A Comparative Effectiveness Study of Newborn Screening Methods for Four Lysosomal Storage Disorders

Area of Science:

• Biochemistry
• Genetics
• Public Health

Background:

• Newborn screening for lysosomal disorders is expanding globally using multiplexed enzyme assays.
• Various analytical approaches, including tandem mass spectrometry, digital microfluidics, and immunocapture, are employed.
• Investigating performance variability across these high-throughput screening assays is crucial.

Purpose of the Study:

• To compare the performance of three high-throughput screening assays for four lysosomal disorders.
• To evaluate the impact of post-analytical interpretive tools (CLIR) on assay performance.
• To assess the effectiveness of confirmatory testing in improving screening accuracy.

Main Methods:

• Prospective comparative effectiveness study of three multiplexed assays using nearly 100,000 newborn dried blood spot specimens.
• Simultaneous screening for Fabry disease, Gaucher disease, mucopolysaccharidosis type I, and Pompe disease.
• Utilized 2nd tier enzyme assays, molecular genetic testing, and the CLIR software for interpretation.

Main Results:

• All three analytical platforms demonstrated high sensitivity for lysosomal disorder screening.
• The CLIR software significantly improved assay performance, reducing 2nd tier testing by 66%–95%.
• Disease-specific biochemical 2nd tier tests maximized positive predictive values and minimized false positives.

Conclusions:

• High-throughput screening assays for lysosomal disorders are effective.
• Post-analytical interpretive tools like CLIR substantially enhance screening efficiency and accuracy.
• Integrated testing strategies, including confirmatory assays, are essential for reliable newborn screening.