Array informatics to understand ploidy concordance

阵列信息学以了解倍性一致性

• 批准号: 7612192
• 负责人: Matthew Rabinowitz
• 金额: $ 20.01万
• 依托单位: NATERA, INC.
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-02-14 至 2009-08-13
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7612192
• 关键词: Address; Affect; Algorithms; Alleles; Aneuploid Cells; Aneuploidy; Bioinformatics; Biological; Biological Assay; Biopsy; Birth; Cell Line; Cells; Characteristics; Child; Childhood; Chromosome Deletion; Chromosome Pairing; Chromosome Positioning; Chromosome abnormality; Chromosomes; Clinic; Communities; Computer Simulation; Congenital chromosomal disease; Couples; Custom; DNA; DNA Microarray Chip; DNA analysis; Data; Detection; Development; Diagnosis; Diagnostic; Diagnostic Services; Down Syndrome; Dropout; Drops; Embryo; Enrollment; Evaluation; Excision; Face; Fathers; Fertilization; Fertilization in Vitro; Fetus; Fluorescent in Situ Hybridization; Frequencies; Funding; Gene Frequency; Genes; Genetic; Genome; Genotype; Goals; Grant; Health; Healthcare; Hour; Human; Human Genetics; Human Genome Project; Implant; In Vitro; Individual; Informatics; Inner Cell Mass; Kinetics; Knowledge; Lead; Letters; Life; Live Birth; Manufacturer Name; Measurement; Measures; Medical; Meiosis; Methods; Minor; Mission; Modeling; Molecular; Morbidity - disease rate; Mothers; Outcome; Output; Parents; Performance; Phase; Physicians; Placenta; Ploidies; Population; Precipitation; Preimplantation Diagnosis; Procedures; Process; Protocols documentation; Proxy; Quality of life; Reagent; Reporting; Research Infrastructure; Risk; Running; Sampling; Screening Result; Screening procedure; Security; Services; Single Nucleotide Polymorphism; Source; Specialist; Spontaneous abortion; Staging; Statistical Methods; Swab; System; Techniques; Technology; Testing; Time; Triad Acrylic Resin; Uterus; Variant; base; blastocyst; cost; design; disease phenotype; embryo stage 2; fetal; follow-up; genetic analysis; genotyping technology; implantation; improved; innovation; innovative technologies; insertion/deletion mutation; interest; mortality; natural Blastocyst Implantation; new technology; novel; offspring; preimplantation; public health relevance; reconstruction; reproductive; response; standard of care; trend

