WO2002008949A2 - Methods and systems for evaluating a matching between measured data and standards - Google Patents
Methods and systems for evaluating a matching between measured data and standards Download PDFInfo
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- WO2002008949A2 WO2002008949A2 PCT/US2001/023630 US0123630W WO0208949A2 WO 2002008949 A2 WO2002008949 A2 WO 2002008949A2 US 0123630 W US0123630 W US 0123630W WO 0208949 A2 WO0208949 A2 WO 0208949A2
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- matching
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- G—PHYSICS
- G06—COMPUTING; CALCULATING OR COUNTING
- G06F—ELECTRIC DIGITAL DATA PROCESSING
- G06F17/00—Digital computing or data processing equipment or methods, specially adapted for specific functions
- G06F17/10—Complex mathematical operations
- G06F17/18—Complex mathematical operations for evaluating statistical data, e.g. average values, frequency distributions, probability functions, regression analysis
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
- G01N27/26—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating electrochemical variables; by using electrolysis or electrophoresis
- G01N27/416—Systems
- G01N27/447—Systems using electrophoresis
-
- G—PHYSICS
- G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
- G16B—BIOINFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR GENETIC OR PROTEIN-RELATED DATA PROCESSING IN COMPUTATIONAL MOLECULAR BIOLOGY
- G16B40/00—ICT specially adapted for biostatistics; ICT specially adapted for bioinformatics-related machine learning or data mining, e.g. knowledge discovery or pattern finding
- G16B40/10—Signal processing, e.g. from mass spectrometry [MS] or from PCR
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/86—Signal analysis
- G01N30/8675—Evaluation, i.e. decoding of the signal into analytical information
-
- G—PHYSICS
- G06—COMPUTING; CALCULATING OR COUNTING
- G06N—COMPUTING ARRANGEMENTS BASED ON SPECIFIC COMPUTATIONAL MODELS
- G06N5/00—Computing arrangements using knowledge-based models
- G06N5/02—Knowledge representation; Symbolic representation
- G06N5/022—Knowledge engineering; Knowledge acquisition
Definitions
- the present invention relates to methods and systems for evaluating a matching between data, in particular a sequence of measured data points, and a pre-defined standard. It has specific, although not necessarily exclusive application in the field of evaluating biological data.
- This problem can be illustrated by taking the biological example of evaluating the size (i.e. length) of DNA fragments (measured in base pairs for instance) . This is not a property that can be measured directly.
- the alternative, indirect measure of fragment size most commonly used is a measure of the rate at which the fragments are transported through a medium in which their mobility varies with size. Typically this is achieved by electrophoresis through lanes in a polyacrylmide gel, the details of which will be well known to the skilled person and need not be repeated here .
- the location of the fragments along the lane, or the point in time at which a particular fragment passes a set point along the lane provides an indirect measure of the fragment size.
- this provides only a measure of the relative sizes of the fragments to one another. What it does not provide is any absolute values for fragment size.
- This in-lane size standard is a kind of "ruler" made up of a set of fragments of known size (i.e. length) . If the location of these size standard fragments can be accurately determined, it is then possible to evaluate the size of an unknown fragment by comparing its location with those of the size standard and interpolating from the known sizes of the size standard fragments .
- Embodiments of the present invention are concerned with providing efficient approaches to carrying out and evaluating such matching processes .
- the present invention proposes an approach to matching measured data points representative of a physical property (for instance the measured peak location or positions of an in-lane size standard which represent DNA fragment length) to a set of standard values of that property (for instance a size standard definition) .
- the matching is evaluated by comparing ratios of intervals between selected pairs of the measured data points with ratios of the intervals between adjacent pairs of the standard values, to find the measured data points that best match the standard values.
- Fig. 1 is a flow diagram illustrating the basis matching process according to an embodiment of the present invention
- Fig. 2 Illustrates Example peaks, sizes and a matching
- Fig. 3 shows execution time for the matching process against number of values in the size standard and additional peaks
- Fig. 4 shows execution time versus the number of values in the size standard definition for different numbers of additional peaks
- Fig. 5 shows execution time versus the number of extra peaks for a series of size standard definitions having differing numbers of size values
- Fig. 6, 7, 8 and 9 show exemplary results from matchings
- Fig. 10 is a table of execution times versus the number of size value in the size standard definition and the number of additional peaks ;
- Fig. 11 is a block diagram illustrating a suitable system architecture for operating embodiments of the invention.
