scholarly journals Use of Molecular Genetic Analyses in Danish Routine Newborn Screening

2021 ◽  
Vol 7 (3) ◽  
pp. 50
Author(s):  
Allan Meldgaard Lund ◽  
Flemming Wibrand ◽  
Kristin Skogstrand ◽  
Marie Bækvad-Hansen ◽  
Niels Gregersen ◽  
...  
Keyword(s):  
Newborn Screening ◽  
False Positive Rate ◽  
Genetic Diseases ◽  
Molecular Genetic ◽  
Negative Consequences ◽  
Genetic Analyses ◽  
Future Possibility ◽  
Targeted Ngs ◽  
Positive Rate ◽  
Second Tier

Historically, the analyses used for newborn screening (NBS) were biochemical, but increasingly, molecular genetic analyses are being introduced in the workflow. We describe the application of molecular genetic analyses in the Danish NBS programme and show that second-tier molecular genetic testing is useful to reduce the false positive rate while simultaneously providing information about the precise molecular genetic variant and thus informing therapeutic strategy and easing providing information to parents. When molecular genetic analyses are applied as second-tier testing, valuable functional data from biochemical methods are available and in our view, such targeted NGS technology should be implemented when possible in the NBS workflow. First-tier NGS technology may be a promising future possibility for disorders without a reliable biomarker and as a general approach to increase the adaptability of NBS for a broader range of genetic diseases, which is important in the current landscape of quickly evolving new therapeutic possibilities. However, studies on feasibility, sensitivity, and specificity are needed as well as more insight into what views the general population has towards using genetic analyses in NBS. This may be sensitive to some and could have potentially negative consequences for the NBS programme.

Reduction of the false-positive rate in newborn screening by implementation of MS/MS-based second-tier tests: The Mayo Clinic experience (2004–2007)

2007 ◽  
Vol 30 (4) ◽  
pp. 585-592 ◽  
Author(s):  
D. Matern ◽  
S. Tortorelli ◽  
D. Oglesbee ◽  
D. Gavrilov ◽  
P. Rinaldo
Keyword(s):  
Newborn Screening ◽  
Mayo Clinic ◽  
False Positive ◽  
False Positive Rate ◽  
Positive Rate ◽  
Clinic Experience ◽  
Second Tier

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 Modelling science trustworthiness under publish or perish pressure

2018 ◽  
Vol 5 (1) ◽  
pp. 171511 ◽  
Author(s):  
David Robert Grimes ◽  
Chris T. Bauch ◽  
John P. A. Ioannidis
Keyword(s):  
Phenomenological Model ◽  
False Positive ◽  
Null Hypothesis ◽  
False Positive Rate ◽  
Scientific Publication ◽  
Negative Consequences ◽  
Publish Or Perish ◽  
Positive Rate ◽  
Positive Results ◽  
Scientific Endeavour

Scientific publication is immensely important to the scientific endeavour. There is, however, concern that rewarding scientists chiefly on publication creates a perverse incentive, allowing careless and fraudulent conduct to thrive, compounded by the predisposition of top-tier journals towards novel, positive findings rather than investigations confirming null hypothesis. This potentially compounds a reproducibility crisis in several fields, and risks undermining science and public trust in scientific findings. To date, there has been comparatively little modelling on factors that influence science trustworthiness, despite the importance of quantifying the problem. We present a simple phenomenological model with cohorts of diligent, careless and unethical scientists, with funding allocated by published outputs. This analysis suggests that trustworthiness of published science in a given field is influenced by false positive rate, and pressures for positive results. We find decreasing available funding has negative consequences for resulting trustworthiness, and examine strategies to combat propagation of irreproducible science.

scholarly journals Incorporation of Second-Tier Biomarker Testing Improves the Specificity of Newborn Screening for Mucopolysaccharidosis Type I

2020 ◽  
Vol 6 (1) ◽  
pp. 10 ◽  
Author(s):  
Dawn S. Peck ◽  
Jean M. Lacey ◽  
Amy L. White ◽  
Gisele Pino ◽  
April L. Studinski ◽  
...  
Keyword(s):  
Newborn Screening ◽  
False Positive ◽  
Dermatan Sulfate ◽  
False Positive Rate ◽  
False Negative ◽  
Type I ◽  
Mucopolysaccharidosis Type ◽  
Mucopolysaccharidosis Type I ◽  
Second Tier ◽  
Mps I

Enzyme-based newborn screening for Mucopolysaccharidosis type I (MPS I) has a high false-positive rate due to the prevalence of pseudodeficiency alleles, often resulting in unnecessary and costly follow up. The glycosaminoglycans (GAGs), dermatan sulfate (DS) and heparan sulfate (HS) are both substrates for α-l-iduronidase (IDUA). These GAGs are elevated in patients with MPS I and have been shown to be promising biomarkers for both primary and second-tier testing. Since February 2016, we have measured DS and HS in 1213 specimens submitted on infants at risk for MPS I based on newborn screening. Molecular correlation was available for 157 of the tested cases. Samples from infants with MPS I confirmed by IDUA molecular analysis all had significantly elevated levels of DS and HS compared to those with confirmed pseudodeficiency and/or heterozygosity. Analysis of our testing population and correlation with molecular results identified few discrepant outcomes and uncovered no evidence of false-negative cases. We have demonstrated that blood spot GAGs analysis accurately discriminates between patients with confirmed MPS I and false-positive cases due to pseudodeficiency or heterozygosity and increases the specificity of newborn screening for MPS I.

scholarly journals The Role of Extended CFTR Gene Sequencing in Newborn Screening for Cystic Fibrosis

