Data processing: measuring – calibrating – or testing – Measurement system in a specific environment – Biological or biochemical
Reexamination Certificate
1997-09-16
2001-03-27
Shah, Kamini (Department: 2857)
Data processing: measuring, calibrating, or testing
Measurement system in a specific environment
Biological or biochemical
C382S129000, C435S005000, C435S009000, C436S161000, C436S163000
Reexamination Certificate
active
06208941
ABSTRACT:
REFERENCE TO MICROFICHE APPENDIX
A microfiche appendix, containing 5 microfiche and 229 total frames is filed herewith.
BACKGROUND OF THE INVENTION
A. Field of the Invention
This invention relates to the field of signal detection and analysis of chromatographic migration patterns as commonly applied to mixtures of molecules. More specifically, this invention relates to a method and apparatus for signal detection and analysis of chromatographic migration patterns as applied to the determination of DNA sequences.
B. Description of Related Art
The ability to efficiently and accurately detect and analyze information-containing signals in chromatographic data is important for handling large amounts of data. Such an ability is particularly important for projects such as the Human Genome Project, where large amounts of information will be generated which must be analyzed and integrated to produce a representative sequence of an entire human genome. To expedite the analysis of DNA sequence information, numerous methods have been developed. For example, a U.S. patent to Clark Tibbetts (U.S. Pat. No. 5,365,455) discloses a method for the automated processing of DNA sequence data. This patent is incorporated by reference herein in its entirety. The Tibbetts' method derives information from informative variables obtained from the input data set. Such informative variables may include the relative intensities between adjacent signals, the relative signal spacing and pattern recognition factors.
The Tibbetts' method is limited, however, by the quality of the chromatographic data. Tibbetts' method relies to a certain extent on the reproducibility of chromatographic data to train the base identification (“calling”) system. The apparatus generating the chromatographic data, therefore, needs to be consistent from run to run to avoid retraining the algorithm. Because chromatographic data frequently contain background noise and migration aberrations which obscure information-containing signals, analyses based on signal spacing may produce errors in signal identification. Similarly, because signal intensity often varies in an unpredictable manner, signal identification based on intensity may also result in significant identification errors.
A U.S. patent of Thomas Stockham and Jeff Ives (U.S. Pat. No. 5,273,632) discloses an alternate method for base identification using blind deconvolution (“BD”). This patent is incorporated by reference herein in its entirety. The method of Stockham and Ives uses blind deconvolution to deblur information-containing signals in chromatographic data. This method, however, is significantly limited in the following manner. First, it relies on data derived from scanned autoradiogram image data. Second, the method requires user input of the BD filter bandwidth and programmer alterations to various thresholds. Third, the Stockham and Ives method does not adequately deal with lane to lane mobility differences. Fourth, the insertion/deletion and correction logic was too simple. Fifth, the putative peak detection was based on thresholds, and therefore, could miss band detections when band amplitudes dropped below the threshold. Sixth, the method of Stockham and Ives lacked the ability to align and merge adjacent sample segments. Finally, that method lacked band quality measures useful in automatic data routing and or sequence assembly.
SUMMARY AND OBJECTS OF THE INVENTION
The present invention includes a method and apparatus for the detection and analysis of information-containing signals in chromatographic data. The invention also includes a method and apparatus for detecting and sharpening signal peaks in chromatographic data. It is an advantage of the present invention that a chromatographic data from a wide variety of separation processes can be analyzed. Such separation processes include, but are not limited to, gel and capillary electrophoresis.
The present invention includes the steps of preprocessing signal data, reading successive sample segments, selecting blocks of high quality sequence and then producing traces of aligned high quality sequences. It is an advantage of the present invention that the chromatographic data may include single fluor samples fractionated in multiple lanes and multiple fluor samples fractionated in single lanes.
It is an object of the present invention to provide a method for preprocessing chromatographic data by baseline subtracting background noise. It is an advantage of the present invention that the method of baseline subtraction may be varied according to the type of chromatographic data being analyzed. It is a further advantage of the invention that sparse chromatographic data may be interpolated during preprocessing.
It is an object of the present invention to read the preprocessed signals in successive sample segments. It is an advantage that the sample segment size may be sufficiently large to provide for rapid and efficient signal analysis.
It is an object of the invention to provide a method and apparatus for detecting information-containing signals which are not uniformly distributed in the chromatographic data. This analytic technique uses iterative blind deconvolution to determine band frequency in sample segments. It is an advantage of the invention that the filter-band width is automatically varied during iteration to optimally detect the signals in the preprocessed chromatographic data. It is a further function of the invention to detect and correct signal data derived from chromatographic data which have segments which are short in one or more signal types (for example, “band-lite” signals).
It is an object of the present invention to provide a method and apparatus to detect and correct for mobility differences. It is a feature of the invention that mobility differences are corrected using a Monte Carlo alignment rather than using band position or spacing information. It is an advantage of the present invention that the Monte Carlo alignment is an iterative process to optimize signal alignment.
It is an object of the invention to enhance band detection using fuzzy logic. It is a feature of the invention that band detection is performed using fuzzy logic blocks, each block providing a particular method of data analysis. It is an object of the invention that each fuzzy logic block may be optimized for a particular analytic function.
It is an object of the present invention that the invention may optionally provide a quality measure for each signal. It is a feature of the invention that the quality measure can be utilized during subsequent alignment steps. It is an advantage of the invention that the quality measure can provide left and right cutoff point to limit subsequent analysis to data above a given quality measure.
These and other objects, features and advantages of the invention will be clear to a person of ordinary skill in the art upon reading this specification in light of the appending drawings.
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Parons Behle & Latimer
Shah Kamini
University of Utah Research Foundation
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