- Embodiments of the invention are described below in the context of the exemplary application of the described approach to the problem of matching an in-line size standard to a size standard definition for the evaluation of nucleic acid information obtained from an electrophoresis procedure. It will be appreciated that the approach has wider applicability
- the method operates by matching data generated with a standard sample to actual sizes that should exist in the standard sample. For example, one may use a standard sample with nucleotide lengths 110, 114, 117, 120, and 125. One runs the standard sample and obtains several data peaks. The size standard matching component predicts the peaks that correspond to the five known nucleotide lengths. Thus, one can subsequently compare data in a sample to those peaks to determine the nucleotide lengths of fragments in a sample.
- an embodiment of the process operates by first selecting a sequence of peaks from those obtained by running the standard sample, the number of peaks selected being equal to the number of values in the size standard, definition. One peak is matched to each of the size standard sizes in sequence. The matching this produces is then evaluated to determine the total cost for the matching. This process is repeated for a number of different sequences of peaks to establish which sequence of the possible variations from the peaks obtained from running the standard sample provides the best matching.
- a matching component uses an algorithm that has three parameters: ratio factor (the importance of peak height vs . the importance of the local linearity) , min acceptable quality (used for ending dynamic programming iteration) , and number of extra peaks (the number of peaks participated in size matching is the number of size standard definition fragments plus the number of extra peaks) .
- the component fixes the ratio factor to 0.6 and min acceptable quality to 0.75.
- the component fixes the number of extra peaks to 10 for Applied Biosystems 310/377 instrument data and 25 for Applied Biosystems 3700 instrument data.
- a statistically based quality value is generated for the matching result.
- one skilled in the art will be able to adjust the number of extra peaks that may be used with a given instrument .
- the component ignores the peaks located within the offscale regions in the sample.
- the component fails the size matching process if the size standard definitions are not fully matched in the matching process .
- the component implements two primer peak detection methods.
- the first is the primer-peak-height- suppression method. This method replaces the peak heights of the highest peaks with the peak height of the middle peak, assuming that the primer peaks are among the highest.
- the second is to find the primer peak location. The method assumes that the primer peak locates within the first half of the signal and the size standard fragments locate in the second half of the signal. For example, one takes the mean peak height of all the peaks in the second half and multiples that mean by five to get the potential primer peak height. The method works backwards in the first half of the signal to find the last primer peak.
- a size-standard matcher takes as input a list of peaks (e.g., from an electropherogram) and a list of fragment sizes (e.g., in nucleotides) . It produces as output a matching, that is, a list of pairs of the form ⁇ peak,size>, where each peak and each fragment size appears at most once.
- a size-standard matcher evaluates a matching, and uses an algorithm for finding good matchings . Certain embodiments employ an algorithm that evaluates a matching by treating its two constituent sequences as sequences of edges between points. A matching is also a correspondence between edges.
- a matching is also a correspondence between ratios. Under the assumption that the relation between peak position and fragment size is "more or less" linear, corresponding ratios typically should be equal.
- the component derives a ratio cost to measure this property. In certain embodiments, the component also concentrates on big peaks by deriving a height cost . The total cost of a matching is a weighted sum of these constituent costs.
- the component formulates the size standard matching problem as finding a matching with maximum cost.
- the cost is separable. That is, with some additional mathematics, the component can maximise subsequences independently.
- the cost also enjoys the advantage of being local, thereby compensating for global deviations from linearity. This cost also leads to a quality value between 0 and 1.
- a size standard is a set of DNA fragments, each of known size. The defini tion of a size standard is simply a list of these sizes. Note that a size-standard definition typically does not depend on the instrument on which the size standard is run, and therefore not on any particular set of run conditions either.
- An in-lane size standard is a set of peaks resulting from running a size standard on an instrument. One determines the positions and the heights of the peaks.
- a size-standard matcher takes as input an in-lane size standard and a size standard definition. It produces as output a matching, that is, a list of pairs of the form (peak, size), where each peak and each fragment size appears at most once.
- a peak has a position (e.g., in scan numbers) and a height (e.g., in fluorescent units). Fragment sizes are given in nucleotides. Assume that there are at least as many peaks as sizes.
- one employs the following components.
- M ⁇ (3, 0), (4, 1), (6, 2), (8, 3), (9, 4) ⁇ .
