Reducing the False-Positive Rate for Isovalerylcarnitine in Expanded Newborn Screening

Poggiali, S; Ombrone, Daniela; Forni, G; Malvagia, Sabrina; Funghini, Silvia; Mura, Massimo; Pasquini, Elisabetta; Santoro, Laura; Bellavia, Vincenzo; Granata, Orazia M.; Castana, Cinzia; McGreevy, Kathleen S.; Aronica, Tommaso Silvano; Marca, Giancarlo la

doi:10.1177/2326409816661355

Cited by 4 publications

(4 citation statements)

References 12 publications

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“…Several papers report on an increased recall rate in newborns due to elevated C5 caused by the intake of pivalic acid derivatives. Pivalic acid contained in some antibiotics or nipple creams can conjugate to free carnitine and became a C5-carnitine isobaric compound [ 26 , 27 , 28 ]. In these babies, organic acid analysis in urine is normal and subsequent analysis on DBS always shows a spontaneous decrease in C5 after the suspension of antibiotic treatment or nipple cream application.…”

Section: Second-tier Test Strategymentioning

confidence: 99%

“…With 2-TT, PPV is near 100% based on the C5 cut off adjustment. However, as reported in the literature [27,28], since true cases are limited, more precise statistics will only be available when more data are collected. Unfortunately, NBS can fail to detect the intermediate form of MSUD, which often only manifests in biochemical alterations during metabolic decompensation.…”

Section: Isovaleric Acidaemiamentioning

confidence: 99%

Section: Isovaleric Acidaemiamentioning

confidence: 99%

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Development of Strategies to Decrease False Positive Results in Newborn Screening

Malvagia

Forni

Ombrone

et al. 2020

IJNS

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The expansion of national newborn screening (NBS) programmes has provided significant benefits in the diagnosis and early treatment of several rare, heritable conditions, preventing adverse health outcomes for most affected infants. New technological developments have enabled the implementation of testing panel covering over 50 disorders. Consequently, the increment of false positive rate has led to a high number of healthy infants recalled for expensive and often invasive additional testing, opening a debate about the harm-benefit ratio of the expanded newborn screening. The false-positive rate represents a challenge for healthcare providers working in NBS systems. Here, we give an overview on the most commonly used strategies for decreasing the adverse effects due to inconclusive screening results. The focus is on NBS performance improvement through the implementation of analytical methods, the application of new and more informative biomarkers, and by using post-analytical interpretive tools. These strategies, used as part of the NBS process, can to enhance the positive predictive value of the test and reduce the parental anxiety and healthcare costs related to the unnecessary tests and procedures.

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Section: Second-tier Test Strategymentioning

confidence: 99%

Section: Isovaleric Acidaemiamentioning

confidence: 99%

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Development of Strategies to Decrease False Positive Results in Newborn Screening

Malvagia

Forni

Ombrone

et al. 2020

IJNS

Self Cite

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“…Second-tier testing—for example, employing a chromatographic separation—can improve the specificity and the diagnostic performances of the screening test [ 39 ].…”

Section: A Putative Role For Second-tier Screeningmentioning

confidence: 99%

Current State and Innovations in Newborn Screening: Continuing to Do Good and Avoid Harm

Marca

Carling

Moat

et al. 2023

IJNS

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In 1963, Robert Guthrie’s pioneering work developing a bacterial inhibition assay to measure phenylalanine in dried blood spots, provided the means for whole-population screening to detect phenylketonuria in the USA. In the following decades, NBS became firmly established as a part of public health in developed countries. Technological advances allowed for the addition of new disorders into routine programmes and thereby resulted in a paradigm shift. Today, technological advances in immunological methods, tandem mass spectrometry, PCR techniques, DNA sequencing for mutational variant analysis, ultra-high performance liquid chromatography (UPLC), iso-electric focusing, and digital microfluidics are employed in the NBS laboratory to detect more than 60 disorders. In this review, we will provide the current state of methodological advances that have been introduced into NBS. Particularly, ‘second-tier’ methods have significantly improved both the specificity and sensitivity of testing. We will also present how proteomic and metabolomic techniques can potentially improve screening strategies to reduce the number of false-positive results and improve the prediction of pathogenicity. Additionally, we discuss the application of complex, multiparameter statistical procedures that use large datasets and statistical algorithms to improve the predictive outcomes of tests. Future developments, utilizing genomic techniques, are also likely to play an increasingly important role, possibly combined with artificial intelligence (AI)-driven software. We will consider the balance required to harness the potential of these new advances whilst maintaining the benefits and reducing the risks for harm associated with all screening.

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Analysis of a second-tier test panel in dried blood spot samples using liquid chromatography-tandem mass spectrometry in Catalonia’s newborn screening programme

Pajares-García,

González de Aledo-Castillo,

Flores-Jiménez

et al. 2023

Clinical Chemistry and Laboratory Medicine (CCLM)

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Objectives Acylcarnitine and amino acid analyses of dried blood spot (DBS) samples using tandem mass spectrometry in newborn screening (NBS) programmes can generate false positive (FP) results. Therefore, implementation of second-tier tests (2TTs) using DBS samples has become increasingly important to avoid FPs. The most widely used 2TT metabolites include methylmalonic acid, 3-hydroxypropionic acid, methylcitric acid, and homocysteine. Methods We simultaneously measured 46 underivatised metabolites, including organic acids, acylglycine and acylcarnitine isomers, homocysteine, and orotic acid, in DBS samples using tandem mass spectrometry. To validate this method, we analysed samples from 147 healthy newborns, 160 patients with genetic disorders diagnosed via NBS, 20 patients with acquired vitamin B12 deficiency, 10 newborns receiving antibiotic treatment, and nine external quality control samples. Results The validation study revealed that 31 metabolites showed good analytical performance. Furthermore, this method detected key metabolites for all diseases associated with increased levels of the following acylcarnitines: C3, C4, C5, C4DC\C5OH, and C5DC. The sensitivity of this method to detect all diseases was 100 %, and the specificity was 74–99 %, except for glutaric aciduria type 1. This method can also be used to diagnose mitochondrial fatty acid β-oxidation disorders (FAODs) and urea cycle defects (UCDs). Conclusions We have described a 2TT panel of 31 metabolites in DBS samples based on an easy and rapid method without derivatisation. Its implementation allowed us to distinguish between different organic acidurias, some FAODs, and UCDs. This new strategy has increased the efficiency of our NBS programme by reducing FP and false negative results, second sample requests, and the time required for diagnosis.

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Reducing the False-Positive Rate for Isovalerylcarnitine in Expanded Newborn Screening

Cited by 4 publications

References 12 publications

Development of Strategies to Decrease False Positive Results in Newborn Screening

Development of Strategies to Decrease False Positive Results in Newborn Screening

Current State and Innovations in Newborn Screening: Continuing to Do Good and Avoid Harm

Analysis of a second-tier test panel in dried blood spot samples using liquid chromatography-tandem mass spectrometry in Catalonia’s newborn screening programme

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