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1. 发明授权

US06303303B1 Method and system for DNA sequence determination and mutation detection 失效
标题翻译：用于DNA序列测定和突变检测的方法和系统
公开(公告)号：US06303303B1
公开(公告)日：2001-10-16
申请号：US09190756
申请日：1998-11-12
申请人： Ronald J. Green , Vrijmoed Chi , Rodney D. Gilchrist , Gregory Dee , John K. Stevens
发明人： Ronald J. Green , Vrijmoed Chi , Rodney D. Gilchrist , Gregory Dee , John K. Stevens
IPC分类号： C12Q168
CPC分类号： G01N27/44721 , G01N27/44717 , G06F19/18 , G06F19/22 , Y10T436/143333
摘要： Normalization of experimental fragment patterns for nucleic acid polymers having putatively known sequences starts with obtaining at least one raw fragment pattern for the experimental sample. The raw fragment pattern represents the positions of a selected nucleic acid base within the polymer as a function of migration time or distance. This raw fragment pattern is conditioned using conventional baseline correction and noise reduction technique to yield a clean fragment pattern. The clean fragment pattern is then evaluated to determine one or more “normalization coefficients.” These normalization coefficients reflect the displacement, stretching or shrinking, and rate of stretching or shrinking of the clean fragment, or segments thereof, which are necessary to obtain a suitably high degree of correlation between the clean fragment pattern and a standard fragment pattern which represents the positions of the selected nucleic acid base within a standard polymer actually having the known sequence as a function of migration time or distance. The normalization coefficients are then applied to the clean fragment pattern to produce a normalized fragment pattern which is used for base-calling in a conventional manner. This method may be implemented in an apparatus comprising a computer processor programmed to determine normalization coefficients for an experimental fragment pattern. This computer may be separate from the electrophoresis apparatus, or part of an integrated unit.
摘要翻译：具有推定已知序列的核酸聚合物的实验片段模式的归一化从获得实验样品的至少一个原始片段图案开始。原始片段图案表示聚合物内所选择的核酸碱基作为迁移时间或距离的函数的位置。使用常规的基线校正和降噪技术调节该原始片段模式以产生干净的片段模式。然后评估干净的片段模式以确定一个或多个“归一化系数”。这些归一化系数反映了清洁片段或其片段的位移，拉伸或缩小以及拉伸或收缩速率，这些片段或片段是清洁片段图案与标示片段图案之间适当高程度的相关性所必需的，实际上具有已知序列的标准聚合物内所选核酸碱基的位置作为迁移时间或距离的函数。然后将归一化系数应用于干净的片段模式以产生用于以常规方式的基本呼叫的归一化的片段模式。该方法可以在包括被编程为确定实验片段模式的归一化系数的计算机处理器的装置中实现。该计算机可以与电泳装置或集成单元的一部分分开。

2. 发明授权

US5853979A Method and system for DNA sequence determination and mutation detection with reference to a standard 失效
标题翻译：参考标准的DNA序列测定和突变检测的方法和系统
公开(公告)号：US5853979A
公开(公告)日：1998-12-29
申请号：US497202
申请日：1995-06-30
申请人： Ronald J. Green , Vrijmoed Chi , Rodney D. Gilchrist , Gregory Dee , John K. Stevens
发明人： Ronald J. Green , Vrijmoed Chi , Rodney D. Gilchrist , Gregory Dee , John K. Stevens
IPC分类号： C12Q1/68 , G01N27/447 , C12Q1/70 , G01N33/48 , G06K9/00
CPC分类号： G01N27/44721 , G01N27/44717 , G06F19/18 , G06F19/22 , Y10T436/143333
摘要： Normalization of experimental fragment patterns for nucleic acid polymers having putatively known sequences starts with obtaining at least one raw fragment pattern for the experimental sample. The raw fragment pattern represents the positions of a selected nucleic acid base within the polymer as a function of migration time or distance. This raw fragment pattern is conditioned using conventional baseline correction and noise reduction technique to yield a clean fragment pattern. The clean fragment pattern is then evaluated to determine one or more "normalization coefficients." These normalization coefficients reflect the displacement, stretching or shrinking, and rate of stretching or shrinking of the clean fragment, or segments thereof, which are necessary to obtain a suitably high degree of correlation between the clean fragment pattern and a standard fragment pattern which represents the positions of the selected nucleic acid base within a standard polymer actually having the known sequence as a function of migration time or distance. The normalization coefficients are then applied to the clean fragment pattern to produce a normalized fragment pattern which is used for base-calling in a conventional manner. This method may be implemented in an apparatus comprising a computer processor programmed to determine normalization coefficients for an experimental fragment pattern. This computer may be separate from the electrophoresis apparatus, or part of an integrated unit.
摘要翻译：具有推定已知序列的核酸聚合物的实验片段模式的归一化从获得实验样品的至少一个原始片段图案开始。原始片段图案表示聚合物内所选择的核酸碱基作为迁移时间或距离的函数的位置。使用常规的基线校正和降噪技术调节该原始片段模式以产生干净的片段模式。然后评估干净的片段模式以确定一个或多个“归一化系数”。这些归一化系数反映了清洁片段或其片段的位移，拉伸或缩小以及拉伸或收缩速率，这些片段或片段是清洁片段图案与标示片段图案之间适当高程度的相关性所必需的，实际上具有已知序列的标准聚合物内所选核酸碱基的位置作为迁移时间或距离的函数。然后将归一化系数应用于干净的片段模式以产生用于以常规方式的基本呼叫的归一化的片段模式。该方法可以在包括被编程为确定实验片段模式的归一化系数的计算机处理器的装置中实现。该计算机可以与电泳装置或集成单元的一部分分开。

