Novel Informatics for Highly Reliable Multi-Locus Allele Calling for Embryo Scree

用于胚胎筛选的高度可靠的多位点等位基因调用的新颖信息学

基本信息

批准号：
7541479
负责人：
Matthew Rabinowitz
金额：
$ 83.55万
依托单位：
NATERA, INC.
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-04-15 至 2010-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7541479
关键词：
Alleles Aneuploidy Appendix Applaud Area Biopsy Blood Blood Cells Blood specimen Boston Caring Cell model Cells Child Chromosomes Clinical Clinical Research Clinical Trials Collaborations Communities Complex Computer Simulation Congresses Consent Forms Couples Cystic Fibrosis DNA Data Diagnosis Diagnostic Diagnostic Procedure Diagnostic Services Diagnostic tests Disease Dropout Embryo Enrollment Ensure Fathers Female Fertility Fertilization Fertilization in Vitro Fluorescent in Situ Hybridization Funding Genes Genetic Genetic Markers Genetic screening method Genome Genotype Germ Cells Goals Grant Growth Guidelines Harvest Health Healthcare Hour Human Genome Human Genome Project Huntington Disease Implant Individual Informatics Information Technology Informed Consent Knowledge Laboratories Laws Letters Link Live Birth Marketing Measurement Measures Meiosis Modeling Monosomy Mothers Multi-Institutional Clinical Trial Numbers Outcome Outcome Study Parents Patients Performance Phase Phase I Clinical Trials Polymerase Chain Reaction Predisposition Prevalence Process Protocols documentation Public Health Quality of life Range Rate Regulation Reporting Research Ethics Committees Research Infrastructure Running Sampling Screening procedure Security Services Simulate Staging Standards of Weights and Measures Statistical Methods Statutes and Laws System Techniques Technology Test Result Testing Triad Acrylic Resin Trisomy United States United States Food and Drug Administration United States National Institutes of Health Validity and Reliability Work X Chromosome base blind cost day disease phenotype embryo stage 2 genome wide association study human data implantation improved innovation male new technology novel reproductive satisfaction sperm cell

项目摘要

DESCRIPTION (provided by applicant): In 2006, across the globe, more than 800,000 in-vitro fertilization (IVF) cycles were run. Of 150,000 cycles run in the US, roughly 10,000 involved pre-implantation genetic diagnosis (PGD). Current PGD techniques are unregulated, expensive and highly unreliable: error rates for screening disease-linked loci or aneuploidy are on the order of 10%; each screening test costs more than $5,000; and a couple is forced to choose between testing aneuploidy, which afflicts roughly 40% of IVF embryos, or screening for disease-linked loci on the single cell. There is a great need for an affordable technology that can reliably determine genetic data from the single cell in order to screen in parallel for aneuploidy, monogenic diseases such as Cystic Fibrosis, and susceptibility to complex disease phenotypes for which the multiple genetic markers are known through whole-genome association (WGA) studies. The process of PGD during IVF involves extracting a single cell from the roughly 8 cells of an early-stage embryo for analysis. Since only a single copy of the DNA is available from one cell, direct measurements of the DNA are highly error-prone, or noisy. Gene Security Network (GSN) has developed a novel technology, termed Parental SupportTM (PS), for determining the embryonic DNA at hundreds of loci together with copy numbers for 23 chromosomes, with error rates below 0.1%, from a single cell. The proprietary technique makes use of genetic data of the mother and the father, together with the knowledge of the mechanism of meiosis and noisy measurements of the embryonic DNA, in order to determine which segments of parent chromosomes contributed to the gametes that fertilized and hence to reconstruct in silico the embryonic DNA with confidence exceeding 99%. Based on the results of our phase I study, GSN has executed letters of intent with the 5 leading IVF centers in the United States to use the GSN diagnostic service. In aim 1 of this proposal, we will demonstrate the ability of the PS technology to reliably reconstruct genetic data using the measured genetic data from isolated single cells from a born child, and parental genetic data. In aim 2 we will demonstrate the ability of the PS technology to detect aneuploidy at all 23 chromosomes, also using isolated single cell genetic data, by means of an innovative single cell model for aneuploidy that does not require direct work on embryos. In Aim 3 we will perform a clinical trial in conjunction with Stanford IVF Center, Boston IVF and Huntington Reproductive Center that applies the techniques from aims 1 and 2 to real blastomeres in the IVF context and compare our predictions with truth measured on the child when born. One goal of the study is to generate data that will be used to obtain approval of this diagnostic technique by the Food and Drug Administration. The PS technology of Gene Security Network will bring the domain of PGD into the realm of reliable diagnostics which can be regulated and used with confidence in clinical decisions. The selection of the embryos to implant is a clinical decision that has direct and absolute impact on outcomes. Narrative and Relevance to Healthcare PUBLIC HEALTH RELEVANCE: As data associating disease phenotypes with genotype continues to grow, the question arises: how can this knowledge be used to improve the quality of life and health? With this grant, Gene Security Network will thoroughly validate a technology for screening embryos during in-vitro fertilization for a multiplicity of disease linked genes and TM aneuploidy. This technology, termed Parental Support (PS) which is built on the fundamental principles of meiosis and data that has recently become available through the human genome project. Compared to existing technologies, PS enables: i) determination of disease linked loci with roughly two orders of magnitude lower error rates; ii) determination of multiple disease-linked loci in parallel; iii) determination of aneuploidy with roughly two orders of magnitude lower error rates; and iv) determination of aneuploidy across all chromosomes together with multiple disease-linked loci all from a single cell. GSN is developing the enhanced reporting system, statistical methods, and wet-lab infrastructure to offer this service to the leading IVF centers who have signed letters of intent to purchase the service, and then to the worldwide IVF community. Funding for this study will enable us to validate the performance of the diagnostic with known truth models on single cells, and to validate predictions made from a single blastomere by comparing those predictions with genetic data measured when a child is born. Roughly 152,000 and 653,000 IVF cycles were performed in 2006 in the US and internationally. The rate of growth of PGD is roughly 33% annually. Funding for this study will enable us to validate the performance of the diagnostic with known truth models on single cells, and to validate predictions made from a single blastomere by comparing those predictions with genetic data measured when a child is born. GSN's PS technology of will bring the domain of PGD into the realm of reliable diagnostics which can be regulated and used as part of the standard of care during in-vitro fertilization.

