Abstract
The expansion of the recommend uniform screening panel to include more than 50 primary and secondary target conditions has resulted in a substantial increase of false positive results. As an alternative to subjective manipulation of cutoff values and overutilization of molecular testing, here we describe the performance outcome of an algorithm for disorders of methionine, cobalamin, and propionate metabolism that includes: (1) first tier screening inclusive of the broadest available spectrum of markers measured by tandem mass spectrometry; (2) integration of all results into a score of likelihood of disease for each target condition calculated by post-analytical interpretive tools created byCollaborative Laboratory Integrated Reports (CLIR), a multivariate pattern recognition software; and (3) further evaluation of abnormal scores by a second tier test measuring homocysteine, methylmalonic acid, and methylcitric acid. This approach can consistently reduce false positive rates to a <0.01% level, which is the threshold of precision newborn screening. We postulate that broader adoption of this algorithm could lead to substantial savings in health care expenditures. More importantly, it could prevent the stress and anxiety experienced by many families when faced with an abnormal newborn screening result that is later resolved as a false positive outcome.
Highlights
Over the last two decades, the introduction of tandem mass spectrometry (MS/MS) for the simultaneous analysis of acylcarnitine and amino acid species in dried blood spots (DBS) [1] has greatly expanded the number of target conditions [2]
Our experience suggests that the 2TT is indicated in approximately 1% of births as follow up for abnormal C3 and/or Met results by first tier testing
Even in the rather unlikely event that all of them are later resolved as false positive cases, there is still a strongly beneficial outcome by preventing ~95% of potential false positive outcomes
Summary
Over the last two decades, the introduction of tandem mass spectrometry (MS/MS) for the simultaneous analysis of acylcarnitine and amino acid species in dried blood spots (DBS) [1] has greatly expanded the number of target conditions [2]. Once a result has been flagged as potentially abnormal, a more in depth evaluation is usually performed through the calculation of ratios to determine its significance according to established protocols, and eventually it triggers referral to follow up. This approach has been and continues to be used extensively, it soon became obvious that false positive test results [5] and the risk of false negative events [6,7] were too common to be resolved without improved strategies. Further method development led to the incorporation of succinylacetone into the first tier analysis [10]
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