Enhancement of Newborn Screening Diagnostic Paradigms to Improve the Efficacy of Treatment for Krabbe Disease, Pompe Disease, and Mucopolysaccharidosis Type 1

项目摘要 新生儿筛查（NBS）自1960年代开始以来，对婴儿有着不可估量的好处。的 国家统计局项目的一个值得称赞的目标是，确定哪些婴儿将发展出致命的或使人衰弱的童年 在症状出现前和治疗最有效时对疾病进行治疗。但是，在这方面， 筛查疾病的诊断范例的准确性问题代表了潜在的 对婴儿和父母都有伤害。一些新生儿筛查的假阳性率过高， 阳性预测值（PPV）不够高，导致诊断不确定性。这种不确定性可以 导致1）诊断延迟和治疗结果恶化，以及2）导致发病率和死亡率 不必要的治疗。此外，父母的焦虑不必要地伴随着假阳性 NBS结果。当前应用的广泛目标是提高Krabbe病的NBS的准确性 (KD)Pompe病（PD）和I型粘多糖样变性（MPSI）。在我们最近完成的R21中 授予，它被确定为KD，NBS的方法，包括双变量正常的发展 两种生物标志物，精神病（PSY）和半乳糖苷酶的量的限度（BVNL） 新生儿干血斑（DBS）中的GalC可以在症状发生之前预测症状。回顾性测试 该工具导致98.5%的非常高的PPV，基本上消除了KD的现有假阳性问题。 (KD在纽约州的筛查导致1.4%PPV。初步研究表明，BVNL工具， PPV接近100%，也可用于MPSI和PD。 该提案将使用特定的NBS生物标志物测试KD，MPSI和PD的新型BVNL工具，并将评估 这些工具用于有效的症状前识别这些疾病。目标1a将前瞻性收集 来自纽约、俄亥俄州、密苏里州KD筛查阳性婴儿DBS的PSY和GalC结果，以及 伊利诺斯州的大都市芝加哥。这些地区，以及日本岐阜、大坂和岛根（只有 将收集MPSI），包括拟定的新生儿筛查双变量分析（BANS）网络， 合作遗传学转介网站。这个缩写反映了BVNL工具在一种方法中的预期用途 这消除了KD、PD和MPSI的NBS后过多假阳性的潜在危害。目标1b将 利用BANS网络对KD筛查阳性的婴儿进行前瞻性监测， 将BVNL工具应用于他们的术前采集的血斑是否预测了随后的 症状出现。目标2将利用BANS网络和从虚拟血液分析仪获得的新生儿血液斑点。 干血斑储存库，以进一步开发MPSI和PD的BVNL工具。Aim 3将再次使用 BANS网络前瞻性地确定BVNL工具对MPSI和PD的预测能力。如果 NBS后KD、MPSI和PD的预测得到改善，将加强对这些疾病的治疗。 毁灭性的疾病和危及婴儿生命的治疗将得到预防。

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.