3. 发明授权

US06554987B1 Method and apparatus for alignment of signals for use in DNA base-calling 有权
标题翻译：用于DNA碱基呼叫中使用的信号对准的方法和装置
公开(公告)号：US06554987B1
公开(公告)日：2003-04-29
申请号：US09147916
申请日：1999-11-04
申请人： Rodney D. Gilchrist , Vrijmoed Chi
发明人： Rodney D. Gilchrist , Vrijmoed Chi
IPC分类号： G01N27447
CPC分类号： G06K9/00543 , G01N27/44717 , G01N27/44721 , G06F19/18 , G06F19/22
摘要： Data traces from four channels of an automated electrophoresis detection apparatus are aligned by identifying peaks in each of the four data traces; optionally normalizing the data traces to achieve a uniform peak height; combining the four data traces in an initial alignment; and determining coefficients of shift and stretch for selected data points within each data trace. The coefficients are determined by optimizing a cost function which reflects the extent of overlap of peaks in the combined normalized data traces to which the coefficients have been applied. The cost function is optimized when the extent of overlap is at a minimum. The coefficients are then used to generate a warp function for each data trace. These warp functions are applied to their respective data traces to produce four warped data traces which are aligned to form an aligned data set. The aligned data set may be displayed on a video screen of a sequencing apparatus, or may be used as the data set for a base-calling process.
摘要翻译：通过识别四个数据迹线中的每一个中的峰值来对齐自动电泳检测装置的四个通道的数据迹线; 可选地归一化数据轨迹以实现均匀的峰高; 在初始对齐中组合四条数据轨迹; 并确定每个数据轨迹内所选数据点的偏移和拉伸系数。通过优化成本函数来确定系数，该成本函数反映了已经应用系数的组合归一化数据轨迹中的峰的重叠程度。当重叠程度最小时，优化成本函数。然后，系数用于为每个数据跟踪生成warp函数。这些翘曲函数被应用于它们各自的数据迹线以产生四个翘曲的数据迹线，其被对准以形成对准的数据集。对准的数据集可以显示在排序装置的视频屏幕上，或者可以用作基本呼叫处理的数据集。

4. 发明授权

US5916747A Method and apparatus for alignment of signals for use in DNA based-calling 失效
标题翻译：用于DNA碱基呼叫中使用的信号对准的方法和装置
公开(公告)号：US5916747A
公开(公告)日：1999-06-29
申请号：US670534
申请日：1996-06-27
申请人： Rodney D. Gilchrist , Vrijmoed Chi
发明人： Rodney D. Gilchrist , Vrijmoed Chi
IPC分类号： C12Q1/68 , G01N27/447
CPC分类号： G06K9/00543 , G01N27/44717 , G01N27/44721 , G06F19/18 , G06F19/22
摘要： Data traces from four channels of an automated electrophoresis detection apparatus are aligned by identifying peaks in each of the four data traces; normalizing the heights of the peaks in each of the data traces to a common value to generate four normalized data traces; combining the four normalized data traces in an initial alignment; and determining coefficients of shift and stretch for selected data points within each normalized data trace. The coefficients are determined by optimizing a cost function which reflects the extent of overlap of peaks in the combined normalized data traces to which the coefficients have been applied. The cost function is optimized when the extent of overlap is at a minimum. The coefficients are then used to generate a warp function for each normalized data trace. These warp function are applied to their respective data traces to produce four warped data traces which are aligned to form an aligned data set. The aligned data set may be displayed on a video screen of a sequencing apparatus, or may be used as the data set for a base-calling process.
摘要翻译：通过识别四个数据迹线中的每一个中的峰值来对齐自动电泳检测装置的四个通道的数据迹线; 将每个数据轨迹中的峰值的高度归一化为公共值，以生成四个标准化数据轨迹; 在初始对准中组合四个归一化数据轨迹; 并确定每个归一化数据轨迹内所选数据点的偏移和拉伸系数。通过优化成本函数来确定系数，该成本函数反映了已经应用系数的组合归一化数据轨迹中的峰的重叠程度。当重叠程度最小时，优化成本函数。然后，系数用于为每个归一化数据轨迹生成翘曲函数。这些翘曲函数被应用于它们各自的数据迹线以产生四个翘曲的数据迹线，其被对准以形成对齐的数据集。对准的数据集可以显示在排序装置的视频屏幕上，或者可以用作基本呼叫处理的数据集。

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