California's Newborn Cystic Fibrosis Screening Shows Promise

Marcia Frellick

November 16, 2015

California's three-step newborn screening model for cystic fibrosis (CF) shows high efficiency, sensitivity, and positive predictive value and low false positives in the first 5 years, according to an analysis published online November 16 in Pediatrics.

The three steps consist of measuring immunoreactive trypsinogen in all dried blood spot specimens, testing from 28 to 40 selected CF transmembrane conductance regulator (CFTR) mutations in specimens with immunoreactive trypsinogen values of at least 62 ng/mL (top 1.6%), and performing DNA sequencing on specimens found to have only one mutation in step 2.

"Program sensitivity was 92%, and the positive predictive value was 34%. CF prevalence was 1 in 6899 births," Martin Kharrazi, PhD, MPH, from the California Department of Public Health, Richmond, and colleagues write.

"A total of 303 CFTR mutations were identified, including 78 novel variants. The median age at referral to a CF care center was 34 days," they report.

Overall, the program identified 345 CF cases, 533 CFTR-related metabolic syndrome (CRMS) cases, and 1617 carriers; 28 cases of CF were missed. Of the 345 patients with CF, 20 (5.8%) infants were initially assessed as having CRMS; their CF diagnosis occurred after age 6 months.

Strengths and Criticisms

The findings came from a large group of more than 2.5 million newborns and the screened group was also highly diverse. Genotyping, as part of screening, was comprehensive in terms of mutations and Intron 8 Poly (T) Tract status before referral to CF specialty care centers.

Also, unlike traditional two-step protocols, which consider any hypertrypsinogenemic newborn with one or more CFTR mutations as screening test–positive, the California program required at least two mutations to be considered positive. Using CFTR sequencing as a third step reduced the number of CF carriers referred for sweat chloride tests by two thirds compared with the two-step model, the authors note.

Patrick R. Sosnay, MD, from the Department of Medicine of Johns Hopkins University, Baltimore, Maryland, and Philip Farrell, MD, PhD, from the Department of Pediatrics and the Department of Population Health Sciences, University of Wisconsin School of Medicine and Public Health in Madison, gave the findings a mixed review in an accompanying editorial.

The California protocol leads to more diagnoses of CRMS, which is not a severe condition, they point out. In other protocols, these cases may be discharged. The benefit of a CRMS diagnosis with uncertain prognosis is unknown, they say.

"This strategy yields the highest positive predictive value ever observed in [CF newborn screening] and allowed California to meet their goal to 'minimize the burden of false positives.' " they write. "On the other hand, the diagnostic outcomes are less desirable than seen with other algorithms because more CRMS than CF cases were detected, creating an unmeasured 'burden' for families and CF centers."

Still, they conclude, the California method "has contributed significantly to our understanding of CF and the impact of [newborn screening] with CFTR sequencing."

Dr Sosnay has done consulting and advised educational material for Genetech and has received grants from Vertex as well as the US Cystic Fibrosis Foundation. The authors and Dr Farrell have disclosed no relevant financial relationships.

Pediatrics. Published online November 16, 2015.

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