Clarification of Laboratory and Clinical Variables That Influence Cystic Fibrosis Newborn Screening With Initial Analysis of Immunoreactive Trypsinogen

Abstract

Floating, rather than fixed, cutoff values for the initial immunoreactive trypsinogen portion of any cystic fibrosis newborn screening protocol are generally necessary on the basis of the seasonal and reagent lot variations observed. Because of its lower sensitivity, immunoreactive trypsinogen/immunoreactive trypsinogen does not optimize detection of patients with cystic fibrosis.

A Decision-Tree Approach to Cost Comparison of Newborn Screening Strategies for Cystic Fibrosis

“…Consequently, for the purposes of our simulation, we used an estimated loss to follow-up average of 10%. Although the percentage of infants with a second IRT above 70 ng/mL has not specifically been reported in the literature, based on expert opinion and mathematical deduction, 6 we estimated that 12.25% of infants with an initially high IRT will have a second high IRT based on expert opinions and mathematical deduction. Infants with a second high IRT are referred for a sweat test for diagnostic evaluation, but this step generally requires a referral, which provides another area for loss to follow-up and delayed diagnosis.…”

“…With nationwide CF NBS underway, the research climate shifted from one focused on identifying the benefits of screening to one focused on identifying the best screening methodology. [5][6][7] Although wide variations in screening methods and cutoff values currently exist throughout the United States and across the world, 6,8 almost all algorithms begin by evaluating IRT 1 levels by using a dried blood specimen collected between 1 and 5 days of age with the second tier being either a second IRT or DNA analysis for CF transmembrane conductance regulator (CFTR) mutations. 9 Further testing and referrals are then made based on the particular screening method in use by the state.…”

“…Based on a large database analysis in a state with ongoing CF surveillance, 37 a survey, and reviewing the literature, Kloosterboer et al (2009) 6 reported an average sensitivity of 80% for an initial IRT cutoff level of 105 ng/mL. For the current study, to assess sensitivity further, we reviewed all the CF NBS articles available through PubMed, focusing on those with CF false negative screening test results, [28][29][30][31][32][33][34][35] and determined from worldwide reports 28,32 that a 78% to 85% range of sensitivity has been observed; then we took into account data presented at a recent conference (Evaluation of IRT as a Biomarker for Cystic Fibrosis: Methodological Issues and Practical Challenges for Newborn Screening; May 23-24, 2011) and concluded that 80% is a reasonable value to apply in the decision tree, despite a claim of higher sensitivity.…”

“…Infants with a second high IRT are referred for a sweat test for diagnostic evaluation, but this step generally requires a referral, which provides another area for loss to follow-up and delayed diagnosis. From Wisconsin 6 and Massachusetts 23 data, we assumed that 5% of infants would be lost at this step.…”

“…For the IRT/DNA method, we based the process on the method used in Wisconsin, which has been applied in 32 states, by using both published 5,6,10,11,37 and some unpublished data available from that program. In the decision tree we created, the newborns were selected for 23 CFTR mutation DNA analyses 22 38 and again a 5% loss was assumed for sweat tests.…”