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

加强新​​生儿筛查诊断范式以提高克拉伯病、庞贝病和 1 型粘多糖贮积症的治疗效果

• 批准号: 10366620
• 负责人: Thomas J Langan
• 金额: $ 76.06万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-18 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10366620
• 关键词: Address; Alpha-glucosidase; Anxiety; Area; Biological Markers; Blood; Blood Screening; Chicago; Childhood; Clinical; Collection; Creatine; Dangerousness; Data; Development; Diagnosis; Diagnostic; Disease; Early treatment; Eligibility Determination; Enrollment; Ensure; Enzymes; Exploratory/Developmental Grant for Diagnostic Cancer Imaging; Genetic; Genetic Diseases; Genotype; Globoid cell leukodystrophy; Glycogen storage disease type II; Glycosaminoglycans; Goals; Grant; Guidelines; Illinois; Infant; Infant Health; Intervention; Japan; L-Iduronidase; Lead; Life; Measures; Missouri; Morbidity - disease rate; Mucopolysaccharidoses; Mucopolysaccharidosis I; Neonatal Screening; New York; Newborn Infant; Ohio; Parents; Pilot Projects; Predictive Value; Psychosine; Reporting; Retrospective Studies; Risk; Screening Result; Screening procedure; Site; Source; Spottings; Stress; Symptoms; Testing; Time; Translational Research; Treatment Efficacy; Treatment outcome; Uncertainty; United States; Work; acronyms; base; diagnostic accuracy; diagnostic screening; diagnostic tool; experimental study; follow-up; galactosylceramidase; high risk; improved; infant monitoring; metropolitan; mortality; novel; novel diagnostics; prevent; programs; prospective; prospective test; screening; screening program; tool; unnecessary treatment; virtual; virtual repository

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.

项目概要 自 20 世纪 60 年代推出以来，新生儿筛查 (NBS) 为婴儿带来了不可估量的益处。这 NBS 计划的值得称赞的目标是识别那些将在童年时期出现致命或衰弱的婴儿 疾病出现症状前且治疗最有效时。然而， 筛查疾病诊断范式的准确性问题是潜在的根源 对婴儿和父母都造成伤害。部分新生儿筛查假阳性率过高，导致 阳性预测值 (PPV) 不够高，会导致诊断不确定性。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 免于不必要的治疗。此外，父母的严重焦虑不必要地伴随着假阳性 国家统计局结果。当前应用的总体目标是提高 NBS 对克拉伯病的准确性 (KD)、庞贝病 (PD) 和 I 型粘多糖贮积症 (MPSI)。在我们最近完成的 R21 期间 拨款，确定了对于 KD，一种 NBS 方法，包括开发双变量正态分布 两种生物标志物：精神氨酸 (PSY) 和半乳糖脑苷脂酶的含量限值 (BVNL) （GalC），新生儿干血斑（DBS）可以在症状出现之前预测它们。回顾性测试 该工具产生了高达 98.5% 的 PPV，从根本上消除了 KD 现有的误报问题。 （纽约州的 KD 筛查结果为 1.4% PPV。）初步研究表明，BVNL 工具具有 PPV 接近 100%，也可以针对 MPSI 和 PD 进行开发。 该提案将使用特定的 NBS 生物标志物测试针对 KD、MPSI 和 PD 的新型 BVNL 工具，并将评估 这些工具可有效识别这些疾病的症状前。目标 1a 将前瞻性收集 来自纽约州、俄亥俄州、密苏里州和密苏里州筛查 KD 呈阳性的婴儿 DBS 的 PSY 和 GalC 结果 伊利诺伊州芝加哥大都市。这些地区以及日本岐阜、大阪和岛根（仅提供以下地区的数据） MPSI 将被收集），包括拟议的新生儿筛查双变量分析 (BANS) 网络 合作遗传学转诊网站。该缩写词反映了 BVNL 工具在方法中的预期使用 消除了KD、PD和MPSI的NBS后过多误报的潜在危害。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 工具应用于症状前收集的血点是否可以预测随后的症状 症状的出现。目标 2 将利用 BANS 网络和从虚拟网络获得的新生儿血点 干血斑存储库，用于进一步开发 MPSI 和 PD 的 BVNL 工具。目标 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 NBS 实现后，KD、MPSI 和 PD 的预测得到改善，这些疾病的治疗将得到加强 毁灭性的疾病和危及婴儿生命的治疗将得到预防。