Abstract
In Austria, newborns have been screened for cystic fibrosis (CF) by analyzing immunoreactive trypsinogen (IRT) from dried blood spots (DBS)s for nearly 20 years. Recently, pancreatitis-associated protein (PAP) analysis was introduced as a second-tier test with the aim of reducing recalls for second DBS cards while keeping sensitivity high. For 28 months, when IRT was elevated (65–130 ng/mL), PAP was measured from the first DBS (n = 198,927) with a two-step cut-off applied. For the last 12 months of the observation period (n = 85,421), an additional IRT×PAP cut-off was introduced. If PAP or IRT×PAP were above cut-off, a second card was analyzed for IRT and in case of elevated values identified as screen-positive. Above 130 ng/mL IRT in the first DBS, newborns were classified as screen-positive. IRT analysis of first DBS resulted in 1961 (1%) tests for PAP. In the first 16 months, 26 of 93 screen-positive were confirmed to have CF. Two false-negatives have been reported (sensitivity = 92.8%). Importantly, less than 30% of families compared to the previous IRT-IRT screening scheme had to be contacted causing distress. Adding IRT×PAP caused a marginally increased number of second cards and sweat tests to be requested during this period (15 and 3, respectively) compared to the initial IRT-PAP scheme. One case of confirmed CF was found due to IRT×PAP, demonstrating an increase in sensitivity. Thus, the relatively simple and economical algorithm presented here performs effectively and may be a useful model for inclusion of CF into NBS panels or modification of existing schemes.
Highlights
Cystic fibrosis (CF) is an autosomal recessive inherited disease characterized by accumulation of viscous secretion in the pancreas, lungs, and other organs, severely impairing their function [1]
Differences between the strategies appear small, but in the first period one confirmed case would have remained undetected by the immunoreactive trypsinogen (IRT)×pancreatitis-associated protein (PAP) only strategy, while in the second period one case would have been missed by IRT-PAP (Figure 2)
This study shows how introducing a PAP measurement into an existing newborn screening (NBS) algorithm using the conventional IRT-IRT protocol reduces the need to request second cards by more than 70%
Summary
Cystic fibrosis (CF) is an autosomal recessive inherited disease characterized by accumulation of viscous secretion in the pancreas, lungs, and other organs, severely impairing their function [1] It is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene, encoding an important regulator for the transport of chloride and bicarbonate ions across epithelial cell membranes. There is no cure for CF, early diagnosis through newborn screening (NBS) combined with appropriate prompt treatment results in significant benefits for children born with CF [2,3]. These benefits outweigh risks of diagnostic uncertainty such as false-positive screening results. If positive (above cut-off), measurement of pancreatitis-associated protein (PAP) and/or DNA mutation analysis of the CFTR gene from the first card and a second card requested for a further
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