Cystic Fibrosis Newborn Screening in Austria Using PAP and the Numeric Product of PAP and IRT Concentrations as Second-Tier Parameters

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 1,961 (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.

The Benefit of Detecting Reduced Intracellular B12 Activity through Newborn Screening Remains Unclear

“…In 34% of the Austrian children suspected by NBS to have B12D in this study, the condition was proven. This PPV of the Austrian algorithm is lower than published before [ 5 ], but exceeds, e.g., the PPV for cystic fibrosis [ 19 ]. Our results suggest that special consideration of Met and the Met/Phe ratio, as well as the time of DBS sampling, may improve the detection ratio towards B12D cases proven at recall.…”

Current Status of Newborn Bloodspot Screening Worldwide 2024: A Comprehensive Review of Recent Activities (2020–2023)

“…In addition to a recent review of the 100-year history of the Austrian national birth registry of IMDs [ 713 ], a 50-year review of the Austrian NBS program is also available [ 714 ]. Recent discussions within the NBS community have focused on whether and how to introduce PAP into the CF screening protocol [ 715 ]. Additionally, the NBS program added SMA in 2021 and SCID in 2022 [ 716 ].…”

Influence of Season, Storage Temperature and Time of Sample Collection in Pancreatitis-Associated Protein-Based Algorithms for Newborn Screening for Cystic Fibrosis

“…Therefore, in the current German CF-NBS programme, a three-stage CF-NBS algorithm is used, in which a search for 31 CFTR variants is included as a third tier. Apart from Germany, PAP-based CF-NBS algorithms are also used in the Netherlands [ 6 , 7 ], Portugal [ 8 ] and Austria [ 9 ], among others, because IRT/PAP algorithms seem to have advantages over genetic algorithms in screening multi-ethnic populations and, depending on the design of the algorithm, the number of false detections of healthy carriers or newborns designated as CFSPID after CF-NBS can be significantly reduced.…”