Optimal DNA tier for the IRT/DNA algorithm determined by CFTR mutation results over 14years of newborn screening

Abstract

Background There has been great variation and uncertainty about how many and what CFTR mutations to include in cystic fibrosis (CF) newborn screening algorithms, and very little research on this topic using large populations of newborns. Methods We reviewed Wisconsin screening results for 1994–2008 to identify an ideal panel. Results Upon analyzing approximately 1 million screening results, we found it optimal to use a 23 CFTR mutation panel as a second tier when an immunoreactive trypsinogen (IRT)/DNA algorithm was applied for CF screening. This panel in association with a 96th percentile IRT cutoff gave a sensitivity of 97.3%, but restricting the DNA tier to F508del was associated with 90% (P<.0001). Conclusions Although CFTR panel selection has been challenging, our data show that a 23 mutation method optimizes sensitivity and is practically advantageous. The IRT cutoff value, however, is actually more critical than DNA in determining CF newborn screening sensitivity.

Improving newborn screening for cystic fibrosis using next-generation sequencing technology: a technical feasibility study

“…22,23 Initially, the two-tier IRT/DNA method incorporated only a single, common mutation, F508del (c.1521_1523delCTT), followed later by an expanded panel of mutations (typically 23–40 mutations). 7,23 These expanded mutation panels add value by improving the sensitivity of CF screening, but they remain insufficient and sometimes include mutations that are not CF-causing alleles.…”

“…6 Moreover, ~90% of infants with one mutation have normal sweat test results and are therefore CF heterozygote carrier infants who are categorized as screening false positive. 7 These CF NBS false-positive results can cause parental anxiety, 8–10 add considerable expense to NBS, 11 and may delay the diagnosis of CF when one mutation is detected 9 or insufficient quantities of sweat are obtained. 6 Therefore, the challenges associated with false positives based on carrier detection in the common IRT/DNA protocol are significant and magnified by the disproportionately large number of carriers in the population with high IRT levels.…”

“…In addition, in a retrospective study designed to assess the potential applicability of an IRT/NGS algorithm to Wisconsin NBS for CF, we performed this NGS assay on 165 residual NBS-positive specimens that were identified with only one of 23 CFTR mutations recommended by the American College of Medical Genetics and Genomics, 15 the panel currently used for NBS in Wisconsin. 7 …”

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

“…6,26 There are some limitations to our study and also some other "hidden" costs in both screening methods that are currently difficult to define with precision. It should be pointed out that some sweat tests need to be repeated because of insufficient quantities of sweat; in fact, up to 10% can be assumed, 47 Another limitation is that we relied heavily on Wisconsin data to have completely accessible costs and outcomes for the models, but their general applicability in the United States has been described 48 recently. On the other hand, certain expenses such as salaries for personnel will vary in other regions and thus the simulations described herein may require revisions (eg, in the United Kingdom where the newborn blood specimens are obtained at home, which causes greater health care personnel costs but lower family expenses).…”

Challenges in Cystic Fibrosis Newborn Screening and Recommendations for Primary Care Physicians

“…These mutations (mostly European derived) were the basis for early CF genetic tests used for diagnosis and screening. 4,5 However, as recognition of CF widened, and knowledge of the CF phenotype expanded to include milder and atypical phenotypes, testing for just the common mutations proved inadequate. Carrier screening and NBS both rely on interpretation of the disease liability of a CFTR variant in the absence of phenotype.…”