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CLIR Applications for Newborn Screening

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A special issue of International Journal of Neonatal Screening (ISSN 2409-515X).

Deadline for manuscript submissions: closed (31 March 2021) | Viewed by 51437

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Special Issue Editors

Dr. Piero Rinaldo

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Guest Editor

Biochemical Genetics Laboratory, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA

Dr. Dietrich Matern

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Guest Editor

Biochemical Genetics Laboratory, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA

Dr. Rolf Zetterström

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Center for Inherited Metabolic Diseases, Karolinska University Hospital, 171 76 Stockholm, Sweden; Department of Molecular Medicine and Surgery, Karolinska Institutet, 171 76 Stockholm, Sweden

Dr. Robert J. Currier

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Department of Pediatrics, University of California, San Francisco and Benioff Children’s Hospital, San Francisco, CA 94158, USA

Dr. Lars Mørkrid

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Guest Editor

Department of Medical Biochemistry, Oslo University Hospital, Oslo, Norway; Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway

Special Issue Information

Dear Colleagues,

Newborn screening (NBS) is based upon laboratory tests performed on a growing proportion of ~130 million children born worldwide every year. Poor performance on a mass scale distresses a multitude of patients and exposes both families and providers to an increasing risk of psychosocial harm while incurring unnecessary expenses. Collaborative Laboratory Integrated Reports (https://clir.mayo.edu) is a second-generation web application that maintains an interactive database of newborn screening results from multiple sites. The long-term goal of CLIR though worldwide collaboration and data sharing is the creation of high-throughput post-analytical interpretive tools to improve NBS performance and achieve a near-zero false positive rate (Genet Med 2018;20:847-854).

CLIR’s defining characteristics are: (1) the replacement of conventional reference intervals with continuous, covariate-adjusted (age, birth weight, sex) moving percentiles. This type of statistical modeling requires big data, and acceptance of the concept that reference intervals could be defined by “recycling” and harmonizing several millions of normal screening test results from a multitude of sources; (2) the replacement of analyte cutoff values with an integrated scoring based on the degree of overlap between reference ranges and condition-specific disease ranges; (3) the integration of primary markers with all informative permutations of ratios. Ratios calculated between markers not directly related at the biochemical level are particularly helpful to correct for pre-analytical factors and potential analytical bias; and (4) harmonization by location is also routinely possible. Access to CLIR is freely available to qualified users worldwide who are willing to share reference data and profiles of positive cases.

This Special Issue of the International Journal of Neonatal Screening (IJNS) showcases a number of applications of CLIR tools to improve performance of primary screening, analyses of limitations and challenges, examples of the use and impact of second tier testing, and relevance to short term follow-up. It also includes an overview of the underlying IT infrastructure and an example of the user training material available online.

Dr. Piero Rinaldo
Dr. Dietrich Matern
Dr. Rolf Zetterström
Dr. Robert J. Currier
Dr. Lars Mørkrid
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Neonatal Screening is an international peer-reviewed open access quarterly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

This Special Issue is dedicated in lasting memory of our dear friend and colleague Fred Lorey (1953–2020)

Published Papers (12 papers)

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Research

20 pages, 3646 KiB

Open AccessArticle

A Novel Approach to Improve Newborn Screening for Congenital Hypothyroidism by Integrating Covariate-Adjusted Results of Different Tests into CLIR Customized Interpretive Tools

by Alexander D. Rowe, Stephanie D. Stoway, Henrik Åhlman, Vaneet Arora, Michele Caggana, Anna Fornari, Arthur Hagar, Patricia L. Hall, Gregg C. Marquardt, Bobby J. Miller, Christopher Nixon, Andrew P. Norgan, Joseph J. Orsini, Rolf D. Pettersen, Amy L. Piazza, Neil R. Schubauer, Amy C. Smith, Hao Tang, Norma P. Tavakoli, Sainan Wei, Rolf H. Zetterström, Robert J. Currier, Lars Mørkrid and Piero Rinaldo Show full author list Hide full author list

Int. J. Neonatal Screen. 2021, 7(2), 23; https://0-doi-org.brum.beds.ac.uk/10.3390/ijns7020023 - 23 Apr 2021