- Example 1 Its peak (index) sequence is [3, 4, 6, 8, 9], which has four edges, (3, 4), (4, 6), (6, 8), and (8, 9). Similarly, its fragment size definition (index) sequence is [0, 1, 2, 3, 4] , which also has four edges: (0, 1), (1, 2), (2, 3), and (3, 4). A matching is also a correspondence between edges .
- peak edge (6, 8) corresponds to definition edge (2, 3). Assume that two edges are adjacent if they share an endpoint. In this example, (4, 6) and (6, 8) are adjacent since they share peak 6.
- Two adjacent edges [ i , j ) and (j , k) define a ratio r ⁇ jk of lengths:
- peak ratio r 6 ⁇ 9 corresponds to size ratio r 2 .
- one may define the height cost c h (i) of a matched peak i to be its height divided by the maximum peak height R. More formally, z max ⁇ , (5)
- 0 ⁇ c h (i) ⁇ 1 for all peaks 0 ⁇ i ⁇ n p , and c h (i) 1, in certain embodiments, corresponds to the ideal of a maximally tall peak.
- an advantage of the above formulation is that the cost is separable. That is, with some additional mathematics, one can maximise subsequences independently. This property leads to an efficient dynamic programming algorithm.
- the algorithm is efficient (runs in low-order polynomial time and space) and guarantees an optimal solution.
- the matcher component computes the individual elements in a consistent order. Furthermore, one may exploit the fact that one can match every size in the definition by limiting the computation. In certain embodiments, the matcher component only needs to compute c (j , k, f) for k > j ⁇ f since j peaks cannot be made to fit all f sizes if j ⁇ f. Similarly, in certain embodiments, the matcher component needs to examine only subproblems c(i, j',f-l) where i ⁇ f - 1 since i peaks could not fit all f-1 sizes if i ⁇ f 1.
- Algorithm 2 solves Equation 10 and Algorithm 3 solves Equation 11.
- n p - 1 do c(j,J, 0) - (1 - ⁇ ) (c h (j) + CaW)
- Algorithm 3 Compute Cost of Matching (when f > 0)
- the algorithm's run time complexity is dominated by the number of times it executes Lines 6 and 7. The lines themselves execute in constant time.
- a test program executes the matcher component 20 times and divides the elapsed time by 20 also, to give the time for each execution in milliseconds.
- Figures 3 to 5 show the results. The execution times themselves, rounded to the nearest millisecond, are provided in Fig. 10.
- One may use m 4.
- An analyst typically should choose a size standard definition that corresponds accurately to the in-lane size standard. However, it may be that an analyst terminated a run early, before the longer fragments have had a chance to elute. In this case, the definition is not accurate, strictly speaking. To provide some robustness in this situation, one may test if the optimal matching satisfies a minimum acceptable quality parameter. If not, one may remove the last definition size and try again, repeating this process until the quality is acceptable. Alternatively, if the quality is unacceptable, one may simply report this without returning a matching.
- Figure 6 shows an example of matching a run of the Applied Biosystems GeneScan 500 size standard on a Manhattan breadboard.
- the top panel shows the matched electropherogram. Again, peak positions are in green, and peak bases are in red.
- the middle panel shows the "errors" obtained by fitting this matching to a straight line and subtracting the assigned size from the size predicted from the linear fit.
- the bottom panel shows the definition points (in green circles) and the predicted peak sizes (in red circles) . The correspondence between the two is shown in blue line segments.
- the primer peak Prior to analysis, the primer peak is removed from the peaks used for the matching, although it is still indicated in the diagram.
- the electropherogram contains an extra peak at its end (around scan 4400) .
- the described approach correctly did not match this peak.
- peak was often assigned 500 nucleotides by prior art matchers .
- the electropherogram also shows a spurious "spike” around scan 2200.
- a peak detector rejected this as a peak since it did not meet the minimum peak width criterion.
- the 250-nucleotide fragment of the size standard is known to migrate anomalously on the 310, and seems to do so on Manhattan, also.
- the 340-nucleotide fragment is also known to migrate anomalously; these two fragments typically are not used for sizing on the 310.
- Figure 7 shows the run from Figure 6 matched with GeneScan 500 less sizes 250 and 340. Note that the matcher correctly ignored the peaks corresponding to these two f agments .
- Figure 8 shows the result of matching GeneScan 500, less sizes 35 and 50 with a run that was terminated early.
