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1.发明申请METHOD FOR IMPROVING THE SENSITIVITY OF DETECTION IN DETERMINING COPY NUMBER VARIATIONS 审中-公开用于提高检测灵敏度以确定复制数变化的方法
公开(公告)号：WO2015061359A1
公开(公告)日：2015-04-30
申请号：PCT/US2014/061635
申请日：2014-10-21
摘要： Disclosed are methods for determining copy number variation (CNV) known or suspected to be associated with a variety of medical conditions. In some embodiments, methods are provided for determining copy number variation (CNV) of fetuses using maternal samples comprising maternal and fetal cell free DNA. In some embodiments, methods are provided for determining CNVs known or suspected to be associated with a variety of medical conditions. Some embodiments disclosed herein provide methods to improve the sensitivity and/or specificity of sequence data analysis by removing within-sample GC-content bias. In some embodiments, removal of within-sample GC-content bias is based on sequence data corrected for systematic variation common across unaffected training samples. Also disclosed are systems and computer program products for evaluation of CNV of sequences of interest.
摘要翻译： 公开了用于确定已知或怀疑与各种医学状况相关联的拷贝数变异（CNV）的方法。 在一些实施方案中，提供了使用包含母体和胎儿无细胞DNA的母体样品来确定胎儿的拷贝数变异（CNV）的方法。 在一些实施例中，提供了用于确定已知或怀疑与各种医疗状况相关联的CNV的方法。 本文公开的一些实施方案提供通过移除样品内含量偏差来提高序列数据分析的灵敏度和/或特异性的方法。 在一些实施方案中，样本内GC含量偏差的去除是基于校正的针对未受影响的训练样本共同的系统变化的序列数据。 还公开了用于评估感兴趣序列的CNV的系统和计算机程序产品。
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2.发明申请NORMALIZING CHROMOSOMES FOR THE DETERMINATION AND VERIFICATION OF COMMON AND RARE CHROMOSOMAL ANEUPLOIDIES 审中-公开正常化染色体用于确定和验证常见和罕见的染色体异常
公开(公告)号：WO2012141712A1
公开(公告)日：2012-10-18
申请号：PCT/US2011/032554
申请日：2011-04-14
发明人： RAVA, Richard, P.
IPC分类号： C12Q1/68
CPC分类号： C12Q1/6809 , G06F19/18 , C12Q2535/122 , C12Q2537/16 , C12Q2539/113
摘要： The present invention provides a method capable of detecting single or multiple fetal chromosomal aneuploidies in a maternal sample comprising fetal and maternal nucleic acids, and verifying that the correct determination has been made. The method is applicable to determining copy number variations (CNV) of any sequence of interest in samples comprising mixtures of genomic nucleic acids derived from two different genomes, and which are known or are suspected to differ in the amount of one or more sequence of interest. The method is applicable at least to the practice of noninvasive prenatal diagnostics, and to the diagnosis and monitoring of conditions associated with a difference in sequence representation in healthy versus diseased individuals.
摘要翻译： 本发明提供了一种能够检测包含胎儿和母体核酸的母体样品中的单胎或多胎胎儿染色体非整倍体的方法，并验证是否进行了正确的确定。 该方法适用于确定样品中的任何感兴趣的序列的拷贝数变异（CNV），其包含衍生自两个不同基因组的基因组核酸的混合物，其已知或被怀疑在一个或多个感兴趣序列的量上不同 。 该方法至少适用于无创产前诊断的实践，以及与健康与患病个体中序列表现差异相关的病症的诊断和监测。
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3.发明申请
公开(公告)号：WO2016094853A1
公开(公告)日：2016-06-16
申请号：PCT/US2015/065362
申请日：2015-12-11
发明人： CHUDOVA, Darya I. , BARBACIORU, Catalin , DUENWALD, Sven , COMSTOCK, David A. , RAVA, Richard P.
CPC分类号： C12Q1/6809 , C12Q1/6869 , C12Q2535/122 , C12Q2537/16 , C12Q2537/165 , C12Q2545/101 , G06F19/18 , G06F19/22
摘要： Disclosed are methods for determining copy number variation (CNV) known or suspected to be associated with a variety of medical conditions. In some embodiments, methods are provided for determining copy number variation (CNV) of fetuses using maternal samples comprising maternal and fetal cell free DNA. In some embodiments, methods are provided for determining CNVs known or suspected to be associated with a variety of medical conditions. Some embodiments disclosed herein provide methods to improve the sensitivity and/or specificity of sequence data analysis by deriving a fragment size parameter, such as a size-weighted coverage or a fraction of fragments in a size range. In some embodiments, the fragment size parameter is adjusted to remove within-sample GC-content bias. In some embodiments, removal of within-sample GC-content bias is based on sequence data corrected for systematic variation common across unaffected training samples. Also disclosed are systems and computer program products for evaluation of CNV of sequences of interest.
