Development of Strategies to Decrease False Positive Results in Newborn Screening

Abstract

The expansion of national newborn screening (NBS) programmes has provided significant benefits in the diagnosis and early treatment of several rare, heritable conditions, preventing adverse health outcomes for most affected infants. New technological developments have enabled the implementation of testing panel covering over 50 disorders. Consequently, the increment of false positive rate has led to a high number of healthy infants recalled for expensive and often invasive additional testing, opening a debate about the harm-benefit ratio of the expanded newborn screening. The false-positive rate represents a challenge for healthcare providers working in NBS systems. Here, we give an overview on the most commonly used strategies for decreasing the adverse effects due to inconclusive screening results. The focus is on NBS performance improvement through the implementation of analytical methods, the application of new and more informative biomarkers, and by using post-analytical interpretive tools. These strategies, used as part of the NBS process, can to enhance the positive predictive value of the test and reduce the parental anxiety and healthcare costs related to the unnecessary tests and procedures.

Keywords: false positives; inborn error of metabolism; newborn screening; second-tier test; tandem mass spectrometry.

Figure 1

Flow-chart for newborn screening analytical process. When a 2-TT is available, the specificity of newborn screening is significantly improved. It may also be possible to reduce primary test cut-off to improve sensitivity.

Figure 2

Chromatographic separation of branched-chain amino acids on DBS from a healthy control (A) and from a MSUD patient (B). The application of LC-MS/MS based testing allows several isobaric compounds, including Alloisoleucine (Allo-Iso), the pathognomic biomarker of MSUD to be identified.

Figure 3

The 2-TT to reduce the false positive rate in expanded newborn screening for isovaleric acidemia (IVA). The contributions from different isobaric molecules can be separated by chromatography coupled with MS-MS as described in Poggiali et al. [26]. Interference causing false abnormal C5-acylcarnitine levels can be observed for pivalic acid supplementation or for 2-methylbutyrylglycinuria, a benign metabolic condition.