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

项目总结 新生儿筛查(NBS)自20世纪60年代开始实施以来，给婴儿带来了不可估量的好处。这个 国家统计局项目值得称赞的目标是识别哪些婴儿会发展成致命或虚弱的童年 在出现症状前和治疗效果最好的时候出现精神障碍。然而， 筛查疾病的诊断范例的准确性问题是潜在的来源 对婴儿和父母都有伤害。一些新生儿筛查的假阳性率过高，导致 阳性预测值(PPV)不够高，增加了诊断的不确定性。这种不确定性可能 导致1)延误诊断和治疗结果恶化，2)导致发病率和死亡率 从不必要的治疗中。此外，严重的父母焦虑不必要地伴随着假阳性 国家统计局的结果。目前应用的主要目标是提高NBS诊断Krabbe病的准确性 (KD)、庞贝病(PD)和粘多糖病I型(MPSI)。在我们最近完成的R21期间 Grant，证明了对于KD，由二元正态发展而成的NBS方法 脑磷脂(PSY)和半乳糖脑苷酶两种生物标志物的限量(BVNL) (GalC)，新生儿干血斑点(DBS)可以在症状发生前预测。追溯性测试 该工具的PPV非常高，达到98.5%，基本上消除了KD现有的假阳性问题。 (纽约州的KD筛查结果为1.4%的PPV。)初步研究表明，BVNL工具，包括 接近100%的PPV也可用于MPSI和PD。 该提案将使用特定的NBS生物标记物测试用于KD、MPSI和PD的新型BVNL工具，并将评估 这些工具用于有效地对这些疾病进行症状前识别。Aim 1a将预期收集 纽约、俄亥俄州、密苏里州和密苏里州DBS筛查KD阳性婴儿的PSY和GalC结果 伊利诺伊州芝加哥大都会。这些地区，以及岐阜市、大阪和岛根市(那里只有 将收集MPSI)，包括拟议的新生儿筛查双变量分析(BANS)网络 合作的遗传学转介网站。此首字母缩写反映了BVNL工具在一种方法中的预期使用 这消除了KD、PD和MPSI NBS后过多假阳性的潜在危害。目标1b将 利用BANS网络对KD筛查呈阳性的婴儿进行前瞻性监测，以确定 将BVNL工具应用于他们症状前采集的血点是否可以预测随后的 症状出现。AIM 2将利用BANS网络和从虚拟医院获得的新生儿血迹 干血斑点资料库，以进一步开发用于MPSI和PD的BVNL工具。Aim 3将再次采用 BANS网络前瞻性地确定BVNL工具对MPSI和PD的预测能力。如果 改善了对KD、MPSI和PD的预测，在NBS实现后，将加强对这些疾病的治疗 对婴儿的破坏性疾病和危及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.