摘要翻译： 公开了用于确定已知或怀疑与各种医学状况相关联的拷贝数变异（CNV）的方法。 在一些实施方案中，提供了使用包含母体和胎儿无细胞DNA的母体样品来确定胎儿的拷贝数变异（CNV）的方法。 在一些实施例中，提供了用于确定已知或怀疑与各种医疗状况相关联的CNV的方法。 本文公开的一些实施方案提供了通过导出片段大小参数（例如大小加权覆盖或片段大小范围的分数）来提高序列数据分析的灵敏度和/或特异性的方法。 在一些实施方案中，调整片段大小参数以除去样品内GC含量偏差。 在一些实施方案中，样本内GC含量偏差的去除是基于校正的针对未受影响的训练样本共同的系统变化的序列数据。 还公开了用于评估感兴趣序列的CNV的系统和计算机程序产品。
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4.发明申请METHOD FOR DETERMINING THE PRESENCE OR ABSENCE OF DIFFERENT ANEUPLOIDIES IN A SAMPLE 审中-公开确定样品中不同反应物存在或不存在的方法
公开(公告)号：WO2013015793A1
公开(公告)日：2013-01-31
申请号：PCT/US2011/045412
申请日：2011-07-26
IPC分类号： C12Q1/68
CPC分类号： C12Q1/6869 , C12Q1/6806 , C12Q1/6883 , C12Q2545/101 , C12Q2535/122 , C12Q2531/113
摘要： ABSTRACT OF THE DISCLOSURE The invention provides a method for determining copy number variations (CNV) of a sequence of interest in a test sample that comprises a mixture of nucleic acids that are known or are suspected to differ in the amount of one or more sequence of interest. The method comprises a statistical approach that accounts for accrued variability stemming from process-related, interchromosomal and inter-sequencing variability. The method is applicable to determining CNV of any fetal aneuploidy, and CNVs known or suspected to be associated with a variety of medical conditions. CNV that can be determined according to the present method include trisomies and monosomies of any one or more of chromosomes 1-22, X and Y, other chromosomal polysomies, and deletions and/or duplications of segments of any one or more of the chromosomes, which can be detected by sequencing only once the nucleic acids of a test sample. Any aneuploidy can be determined from sequencing information that is obtained by sequencing only once the nucleic acids of a test sample.
摘要翻译： 发明内容本发明提供了一种确定测试样品中感兴趣的序列的拷贝数变异（CNV）的方法，该方法包括已知或怀疑在一个或多个序列的量中不同的核酸的混合物 利益。 该方法包括统计方法，其考虑了由过程相关的染色体间和序列间变异性引起的应变变异性。 该方法适用于确定任何胎儿非整倍性的CNV，以及已知或怀疑与各种医学状况相关的CNV。 可以根据本方法确定的CNV包括染色体1-22，X和Y中的任何一个或多个的三体和单体，其他染色体多糖体，以及任何一个或多个染色体的区段的缺失和/或重复， 其可以通过仅测试一次测试样品的核酸来检测。 任何非整倍体都可以从通过测序一次核酸测试获得的测序信息来确定。
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公开(公告)号：WO2012135730A2
公开(公告)日：2012-10-04
申请号：PCT/US2012/031625
申请日：2012-03-30
CPC分类号： C12Q1/6874 , C12Q1/6806 , C12Q2535/122 , C12Q2545/101 , C12Q2563/179 , C12Q2563/185
摘要： The present invention relates to a method for verifying the integrity of biological source samples subjected to multistep bioassays that comprise massively parallel sequencing of she sample genomic nucleic acids. The integrity of the biological source samples is verified using unique marker nucleic acids that are combined with the biological source sample, and are sequenced concomitantly with the genomic nucleic acids of the biological source sample. The method provides verification of individual samples in single and multiplex massively parallel sequencing assays.
