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

Abstract

<jats:p>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.</jats:p>

Neonatal Screening in Europe Revisited: An ISNS Perspective on the Current State and Developments Since 2010

“…Tandem mass spectrometry (MS/MS) technology also has become a routine method in many countries. Croatia plans to introduce next-generation sequencing (NGS) technology as a second-tier for some conditions, which is already done in Norway to detect CF mutations and to detect mutations underlying many disorders in the programme [ 26 ].…”

“…We considered the use of next-generation sequencing technology, reduced costs and greater access to MS/MS and the use of big data technology (e.g., the application of R4S/CLIR to evaluate screening results) as important changes [ 34 , 35 , 36 , 37 ]. Finland, Iceland, Norway and Sweden use CLIR for evaluation of individual screening results [ 26 , 38 ]. The Czech Republic uses the CLIR website to evaluate cut-off levels.…”

“…Norway is an early adaptor to this methodology and already published an analysis of NGS for CF screening in 2016 [ 39 ]. Norway has also started to use this technology as second-tier tests for IEMs and SCID [ 26 ]. The UK has conducted a limited trial of the use of NGS as part of the screening algorithm for CF and the results are being evaluated.…”

Development of Strategies to Decrease False Positive Results in Newborn Screening

“…Most laboratories use commercial kits that screen for a predefined mutation panel covering the more prevalent pathogenic variants. In recent years, many pilot projects have introduced DNA analysis into NBS before the family is alerted [ 85 , 86 , 87 , 88 ]. A retrospective study conducted in Pennsylvania evaluated the feasibility of a DNA-based 2-TT, covering the most common GALT mutations (seven mutations and two variants), to improve the specificity of NBS for Galactosemia.…”

Expanded Newborn Screening and Genomic Sequencing in Latin America and the Resulting Social Justice and Ethical Considerations

“…It was found that sensitivity and specificity of WES was in fact lower than the MS/MS method but there was possible utility of WES as a second tier [ 10 ]. In Norway, a study looked at the utility of Next Generation Sequencing (NGS) as a second tier to supplement NBS and showed benefit [ 11 ]. Pilot programs in the United States at several different sites used various genomic sequencing technologies to screen for conditions beyond the traditional NBS and looked at the utility both in populations of sick newborns and in those that are healthy [ 12 ].…”