scholarly journals Introduction of a Simple Second Tier Screening Test for C5 Isobars in Dried Blood Spots: Reducing the False Positive Rate for Isovaleric Acidaemia in Expanded Newborn Screening

2017 ◽  
pp. 75-80 ◽  
Author(s):  
R. S. Carling ◽  
D. Burden ◽  
I. Hutton ◽  
R. Randle ◽  
K. John ◽  
...  
Keyword(s):  
Newborn Screening ◽  
False Positive ◽  
Screening Test ◽  
False Positive Rate ◽  
Dried Blood Spots ◽  
Isovaleric Acidaemia ◽  
Blood Spots ◽  
Expanded Newborn Screening ◽  
Positive Rate ◽  
Second Tier

scholarly journals Evaluation of Multiple Methods for Quantification of Glycosaminoglycan Biomarkers in Newborn Dried Blood Spots from Patients with Severe and Attenuated Mucopolysaccharidosis-I

2020 ◽  
Vol 6 (3) ◽  
pp. 69 ◽  
Author(s):  
Zackary M. Herbst ◽  
Leslie Urdaneta ◽  
Terri Klein ◽  
Maria Fuller ◽  
Michael H. Gelb
Keyword(s):  
False Positive ◽  
Reference Range ◽  
Severe Disease ◽  
False Positive Rate ◽  
Dried Blood Spots ◽  
Mucopolysaccharidosis I ◽  
Blood Spots ◽  
Positive Rate ◽  
Second Tier ◽  
Mps I

All newborn screening (NBS) for mucopolysaccharidosis-I (MPS-I) is carried out by the measurement of α-iduronidase (IDUA) enzymatic activity in dried blood spots (DBS). The majority of low enzyme results are due to pseudodeficiencies, and studies from the Mayo Clinic have shown that the false positive rate can be greatly reduced by including a second-tier analysis of glycosaminoglycans (GAGs) in DBS as part of NBS. In the present study, we obtained newborn DBS from 13 patients with severe MPS-I and 2 with attenuated phenotypes. These samples were submitted to four different GAG mass spectrometry analyses in a comparative study: (1) internal disaccharide; (2) endogenous disaccharide; (3) Sensi-Pro; (4) Sensi-Pro Lite (a variation of Sensi-Pro with a simplified workflow). Patients with attenuated MPS-I show less GAG elevation than those with severe disease, and all MPS-I patients were separated from the reference range using all four methods. The minimal differential factor (lowest GAG marker level in MPS-I samples divided by highest level in the reference range of 30 random newborns) was about two for internal disaccharide, Sensi-Pro, and Sensi-Pro Lite methods. The endogenous disaccharide was clearly the best method with a minimal differential of 16-fold. This study supports use of second-tier GAG analysis of newborn DBS, especially the endogenous disaccharide method, as part of NBS to reduce the false positive rate.

Cortisol assay in dried blood spots to reduce false positive rate in congenital adrenal hyperplasia screening

2012 ◽  
Vol 413 (15-16) ◽  
pp. 1306-1307
Author(s):  
Julie Brossaud ◽  
Pascal Barat ◽  
Laurence Fagour ◽  
Jean-Benoît Corcuff
Keyword(s):  
Congenital Adrenal Hyperplasia ◽  
False Positive ◽  
False Positive Rate ◽  
Dried Blood Spots ◽  
Adrenal Hyperplasia ◽  
Blood Spots ◽  
Positive Rate

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

2016 ◽  
Vol 4 ◽  
pp. 232640981666135 ◽  
Author(s):  
Sara Poggiali ◽  
Daniela Ombrone ◽  
Giulia Forni ◽  
Sabrina Malvagia ◽  
Silvia Funghini ◽  
...  
Keyword(s):  
Newborn Screening ◽  
False Positive ◽  
False Positive Rate ◽  
Expanded Newborn Screening ◽  
Positive Rate

scholarly journals Quantification of Differential Metabolites in Dried Blood Spots Using Second-Tier Testing for SCADD/IBDD Disorders Based on Large-Scale Newborn Screening in a Chinese Population

2021 ◽  
Vol 9 ◽  
Author(s):  
Wei Zhou ◽  
Heng Cai ◽  
Huizhong Li ◽  
Zhe Ji ◽  
Maosheng Gu
Keyword(s):  
Newborn Screening ◽  
Large Scale ◽  
Dehydrogenase Deficiency ◽  
Clinical Performance ◽  
False Positive Rate ◽  
Dried Blood Spots ◽  
Care Hospital ◽  
Blood Spots ◽  
Metabolic Defects ◽  
Second Tier

Background: Although newborn screening (NBS) for metabolic defects using the marker butyl carnitine (C4) combined with the C4-to-acetylcarnitine ratio is adequate, the incorporation of novel parameters may improve differential testing for these disorders without compromising sensitivity.Methods: Analytical and clinical performance was evaluated by MS/MS using 237 initially positive neonatal samples between March 2019 and March 2020 at the Newborn Screening Center of Xuzhou Maternity and Child Health Care Hospital. Additionally, second-tier testing by ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) combined with the quantification of ethylmalonate (EMA) or isobutyryl-glycine (IBG) in dried blood spots (DBSs) was performed to reduce the false-positive rate.Results: We reviewed initial MS/MS data for DBSs from 469,730 neonates, and a second-tier test was performed using 237 samples that exceeded the C4 concentration cutoff value. Eleven variants of the ACADS gene were identified, with c.1031A>G (p.E344G) being the most common. Fifteen ACAD8 mutations were identified in seven patients, and Swiss modeling and amino acid conservation analyses were conducted for the novel variants. Based on a retrospective analysis of EMA and IBG, the application of second-tier tests before the release of neonatal screening results reduced referrals by over 91.89% and improved the positive predictive value (PPV) for short-chain acyl-CoA dehydrogenase deficiency/isobutyryl-CoA dehydrogenase deficiency (SCADD/IBDD) screening.Conclusion: A screening algorithm including EMA/IBG improves target differential testing for NBS and may eliminate unnecessary referrals while maintaining 100% sensitivity. Second-tier screening using UPLC-MS/MS as a rapid and convenient supplemental DNA sequencing method may be beneficial for differential detection.