摘要翻译： 本发明涉及一种用于验证经受多步生物测定的生物源样品的完整性的方法，其包括对样品基因组核酸进行大规模平行测序。 使用与生物源样品组合的独特标记核酸验证生物源样品的完整性，并与生物源样品的基因组核酸同时测序。 该方法提供单次和多次大规模并行测序测定中各个样本的验证。
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公开(公告)号：WO2014204991A1
公开(公告)日：2014-12-24
申请号：PCT/US2014/042785
申请日：2014-06-17
发明人： ABDUEVA, Diana
CPC分类号： G06F19/22 , C12Q1/6827 , G06F19/18 , C12Q2537/16 , C12Q2537/165
摘要： The invention provides methods for determining copy number of the Y chromosome, including, but not limited to, methods for gender determination or Y chromosome aneuploidy of fetus using maternal samples comprising maternal and fetal cell free DNA. Some embodiments disclosed herein describe a strategy for filtering out (or masking) non-discriminant sequence reads on chromosome Y using representative training set of female samples. In some embodiments, this filtering strategy is also applicable to filtering autosomes for evaluation of copy number variation of sequences on the autosomes. In some embodiments, methods are provided for determining copy number variation (CNV) of any fetal aneuploidy, and CNVs known or suspected to be associated with a variety of medical conditions. Also disclosed are systems for evaluation of CNV of sequences of interest on the Y chromosome and other chromosomes.
摘要翻译： 本发明提供用于确定Y染色体的拷贝数的方法，包括但不限于使用包含母体和胎儿无细胞DNA的母体样品进行性别测定或胎儿Y染色体非整倍性的方法。 本文公开的一些实施例描述了使用女性样本的代表训练集来过滤（或掩蔽）染色体Y上的非判别序列读取的策略。 在一些实施方案中，该过滤策略也适用于过滤用于评估常染色体上序列的拷贝数变异的常数。 在一些实施方案中，提供了用于确定任何胎儿非整倍性的拷贝数变异（CNV）和已知或怀疑与各种医学状况相关联的CNV的方法。 还公开了用于评估Y染色体和其他染色体上感兴趣序列的CNV的系统。
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公开(公告)号：WO2014015319A1
公开(公告)日：2014-01-23
申请号：PCT/US2013/051399
申请日：2013-07-19
发明人： RAVA, Richard, P.
CPC分类号： G06F19/3431 , C12Q1/6883 , G06F19/00 , G06F19/22 , G06F19/24 , G16H50/30
摘要： The invention provides a method for determining copy number variations (CNV) of a sequence of interest in a test sample that comprises a mixture of nucleic acids that are known or are suspected to differ in the amount of one or more sequence of interest. The method comprises a statistical approach that accounts for accrued variability stemming from process-related, interchromosomal and inter-sequencing variability. The method is applicable to determining CNV of any fetal aneuploidy, and CNVs known or suspected to be associated with a variety of medical conditions. CNV that can be determined accord ing to the method include trisomies and monosomies of any one or more of chromosomes 1 -22, X and Y, other chromosomal polysomies, and deletions and/or duplications of segments of any one or more of the chromosomes, which can be detected by sequencing only once the nucleic acids of a test sample.
摘要翻译： 本发明提供了一种用于确定测试样品中感兴趣的序列的拷贝数变异（CNV）的方法，其包括已知或怀疑在一个或多个感兴趣序列的量上不同的核酸的混合物。 该方法包括统计方法，其考虑了由过程相关的染色体间和序列间变异性引起的应变变异性。 该方法适用于确定任何胎儿非整倍性的CNV，以及已知或怀疑与各种医学状况相关的CNV。 可以根据该方法确定的CNV包括染色体1-22，X和Y中的任何一个或多个的三体和单体，其他染色体多糖，以及任何一个或多个染色体的区段的缺失和/或重复， 其可以通过仅测试一次测试样品的核酸来检测。
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公开(公告)号：WO2014014498A1
公开(公告)日：2014-01-23
申请号：PCT/US2013/023909
申请日：2013-01-30
申请人： VERINATA HEALTH, INC. , RAVA, Richard, P. , CHINNAPPA, Manjula , COMSTOCK, David, A. , SRINIVASAN, Anupama
CPC分类号： C12Q1/6809 , G06F19/18 , G06F19/22 , C12Q2537/16 , C12Q2537/165 , C12Q2545/101
摘要： The invention provides a method for determining copy number variations (CNV) of a sequence of interest in a test sample that comprises a mixture of nucleic acids that are known or are suspected to differ in the amount of one or more sequence of interest. The method comprises a statistical approach that accounts for accrued variability stemming from process-related, interchromosomal and inter-sequencing variability. The method is applicable to determining CNV of any fetal aneuploidy, and CNVs known or suspected to be associated with a variety of medical conditions. CNV that can be determined according to the method include trisomies and monosomies of any one or more of chromosomes 1-22, X and Y, other chromosomal polysomies, and deletions and/or duplications of segments of any one or more of the chromosomes, which can be detected by sequencing only once the nucleic acids of a test sample.
