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

Martin Kharrazi; Charlene Sacramento; Anne Marie Comeau; Jaime E Hale; Michele Caggana; Denise M Kay; Rachel Lee; Brendan Reilly; John D Thompson; Samya Z Nasr; Mary Kleyn; Gary Hoffman; Mei W Baker; Colleen Clarke; Cheryl L Harris; M Christine Dorley; Hilary Fryman; Ankit Sutaria; Amy Hietala; Holly Winslow; Holly Richards; Bradford L Therrell

doi:10.3390/ijns8040058

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

Int J Neonatal Screen. 2022 Oct 27;8(4):58. doi: 10.3390/ijns8040058.

Authors

Martin Kharrazi^{1

2}, Charlene Sacramento², Anne Marie Comeau³, Jaime E Hale³, Michele Caggana⁴, Denise M Kay⁴, Rachel Lee⁵, Brendan Reilly⁵, John D Thompson⁶, Samya Z Nasr⁷, Mary Kleyn⁸, Gary Hoffman⁹, Mei W Baker⁹, Colleen Clarke¹⁰, Cheryl L Harris¹⁰, M Christine Dorley¹¹, Hilary Fryman¹¹, Ankit Sutaria¹², Amy Hietala¹³, Holly Winslow¹³, Holly Richards¹⁴, Bradford L Therrell^{15

16}

Affiliations

¹ California Department of Public Health, Richmond, CA 94804, USA.
² Sequoia Foundation, La Jolla, CA 92037, USA.
³ New England Newborn Screening Program, UMass Chan Medical School, Worcester, MA 01605, USA.
⁴ New York State Newborn Screening Program, Wadsworth Center, New York State Department of Health, Albany, NY 12208, USA.
⁵ Texas Department of State Health Services, Austin, TX 78756, USA.
⁶ Washington State Department of Health, Public Health Laboratories, Newborn Screening Program, Shoreline, WA 98155, USA.
⁷ Michigan Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
⁸ Michigan Department of Health and Human Services, Lansing, MI 48913, USA.
⁹ Wisconsin Newborn Screening Laboratory at Wisconsin State Laboratory of Hygiene, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706, USA.
¹⁰ Louisiana Office of Public Health, Baton Rouge, LA 70802, USA.
¹¹ Tennessee Department of Health, Newborn Screening Laboratory and Follow-Up Program, Nashville, TN 37216, USA.
¹² Georgia Department of Public Health, Atlanta, GA 30303, USA.
¹³ Minnesota Department of Health, Public Health Laboratory, Newborn Screening, St. Paul, MN 55164, USA.
¹⁴ Maine Newborn Screening Program, Augusta, ME 04333, USA.
¹⁵ National Newborn Screening and Global Resource Center, Austin, TX 78759, USA.
¹⁶ Department of Pediatrics, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78249, USA.

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.

Abstract

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