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    • 1. 发明授权
    • Iterative probe design and detailed expression profiling with flexible in-situ synthesis arrays
    • 迭代探针设计和具有灵活原位合成阵列的详细表达谱
    • US07013221B1
    • 2006-03-14
    • US09561487
    • 2000-04-28
    • Stephen H. FriendRoland StoughtonPeter S. LinsleyJulja Burchard
    • Stephen H. FriendRoland StoughtonPeter S. LinsleyJulja Burchard
    • G01N33/48C12Q1/68
    • G06F19/20
    • Methods and compositions are provided that are useful for detecting and reporting a plurality of different target polynucleotide sequences in a sample, such as polynucleotides corresponding to a plurality of different genes expressed by a cell or cells. In particular, the invention provides methods for screening a plurality of candidate polynucleotide probes to evaluate both the sensitivity and the specificity with which each candidate probe hybridizes to a target polynucleoide sequence. Candidate polynucleotide probes can then be ranked according to both their sensitivity and specificity, and probes that have optimal sensitivity and specificity for a target polynucleotide sequence can be selected. In one embodiment, polynucleotide probes can be selected according to the methods described herein to prepare “screening chips” wherein a large number of target polynucleotide sequences are detected using a single microarray have a few (e.g., 1–5) probes for each target polynucleotide sequence. In a particularly preferred embodiment, the invention provides a screening chip that can detect genetic transcripts from the entire genome of an organism. In an alternative embodiment, polynucleotide probes can be selected according to the methods described herein to prepare “signature chips” to more accurately detect certain selected “signature genes” using several polynucleotide probes (e.g., 10–20) for each signature gene. The invention additionally provides microarrays containing polynucleotide probes for a large number of genes expressed by a cell or organism. Further, methods for detecting a plurality of polynucleotide molecules, including a large number of genes expressed by a cell or organism, are also provided.
    • 提供了可用于检测和报告样品中多个不同靶多核苷酸序列的方法和组合物,例如对应于由细胞或细胞表达的多种不同基因的多核苷酸。 特别地,本发明提供了筛选多个候选多核苷酸探针以评估每个候选探针与目标多核苷酸序列杂交的灵敏度和特异性的方法。 然后可以根据其灵敏度和特异性对候选多核苷酸探针进行排序,并且可以选择对靶多核苷酸序列具有最佳敏感性和特异性的探针。 在一个实施方案中,可以根据本文所述的方法选择多核苷酸探针以制备“筛选芯片”,其中使用单个微阵列检测大量目标多核苷酸序列,其中每个靶多核苷酸具有少量(例如1-5)探针 序列。 在一个特别优选的实施方案中,本发明提供了可以检测来自生物体的整个基因组的遗传转录物的筛选芯片。 在替代实施方案中,可以根据本文所述的方法选择多核苷酸探针以通过使用每个特征基因的多个多核苷酸探针(例如10-20)来制备“签名芯片”以更精确地检测某些所选择的“特征基因”。 本发明另外提供含有由细胞或生物表达的大量基因的多核苷酸探针的微阵列。 此外,还提供了用于检测多个多核苷酸分子的方法,包括由细胞或生物体表达的大量基因。
    • 3. 发明授权
    • Methods for determining cross-hybridization
    • 确定交叉杂交的方法
    • US06171794B2
    • 2001-01-09
    • US09335971
    • 1999-06-18
    • Julja BurchardRoland StoughtonStephen H. Friend
    • Julja BurchardRoland StoughtonStephen H. Friend
    • C12Q168
    • C12Q1/6832C07B2200/11C12Q2527/107
    • The present invention provides methods for distinguishing the fractions of polynucleotide sequences which hybridize to any given probe, including probes on microarrays such as those described herein. In particular, the present invention enables users to identify the fraction of sequences which are perfectly complementary to a probe, thereby correcting for effects of cross hybridization in a hybridization assay. The methods of the invention work by monitoring the kinetics of dissociation of sequences from the probe so that a resulting “dissociation curve” may be compared to a combination of the individual “dissociation profiles” for each sequence which hybridizes. In alternative embodiments, the invention also provides computer systems for performing the present methods, as well as databases of the dissociation profiles.