描述（由申请人提供）：2006 年，全球范围内进行了超过 800,000 次体外受精 (IVF) 周期。在美国运行的 150,000 个周期中，大约 10,000 个涉及植入前遗传学诊断 (PGD)。目前的 PGD 技术不受监管、昂贵且高度不可靠：筛查疾病相关位点或非整倍体的错误率约为 10%；每次筛查测试费用超过 5,000 美元；一对夫妇被迫在测试非整倍性（影响大约 40% 的 IVF 胚胎）和筛查单细胞上与疾病相关的基因座之间做出选择。迫切需要一种经济实惠的技术，能够可靠地确定单细胞的遗传数据，以便并行筛选非整倍体、囊性纤维化等单基因疾病，以及通过多种遗传标记已知的复杂疾病表型的易感性全基因组关联（WGA）研究。 IVF 期间的 PGD 过程涉及从早期胚胎的大约 8 个细胞中提取单个细胞进行分析。由于一个细胞只能获得 DNA 的单个拷贝，因此直接测量 DNA 非常容易出错或存在噪音。 Gene Security Network (GSN) 开发了一种名为 Parental SupportTM (PS) 的新技术，用于从单个细胞中确定数百个位点的胚胎 DNA 以及 23 条染色体的拷贝数，错误率低于 0.1%。该专有技术利用母亲和父亲的遗传数据，以及减数分裂机制的知识和胚胎 DNA 的噪声测量，以确定亲本染色体的哪些片段对受精的配子做出了贡献，从而确定了配子的受精过程。通过计算机重建胚胎 DNA，置信度超过 99%。根据我们第一阶段研究的结果，GSN 已与美国 5 家领先的 IVF 中心签署了使用 GSN 诊断服务的意向书。在本提案的目标 1 中，我们将证明 PS 技术能够使用从出生的孩子分离的单细胞中测量到的遗传数据以及父母的遗传数据来可靠地重建遗传数据。在目标 2 中，我们将展示 PS 技术检测所有 23 条染色体的非整倍性的能力，同时使用分离的单细胞遗传数据，通过创新的非整倍性单细胞模型，不需要直接对胚胎进行研究。在目标 3 中，我们将与斯坦福 IVF 中心、波士顿 IVF 和亨廷顿生殖中心联合进行一项临床试验，将目标 1 和 2 的技术应用于 IVF 背景下的真实卵裂球，并将我们的预测与孩子出生时测量的真实情况进行比较。该研究的一个目标是生成数据，用于获得美国食品和药物管理局对这种诊断技术的批准。 Gene Security Network的PS技术将把PGD领域带入可靠的诊断领域，可以在临床决策中放心地进行监管和使用。选择植入的胚胎是一项临床决策，对结果有直接和绝对的影响。叙述及其与医疗保健的相关性公共卫生相关性：随着疾病表型与基因型相关的数据不断增长，问题出现了：如何利用这些知识来改善生活和健康质量？借助这笔资金，基因安全网络将彻底验证一项在体外受精过程中筛选胚胎的技术，以检测多种疾病相关基因和 TM 非整倍体。这项技术被称为亲本支持（PS），它建立在减数分裂的基本原理和最近通过人类基因组计划获得的数据的基础上。与现有技术相比，PS 能够： i) 确定疾病相关位点，错误率大约降低两个数量级； ii) 并行确定多个疾病相关基因座； iii) 确定非整倍性，错误率大约降低两个数量级； iv) 确定来自单个细胞的所有染色体的非整倍性以及多个与疾病相关的基因座。 GSN 正在开发增强的报告系统、统计方法和湿实验室基础设施，以便向已签署购买服务意向书的领先 IVF 中心提供这项服务，然后向全球 IVF 社区提供这项服务。这项研究的资助将使我们能够利用已知的单细胞真实模型来验证诊断的性能，并通过将单个卵裂球的预测与孩子出生时测量的遗传数据进行比较来验证这些预测。 2006 年，美国和国际上分别进行了大约 152,000 和 653,000 个 IVF 周期。 PGD每年的增长率约为33%。这项研究的资助将使我们能够利用已知的单细胞真实模型来验证诊断的性能，并通过将单个卵裂球的预测与孩子出生时测量的遗传数据进行比较来验证这些预测。 GSN 的 PS 技术将把 PGD 领域带入可靠的诊断领域，可以对其进行监管并用作体外受精期间护理标准的一部分。