2020 ◽  
Vol 6 (1) ◽  
pp. 23 ◽  
Author(s):  
Anne Bergougnoux ◽  
Maureen Lopez ◽  
Emmanuelle Girodon
Keyword(s):  
Cystic Fibrosis ◽  
Newborn Screening ◽  
Dna Analysis ◽  
Genetic Diseases ◽  
Major Drawback ◽  
Coding Regions ◽  
Sequencing Technologies ◽  
Second Tier ◽  
Real Challenge

There has been considerable progress in the implementation of newborn screening (NBS) programs for cystic fibrosis (CF), with DNA analysis being part of an increasing number of strategies. Thanks to advances in genomic sequencing technologies, CFTR-extended genetic analysis (EGA) by sequencing its coding regions has become affordable and has already been included as part of a limited number of core NBS programs, to the benefit of admixed populations. Based on results analysis of existing programs, the values and challenges of EGA are reviewed in the perspective of its implementation on a larger scale. Sensitivity would be increased at best by using EGA as a second tier, but this could be at the expense of positive predictive value, which improves, however, if EGA is applied after testing a variant panel. The increased detection of babies with an inconclusive diagnosis has proved to be a major drawback in programs using EGA. The lack of knowledge on pathogenicity and penetrance associated with numerous variants hinders the introduction of EGA as a second tier, but EGA with filtering for all known CF variants with full penetrance could be a solution. The issue of incomplete knowledge is a real challenge in terms of the implemention of NBS extended to many genetic diseases.

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 Second Tier Molecular Genetic Testing in Newborn Screening for Pompe Disease: Landscape and Challenges

2020 ◽  
Vol 6 (2) ◽  
pp. 32 ◽  
Author(s):  
Laurie D. Smith ◽  
Matthew N. Bainbridge ◽  
Richard B. Parad ◽  
Arindam Bhattacharjee
Keyword(s):  
Genetic Testing ◽  
Newborn Screening ◽  
Pompe Disease ◽  
False Positive ◽  
Clinical Decision Making ◽  
Molecular Genetic ◽  
Screening Tests ◽  
Molecular Genetic Testing ◽  
Second Tier ◽  
Positive Results

Pompe disease (PD) is screened by a two tier newborn screening (NBS) algorithm, the first tier of which is an enzymatic assay performed on newborn dried blood spots (DBS). As first tier enzymatic screening tests have false positive results, an immediate second tier test on the same sample is critical in resolving newborn health status. Two methodologies have been proposed for second tier testing: (a) measurement of enzymatic activities such as of Creatine/Creatinine over alpha-glucosidase ratio, and (b) DNA sequencing (a molecular genetics approach), such as targeted next generation sequencing. (tNGS). In this review, we discuss the tNGS approach, as well as the challenges in providing second tier screening and follow-up care. While tNGS can predict genotype-phenotype effects when known, these advantages may be diminished when the variants are novel, of unknown significance or not discoverable by current test methodologies. Due to the fact that criticisms of screening algorithms that utilize tNGS are based on perceived complexities, including variant detection and interpretation, we clarify the actual limitations and present the rationale that supports optimizing a molecular genetic testing approach with tNGS. Second tier tNGS can benefit clinical decision-making through the use of the initial NBS DBS punch and rapid turn-around time methodology for tNGS, that includes copy number variant analysis, variant effect prediction, and variant ‘cut-off’ tools for the reduction of false positive results. The availability of DNA sequence data will contribute to the improved understanding of genotype-phenotype associations and application of treatment. The ultimate goal of second tier testing should enable the earliest possible diagnosis for the earliest initiation of the most effective clinical interventions in infants with PD.

Comparing the clinical and economic effects of clinical examination, pulse oximetry, and echocardiography in newborn screening for congenital heart defects: A probabilistic cost-effectiveness model and value of information analysis

2007 ◽  
Vol 23 (2) ◽  
pp. 192-204 ◽  
Author(s):  
Ingolf Griebsch ◽  
Rachel L. Knowles ◽  
Jacqueline Brown ◽  
Catherine Bull ◽  
Christopher Wren ◽  
...  
Keyword(s):  
Cost Effectiveness ◽  
Newborn Screening ◽  
Pulse Oximetry ◽  
Clinical Examination ◽  
Heart Defects ◽  
False Positive Rate ◽  
Research Priorities ◽  
Cost Effective ◽  
Positive Rate ◽  
Clinically Significant

Objectives: Congenital heart defects (CHD) are an important cause of death and morbidity in early childhood, but the effectiveness of alternative newborn screening strategies in preventing the collapse or death—before diagnosis—of infants with treatable but life-threatening defects is uncertain. We assessed their effectiveness and efficiency to inform policy and research priorities.Methods: We compared the effectiveness of clinical examination alone and clinical examination with either pulse oximetry or screening echocardiography in making a timely diagnosis of life-threatening CHD or in diagnosing clinically significant CHD. We contrasted their cost-effectiveness, using a decision-analytic model based on 100,000 live births, and assessed future research priorities using value of information analysis.Results: Clinical examination alone, pulse oximetry, and screening echocardiography achieved 34.0, 70.6, and 71.3 timely diagnoses per 100,000 live births, respectively. This finding represents an additional cost per additional timely diagnosis of £4,894 and £4,496,666 for pulse oximetry and for screening echocardiography. The equivalent costs for clinically significant CHD are £1,489 and £36,013, respectively. Key determinants of cost-effectiveness are detection rates and screening test costs. The false-positive rate is very high with screening echocardiography (5.4 percent), but lower with pulse oximetry (1.3 percent) or clinical examination alone (.5 percent).Conclusions: Adding pulse oximetry to clinical examination is likely to be a cost-effective newborn screening strategy for CHD, but further research is required before this policy can be recommended. Screening echocardiography is unlikely to be cost-effective, unless the detection of all clinically significant CHD is considered beneficial and a 5 percent false-positive rate acceptable.

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