A systematic framework for selecting gene-condition pairs for inclusion in newborn sequencing panels: Early Check implementation

Purpose: Research is underway worldwide to investigate the feasibility, acceptability, and utility of sequencing-based newborn screening. Different methods have been used to select gene-condition pairs for screening, leading to highly inconsistent gene lists across studies.

Methods: Early Check developed and utilized actionability-based frameworks for evaluating gene-condition pairs for inclusion in newborn panels (panel 1-high actionability, panel 2-possible actionability). A previously developed framework, the Age-based Semi Quantitative Metric (ASQM), was adapted. Increasing ASQM scores, with a maximum of 15, suggest greater actionability. Wilcoxon tests were performed to compare panel 1 gene-condition pairs on the Recommended Uniform Screening Panel (RUSP) with non-RUSP pairs.

Results: In our first round of assessment, Early Check identified 178 gene-condition pairs for inclusion in panel 1 and 29 for panel 2. Median ASQM scores of RUSP conditions on panel 1 was 12 (range 4 to 15) and non-RUSP was 13 (range 9 to 15). Median scores for panel 2 was 10 (range 6 to 14).

Conclusion: The Early Check frameworks provide a transparent, semiquantitative, and reproducible methodology for selecting gene-condition pairs for newborn screening sequencing pilot studies that may inform future integration of genomic sequencing into population-level newborn screening. Collaborative efforts among newborn sequencing studies to establish shared criteria is needed to enhance cross-study comparisons.