Cystic fibrosis newborn screening in Switzerland - evaluation and scenarios for improvement after 11 years of follow-up

Esl Pedersen; C M de Jong Carmen; M Jurca; D O Berger; J Sanz; Shm Sluka; M Poms; M R Baumgartner; N Regamey; C E Kuehni; J Barben; C S Rueegg; Swiss Cystic Fibrosis Newborn Screening Group

doi:10.1016/j.jcf.2024.04.008

Cystic fibrosis newborn screening in Switzerland - evaluation and scenarios for improvement after 11 years of follow-up

J Cyst Fibros. 2024 Apr 23:S1569-1993(24)00053-5. doi: 10.1016/j.jcf.2024.04.008. Online ahead of print.

Authors

Esl Pedersen¹, C M de Jong Carmen², M Jurca³, D O Berger¹, J Sanz⁴, Shm Sluka⁵, M Poms⁶, M R Baumgartner⁶, N Regamey⁷, C E Kuehni⁸, J Barben⁹, C S Rueegg¹⁰; Swiss Cystic Fibrosis Newborn Screening Group

Affiliations

¹ Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland.
² Division of Paediatric Respiratory Medicine and Allergy, Department of Paediatrics, University Children's Hospital Bern, Bern, Switzerland.
³ Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland; The University Children's Hospital Basel, Basel, Switzerland.
⁴ Department of Human Genetics, Inselspital, University Hospital Bern, Bern, Switzerland.
⁵ Newborn Screening Switzerland, University Children's Hospital Zurich, University of Zurich, Zurich, Switzerland.
⁶ Division of Metabolism and Swiss Newborn Screening, University Children's Hospital Zurich, University of Zurich, Zurich, Switzerland.
⁷ Division of Paediatric Pulmonology, Children's Hospital Lucerne, Lucerne, Switzerland.
⁸ Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland; Division of Paediatric Respiratory Medicine and Allergy, Department of Paediatrics, University Children's Hospital Bern, Bern, Switzerland.
⁹ Paediatric Pulmonology & CF Centre, Children's Hospital of Eastern Switzerland, St. Gallen, Switzerland. Electronic address: juerg.barben@kispisg.ch.
¹⁰ Oslo Centre for Biostatistics and Epidemiology, Oslo University Hospital, Oslo, Norway.

PMID: 38658252
DOI: 10.1016/j.jcf.2024.04.008

Abstract

Background: Newborn bloodspot screening (NBS) for cystic fibrosis (CF) is important for early diagnosis and treatment. However, screening can lead to false-positive results leading to unnecessary follow-up tests and distress. This study evaluated the 11-year performance of the Swiss CF-NBS programme, estimated optimal cut-offs for immunoreactive trypsinogen (IRT), and examined how simulated algorithms would change performance.

Methods: The Swiss CF-NBS is based on an IRT-DNA algorithm with a second IRT (IRT-2) as safety net. We analysed data from 2011 to 2021, covering 959,006 IRT-1 analyses and 282 children with CF. We studied performance based on European Cystic Fibrosis Society (ECFS) standards including sensitivity, specificity, positive predictive value (PPV), false negative rate, and second heel-prick tests; identified optimal IRT cut-offs using receiver operating characteristics (ROC) curves; and calculated performance for simulated algorithms with different cut-offs for IRT-1, IRT-2, and safety net.

Results: The Swiss CF-NBS showed excellent sensitivity (96 %, 10 false negative cases) but moderate PPV (25 %). Optimal IRT-1 and IRT-2 cut-offs were identified at 2.7 (>99th percentile) and 5.9 (>99.8th percentile) z-scores, respectively. Analysis of simulated algorithms showed that removing the safety net from the current algorithm could increase PPV to 30 % and eliminate >200 second heel-prick tests per year, while keeping sensitivity at 95 %.

Conclusion: The Swiss CF-NBS program performed well over 11 years but did not achieve the ECFS standards for PPV (≥30 %). Modifying or removing the safety net could improve PPV and reduce unnecessary follow-up tests while maintaining the ECFS standards for sensitivity.

Keywords: Cystic fibrosis; Evaluation; Newborn screening; Performance; Positive predictive value; Safety net; Screening algorithm; Sensitivity; Simulation; Specificity.