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Optimizing the Phenylalanine Cut-Off Value in a Newborn Screening Program

Phenylketonuria (PKU) was the first disorder for which newborn screening (NBS) was introduced in the early 1960s. Slovenia started the NBS program for PKU in 1979, and the fluorimetric method was implemented in 1992, with a phenylalanine (Phe) cut-off set at 120 mol/L. This value has been in use for...

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Autores principales: Perko, Dasa, Repic Lampret, Barbka, Remec, Ziga Iztok, Zerjav Tansek, Mojca, Drole Torkar, Ana, Krhin, Blaz, Bicek, Ajda, Oblak, Adrijana, Battelino, Tadej, Groselj, Urh
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8955183/
https://www.ncbi.nlm.nih.gov/pubmed/35328070
http://dx.doi.org/10.3390/genes13030517
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author Perko, Dasa
Repic Lampret, Barbka
Remec, Ziga Iztok
Zerjav Tansek, Mojca
Drole Torkar, Ana
Krhin, Blaz
Bicek, Ajda
Oblak, Adrijana
Battelino, Tadej
Groselj, Urh
author_facet Perko, Dasa
Repic Lampret, Barbka
Remec, Ziga Iztok
Zerjav Tansek, Mojca
Drole Torkar, Ana
Krhin, Blaz
Bicek, Ajda
Oblak, Adrijana
Battelino, Tadej
Groselj, Urh
author_sort Perko, Dasa
collection PubMed
description Phenylketonuria (PKU) was the first disorder for which newborn screening (NBS) was introduced in the early 1960s. Slovenia started the NBS program for PKU in 1979, and the fluorimetric method was implemented in 1992, with a phenylalanine (Phe) cut-off set at 120 mol/L. This value has been in use for almost thirty years and has never been revised. We aimed to analyze the DBS samples and review the data from a large nationwide cohort of newborns to optimize the cut-off values for HFA screening to minimize the number of false positives while maintaining the highest level of sensitivity by detecting all those who needed to be treated. In the first prospective part of the study, we analyzed samples of all newborns in Slovenia in 2019 and 2020, and in the second retrospective part, we reviewed data from all known patients with hyperphenylalaninemia (HFA) in Slovenia born from 2000 to 2018. We defined true screening-positive cases as those that required a low-Phe diet. The sensitivity, specificity and positive predictive values of the modeling elevation of the Phe cut-off value from 120 µmol/L to 200 µmol/L were assessed. The number of recalls at the cut-off of 120 µmol/L was 108 out of 37,784 samples at NBS (2019–2020). Six newborns were defined as true positives and 102 samples as false positives. If the cut-off value was adjusted to 160 µmol/L, only 12 samples exceeded it and all six true positive newborns would be detected. Among the 360,000 samples collected at the NBS between 2000 and 2018, 72 HFA patients in need of a low-Phe diet were found. All the diagnosed cases would have been detected if the cut-off was set to 160 µmol/L. We demonstrated in a large group of newborns (400,000 in 20 years) that using the fluorimetric approach, a cut-off value of 160 µmol/L, rather than 120 mol/L, is safe and that there were no missing true positive patients who required treatment. By increasing the cut-off, this method becomes more precise, resulting in a significantly reduced rate of false positives and thus being less burdensome on both families and the healthcare system.
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spelling pubmed-89551832022-03-26 Optimizing the Phenylalanine Cut-Off Value in a Newborn Screening Program Perko, Dasa Repic Lampret, Barbka Remec, Ziga Iztok Zerjav Tansek, Mojca Drole Torkar, Ana Krhin, Blaz Bicek, Ajda Oblak, Adrijana Battelino, Tadej Groselj, Urh Genes (Basel) Article Phenylketonuria (PKU) was the first disorder for which newborn screening (NBS) was introduced in the early 1960s. Slovenia started the NBS program for PKU in 1979, and the fluorimetric method was implemented in 1992, with a phenylalanine (Phe) cut-off set at 120 mol/L. This value has been in use for almost thirty years and has never been revised. We aimed to analyze the DBS samples and review the data from a large nationwide cohort of newborns to optimize the cut-off values for HFA screening to minimize the number of false positives while maintaining the highest level of sensitivity by detecting all those who needed to be treated. In the first prospective part of the study, we analyzed samples of all newborns in Slovenia in 2019 and 2020, and in the second retrospective part, we reviewed data from all known patients with hyperphenylalaninemia (HFA) in Slovenia born from 2000 to 2018. We defined true screening-positive cases as those that required a low-Phe diet. The sensitivity, specificity and positive predictive values of the modeling elevation of the Phe cut-off value from 120 µmol/L to 200 µmol/L were assessed. The number of recalls at the cut-off of 120 µmol/L was 108 out of 37,784 samples at NBS (2019–2020). Six newborns were defined as true positives and 102 samples as false positives. If the cut-off value was adjusted to 160 µmol/L, only 12 samples exceeded it and all six true positive newborns would be detected. Among the 360,000 samples collected at the NBS between 2000 and 2018, 72 HFA patients in need of a low-Phe diet were found. All the diagnosed cases would have been detected if the cut-off was set to 160 µmol/L. We demonstrated in a large group of newborns (400,000 in 20 years) that using the fluorimetric approach, a cut-off value of 160 µmol/L, rather than 120 mol/L, is safe and that there were no missing true positive patients who required treatment. By increasing the cut-off, this method becomes more precise, resulting in a significantly reduced rate of false positives and thus being less burdensome on both families and the healthcare system. MDPI 2022-03-15 /pmc/articles/PMC8955183/ /pubmed/35328070 http://dx.doi.org/10.3390/genes13030517 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Perko, Dasa
Repic Lampret, Barbka
Remec, Ziga Iztok
Zerjav Tansek, Mojca
Drole Torkar, Ana
Krhin, Blaz
Bicek, Ajda
Oblak, Adrijana
Battelino, Tadej
Groselj, Urh
Optimizing the Phenylalanine Cut-Off Value in a Newborn Screening Program
title Optimizing the Phenylalanine Cut-Off Value in a Newborn Screening Program
title_full Optimizing the Phenylalanine Cut-Off Value in a Newborn Screening Program
title_fullStr Optimizing the Phenylalanine Cut-Off Value in a Newborn Screening Program
title_full_unstemmed Optimizing the Phenylalanine Cut-Off Value in a Newborn Screening Program
title_short Optimizing the Phenylalanine Cut-Off Value in a Newborn Screening Program
title_sort optimizing the phenylalanine cut-off value in a newborn screening program
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8955183/
https://www.ncbi.nlm.nih.gov/pubmed/35328070
http://dx.doi.org/10.3390/genes13030517
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