- the matcher correctly ignores the corresponding peaks .
- the matcher does initially match all sizes, including the unrepresented large ones, to the available peaks, but the matching quality was not high enough. Consequently, The matcher then strips one size at a time off the end of the definition until the resulting match is of sufficient quality.
- Figure 9 shows a matching with the GeneScan 400HD size standard.
- This electropherogram also contains a spike (between size 90 and 100) .
- a peak detector ignored this peak due to a minimum peak width parameter.
- the primer peak is not visible since the analyst set an analysis range that excludes it. Note from the middle panel that the extremes (sizes 50, 60, 380, and 400) of the standard did not run "as linearly" as the rest. These extremes would cause previous matchers some problems, though their errors are quite small here.
- embodiments of the present invention provide a simple formulation of the size-standard matching problem which leads to a simple algorithm for its solution.
- the formulation emphasises corresponding ratios of edge lengths combined with the heights of the matched peaks .
- Preferred embodiments of the invention employ an algorithm that requires just a very few (three) parameters:
- FIG 11 is a block diagram that illustrates a computer system 500, according to certain embodiments, upon which embodiments of the invention may be implemented.
- Computer system 500 includes a bus 502 or other communication mechanism for communicating information, and a processor 504 coupled with bus 502 for processing information.
- Computer system 500 also includes a memory 506, which can be a random access memory (RAM) or other dynamic storage device, coupled to bus 502 for determining size matches, and instructions to be executed by processor 50 .
- Memory 506 also may be used for storing temporary variables or other intermediate information during execution of instructions to be executed by processor 504.
- Computer system 500 further includes a read only memory (ROM) 508 or other static storage device coupled to bus 502 for storing static information and instructions for processor 504.
- ROM read only memory
- a storage device 510 such as a magnetic disk or optical disk, is provided and coupled to bus 502 for storing information and instructions.
- Computer system 500 may be coupled via bus 502 to a display 512, such as a cathode ray tube (CRT) or liquid crystal display (LCD) , for displaying information to a computer user.
- a display 512 such as a cathode ray tube (CRT) or liquid crystal display (LCD)
- An input device 514 is coupled to bus 502 for communicating information and command selections to processor 504.
- cursor control 516 is Another type of user input device, such as a mouse, a trackball or cursor direction keys for communicating direction information and command selections to processor 504 and for controlling cursor movement on display 512.
- This input device typically has two degrees of freedom in two axes, a first axis (e.g., x) and a second axis (e.g., y) , that allows the device to specify positions in a plane.
- a computer system 500 evaluates size matchings and provides a quality level for each matching. Consistent with certain implementations of the invention, a matching and associated quality is provided by computer system 500 in response to processor 504 executing one or more sequences of one or more instructions contained in memory 506. Such instructions may be read into memory 506 from another computer-readable medium, such as storage device 510. Execution of the sequences of instructions contained in memory 506 causes processor 504 to perform the process states described herein. Alternatively hard-wired circuitry may be used in place of or in combination with software instructions to implement the invention. Thus implementations of the invention are not limited to any specific combination of hardware circuitry and software.
- Non-volatile media includes, for example, optical or magnetic disks, such as storage device 510.
- Volatile media includes dynamic memory, such as memory 506.
- Transmission media includes coaxial cables, copper wire, and fiber optics, including the wires that comprise bus 502. Transmission media can also take the form of acoustic or light waves, such as those generated during radio-wave and infra-red data communications.
- Computer-readable media include, for example, a floppy disk, a flexible disk, hard disk, magnetic tape, or any other magnetic medium, a CD-ROM, any other optical medium, punch cards, papertape, any other physical medium with patterns of holes, a RAM, PROM, and EPROM, a FLASH-EPROM, any other memory chip or cartridge, a carrier wave as described hereinafter, or any other medium from which a computer can read.
- Various forms of computer readable media may be involved in carrying one or more sequences of one or more instructions to processor 504 for execution.
- the instructions may initially be carried on magnetic disk of a remote computer.
- the remote computer can load the instructions into its dynamic memory and send the instructions over a telephone line using a modem.
- a modem local to computer system 500 can receive the data on the telephone line and use an infra-red transmitter to convert the data to an infra-red signal.
- An infra-red detector coupled to bus 502 can receive the data carried in the infra-red signal and place the data on bus 502.
