According to a recent study published in the International Journal of Neonatal Screening, harmonization can effectively minimize false-negative and false-positive results in newborn screening for Pompe disease and mucopolysaccharidosis type 1 (MPS 1).
The study observed a reasonable agreement in the enzyme activities and cutoffs with harmonization; however, it could not identify how a value (positive or negative) would be reported since it depended on the cutoff placement, the researchers noted.
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“We wanted to determine whether the same outcomes would be achieved: the correct identification of specimens exhibiting low or deficient activities (positive cases) and specimens exhibiting normal activities (negative cases),” the authors wrote.
The research team harmonized enzyme activities for the Pompe disease and MPS 1 across multiple laboratories and testing methods Tandem Mass Spectrometry (MS/MS) or Digital Microfluidics (DMF).
Study results revealed various cutoffs among the laboratories. Six of the 7 MS/MS labs reported enzyme activities for 1 specimen for MPS 1 marginally above their respective cutoffs, with results classified as negative. On the other hand, all DMF labs reported this specimen’s enzyme activity below their respective cutoffs, with results classified as positive. A reasonable agreement in the enzyme activities and cutoffs was achieved with harmonization.
The above findings suggest that harmonization has the potential for interpreting enzyme activities to increase the comparability in reported results across various labs. Moreover, data generated during the study might assist the newborn screening (NBS) laboratories refine their enzyme activity cutoffs to achieve greater uniformity by decreasing the testing variabilities, reducing false-positive rates, and improving the positive predictive values.
The study also found that both DMF and MS/MS platforms have the potential to be used for NBS of PD and MPS 1; however, these 2 methods give different enzyme values and even different values by the same method performed by other laboratories, which can be challenging in deciding the cutoff placement.
“Even if all labs were harmonized in data they produce, the difficulty still remains in deciding cutoff placement, as this may be greatly affected by case definitions and the overall goals of the screening program,” the authors highlighted.
Recently, there has been an increased focus on quality improvement processes for newborn screening labs to improve the reporting time for screening results and reduce false-negative results that can lead to disabilities and even death. However, challenges arise in detecting late-onset variants of certain diseases, which causes stress and anxiety for families. While the recommended uniform screening panel serves as a guide for establishing state NBS panels, NBS programs ultimately decide which diseases to screen for and place their screening cutoffs conservatively to avoid missed cases. As a result, some programs report more false-positive results than others.
Data harmonization is also suggested to achieve greater uniformity of results and clinical conclusions. While some NBS labs have successfully used multiples of the median and other methods to harmonize results for MPS 1, differences in instrumentation, methods, and populations screened can make result comparisons problematic.
Dorley MC, Dizikes GJ, Pickens, CA, et al. Harmonization of newborn screening results for Pompe Disease and Mucopolysaccharidosis type 1. Int. J. Neonatal Screen. Published online February 27, 2023. doi:10.3390/ijns9010011