Clinical validation of cutoff target ranges in newborn screening of metabolic disorders by tandem mass spectrometry: A worldwide collaborative project

Abstract

, Melissa Yssel, MB ChB, FC Path(SA) Chem 139, and Wendy M. Zakowicz, BS 79 Purpose: To achieve clinical validation of cutoff values for newborn screening by tandem mass spectrometry through a worldwide collaborative effort. Methods: Cumulative percentiles of amino acids and acylcarnitines in dried blood spots of approximately 25-30 million normal newborns and 10,742 deidentified true positive cases are compared to assign clinical significance, which is achieved when the median of a disorder range is, and usually markedly outside, either the 99th or the 1st percentile of the normal population. The cutoff target ranges of analytes and ratios are then defined as the interval between selected percentiles of the two populations. When overlaps occur, adjustments are made to maximize sensitivity and specificity taking all available factors into consideration.

Phenylalanine hydroxylase deficiency: diagnosis and management guideline

“…An international database of 133 contributing laboratories reports a mean cutoff for PHE of 130 µmol/l (with a range of 65-234 µmol/l) and a PHE:TYR ratio >3 as abnormal. 13 Elevated levels should trigger further evaluation, and assessment should include tests to identify defects in BH 4 synthesis or regeneration. Further guidance on follow-up of an abnormal NBS test for PHE can be found in the ACMG ACT sheets for newborns along with confirmatory testing algorithms (www.…”

Performance of succinylacetone assays and their associated proficiency testing outcomes

“…These results suggest that patient sample reference ranges may be test-method-specific because of analytic bias similar to that reported for PT specimens; however, the number of patient sample results shown here is small and not comprehensive. An ongoing compilation of MS/MS NBS results from laboratories worldwide has been undertaken by the MS/MS Collaborative Project in Region 4 of the US Regional Genetics and Newborn Screening Collaboration [12].…”

Cobalamin C Disease Missed by Newborn Screening in a Patient with Low Carnitine Level

“…However, this would greatly increase the rate of false-positive tests. The C3/C2 ratio can also be used as a marker for CblC (McHugh et al 2011). In retrospective analysis, this ratio was actually elevated in our patient (Table 1).…”