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. 2022 Oct 27;8(4):58.
doi: 10.3390/ijns8040058.

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

Martin Kharrazi  1   2 , Charlene Sacramento  2 , Anne Marie Comeau  3 , Jaime E Hale  3 , Michele Caggana  4 , Denise M Kay  4 , Rachel Lee  5 , Brendan Reilly  5 , John D Thompson  6 , Samya Z Nasr  7 , Mary Kleyn  8 , Gary Hoffman  9 , Mei W Baker  9 , Colleen Clarke  10 , Cheryl L Harris  10 , M Christine Dorley  11 , Hilary Fryman  11 , Ankit Sutaria  12 , Amy Hietala  13 , Holly Winslow  13 , Holly Richards  14 , Bradford L Therrell  15   16
Affiliations

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

Martin Kharrazi et al. Int J Neonatal Screen. .

Abstract

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.

Keywords: CF; IRT; cystic fibrosis; immunoreactive trypsinogen; missed cases; newborn screening.

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Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Figures

Figure 1
Figure 1
State median (gray bars) and weighted average median (black bars) IRT value for study groups in 7 one-specimen (a) and 3 two-specimen (b) states. CFFN, false screen negative CF cases due to IRT below program cutoffs; CFTP, true screen positive CF infants; IRT, immunoreactive trypsinogen; LB, all screened newborns.
Figure 2
Figure 2
IRT values (ng/mL) and median for 61 CFFN cases in 11 states (sorted lowest to highest). CFFN, false screen negative CF cases due to IRT below program cutoffs; IRT, immunoreactive trypsinogen.
Figure 3
Figure 3
Percentage of 41 CFFN and 1545 CFTP cases by age at CF diagnosis in 12 states.
Figure 4
Figure 4
Weighted average median age at specimen collection and laboratory testing for all study groups in 6 one-specimen states.
Figure 5
Figure 5
Weighted average median age at specimen collection and laboratory testing for all study groups in 3 two-specimen states: Specimen 1. (Median ages for CFFNs with IRT ≥40 ng/mL based on 2 states).
Figure 6
Figure 6
Weighted average median age at specimen collection and laboratory testing for all study groups in 3 two-specimen states: Specimen 2. (Median ages for CFFNs with IRT ≥40 ng/mL based on 2 states).
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