Utility of a very high IRT/No mutation referral category in cystic fibrosis newborn screening

Abstract

Newborn screening for Cystic Fibrosis (CF) began in New York in October, 2002 using immunoreactive trypsinogen (IRT)/DNA methodology. Infants with at least one CFTR mutation or very high IRT and no mutations (VHIRT) are referred for sweat testing. In a preliminary analysis, we noted a very low positive predictive value (PPV) and preponderance of Hispanic infants in the group of infants with CF referred for VHIRT, which led to a decision to revise, but not eliminate, the VHIRT category. Automatic referral for specimens with VHIRT collected on the day of birth was eliminated, and the VHIRT threshold was raised from 0.2% to 0.1%. In this report, we describe outcomes from VHIRT referrals among 2.4 million infants screened between March 2003 and February 2013. Following the algorithm change, referrals decreased by 37.8% overall (annual mean 1,485 vs. 923), and the VHIRT PPV improved (0.6-1.0%). The number of infants diagnosed has remained consistent at 1 in 4,400 births. The proportion of Black/Hispanic/Asian/Other infants with confirmed CF, CFTR-related metabolic syndrome (CRMS), or possible CF/CRMS was 21.3% in infants with 1-2 mutations, but 75.8% in the VHIRT group. In conclusion, although the PPV among VHIRT referrals remains low, had this category never been implemented, 24 infants with confirmed CF, and 9 infants with CRMS or possible CF/CRMS, most of whom were Hispanic, would have been missed over the 10 years. Information from this study may be helpful in assessing the need for the VHIRT category and algorithm changes in other screening programs.

Clinical Sensitivity of Cystic Fibrosis Mutation Panels in a Diverse Population

“…More than 2,000 CFTR variants have been documented in the “SickKids” Cystic Fibrosis Mutation Database (now referred to as CFTR1) (http://www.genet.sickkids.on.ca). Rare CFTR mutations are known to exist in the diverse NYS CF population [Kay et al., ]. In the absence of complete CFTR analysis, which is labor intensive and expensive, all possible relevant mutations cannot be tested.…”

“…To maximize screening sensitivity, the NYS NBS program refers all infants with at least one panel mutation or an extremely elevated IRT (VHIRT; since 2010, highest 0.1%) in the absence of mutations to CF Specialty Care Centers (SCC) for confirmatory diagnostic testing. Because IRT specificity for CF is low, many healthy carriers of single CFTR mutations and healthy infants with VHIRT are referred each year [Kay et al., ].…”

Pediatric Pulmonologyyear in review 2015: Part 4

“…Blood spots obtained on the first day of life are much more likely to have VHIRT and thus increase the number of false positive screens. In New York State, 22% of VHIRT specimens were obtained in the first 24 hr of life, but only 0.5% of positive screens led to a CF diagnosis . A change in protocol that defined a positive screen as IRT ≥170 ng/ml or in the top 0.1% obtained after 24 hr of life led to a reduction in VHIRT positive screens by almost two‐thirds without compromising CF detection rate.…”

“…In New York State, 22% of VHIRT specimens were obtained in the first 24 hr of life, but only 0.5% of positive screens led to a CF diagnosis. 1 A change in protocol that defined a positive screen as IRT !170 ng/ ml or in the top 0.1% obtained after 24 hr of life led to a reduction in VHIRT positive screens by almost two-thirds without compromising CF detection rate. The reduction in false positives also reduced cost and parental anxiety.…”

Newborn screening for cystic fibrosis: can one algorithm fit all?

“…For example, the New York State NBS program elected to refer any infant with a very high IRT (VHIRT) level even if no mutations were detected. In the VHIRT group, only about 1 in 250 referred infants (24 CF cases/6140 referrals) was diagnosed with CF, but of the 24 infants diagnosed in this manner between 2003 and 2013, 19 were not White and half (n = 12) were Hispanic [13]. Recently, it has been shown an IRT/IRT/targeted DNA algorithm has higher sensitivity and specificity [14].…”