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

•The Swiss CF-newborn screening programme showed sensitivity of 96 % and PPV of 25 %.•Modifying the safety net alone could increase PPV to 30 % and keeps sensitivity at 95 %.•Removing the safety net could eliminate more than 200 unnecessary second heel-prick tests per year.•Continued data collection and evaluation of screening programmes is essential. 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. 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. 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 %. 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.