challenges in newborn dried blood spot screening. , 2012, Molecular genetics and metabolism.

[6]  P. Farrell,et al.  Factors accounting for a missed diagnosis of cystic fibrosis after newborn screening , 2011, Pediatric pulmonology.

[7]  B. Adam,et al.  The stability of markers in dried-blood spots for recommended newborn screening disorders in the United States. , 2011, Clinical biochemistry.

[8]  P. Farrell,et al.  Clarification of Laboratory and Clinical Variables That Influence Cystic Fibrosis Newborn Screening With Initial Analysis of Immunoreactive Trypsinogen , 2009, Pediatrics.

[9]  G. Cutting,et al.  Guidelines for diagnosis of cystic fibrosis in newborns through older adults: Cystic Fibrosis Foundation consensus report. , 2008, The Journal of pediatrics.

[10]  A. Clark,et al.  Cystic Fibrosis Diagnosed After 2 Months of Age Leads to Worse Outcomes and Requires More Therapy , 2007, Pediatrics.

[11]  M. Corey,et al.  Genetic and physiologic correlates of longitudinal immunoreactive trypsinogen decline in infants with cystic fibrosis identified through newborn screening. , 2006, The Journal of pediatrics.

[12]  R. Laessig,et al.  Newborn screening for cystic fibrosis in Wisconsin: nine-year experience with routine trypsinogen/DNA testing. , 2005, The Journal of pediatrics.

[13]  J. Zieleński,et al.  Two-tiered immunoreactive trypsinogen-based newborn screening for cystic fibrosis in Colorado: screening efficacy and diagnostic outcomes. , 2005, The Journal of pediatrics.

[14]  R. Parad,et al.  Population-based newborn screening for genetic disorders when multiple mutation DNA testing is incorporated: a cystic fibrosis newborn screening model demonstrating increased sensitivity but more carrier detections. , 2004, Pediatrics.

[15]  T J David,et al.  Newborn Screening for Cystic Fibrosis , 2004, Journal of the Royal Society of Medicine.

[16]  M. Kosorok,et al.  Newborn screening for cystic fibrosis in Wisconsin: comparison of biochemical and molecular methods. , 1997, Pediatrics.

[17]  Lee-Jen Wei,et al.  Newborn Screening for Cystic Fibrosis Is Complicated by Age-Related Decline in Immunoreactive Trypsinogen Levels , 1990, Pediatrics.

[18]  M. Seia,et al.  Cystic fibrosis newborn screening: distribution of blood immunoreactive trypsinogen concentrations in hypertrypsinemic neonates. , 2012, JIMD reports.

[19]  C. Castellani,et al.  A survey of newborn screening for cystic fibrosis in Europe. , 2007, Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society.