1. This 5-year review of California’s 3-step model for newborn screening for cystic fibrosis (CF) demonstrated that it is highly sensitive and effective.
2. The median age to referral to a CF center for infants that tested positive at step 2 was 18 days, and for infants who were identified at step 3, was 37 days.
Study Rundown: CF is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene and is the most common life-limiting disease in Caucasian populations that is inherited in an autosomal recessive pattern. Every state has implemented newborn screening for CF in various forms as early intervention is known to make a substantial difference in the disease course. This study sought to evaluate the 3-step screen for CF in California. The 3-step model involves: measurement of immunoreactive trypsinogen (IRT), testing for 28 to 40 selected CFTR mutations if IRT is found to be > 62 ng/mL, and referral to a CF center for those with ≥ 2 or DNA sequencing for those with 1 mutation. In the over 2 million newborns screened using this model from 2007 to 2012, only 28 cases of CF were missed. The model was highly sensitive. This 3-step screen is limited by the length of time it takes for complete DNA sequencing and potentially delays diagnosis of CF in infants. However, physicians can use this large study to better understand the process of CF diagnosis via newborn screening and how California has successfully tailored their newborn screen to its diverse population with high effectiveness.
In-Depth [cross-sectional study]: A total of 2 573 293 infants underwent IRT testing from 2007 to 2012, which was a total of 98.8% of the births in California during this period. Among these infants, 40 646 (1.6%) had an IRT > 62 ng/mL and underwent testing for 28 to 40 known CFTR mutations. Of these infants, 0.5% had 2 panel mutations identified and were referred to a cystic fibrosis center. However, 38 149 (93.9%) had no panel mutations identified. The 5.7% who had 1 panel mutation identified subsequently underwent full DNA sequencing, after which 36.5% of newborns had ≥ 2 mutations identified. These infants were then referred to a cystic fibrosis center. The median age to referral to the cystic fibrosis center in infants who tested positive on the initial mutation panel was 18 days (25-75%ile: 16-20 days) compared to a median time of 37 days (25-75%ile: 31-45 days) for infants who tested positive on the DNA sequencing. The median days to diagnosis was 25 days (25-75%: 18-41 days) for panel positive infants and 148 days (25-75%ile: 60-296 days) for infants positive via sequencing. The overall sensitivity of the screen was 92% and the positive predictive value of the screen was 34%.
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