Cited by 17 | Viewed by 6108

Abstract

Newborn screening for congenital hypothyroidism remains challenging decades after broad implementation worldwide. Testing protocols are not uniform in terms of targets (TSH and/or T4) and protocols (parallel vs. sequential testing; one or two specimen collection times), and specificity (with or without collection of a second specimen) is overall poor. The purpose of this retrospective study is to investigate the potential impact of multivariate pattern recognition software (CLIR) to improve the post-analytical interpretation of screening results. Seven programs contributed reference data (N = 1,970,536) and two sets of true (TP, N = 1369 combined) and false (FP, N = 15,201) positive cases for validation and verification purposes, respectively. Data were adjusted for age at collection, birth weight, and location using polynomial regression models of the fifth degree to create three-dimensional regression surfaces. Customized Single Condition Tools and Dual Scatter Plots were created using CLIR to optimize the differential diagnosis between TP and FP cases in the validation set. Verification testing correctly identified 446/454 (98%) of the TP cases, and could have prevented 1931/5447 (35%) of the FP cases, with variable impact among locations (range 4% to 50%). CLIR tools either as made here or preferably standardized to the recommended uniform screening panel could improve performance of newborn screening for congenital hypothyroidism. Full article

(This article belongs to the Special Issue CLIR Applications for Newborn Screening)

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6 pages, 180 KiB

Open AccessArticle

The Impact of Post-Analytical Tools on New York Screening for Krabbe Disease and Pompe Disease

by Monica M. Martin, Ryan Wilson, Michele Caggana and Joseph J. Orsini

Int. J. Neonatal Screen. 2020, 6(3), 65; https://0-doi-org.brum.beds.ac.uk/10.3390/ijns6030065 - 14 Aug 2020

Cited by 9 | Viewed by 2426

Abstract

New York uses a two-tier assay to screen newborns for Krabbe disease and Pompe disease. Individual enzyme activities are measured in the first-tier, and specimens from newborns with low activity are reflexed to second tier Sanger sequencing of the associated gene. Using only this two-tiered approach, the screen positive and false positive rates were high. In this study, we added an additional step that examines the activity of four additional lysosomal enzymes. Results for all enzymes are integrated using the multivariate pattern recognition software called Collaborative Laboratory Integrated Reports (CLIR) to assess the risk for disease. Results after one year of screening using the new algorithm are compared to the prior year of screening without consideration of the additional enzymes and use of CLIR. With CLIR the number of babies referred for Krabbe disease was reduced by almost 80% (from 48 to 10) and the number of babies referred for Pompe disease was reduced by almost 32% (22 to 15). Full article

(This article belongs to the Special Issue CLIR Applications for Newborn Screening)

9 pages, 443 KiB

Open AccessArticle

The Clinical Impact of CLIR Tools toward Rapid Resolution of Post-Newborn Screening Confirmatory Testing for X-Linked Adrenoleukodystrophy in California

by Hao Tang, Jamie Matteson, Piero Rinaldo, Silvia Tortorelli, Robert Currier and Stanley Sciortino

Int. J. Neonatal Screen. 2020, 6(3), 62; https://0-doi-org.brum.beds.ac.uk/10.3390/ijns6030062 - 05 Aug 2020

Cited by 5 | Viewed by 2491

Abstract

Since the start of X-linked adrenoleukodystrophy (ALD) newborn screening in California, more than half of the diagnosed cases were found to have an ATP binding cassette subfamily D member 1 (ABCD1) gene variant of uncertain significance (VUS). To determine retrospectively the likelihood that these were true positive cases, we used a web-based post-analytical tool in Collaborative Laboratory Integrated Reports (CLIR). Confirmatory plasma very long-chain fatty-acids (VLCFA) profiles for ALD screen positive infant boys were run through the CLIR ALD tool. We compared the distribution by ABCD1 variant classification (pathogenic, likely pathogenic, VUS, and no variant) with the CLIR tool score interpretation (non-informative, possibly ALD, likely ALD, and very likely ALD) and the current case diagnosis. The study showed that CLIR tool positive interpretations were consistent with 100% of the pathogenic and likely pathogenic variants on the ABCD1 gene if a more conservative guideline was used. The tool interpretations were also consistent with screened cases that were determined to not have disease (our no-disorder group). The CLIR tool identified 19 diagnosed ALD cases with VUS to be potential false positives, representing a 40% reduction among all diagnosed ALD cases with VUS. The reduction could be extended to 65% if a more aggressive threshold was used. Identifying such preventable false positives could alleviate the follow-up burden for patients, their families, and California Special Care Centers. Full article