摘要翻译： 本发明提供了一种用于确定测试样品中感兴趣的序列的拷贝数变异（CNV）的方法，其包括已知或怀疑在一个或多个感兴趣序列的量上不同的核酸的混合物。 该方法包括统计方法，其考虑了由过程相关的染色体间和序列间变异性引起的应变变异性。 该方法适用于确定任何胎儿非整倍性的CNV，以及已知或怀疑与各种医学状况相关的CNV。 可以根据该方法确定的CNV包括染色体1-22，X和Y，其他染色体多糖体中的任何一个或多个的三体和单体，以及任何一个或多个染色体的区段的缺失和/或重复，其中 只能通过测试一次测试样品的核酸来检测。
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公开(公告)号：WO2013062856A1
公开(公告)日：2013-05-02
申请号：PCT/US2012/060892
申请日：2012-10-18
发明人： BLUME, Erich, D. , BURKE, John, P. , HUANG, Hui
摘要： Disclosed are methods and tools for rapidly aligning reads to a reference sequence. These methods and tools employ Bloom filters or similar set membership testers to perform the alignment. The reads may be short sequences of nucleic acids or other biological molecules and the reference sequences may be sequences of genomes, chromosomes, etc. The Bloom filters include a collection of hash functions, a bit array, and associated logic for applying reads to the filter. Each filter, and there may be multiple of these used in a particular application, is used to determine whether an applied read is present in a reference sequence. Each Bloom filter is associated with a single reference sequence such as the sequence of a particular chromosome. In one example, chromosomal abundance is determined by aligning reads from a sequencer to multiple chromosomes, each having an associated Bloom filter or other set membership tester.
摘要翻译： 公开了用于将读取快速对准到参考序列的方法和工具。 这些方法和工具使用Bloom过滤器或类似的集成员测试器来执行对齐。 读取可以是核酸或其他生物分子的短序列，并且参考序列可以是基因组，染色体等的序列。Bloom过滤器包括哈希函数的集合，位阵列和用于将读取应用于过滤器的相关逻辑 。 每个过滤器，并且在特定应用中可以使用这些过滤器中的多个，用于确定在参考序列中是否存在应用的读取。 每个Bloom过滤器与单个参考序列相关联，例如特定染色体的序列。 在一个实例中，染色体丰度通过将来自测序仪的读数与多个染色体对齐来确定，每个染色体具有相关的Bloom过滤器或其他集合隶属度测试器。
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公开(公告)号：WO2012142334A3
公开(公告)日：2013-04-25
申请号：PCT/US2012033391
申请日：2012-04-12
发明人： RAVA RICHARD P , RHEES BRIAN K , BURKE JOHN P
IPC分类号： C12Q1/68
CPC分类号： G06F19/22 , C12Q1/6809 , C12Q1/6827 , C12Q1/6876 , C12Q1/6883 , C12Q2600/156 , G06F19/18 , G06F19/24 , G06F19/26 , C12Q2535/122 , C12Q2537/16 , C12Q2537/165
摘要： Methods of reliably estimating genomic fraction (e.g., fetal fraction) from polymorphisms such as small base variations or insertions-deletions are disclosed. Sequenced data from a multigenomic source is used to determine allele counts for one or more of the polymorphisms. For one or more of the polymorphisms, zygosity is assigned, and genomic fraction is determined from the zygosity and allele counts. Certain embodiments employ SNPs as the relevant polymorphism. The disclosed methods can be applied as part of an intentional, pre-designed re-sequencing study targeted against known polymorphisms or can be used in a retrospective analysis of variations found by coincidence in overlapping sequences generated from maternal plasma (or any other setting where a mixture of DNA from several people are present).
摘要翻译： 公开了从诸如小碱基变异或插入缺失的多态性可靠地估计基因组分数（例如胎儿级分）的方法。 来自多基因组源的序列数据用于确定一个或多个多态性的等位基因计数。 对于一个或多个多态性，分配接合性，并且从接合度和等位基因计数确定基因组分数。 某些实施方案使用SNP作为相关多态性。 所公开的方法可以作为针对已知多态性的有意的，预先设计的重排序研究的一部分来应用，或者可用于回顾性分析由母体血浆产生的重叠序列（或任何其他设置 来自几个人的DNA的混合物存在）。
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