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.

项目摘要 自1960年代成立以来，新生儿筛查（NB）对婴儿的好处是无法估量的。这 NBS计划的值得称赞的目标是确定会发展致死或使人衰弱的婴儿 疾病在症状症状且治疗具有最大有效的时候。然而， 筛查疾病的诊断范例准确性的问题是潜在的来源 对婴儿和父母的伤害。某些新生儿屏幕过多的假阳性率 不足的高积极预测值（PPV）导致诊断不确定性。这种不确定性可以 导致1）诊断和治疗结果的恶化延迟，以及2）导致的发病率和死亡率 来自不必要的治疗。此外，不必要的父母焦虑不必要伴随 NBS结果。当前应用的广泛目标是提高NBS krabbe病的准确性 （KD），庞贝病（PD）和I型粘二糖（MPSI）。在我们最近完成的R21期间 格兰特（Grant 两种生物标志物（Psy）和酶半乳脑脑苷酶的量的限制（BVNL） （galc），在新生的干血点（DBS）中可以预测症状在发生之前。回顾性测试 该工具的PPV非常高98.5％，从本质上消除了KD的现有假阳性问题。 （纽约州的KD筛查导致1.4％ppv。）初步研究表明，BVNL工具具有带有的工具 接近100％的PPV也可以针对MPSI和PD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 这些工具是有效地预诊断这些疾病的工具。 AIM 1A将前景收集 来自婴儿DB的PSY和GALC的结果，他们在纽约，俄亥俄州，密苏里州和 伊利诺伊州芝加哥大都会。这些领域以及日本日本的GIFU，大阪和Shimane（只有数据 将收集MPSI），包括针对新生儿筛查（BANS）网络的拟议的双变量分析 协作遗传转介网站。该首字母缩写反映了在方法中预期使用BVNL工具的使用 这消除了KD，PD和MPSI NB后过度假阳性的潜在危害。目标1B会 利用禁令网络来预期监测对KD呈阳性的婴儿 将BVNL工具应用于其预受到预测的血点是否会预测随后的 症状出现。 AIM 2将利用禁止网络和从虚拟获得的新生儿斑点 干血点的存储库，以进一步开发用于MPSI和PD的BVNL工具。 AIM 3将再次采用 禁止网络前瞻性确定MPSI和PD工具的预测能力。如果是 实现NBS后KD，MPSI和PD的预测改进，将增强治疗 将防止毁灭性的疾病和威胁生命的婴儿治疗。