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

Applicant: VERINATA HEALTH, INC.

Inventor： CHUDOVA, Darya I. ,  ABDUEVA, Diana ,  RAVA, Richard P.

IPC: G06F19/20 ,  G06F19/22

CPC classification number: G06F19/20 ,  G06F19/00 ,  G16H50/20

Abstract: 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.

Abstract translation: 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。

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

Applicant: VERINATA HEALTH, INC.

Inventor： CHUDOVA, Darya I. ,  BARBACIORU, Catalin ,  DUENWALD, Sven ,  COMSTOCK, David A. ,  RAVA, Richard P.

IPC: C12Q1/68 ,  G06F19/18 ,  G06F19/22

CPC classification number: C12Q1/6809 ,  C12Q1/6869 ,  C12Q2535/122 ,  C12Q2537/16 ,  C12Q2537/165 ,  C12Q2545/101 ,  G06F19/18 ,  G06F19/22

Abstract: 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.

Abstract translation: 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。

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

Applicant: VERINATA HEALTH, INC. ,  RAVA, Richard P. ,  COMSTOCK, David A. ,  RHEES, Brian K.

Inventor： RAVA, Richard P. ,  COMSTOCK, David A. ,  RHEES, Brian K.

IPC: C12Q1/68

CPC classification number: C12Q1/6869 ,  C12Q1/6806 ,  C12Q1/6883 ,  C12Q2545/101 ,  C12Q2535/122 ,  C12Q2531/113

Abstract: 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.

Abstract translation: 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。

公开(公告)号：WO2017136059A1

公开(公告)日：2017-08-10

申请号：PCT/US2016/067886

申请日：2016-12-20

Applicant: VERINATA HEALTH, INC.

Inventor： DUENWALD, Sven ,  COMSTOCK, David A. ,  BARBACIORU, Catalin ,  CHUDOVA, Darya I., ,  RAVA, Richard P. ,  JONES, Keith W. ,  CHEN, Gengxin ,  SKVORTSOV, Dimitri

IPC: C12Q1/68 ,  G06F19/24 ,  G06F19/18 ,  G06F19/22 ,  G06F19/00

CPC classification number: G06F19/22 ,  C12Q1/6869 ,  C12Q1/6883 ,  C12Q2600/154 ,  C12Q2600/156 ,  G06F19/00 ,  G06F19/18 ,  G06F19/20 ,  G06F19/24 ,  G06F19/34 ,  G16H50/20 ,  C12Q2537/16 ,  C12Q2537/165

Abstract: 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 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. In some implementations, information from fragments of different sizes are used to evaluate copy number variations. In some implementations, one or more t-statistics obtained from coverage information of the sequence of interest is used to evaluate copy number variations. In some implementations, one or more fetal fraction estimates are combined with one or more t-statistics to determine copy number variations.

Abstract translation: 公开了用于确定已知或怀疑与多种医学病症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的母体样品确定胎儿拷贝数变异的方法。 在一些实施方案中，提供了用于确定已知或怀疑与各种医学病症相关的CNV的方法。 本文公开的一些实施方式提供了通过导出片段大小参数来改善序列数据分析的灵敏度和/或特异性的方法。 在一些实现中，来自不同大小的片段的信息被用于评估拷贝数变化。 在一些实施方式中，从感兴趣的序列的覆盖信息中获得的一个或多个t统计被用于评估拷贝数变化。 在一些实施方式中，将一个或多个胎儿分数估计值与一个或多个t统计量组合以确定拷贝数变化。

公开(公告)号：WO2014145078A1

公开(公告)日：2014-09-18

申请号：PCT/US2014/029739

申请日：2014-03-14

Applicant: VERINATA HEALTH, INC.

Inventor： SRINIVASAN, Anupama ,  RAVA, Richard P.

IPC: C12Q1/68

CPC classification number: C12Q1/6809 ,  C12Q1/6806 ,  C12Q1/6855 ,  C12Q2537/16

Abstract: The disclosure provides methods and kits for preparing sequencing library to detect chromosomal abnormality using cell-free DNA (cfDNA) without the need of first isolating the cfDNA from a liquid fraction of a test sample. In some embodiments, the method involves reducing the binding between the cfDNA and nucleosomal proteins without unwinding the cfDNA from the nucleosomal proteins. In some embodiments, the reduction of binding may be achieved by treating with a detergent or heating. In some embodiments, the method further involves freezing and thawing the test sample before reducing the binding between the cfDNA and the nucleosomal proteins. In some embodiments, the test sample is a peripheral blood sample from a pregnant woman including cfDNA of both a mother and a fetus, wherein the methods may be used to detect fetal chromosomal abnormality such as copy number variation. In other embodiments, the test sample is a peripheral blood sample from a patient known or suspected to have cancer, wherein the methods can be used to detect chromosomal abnormalities in the cfDNA of the patient. Kits for detection of copy number variation of the fetus using the disclosed methods are also provided.

Abstract translation: 本公开提供用于制备测序文库以使用无细胞DNA（cfDNA）检测染色体异常而不需要首先从测试样品的液体部分分离cfDNA的方法和试剂盒。 在一些实施方案中，该方法包括减少cfDNA和核小体蛋白之间的结合，而不从核小体蛋白中解离出cfDNA。 在一些实施方案中，结合的减少可以通过用洗涤剂或加热处理来实现。 在一些实施方案中，该方法还包括在减少cfDNA和核小体蛋白之间的结合之前冻结和解冻测试样品。 在一些实施方案中，测试样品是来自孕妇的外周血样品，包括母体和胎儿的cfDNA，其中所述方法可用于检测胎儿染色体异常，例如拷贝数变异。 在其他实施方案中，测试样品是来自已知或怀疑具有癌症的患者的外周血样品，其中所述方法可用于检测患者的cfDNA中的染色体异常。 还提供了使用所公开的方法检测胎儿的拷贝数变异的试剂盒。