(This article belongs to the Special Issue CLIR Applications for Newborn Screening)

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25 pages, 1055 KiB

Open AccessArticle

Performance of Expanded Newborn Screening in Norway Supported by Post-Analytical Bioinformatics Tools and Rapid Second-Tier DNA Analyses

by Trine Tangeraas, Ingjerd Sæves, Claus Klingenberg, Jens Jørgensen, Erle Kristensen, Gunnþórunn Gunnarsdottir, Eirik Vangsøy Hansen, Janne Strand, Emma Lundman, Sacha Ferdinandusse, Cathrin Lytomt Salvador, Berit Woldseth, Yngve T. Bliksrud, Carlos Sagredo, Øyvind E. Olsen, Mona C. Berge, Anette Kjoshagen Trømborg, Anders Ziegler, Jin Hui Zhang, Linda Karlsen Sørgjerd, Mari Ytre-Arne, Silje Hogner, Siv M. Løvoll, Mette R. Kløvstad Olavsen, Dionne Navarrete, Hege J. Gaup, Rina Lilje, Rolf H. Zetterström, Asbjørg Stray-Pedersen, Terje Rootwelt, Piero Rinaldo, Alexander D. Rowe and Rolf D. Pettersen Show full author list Hide full author list

Int. J. Neonatal Screen. 2020, 6(3), 51; https://0-doi-org.brum.beds.ac.uk/10.3390/ijns6030051 - 27 Jun 2020

Cited by 31 | Viewed by 6117

Abstract

In 2012, the Norwegian newborn screening program (NBS) was expanded (eNBS) from screening for two diseases to that for 23 diseases (20 inborn errors of metabolism, IEMs) and again in 2018, to include a total of 25 conditions (21 IEMs). Between 1 March 2012 and 29 February 2020, 461,369 newborns were screened for 20 IEMs in addition to phenylketonuria (PKU). Excluding PKU, there were 75 true-positive (TP) (1:6151) and 107 (1:4311) false-positive IEM cases. Twenty-one percent of the TP cases were symptomatic at the time of the NBS results, but in two-thirds, the screening result directed the exact diagnosis. Eighty-two percent of the TP cases had good health outcomes, evaluated in 2020. The yearly positive predictive value was increased from 26% to 54% by the use of the Region 4 Stork post-analytical interpretive tool (R4S)/Collaborative Laboratory Integrated Reports 2.0 (CLIR), second-tier biochemical testing and genetic confirmation using DNA extracted from the original dried blood spots. The incidence of IEMs increased by 46% after eNBS was introduced, predominantly due to the finding of attenuated phenotypes. The next step is defining which newborns would truly benefit from screening at the milder end of the disease spectrum. This will require coordinated international collaboration, including proper case definitions and outcome studies. Full article

(This article belongs to the Special Issue CLIR Applications for Newborn Screening)

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19 pages, 880 KiB

Open AccessArticle

A Comparative Effectiveness Study of Newborn Screening Methods for Four Lysosomal Storage Disorders

by Karen A. Sanders, Dimitar K. Gavrilov, Devin Oglesbee, Kimiyo M. Raymond, Silvia Tortorelli, John J. Hopwood, Fred Lorey, Ramanath Majumdar, Charles A. Kroll, Amber M. McDonald, Jean M. Lacey, Coleman T. Turgeon, Justin N. Tucker, Hao Tang, Robert Currier, Grazia Isaya, Piero Rinaldo and Dietrich Matern

Int. J. Neonatal Screen. 2020, 6(2), 44; https://0-doi-org.brum.beds.ac.uk/10.3390/ijns6020044 - 30 May 2020