    • 本发明提供了用于区分与任何给定探针杂交的多核苷酸序列的级分的方法,包括在诸如本文所述的微阵列之类的微阵列上的探针。 特别地,本发明使得用户能够鉴定与探针完全互补的序列部分,从而在杂交测定中校正交叉杂交的作用。 本发明的方法通过监测序列从探针中解离的动力学来起作用,从而可将所得到的“解离曲线”与杂交的每个序列的单独“解离曲线”的组合进行比较。 在替代实施例中,本发明还提供用于执行本方法的计算机系统以及解离曲线的数据库。
    • 4. 发明授权
    • Methods of characterizing drug activities using consensus profiles
    • 使用共识的形式表征药物活动的方法
    • US06801859B1
    • 2004-10-05
    • US09220142
    • 1998-12-23
    • Stephen H. FriendRoland StoughtonYudong He
    • Stephen H. FriendRoland StoughtonYudong He
    • G01N3348
    • G06F19/24G06F19/20
    • The present invention provides methods for enhanced detection of biological response profiles. In particular, the methods of this invention allow for the detection of biological response patterns, such as gene expression patterns, in response to different drug treatments. The methods of the invention also allow the determination of a “consensus profile” which describes a particular class or type of biological response. In certain embodiments the consensus profile may describe the biological response of a particular group or class of drugs. In other embodiments, the consensus profile may describe an “ideal” biological response such as one associated with a desired therapeutic effect. The methods of the present invention also allow for the comparison of different biological responses. Thus, the methods of the invention may be used, e.g., to identify and/or study new drugs.
    • 本发明提供用于增强生物反应曲线检测的方法。 特别地,本发明的方法允许响应于不同的药物治疗来检测生物反应模式,如基因表达模式。 本发明的方法还允许确定描述特定类别或类型的生物反应的“共有概况”。 在某些实施方案中,共有概况可以描述特定组或一类药物的生物反应。 在其它实施方案中,共有概况可以描述“理想”生物反应,例如与期望的治疗效果相关联的生物反应。 本发明的方法还允许比较不同的生物反应。 因此,本发明的方法可以用于例如鉴定和/或研究新的药物。
    • 8. 发明授权
    • Methods for using co-regulated genesets to enhance detection and classification of gene expression patterns
    • 使用共同调控的基因组来增强基因表达模式的检测和分类的方法
    • US07599799B2
    • 2009-10-06
    • US10273489
    • 2002-10-18
    • Stephen H. FriendRoland StoughtonYudong He
    • Stephen H. FriendRoland StoughtonYudong He
    • G06F19/00C12Q1/68C12P21/06G06G7/58
    • G06F19/24C12Q1/6809C12Q1/6834G01N33/6803G06F19/20
    • The present invention provides methods for enhanced detection of biological response patterns. In one embodiment of the invention, genes are grouped into basis genesets according to the co-regulation of their expression. Expression of individual genes within a geneset is indicated with a single gene expression value for the geneset by a projection process. The expression values of genesets, rather than the expression of individual genes, are then used as the basis for comparison and detection of biological response with greatly enhanced sensitivity. In another embodiment of the invention, biological responses are grouped according to the similarity of their biological profile.The methods of the invention have many useful applications, particularly in the fields of drug development and discovery. For example, the methods of the invention may be used to compare biological responses with greatly enhanced sensitivity. The biological responses that may be compared according to these methods include responses to single perturbations, such as a biological response to a mutation or temperature change, as well as graded perturbations such as titration with a particular drug. The methods are also useful to identify cellular constituents, particularly genes, associated with a particular type of biological response. Further, the methods may also be used to identify perturbations, such as novel drugs or mutations, which effect one or more particular genesets. The methods may still further be used to remove experimental artifacts in biological response data.
