Precision Medicine in the Diagnosis of Genetic Disorders in Neonates

精准医学在新生儿遗传性疾病诊断中的应用

• 批准号: 9983229
• 负责人: Jonathan M. Davis
• 金额: $ 155.68万
• 依托单位: TUFTS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-15 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9983229
• 关键词: Admission activity; Adopted; Adult; Affect; Birth Weight; Blood; Caring; Child; Clinical; Clinical Management; Clinical Trials; Computerized Medical Record; Congenital Abnormality; Copy Number Polymorphism; Data; Data Analyses; Detection; Diagnosis; Diagnostic; Diagnostic Procedure; Diagnostic tests; Diet; Disease; Documentation; Economics; Emerging Technologies; Enrollment; Ethics; Etiology; Fathers; Foundations; Genes; Genetic; Genetic Diseases; Genome; Genomics; Genotype; Goals; Guidelines; Health; Health Insurance Portability and Accountability Act; Health Personnel; Hereditary Disease; Hospital Costs; Hospitals; Incidence; Industry; Infant; Infant Mortality; Infrastructure; Intervention; Investigation; Length of Stay; Life Cycle Stages; Measures; Medical; Medicine; Mendelian disorder; Methodology; Modality; Modeling; Molecular Diagnosis; Morbidity - disease rate; Mothers; Neonatal; Neonatal Intensive Care Units; Neonatal Mortality; Neonatal Screening; North Carolina; Notification; Onset of illness; Operative Surgical Procedures; Outcome; Palliative Care; Patients; Pharmaceutical Preparations; Phenotype; Philosophy; Population; Pregnancy; Prospective Studies; Provider; Reflex action; Repetitive Sequence; Signs and Symptoms; Site; Spottings; Support Groups; Technology; Testing; Therapeutic; Time; Translations; Universities; Update; Variant; base; care costs; clinically relevant; comparative; cost; cost effective; diagnostic accuracy; direct application; economic evaluation; economic impact; exome; exome sequencing; experimental study; functional disability; gene panel; genetic disorder diagnosis; genome sequencing; genome-wide; high risk; high risk infant; improved; improved outcome; infant morbidity/mortality; models and simulation; mortality; neonatal care; neonatal morbidity; neonatal period; neonate; next generation sequencing; novel strategies; precision medicine; proband; programs; prospective; public-private partnership; research clinical testing; sequencing platform; standard of care; targeted treatment; tool; treatment planning; user-friendly; variant of unknown significance; web portal; whole genome

Abstract: Congenital abnormalities and genetic diseases are a leading cause of infant mortality in the US1. While newborn screening (NBS) has dramatically reduced infant morbidity and mortality for some genetic disorders, these improvements have not had a significant impact in Neonatal Intensive Care Units (NICU) where 10 - 25% of all NICU admissions are the result of a genetic disease, with these infants staying in the hospital approximately 40% longer than those without genetic conditions. Due to the non-specific presentation of many of these genetic disorders, many infants do not receive a definitive diagnosis in a timely fashion, if at all. Large, comprehensive studies to determine the overall incidence of genetic disease in the neonatal population are lacking and have only recently been possible with the advent of next generation sequencing methodology such as exome and whole genome sequencing (WGS). Precise and rapid molecular diagnosis is needed to optimize clinical outcomes while reducing mortality and morbidity. In order to avoid the ethical, financial and technical aspects of exome and genome sequencing, we are introducing a rapid, targeted, next-generation sequencing (TNGS) panel that interrogates standard dried blood spots for genes matched to phenotypes affecting the neonatal population and has the potential to detect >98% of clinically relevant sequence variants for Mendelian inherited disorders with the highest morbidity and mortality. Here, we will conduct a multicenter prospective trial to examine the diagnostic efficacy, clinical utility and economic impact of a precision neonatal medicine approach through a public-private partnership among six leading CTSA sites and industry to further develop the TNGS methodology. We will characterize the time to diagnosis, time to initiation of appropriate treatment (or palliative care), and total costs in 400 high-risk neonates with signs/symptoms consistent with a genetic disorder, comparing standard diagnostic procedures to TNGS and WGS. This study aims to: 1) Assess the efficacy and the clinical utility of multiplexed (multi-gene) diagnostic tests (TNGS, WGS) for infants admitted to the NICU; 2) Examine the economic impact of clinical multiplexed sequencing in high-risk neonates compared with current standard of care diagnostic testing; and 3) Develop and evaluate the use of an electronic mechanism for accelerated results return (including any supporting documentation of existing treatments and open clinical trials). The overarching goal of this proposal is to examine the clinical utility and operational infrastructure of a neonatal gene panel in high-risk neonates in order to determine if it will provide a more timely diagnosis and better care at significantly lower cost than standard diagnostic care or WGS, establishing the foundation for a CTSA wide Neonatal Precision Medicine Program.

摘要： 先天性异常和遗传性疾病是美国婴儿死亡的主要原因1。而 新生儿筛查（NBS）显著降低了某些遗传疾病的婴儿发病率和死亡率， 这些改善对新生儿重症监护病房（NICU）没有显著影响， 25%的新生儿重症监护室入院是遗传疾病的结果，这些婴儿留在医院 比没有遗传疾病的人长40%。由于许多非特定的介绍， 在这些遗传疾病中，许多婴儿没有及时得到明确的诊断，如果有的话。大号、 全面的研究，以确定遗传性疾病的总体发病率在新生儿人口是 缺乏，并且直到最近才随着下一代测序方法的出现而成为可能， 如外显子组和全基因组测序（WGS）。需要精确和快速的分子诊断来优化 临床结果，同时降低死亡率和发病率。为了避免道德、财务和技术上的 在外显子组和基因组测序方面，我们正在引入一种快速，有针对性的下一代测序方法， （TNGS）面板，询问标准干血斑的基因匹配的表型影响 新生儿群体，并有可能检测>98%的临床相关的序列变异孟德尔 发病率和死亡率最高的遗传性疾病。在此，我们将进行一项多中心前瞻性试验 检查精确新生儿药物的诊断功效、临床效用和经济影响 通过六个领先的CTSA网站和行业之间的公私合作伙伴关系，进一步发展 TNGS方法。我们将描述诊断时间、开始适当治疗的时间 (or姑息治疗），以及400例具有与遗传相关的体征/症状的高危新生儿的总成本。 将标准诊断程序与TNGS和WGS进行比较。本研究旨在：1）评估 多重（多基因）诊断测试（TNGS，WGS）对入院婴儿的疗效和临床实用性 2）检查临床多重测序对高危新生儿的经济影响， 与当前的护理标准诊断测试;和3）开发和评估电子 加速结果返回的机制（包括现有治疗的任何支持文件， 开放临床试验）。本提案的总体目标是检查临床实用性， 在高危新生儿中建立新生儿基因小组的操作基础设施，以确定它是否 以比标准诊断更低的成本提供更及时的诊断和更好的护理 护理或WGS，为CTSA范围内的新生儿精准医学计划奠定基础。