Cited by 23 | Viewed by 3904

Abstract

Newborn screening for one or more lysosomal disorders has been implemented in several US states, Japan and Taiwan by multiplexed enzyme assays using either tandem mass spectrometry or digital microfluidics. Another multiplex assay making use of immunocapture technology has also been proposed. To investigate the potential variability in performance of these analytical approaches, we implemented three high-throughput screening assays for the simultaneous screening for four lysosomal disorders: Fabry disease, Gaucher disease, mucopolysaccharidosis type I, and Pompe disease. These assays were tested in a prospective comparative effectiveness study using nearly 100,000 residual newborn dried blood spot specimens. In addition, 2nd tier enzyme assays and confirmatory molecular genetic testing were employed. Post-analytical interpretive tools were created using the software Collaborative Laboratory Integrated Reports (CLIR) to determine its ability to improve the performance of each assay vs. the traditional result interpretation based on analyte-specific reference ranges and cutoffs. This study showed that all three platforms have high sensitivity, and the application of CLIR tools markedly improves the performance of each platform while reducing the need for 2nd tier testing by 66% to 95%. Moreover, the addition of disease-specific biochemical 2nd tier tests ensures the lowest false positive rates and the highest positive predictive values for any platform. Full article

(This article belongs to the Special Issue CLIR Applications for Newborn Screening)

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12 pages, 1101 KiB

Open AccessArticle

Expanded Screening of One Million Swedish Babies with R4S and CLIR for Post-Analytical Evaluation of Data

by Lene Sörensen, Ulrika von Döbeln, Henrik Åhlman, Annika Ohlsson, Martin Engvall, Karin Naess, Carolina Backman-Johansson, Yvonne Nordqvist, Anna Wedell and Rolf H. Zetterström

Int. J. Neonatal Screen. 2020, 6(2), 42; https://0-doi-org.brum.beds.ac.uk/10.3390/ijns6020042 - 27 May 2020

Cited by 13 | Viewed by 4597

Abstract

Sweden has one neonatal screening laboratory, receiving 115 to 120 thousand samples per year. Among the one million babies screened by tandem mass spectrometry from November 2010 until July 2019, a total of 665 babies were recalled and 311 verified as having one of the diseases screened for with this methodology, giving a positive predictive value (PPV) of 47% and an incidence of 1:3200. The PPV was high (41%) already in the first year after start of screening, thanks to the availability of the collaborative project Region 4 Stork database. The PPV is presently 58%. This improvement was achieved by the implementation of second-tier analyses in the screening for methylmalonic aciduria, propionic aciduria, isovaleric aciduria, and homocystinuria, and the employment of various post analytical tools of the Region 4 Stork, and its successor the collaborative laboratory integrated reports. Full article

(This article belongs to the Special Issue CLIR Applications for Newborn Screening)

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9 pages, 220 KiB

Open AccessArticle

Genomic Analysis of Historical Cases with Positive Newborn Screens for Short-Chain Acyl-CoA Dehydrogenase Deficiency Shows That a Validated Second-Tier Biochemical Test Can Replace Future Sequencing

by Aashish N. Adhikari, Robert J. Currier, Hao Tang, Coleman T. Turgeon, Robert L. Nussbaum, Rajgopal Srinivasan, Uma Sunderam, Pui-Yan Kwok, Steven E. Brenner, Dimitar Gavrilov, Jennifer M. Puck and Renata Gallagher

Int. J. Neonatal Screen. 2020, 6(2), 41; https://0-doi-org.brum.beds.ac.uk/10.3390/ijns6020041 - 26 May 2020

Cited by 9 | Viewed by 3253

Abstract

Short-chain acyl-CoA dehydrogenase deficiency (SCADD) is a rare autosomal recessive disorder of β-oxidation caused by pathogenic variants in the ACADS gene. Analyte testing for SCADD in blood and urine, including newborn screening (NBS) using tandem mass spectrometry (MS/MS) on dried blood spots (DBSs), is complicated by the presence of two relatively common ACADS variants (c.625G>A and c.511C>T). Individuals homozygous for these variants or compound heterozygous do not have clinical disease but do have reduced short-chain acyl-CoA dehydrogenase (SCAD) activity, resulting in elevated blood and urine metabolites. As part of a larger study of the potential role of exome sequencing in NBS in California, we reviewed ACADS sequence and MS/MS data from DBSs from a cohort of 74 patients identified to have SCADD. Of this cohort, approximately 60% had one or more of the common variants and did not have the two rare variants, and thus would need no further testing. Retrospective analysis of ethylmalonic acid, glutaric acid, 2-hydroxyglutaric acid, 3-hydroxyglutaric acid, and methylsuccinic acid demonstrated that second-tier testing applied before the release of the newborn screening result could reduce referrals by over 50% and improve the positive predictive value for SCADD to above 75%. Full article