DESCRIPTION (provided by applicant): In each IVF cycle, a decision must be made as to which embryo(s) will be selected for transfer. This decision has a far reaching impact on the outcome of an IVF cycle, namely whether the embryo will develop into a healthy child. It is estimated that at least 50% of human embryos are affected by chromosomal abnormalities such as aneuploidy, and implantation of such embryos can lead to undesired outcomes such as failed implantation, spontaneous abortion, or birth of a trisomic offspring. Reproductive specialists have been increasingly turning to pre-implantation genetic diagnosis (PGD) in efforts to identify embryos with the best chance of developing into healthy children. However, current techniques are expensive, unreliable and typically test only a small selection of chromosomes. GSN has developed an innovative technology termed Parental SupportTM (PS) whose output is an in silico reconstruction of the embryonic DNA at thousands of loci with confidence exceeding 99%. This technology will, for the first time, allow IVF physicians to screen embryos for chromosomal abnormalities including aneuploidy, translocations and deletions across all 23 pairs of chromosomes with an error rate below 0.1%. The Phase I objective of this application is to integrate our PS technology with a new, highly parallelized custom Infinium-based genotyping platform to dramatically reduce costs that will, in turn, enable GSN to offer PGD service with superior accuracy, scope and at a cost equivalent to current, less reliable FISH methods. The new customized platform will then be applied in Phase II where we propose to evaluate the concordance between a new trophectoderm biopsy technique on day 5, traditional blastomere biopsy on day 3, and the actual child. The results from these studies will allow us to assess the value of the new biopsy technique, evaluate the largely unstudied phenomenon of embryo self-correction between day 3 and day 5, and provide IVF physicians with powerful and far-reaching knowledge about the developmental potential of each embryo. PUBLIC HEALTH RELEVANCE: With the accumulating knowledge of how disease phenotypes are associated with genotypes, the question arises how this knowledge can be applied to improve the quality of life and health. Chromosomal disorders such as aneuploidy have been important causes of childhood morbidity and mortality, and the quality of life of the affected children will vary depending on which chromosome(s) is involved. In the context of in vitro fertilization (IVF), it is estimated that at least 50% of human embryos are affected by aneuploidy and other chromosomal abnormalities. Implantation of these embryos can lead to universally undesired medical outcomes such as failed embryo implantation, spontaneous abortion, or birth of a trisomic child. It is, therefore, not surprising that reproductive specialists are increasingly turning to preimplantation genetic diagnosis (PGD) testing in efforts to identify embryos with the best chance of development into healthy children. With this grant, Gene Security Network (GSN) will develop a new customized technology platform that integrates GSN's proprietary bioinformatics technology with Illumina-based genotyping technology. This customized platform will enable IVF physicians to screen embryos for aneuploidy, deletions, insertions and translocations across all chromosomes with unprecedented accuracy and scope, and at a similar cost compared to other methods. This technology, termed Parental SupportTM (PS), is built on the fundamental principles of meiosis and Human Genome Project data. In comparison to other existing PGD methods, GSN's new customized platform enables: i) determination of aneuploidy with roughly two orders of magnitude lower error rates; ii) determination of aneuploidy across all chromosomes; and iii) determination of aneuploidy simultaneously with common chromosomal deletions, insertions and translocations. GSN is developing the enhanced reporting system, statistical methods, and wet- lab infrastructure to offer this service to six of the leading IVF centers in the US (all of which have already signed letters of intent to purchase the service) and subsequently to the worldwide IVF community. Roughly 152,000 and 653,000 IVF cycles were performed in 2006 in the US and internationally, and PGD continues to grow at roughly 33% annually. In summary, funding for this study will enable GSN to design and develop a custom technology platform for simultaneous detection of aneuploidy, translocations, deletions, and insertions; validate the performance of the new technology; and apply the technology to investigate the utility of an emerging embryo biopsy technique. GSN's technology will bring the domain of embryo pre-implantation diagnosis 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）：在每个 IVF 周期中，必须决定选择哪个胚胎进行移植。这一决定对试管婴儿周期的结果产生深远的影响，即胚胎是否会发育成健康的孩子。据估计，至少 50% 的人类胚胎受到非整倍体等染色体异常的影响，此类胚胎的植入可能会导致不良结果，例如植入失败、自然流产或三体后代的诞生。生殖专家越来越多地转向植入前遗传学诊断（PGD），以努力识别最有可能发育成健康儿童的胚胎。然而，当前的技术昂贵、不可靠，并且通常仅测试一小部分染色体。 GSN 开发了一种名为 Parental SupportTM (PS) 的创新技术，其输出是对数千个位点的胚胎 DNA 进行计算机重建，置信度超过 99%。这项技术将首次允许 IVF 医生筛查胚胎的染色体异常，包括所有 23 对染色体的非整倍体、易位和缺失，错误率低于 0.1%。该应用的第一阶段目标是将我们的 PS 技术与基于 Infinium 的新型高度并行定制基因分型平台集成，以大幅降低成本，从而使 GSN 能够以与当前不太可靠的 FISH 方法相当的成本提供具有卓越准确性和范围的 PGD 服务。然后，新的定制平台将应用于第二阶段，我们建议评估第 5 天的新滋养外胚层活检技术、第 3 天的传统卵裂球活检技术与实际儿童之间的一致性。这些研究的结果将使我们能够评估新活检技术的价值，评估第 3 天到第 5 天之间胚胎自我校正的大部分未经研究的现象，并为 IVF 医生提供有关每个胚胎发育潜力的强大而深远的知识。公共卫生相关性：随着关于疾病表型与基因型之间关系的知识不断积累，问题出现了如何应用这些知识来改善生活和健康质量。非整倍体等染色体疾病是儿童发病和死亡的重要原因，受影响儿童的生活质量将根据涉及的染色体而有所不同。在体外受精 (IVF) 的背景下，估计至少 50% 的人类胚胎受到非整倍体和其他染色体异常的影响。这些胚胎的植入可能会导致普遍不希望的医疗结果，例如胚胎植入失败、自然流产或三体婴儿的出生。因此，生殖专家越来越多地转向植入前遗传学诊断（PGD）测试，以努力识别最有可能发育成健康儿童的胚胎，也就不足为奇了。借助这笔资金，Gene Security Network (GSN) 将开发一个新的定制技术平台，将 GSN 专有的生物信息学技术与基于 Illumina 的基因分型技术相集成。这个定制平台将使 IVF 医生能够以前所未有的准确性和范围筛查胚胎所有染色体的非整倍体、缺失、插入和易位，并且与其他方法相比成本相似。这项技术被称为 Parental SupportTM (PS)，建立在减数分裂和人类基因组计划数据的基本原理之上。与其他现有的 PGD 方法相比，GSN 的新定制平台能够： i) 确定非整倍性，错误率大约降低两个数量级； ii) 确定所有染色体的非整倍性； iii) 与常见染色体缺失、插入和易位同时测定非整倍性。 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，以便向美国六家领先的 IVF 中心（所有这些中心都已签署了购买该服务的意向书）以及随后向全球 IVF 社区提供这项服务。 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 继续以每年约 33% 的速度增长。总之，这项研究的资助将使 GSN 能够设计和开发一个定制技术平台，用于同时检测非整倍性、易位、缺失和插入；验证新技术的性能；并应用该技术来研究新兴胚胎活检技术的实用性。 GSN 的技术将把胚胎植入前诊断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。