scholarly journals Newborn Screening for Methylmalonic Acidemia/propionic Acidemia: Systematic Evaluation of a Two-pronged Approach Based on MS/MS and UPLC-MS/MS

2021 ◽  
Author(s):  
Wei Zhou ◽  
Jinxiu Song ◽  
Huizhong Li ◽  
Zhe Ji ◽  
Xin Yin ◽  
...  
Keyword(s):  
Birth Weight ◽  
Newborn Screening ◽  
False Positive ◽  
False Positive Rate ◽  
Propionic Acidemia ◽  
Methylmalonic Acidemia ◽  
Systematic Evaluation ◽  
Care Hospital ◽  
Positive Rate ◽  
Second Tier

Abstract Background: An improved second-tier test is needed to reduce the false-positive rate of newborn screening (NBS) for inborn metabolic disorders in Xuzhou, China.Methods: We designed an expanded second-tier assay using newborn dried blood spots (DBSs). Analytical and clinical performance were evaluated in 53 newborns with methylmalonic acidemia (MMA) or propionic acidemia (PA) reported by the Xuzhou Maternity and Child Health Care Hospital NBS program. Additionally, we analyzed NBS data regarding seasonal variation of metabolites, birth weight and gestational age to improve the identification of true positive MMA/PA individuals.Results: Among the 53 MMA/PA individuals assessed, two pathogenic or likely pathogenic (P/LP) variants in an MMA/PA-associated gene were identified in 46 patients, and a pathogenic variant and a variant of unknown significance (VUS) were identified in 7 patients. No such variants were detected in MMA/PA false-positive individuals or healthy controls. Ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS)-based analysis of the initial NBS metabolic profile correctly identified MMA/PA individuals and reduced the initial NBS false-positive rate by 98.86%. MMA/PA false-positive infants in Xuzhou, China, were most likely to be summer-born.Conclusion: We established a two-pronged approach to reduce false positives by nearly 99% and provided a novel NBS strategy. Challenges in neonate metabolic testing and DNA variant interpretation regarding season, birth weight and pregnancy status remain for this Chinese population.

scholarly journals Development of Strategies to Decrease False Positive Results in Newborn Screening

2020 ◽  
Vol 6 (4) ◽  
pp. 84
Author(s):  
Sabrina Malvagia ◽  
Giulia Forni ◽  
Daniela Ombrone ◽  
Giancarlo la Marca
Keyword(s):  
Newborn Screening ◽  
False Positive ◽  
False Positive Rate ◽  
Healthcare Providers ◽  
Adverse Health Outcomes ◽  
Healthy Infants ◽  
Expanded Newborn Screening ◽  
Positive Rate ◽  
Technological Developments ◽  
Positive Results

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.

scholarly journals Determination of Total Homocysteine, Methylmalonic Acid, and 2-Methylcitric Acid in Dried Blood Spots by Tandem Mass Spectrometry

2010 ◽  
Vol 56 (11) ◽  
pp. 1686-1695 ◽  
Author(s):  
Coleman T Turgeon ◽  
Mark J Magera ◽  
Carla D Cuthbert ◽  
Perry R Loken ◽  
Dimitar K Gavrilov ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Tandem Mass Spectrometry ◽  
False Positive ◽  
Methylmalonic Acid ◽  
False Positive Rate ◽  
Dried Blood Spots ◽  
Tandem Mass ◽  
Blood Spots ◽  
Total Homocysteine ◽  
Second Tier

BACKGROUND Newborn screening (NBS) for inborn errors of propionate, methionine, and cobalamin metabolism relies on finding abnormal concentrations of methionine and propionylcarnitine. These analytes are not specific for these conditions and lead to frequent false-positive results. More specific markers are total homocysteine (tHCY), methylmalonic acid (MMA), and methylcitric acid (MCA), but these markers are not detected by current NBS methods. To improve this situation, we developed a method for the detection of tHCY, MMA, and MCA in dried blood spots (DBSs) by liquid chromatography–tandem mass spectrometry (LC-MS/MS). METHODS The analytes were extracted from a single 4.8-mm DBS punch with acetonitrile:water:formic acid (59:41:0.42) containing dithiothreitol and isotopically labeled standards (d3-MMA, d3-MCA, d8-homocystine). The extract was dried and treated with 3 N HCl in n-butanol to form butylesters. After evaporation of the butanol, the residue was reconstituted and centrifuged and the supernatant was subjected to LC-MS/MS analysis. Algorithms were developed to apply this method as an efficient and effective second-tier assay on samples with abnormal results by primary screening. RESULTS The 99th percentiles determined from the analysis of 200 control DBSs for MMA, MCA, and HCY were 1.5, 0.5, and 9.8 μmol/L, respectively. Since 2005, prospective application of this second-tier analysis to 2.3% of all NBS samples led to the identification of 13 affected infants. CONCLUSIONS Application of this assay reduced the false-positive rate and improved the positive predictive value of NBS for conditions associated with abnormal propionylcarnitine and methionine concentrations.

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