(This article belongs to the Special Issue CLIR Applications for Newborn Screening)

12 pages, 1155 KiB

Open AccessArticle

The Combined Impact of CLIR Post-Analytical Tools and Second Tier Testing on the Performance of Newborn Screening for Disorders of Propionate, Methionine, and Cobalamin Metabolism

by Dimitar K. Gavrilov, Amy L. Piazza, Gisele Pino, Coleman Turgeon, Dietrich Matern, Devin Oglesbee, Kimiyo Raymond, Silvia Tortorelli and Piero Rinaldo

Int. J. Neonatal Screen. 2020, 6(2), 33; https://0-doi-org.brum.beds.ac.uk/10.3390/ijns6020033 - 10 Apr 2020

Cited by 19 | Viewed by 3134

Abstract

The expansion of the recommend uniform screening panel to include more than 50 primary and secondary target conditions has resulted in a substantial increase of false positive results. As an alternative to subjective manipulation of cutoff values and overutilization of molecular testing, here we describe the performance outcome of an algorithm for disorders of methionine, cobalamin, and propionate metabolism that includes: (1) first tier screening inclusive of the broadest available spectrum of markers measured by tandem mass spectrometry; (2) integration of all results into a score of likelihood of disease for each target condition calculated by post-analytical interpretive tools created byCollaborative Laboratory Integrated Reports (CLIR), a multivariate pattern recognition software; and (3) further evaluation of abnormal scores by a second tier test measuring homocysteine, methylmalonic acid, and methylcitric acid. This approach can consistently reduce false positive rates to a <0.01% level, which is the threshold of precision newborn screening. We postulate that broader adoption of this algorithm could lead to substantial savings in health care expenditures. More importantly, it could prevent the stress and anxiety experienced by many families when faced with an abnormal newborn screening result that is later resolved as a false positive outcome. Full article

(This article belongs to the Special Issue CLIR Applications for Newborn Screening)

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8 pages, 1008 KiB

Open AccessArticle

Post-Analytical Tools for the Triage of Newborn Screening Results in Follow-up Can Reduce Confirmatory Testing and Guide Performance Improvement

by Patricia L. Hall, Angela Wittenauer and Arthur Hagar

Int. J. Neonatal Screen. 2020, 6(1), 20; https://0-doi-org.brum.beds.ac.uk/10.3390/ijns6010020 - 14 Mar 2020

Cited by 8 | Viewed by 2839

Abstract

Georgia uses post-analytical tools through Collaborative Laboratory Integrated Reports (CLIR) to triage abnormal newborn screening (NBS) results for follow-up. Condition specific tools are used to assign each case a risk level, which is used to guide follow-up recommendations. Follow-up recommendations include assessment by the child’s primary care provider as well as testing, either a repeat NBS or confirmatory testing. Triaging abnormal cases using these tools has been advantageous in managing the workflow for the follow-up team, as well as prioritizing cases that appropriately require more attention and resources. The initial goal in utilizing these tools was to reduce the amount of confirmatory testing, particularly for disorders where there are many false positives. We assessed the performance of these tools retrospectively for three of the most commonly detected conditions by tandem mass spectrometry in Georgia: phenylketonuria, medium chain acyl-CoA dehydrogenase deficiency and very long chain dehydrogenase deficiency. The post-analytical tools appropriately assigned all true positive cases to the higher levels of follow-up testing and reduced the level of intervention for a significant number of cases as well. Based on the experience gained from our utilization of the tools in the follow-up program, we are well situated to move forward with using the tools in a more prospective manner, and reduce the number of cases that will be reported, rather than just assigning resources appropriately at follow-up. Post-analytical tools are an improvement over trying to capture the variation in the newborn population using multiple cutoffs. It also easily identifies significant abnormalities that are unrelated to inherited disease, such as large amino acid elevations due to total parenteral nutrition. Full article

(This article belongs to the Special Issue CLIR Applications for Newborn Screening)

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12 pages, 1534 KiB

Open AccessArticle

Reducing False-Positive Results in Newborn Screening Using Machine Learning

by Gang Peng, Yishuo Tang, Tina M. Cowan, Gregory M. Enns, Hongyu Zhao and Curt Scharfe

