Abstract
Newborn screening for one or more lysosomal disorders has been implemented in several US states, Japan and Taiwan by multiplexed enzyme assays using either tandem mass spectrometry or digital microfluidics. Another multiplex assay making use of immunocapture technology has also been proposed. To investigate the potential variability in performance of these analytical approaches, we implemented three high-throughput screening assays for the simultaneous screening for four lysosomal disorders: Fabry disease, Gaucher disease, mucopolysaccharidosis type I, and Pompe disease. These assays were tested in a prospective comparative effectiveness study using nearly 100,000 residual newborn dried blood spot specimens. In addition, 2nd tier enzyme assays and confirmatory molecular genetic testing were employed. Post-analytical interpretive tools were created using the software Collaborative Laboratory Integrated Reports (CLIR) to determine its ability to improve the performance of each assay vs. the traditional result interpretation based on analyte-specific reference ranges and cutoffs. This study showed that all three platforms have high sensitivity, and the application of CLIR tools markedly improves the performance of each platform while reducing the need for 2nd tier testing by 66% to 95%. Moreover, the addition of disease-specific biochemical 2nd tier tests ensures the lowest false positive rates and the highest positive predictive values for any platform.
Highlights
With the availability of more treatment options and population screening assays for an increasing number of lysosomal storage disorders (LSDs), the inclusion of these conditions into newborn screening programs seems reasonable because existing evidence suggests that early treatment initiation has the greatest benefit
100,000 newborn dried blood spots (DBS) were screened for Fabry disease, Gaucher disease, MPS I, and Pompe disease by the immunocapture (n = 99,798), the MS/MS (n = 99,627), and the digital microfluidics (DMF) assay (n = 90,498)
Another major setback for the study occurred when the planned three-year study period came to an end because the NICHD had to apply a new rule that precluded no-cost extensions. This meant that a third of the original funding became suddenly unavailable, and to complete the study, additional time needed to be invested to obtain new grant support. This unique comparative effectiveness study of three primary screening platforms showed that each platform by itself is incapable of ensuring a cost-effective screening program for the four LSDs
Summary
With the availability of more treatment options and population screening assays for an increasing number of lysosomal storage disorders (LSDs), the inclusion of these conditions into newborn screening programs seems reasonable because existing evidence suggests that early treatment initiation has the greatest benefit. A similar multiplex approach does not measure enzyme activities, but enzyme concentration, as an indicator for disease, because in most LSDs the pathogenic mutations lead to a decreased amount of protein with subsequent abnormally low enzyme activity [9,10]. This assay applies microbead array technology for the immune quantification of lysosomal proteins in DBS and requires protein-specific antibodies that—in contrast to the reagents needed for the MS/MS and DMF assays—are currently not commercially available. To screen for a subgroup of LSDs, the mucopolysaccharidoses (including MPS I), the measurement of glycosaminoglycans in DBS has been suggested, but this approach cannot be limited to a single condition, such as MPS I, and it has not yet been applied in a prospective screening study [11]
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