, 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.

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A in-line desorption device was developed, which allows for direct analysis of dried blood spots eliminating the need for punching disks from the filter paper cards. Using this device, we have validated a method to quantify biomarkers related to maple syrup urine disease (MSUD), a metabolism disorder that often requires a second-tier test for confirmation. Direct analysis of newborn screening cards is conducted in-line with a high-resolution chromatographic separation with mass spectrometry using electrospray ionization and multiple-reaction monitoring. Quantification of leucine and isoleucine using an isotopically labeled internal standard encompasses a range suitable for MSUD assessment. Precision and accuracy of the technique was acceptable with relative standard deviations within 10% at three fortified concentrations and an unfortified level. A post-column infusion test shows minimum matrix suppression was observed using this direct sampling technique.