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，必须决定选择哪种胚胎进行转移。该决定对IVF周期的结果产生了很大的影响，即胚胎是否会发展成为健康的孩子。据估计，至少有50％的人类胚胎受诸如非整倍性等染色体异常的影响，并且这种胚胎的植入可能会导致不希望的结果，例如失败的植入，自发流产或三体性下降的出生。生殖专家一直在越来越多地转向植入前遗传诊断（PGD），以识别胚胎以最佳机会发展成为健康儿童的胚胎。但是，当前技术是昂贵的，不可靠的，通常仅测试一小部分染色体。 GSN开发了一种创新的技术，称为父母支持TM（PS），其输出是数千个基因座的胚胎DNA的计算机重建，其置信度超过99％。这项技术将首次允许IVF医师筛选胚胎的染色体异常，包括非整倍性，易位和所有23对染色体的缺失，错误率低于0.1％。该应用程序的第一阶段目标是将我们的PS技术与一个新的，高度平行的基于自定义的基因分型平台集成在一起，以大大降低成本，这将使GSN能够以优越的准确性，范围和成本等同于当前的，较不可靠的鱼类方法提供PGD服务。然后，新的定制平台将应用于第二阶段，我们建议在第5天，第3天的传统胚泡活检和实际的孩子评估新的滋养剂活检技术之间的一致性。这些研究的结果将使我们能够评估新的活检技术的价值，评估第3天和第5天之间在很大程度上未研究的胚胎自我纠正现象，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：随着对疾病表型与基因型如何相关的知识，问题出现了如何应用这些知识来改善生活质量和健康的质量。诸如非整倍性的染色体疾病一直是儿童发病率和死亡率的重要原因，受影响儿童的生活质量会因涉及哪种染色体而异。在体外受精（IVF）的背景下，据估计，至少50％的人类胚胎受到非整倍性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学结果，例如失败的胚胎植入，自发流产或三体儿童的出生。因此，毫不奇怪的是，生殖专家越来越多地转向植入前遗传诊断（PGD）测试，以识别具有最佳发展机会成为健康儿童的胚胎。有了这项赠款，基因安全网络（GSN）将开发一个新的定制技术平台，该平台将GSN的专有生物信息学技术与基于Illumina的基因分型技术集成在一起。这个自定义的平台将使IVF医生能够筛选胚胎的胚胎，以筛选所有染色体的删除，插入和易位，并具有前所未有的精度和范围，并且与其他方法相比，成本类似。该技术称为父母支持（PS），是基于减数分裂和人类基因组项目数据的基本原理。与其他现有的PGD方法相比，GSN的新定制平台启用：i）确定非整倍性，大约两个数量级错误率； ii）确定所有染色体的非整倍性； iii）同时确定非整倍性与常见的染色体缺失，插入和易位。 GSN正在开发增强的报告系统，统计方法和湿实验室基础架构，以向美国的六个领先的IVF中心提供此服务（所有这些都已经签署了购买该服务的意向书），随后是全球IVF社区。 2006年在美国和国际上进行了大约152,000和653,000 IVF周期，PGD每年继续增长约33％。总而言之，这项研究的资金将使GSN能够设计和开发一个自定义技术平台，以同时检测非整倍性，易位，删除和插入；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的技术将将胚胎前植入前诊断的领域带入可靠的诊断领域，可以在体外受精期间调节并用作护理标准的一部分。