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

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; Rolf D Pettersen

doi:10.3390/ijns6030051

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

Int J Neonatal Screen. 2020 Jun 27;6(3):51. doi: 10.3390/ijns6030051. eCollection 2020 Sep.

Authors

Trine Tangeraas¹, Ingjerd Sæves¹, Claus Klingenberg^{2

3}, Jens Jørgensen¹, Erle Kristensen^{1

3}, Gunnþórunn Gunnarsdottir⁴, Eirik Vangsøy Hansen⁵, Janne Strand¹, Emma Lundman¹, Sacha Ferdinandusse⁶, Cathrin Lytomt Salvador⁷, Berit Woldseth⁷, Yngve T Bliksrud⁷, Carlos Sagredo¹, Øyvind E Olsen¹, Mona C Berge¹, Anette Kjoshagen Trømborg¹, Anders Ziegler¹, Jin Hui Zhang¹, Linda Karlsen Sørgjerd¹, Mari Ytre-Arne¹, Silje Hogner¹, Siv M Løvoll¹, Mette R Kløvstad Olavsen¹, Dionne Navarrete¹, Hege J Gaup¹, Rina Lilje⁴, Rolf H Zetterström⁸, Asbjørg Stray-Pedersen¹, Terje Rootwelt^{4

9}, Piero Rinaldo¹⁰, Alexander D Rowe¹, Rolf D Pettersen¹

Affiliations

¹ Norwegian National Unit for Newborn Screening, Division of Paediatric and Adolescent Medicine, Oslo University Hospital, 0424 Oslo, Norway; insaev@ous-hf.no (I.S.); jejorgen@ous-hf.no (J.J.); erkris@ous-hf.no (E.K.); jstran@ous-hf.no (J.S.); emlund@ous-hf.no (E.L.); carsag@ous-hf.no (C.S.); oeols@ous-hf.no (Ø.E.O.); mocber@ous-hf.no (M.C.B.); ankjaa@ous-hf.no (A.K.T.); andzie@ous-hf.no (A.Z.); jinzha@ous-hf.no (J.H.Z.); likaso@ous-hf.no (L.K.S.); maytre@ous-hf.no (M.Y.-A.); silhog@ous-hf.no (S.H.); sivloe@ous-hf.no (S.M.L.); molafsen@ous-hf.no (M.R.K.O.); dionav@online.no (D.N.); junitagaup@hotmail.com (H.J.G.); astraype@ous-hf.no (A.S.-P.); alerow@ous-hf.no (A.D.R.); rdpetter@ous-hf.no (R.D.P.).
² Department of Paediatrics, University Hospital of North Norway, 9019 Tromsø, Norway; Claus.Klingenberg@unn.no.
³ Paediatric Research Group, Department of Clinical Medicine, UiT The Artic University of Norway, 9019 Tromsø, Norway.
⁴ Department of Paediatrics, Division of Paediatric and Adolescent Medicine, Oslo University Hospital, 0424 Oslo, Norway; gunngu@ous-hf.no (G.G.); rlilje@ous-hf.no (R.L.); trootwel@ous-hf.no (T.R.).
⁵ Department of Paediatrics, Haukeland University Hospital, 5021 Bergen, Norway; eirik.vangsoey.hansen@helse-bergen.no.
⁶ Laboratory Genetic Metabolic Diseases, Department of Clinical Chemistry, Amsterdam University Medical Centers, University of Amsterdam, AZ 1105 Amsterdam, The Netherlands; s.ferdinandusse@amsterdamumc.nl.
⁷ Norwegian National Unit for Diagnostics of Congenital Metabolic Disorders, Department of Medical Biochemistry, Oslo University Hospital, 0424 Oslo, Norway; catsal@ous-hf.no (C.L.S.); bwoldset@ous-hf.no (B.W.); ybliksru@ous-hf.no (Y.T.B.).
⁸ Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Solna, Sweden, Department of Molecular Medicine and Surgery, Karolinska Institutet, SE-171 76 Stockholm, Sweden; rolf.zetterstrom@sll.se.
⁹ Institute of Clinical Medicine, University of Oslo, 0318 Oslo, Norway.
¹⁰ Biochemical Genetics Laboratory, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, NY 55902, USA; Rinaldo@mayo.edu.

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.

Keywords: CLIR; cut-off values; dried blood spots; newborn screening; outcome; second-tier DNA testing.