    • 本发明提供了用于增强生物反应模式检测的方法。 在本发明的一个实施方案中,根据其表达的共调节将基因分组成基因基因组。 个体基因在基因组中的表达用投影过程的基因表达值表示。 然后将基因的表达值,而不是单个基因的表达值作为比较和检测生物反应的基础,大大提高敏感性。 在本发明的另一个实施方案中,根据生物学特性的相似性对生物反应进行分组。 本发明的方法具有许多有用的应用,特别是在药物开发和发现领域。 例如,本发明的方法可用于比较具有极大增强的灵敏度的生物反应。 可以根据这些方法比较的生物反应包括对单一扰动的反应,例如对突变或温度变化的生物反应,以及分级扰动,例如用特定药物滴定。 所述方法还可用于鉴定与特定类型的生物反应相关的细胞成分,特别是基因。 此外,所述方法还可用于鉴定影响一个或多个特定基因组的扰动,例如新型药物或突变。 这些方法还可以进一步用于去除生物反应数据中的实验伪影。
    • 9. 发明申请
    • METHODS FOR USING CO-REGULATED GENESETS TO ENHANCE DETECTION AND CLASSIFICATION OF GENE EXPRESSION PATTERNS
    • 使用协调调节基因以加强基因表达模式的检测和分类的方法
    • US20090204333A1
    • 2009-08-13
    • US10273489
    • 2002-10-18
    • Stephen H. FriendRoland StoughtonYudong He
    • Stephen H. FriendRoland StoughtonYudong He
    • G06F19/00
    • G06F19/24C12Q1/6809C12Q1/6834G01N33/6803G06F19/20
    • The present invention provides methods for enhanced detection of biological response patterns. In one embodiment of the invention, genes are grouped into basis genesets according to the co-regulation of their expression. Expression of individual genes within a geneset is indicated with a single gene expression value for the geneset by a projection process. The expression values of genesets, rather than the expression of individual genes, are then used as the basis for comparison and detection of biological response with greatly enhanced sensitivity. In another embodiment of the invention, biological responses are grouped according to the similarity of their biological profile.The methods of the invention have many useful applications, particularly in the fields of drug development and discovery. For example, the methods of the invention may be used to compare biological responses with greatly enhanced sensitivity. The biological responses that may be compared according to these methods include responses to single perturbations, such as a biological response to a mutation or temperature change, as well as graded perturbations such as titration with a particular drug. The methods are also useful to identify cellular constituents, particularly genes, associated with a particular type of biological response. Further, the methods may also be used to identify perturbations, such as novel drugs or mutations, which effect one or more particular genesets. The methods may still further be used to remove experimental artifacts in biological response data.
    • 本发明提供了用于增强生物反应模式检测的方法。 在本发明的一个实施方案中,根据其表达的共调节将基因分组成基因基因组。 个体基因在基因组中的表达用投影过程的基因表达值表示。 然后将基因的表达值,而不是单个基因的表达值作为比较和检测生物反应的基础,大大提高敏感性。 在本发明的另一个实施方案中,根据生物学特性的相似性对生物反应进行分组。 本发明的方法具有许多有用的应用,特别是在药物开发和发现领域。 例如,本发明的方法可用于比较具有极大增强的灵敏度的生物反应。 可以根据这些方法比较的生物反应包括对单一扰动的反应,例如对突变或温度变化的生物反应,以及分级扰动,例如用特定药物滴定。 所述方法还可用于鉴定与特定类型的生物反应相关的细胞成分,特别是基因。 此外,所述方法还可用于鉴定影响一个或多个特定基因组的扰动,例如新型药物或突变。 这些方法还可以进一步用于去除生物反应数据中的实验伪影。
    • 10. 发明授权
    • Computer systems and computer programs for determining protein activity levels using gene expression profiles
    • 使用基因表达谱测定蛋白质活性水平的计算机系统和计算机程序
    • US07130746B2
    • 2006-10-31
    • US09975843
    • 2001-10-12
    • Stephen H. FriendRoland Stoughton
    • Stephen H. FriendRoland Stoughton
    • G01N33/48G06F19/00G06G7/48
    • C07K14/4702A61K38/00
    • The present invention provides methods for determining the level of protein activity in a cell by: (i) measuring abundances of cellular constituents in a cell in which the activity of a specific protein is to be determined so that a diagnostic profile is thus obtained; (ii) measuring abundances of cellular constituents that occur in a cell in response to perturbations in the activity of said protein to obtain response profiles and interpolating said response profiles to generate response curves; and (iii) determining a protein activity level at which the response profile extracted from the response curves best fits the measured diagnostic profile, according to some objective measure. In alternative embodiments, the present invention also provides methods for identifying individuals having genetic mutations or polymorphisms that disrupt protein activity, and methods for identifying drug activity in vivo by determining the activity levels of proteins which interact with said drugs.
    • 本发明提供了通过以下步骤确定细胞中蛋白质活性水平的方法:(i)测量要确定特定蛋白质的活性的细胞中细胞成分的丰度,从而获得诊断特征; (ii)测量在细胞中发生的细胞成分的丰度以响应所述蛋白质的活动中的扰动以获得反应谱并内插所述响应谱以产生响应曲线; 和(iii)根据一些客观的测定,确定从响应曲线提取的反应曲线最适合测量的诊断谱的蛋白质活性水平。 在替代实施方案中,本发明还提供了用于鉴定具有破坏蛋白质活性的遗传突变或多态性的个体的方法,以及通过测定与所述药物相互作用的蛋白质的活性水平来鉴定体内药物活性的方法。