Digital-Tier Strategy Improves Newborn Screening for Glutaric Aciduria Type 1

Glutaric aciduria type 1 (GA1) is a rare inherited metabolic disease increasingly included in newborn screening (NBS) programs worldwide. Because of the broad biochemical spectrum of individuals with GA1 and the lack of reliable second-tier strategies, NBS for GA1 is still confronted with a high rate of false positives. In this study, we aim to increase the specificity of NBS for GA1 and, hence, to reduce the rate of false positives through machine learning methods. Therefore, we studied NBS profiles from 1,025,953 newborns screened between 2014 and 2023 at the Heidelberg NBS Laboratory, Germany. We identified a significant sex difference, resulting in twice as many false-positives male than female newborns. Moreover, the proposed digital-tier strategy based on logistic regression analysis, ridge regression, and support vector machine reduced the false-positive rate by over 90% compared to regular NBS while identifying all confirmed individuals with GA1 correctly. An in-depth analysis of the profiles revealed that in particular false-positive results with high associated follow-up costs could be reduced significantly. In conclusion, understanding the origin of false-positive NBS and implementing a digital-tier strategy to enhance the specificity of GA1 testing may significantly reduce the burden on newborns and their families from false-positive NBS results.