PROJECT SUMMARY Newborn screening (NBS) has been of incalculable benefit to infants since its inception in the 1960s. The laudable goal of NBS programs has been to identify infants who will develop lethal or debilitating childhood disorders at a time when they are pre-symptomatic and when treatment is maximally effective. However, problems with the accuracy of the diagnostic paradigms for screened disorders represent a potential source of harm to infants and parents alike. Excessive false positive rates of some newborn screens, which cause insufficiently high positive predictive values (PPVs), contribute to diagnostic uncertainty. This uncertainty can lead to 1) a delay in diagnosis and worsening of treatment outcomes, and 2) morbidity and mortality resulting from unnecessary treatment. Furthermore, significant parental anxiety needlessly accompanies false positive NBS results. The broad goal of the current application is to improve the accuracy of NBS for Krabbe disease (KD), Pompe disease (PD), and Mucopolysaccharidosis type I (MPSI). During our recently completed R21 grant, it was established that for KD, an approach to NBS consisting of the development of bivariate normal limits (BVNL) for the amounts of two biomarkers, psychosine (PSY) and the enzyme galactocerebrosidase (GalC), in newborn dried blood spots (DBS) can predict symptoms before they occur. Retrospective testing of this tool resulted in a very high PPV of 98.5%, essentially eliminating the existing false positive problem for KD. (KD screening in New York State resulted in 1.4 % PPV.) Preliminary studies indicate that BVNL tools, with PPVs approaching 100%, can also be developed for MPSI and PD. This proposal will test novel BVNL tools for KD, MPSI, and PD using specific NBS biomarkers, and will assess these tools for effective pre-symptomatic identification of these disorders. Aim 1a will prospectively collect results of PSY and GalC from DBS of infants who screen positively for KD in New York, Ohio, Missouri, and metropolitan Chicago, Illinois. These areas, as well as Gifu, Osaka, and Shimane, Japan (where only data for MPSI will be collected), comprise the proposed Bivariate Analysis for Newborn Screening (BANS) Network of collaborating genetics referral sites. This acronym reflects the anticipated use of BVNL tools in an approach that eliminates the potential harm of excessive false positives after NBS of KD, PD and MPSI. Aim 1b will utilize the BANS Network for prospective monitoring of infants who have screened positive for KD to determine whether application of the BVNL tool to their pre-symptomatically collected blood spots predicts subsequent symptom emergence. Aim 2 will utilize the BANS network and newborn blood spots obtained from the Virtual Repository of Dried Blood Spots to further develop BVNL tools for MPSI and PD. Aim 3 will again employ the BANS Network to prospectively determine the predictive capacity of the BVNL tools for MPSI and PD. If the improved prediction of KD, MPSI, and PD after NBS is achieved, treatment will be enhanced for these devastating illnesses, and life-threatening treatments for infants will be prevented.

PROJECT NARRATIVE Newborn screening has immense benefits for babies with genetic diseases; however, some newborn screening tests have inherent inaccuracies that can cause delays in treatment or can subject some babies to unnecessary therapies. Improving diagnostic tools for the three genetic disorders targeted by this grant (Krabbe Disease, Pompe Disease and Mucopolysaccharidosis type I) will ensure that newborn babies who will benefit from treatment for these disorders will receive it promptly, and that the health of infants who do not require intervention will not be jeopardized by potentially dangerous treatments.