Int. J. Neonatal Screen. 2020, 6(1), 16; https://0-doi-org.brum.beds.ac.uk/10.3390/ijns6010016 - 03 Mar 2020

Cited by 41 | Viewed by 5220

Abstract

Newborn screening (NBS) for inborn metabolic disorders is a highly successful public health program that by design is accompanied by false-positive results. Here we trained a Random Forest machine learning classifier on screening data to improve prediction of true and false positives. Data included 39 metabolic analytes detected by tandem mass spectrometry and clinical variables such as gestational age and birth weight. Analytical performance was evaluated for a cohort of 2777 screen positives reported by the California NBS program, which consisted of 235 confirmed cases and 2542 false positives for one of four disorders: glutaric acidemia type 1 (GA-1), methylmalonic acidemia (MMA), ornithine transcarbamylase deficiency (OTCD), and very long-chain acyl-CoA dehydrogenase deficiency (VLCADD). Without changing the sensitivity to detect these disorders in screening, Random Forest-based analysis of all metabolites reduced the number of false positives for GA-1 by 89%, for MMA by 45%, for OTCD by 98%, and for VLCADD by 2%. All primary disease markers and previously reported analytes such as methionine for MMA and OTCD were among the top-ranked analytes. Random Forest’s ability to classify GA-1 false positives was found similar to results obtained using Clinical Laboratory Integrated Reports (CLIR). We developed an online Random Forest tool for interpretive analysis of increasingly complex data from newborn screening. Full article

(This article belongs to the Special Issue CLIR Applications for Newborn Screening)

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10 pages, 1964 KiB

Open AccessArticle

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

by Dawn S. Peck, Jean M. Lacey, Amy L. White, Gisele Pino, April L. Studinski, Rachel Fisher, Ayesha Ahmad, Linda Spencer, Sarah Viall, Natalie Shallow, Amy Siemon, J. Austin Hamm, Brianna K. Murray, Kelly L. Jones, Dimitar Gavrilov, Devin Oglesbee, Kimiyo Raymond, Dietrich Matern, Piero Rinaldo and Silvia Tortorelli

Int. J. Neonatal Screen. 2020, 6(1), 10; https://0-doi-org.brum.beds.ac.uk/10.3390/ijns6010010 - 07 Feb 2020

Cited by 27 | Viewed by 5632

Abstract

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. Full article

(This article belongs to the Special Issue CLIR Applications for Newborn Screening)

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11 pages, 737 KiB

Open AccessArticle

Two-Tiered Newborn Screening with Post-Analytical Tools for Pompe Disease and Mucopolysaccharidosis Type I Results in Performance Improvement and Future Direction

by Patricia L. Hall, Rossana Sanchez, Arthur F. Hagar, S. Caleb Jerris, Angela Wittenauer and William R. Wilcox

Int. J. Neonatal Screen. 2020, 6(1), 2; https://0-doi-org.brum.beds.ac.uk/10.3390/ijns6010002 - 14 Jan 2020

Cited by 23 | Viewed by 3133

Abstract

We conducted a pilot newborn screening (NBS) study for Pompe disease (PD) and mucopolysaccharidosis type I (MPS I) in the multiethnic population of Georgia. We screened 59,332 infants using a two-tier strategy of flow injection tandem mass spectrometry (FIA-MSMS) enzyme assays. The first tier of testing was a 2-plex assay measuring PD and MPS I enzyme activity, followed by a second-tier test with additional enzymes to improve specificity. Interpretation of results was performed using post-analytical tools created using Collaborative Laboratory Integrated Reports (CLIR). We identified a single case of infantile onset PD, two cases of late onset PD, and one pseudodeficiency. The positive predictive value (PPV) for PD screening during the study was 66.7%. No cases of MPS I were identified during the study period, but there were 2 confirmed cases of pseudodeficiency and 6 cases lost to follow up. The two-tier screening strategy was successful in reducing false positive results and allowed for the identification and early treatment of a case of infantile PD but the frequency of pseudodeficiency in MPS I is problematic. Molecular testing is required and should be covered by the screening program to avoid delays in case resolution. Full article

(This article belongs to the Special Issue CLIR Applications for Newborn Screening)

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