- Bus 502 carries the data to memory 506, from which processor 504 retrieves and executes the instructions.
- the instructions received by memory 506 may optionally be stored on storage device 510 either before or after execution by processor 504.
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Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
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AU2001283003A AU2001283003B2 (en) | 2000-07-21 | 2001-07-23 | Methods and systems for evaluating a matching between measured data and standards |
AU8300301A AU8300301A (en) | 2000-07-21 | 2001-07-23 | Methods and systems for evaluating a matching between measured data and standards |
JP2002514583A JP2004505254A (en) | 2000-07-21 | 2001-07-23 | Method and system for evaluating the match between measured data and a standard |
CA002416611A CA2416611A1 (en) | 2000-07-21 | 2001-07-23 | Methods and systems for evaluating a matching between measured data and standards |
EP01961761A EP1350179A2 (en) | 2000-07-21 | 2001-07-23 | Methods and systems for evaluating a matching between measured data and standards |
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US21969700P | 2000-07-21 | 2000-07-21 | |
US60/219,697 | 2000-07-21 |
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WO2002008949A2 true WO2002008949A2 (en) | 2002-01-31 |
WO2002008949A3 WO2002008949A3 (en) | 2003-07-31 |
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EP (1) | EP1350179A2 (en) |
JP (1) | JP2004505254A (en) |
AU (2) | AU2001283003B2 (en) |
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WO (1) | WO2002008949A2 (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2012002930A1 (en) * | 2010-06-29 | 2012-01-05 | Analogic Corporation | Internal sizing/lane standard signal verification |
WO2017001597A1 (en) * | 2015-07-01 | 2017-01-05 | Ge Healthcare Bio-Sciences Ab | Method for determining a size of biomolecules |
Citations (5)
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WO1993014224A1 (en) * | 1992-01-14 | 1993-07-22 | Applied Biosystems, Inc. | Size-calibration dna fragment mixture and method |
US5876933A (en) * | 1994-09-29 | 1999-03-02 | Perlin; Mark W. | Method and system for genotyping |
WO2000016087A1 (en) * | 1998-09-16 | 2000-03-23 | The Perkin-Elmer Corporation | Spectral calibration of fluorescent polynucleotide separation apparatus |
US6054268A (en) * | 1994-06-17 | 2000-04-25 | Perlin; Mark W. | Method and system for genotyping |
EP1128311A2 (en) * | 2000-02-15 | 2001-08-29 | Mark W. Perlin | A method and system for DNA analysis |
-
2001
- 2001-07-23 AU AU2001283003A patent/AU2001283003B2/en not_active Ceased
- 2001-07-23 EP EP01961761A patent/EP1350179A2/en not_active Withdrawn
- 2001-07-23 JP JP2002514583A patent/JP2004505254A/en active Pending
- 2001-07-23 CA CA002416611A patent/CA2416611A1/en not_active Abandoned
- 2001-07-23 AU AU8300301A patent/AU8300301A/en active Pending
- 2001-07-23 WO PCT/US2001/023630 patent/WO2002008949A2/en active IP Right Grant
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
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WO1993014224A1 (en) * | 1992-01-14 | 1993-07-22 | Applied Biosystems, Inc. | Size-calibration dna fragment mixture and method |
US6054268A (en) * | 1994-06-17 | 2000-04-25 | Perlin; Mark W. | Method and system for genotyping |
US5876933A (en) * | 1994-09-29 | 1999-03-02 | Perlin; Mark W. | Method and system for genotyping |
WO2000016087A1 (en) * | 1998-09-16 | 2000-03-23 | The Perkin-Elmer Corporation | Spectral calibration of fluorescent polynucleotide separation apparatus |
EP1128311A2 (en) * | 2000-02-15 | 2001-08-29 | Mark W. Perlin | A method and system for DNA analysis |
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2012002930A1 (en) * | 2010-06-29 | 2012-01-05 | Analogic Corporation | Internal sizing/lane standard signal verification |
US20130090861A1 (en) * | 2010-06-29 | 2013-04-11 | Analogic Corporation | Internal sizing/lane standard signal verification |
US10503573B2 (en) * | 2010-06-29 | 2019-12-10 | Analogic Corporation | Internal sizing/lane standard signal verification |
WO2017001597A1 (en) * | 2015-07-01 | 2017-01-05 | Ge Healthcare Bio-Sciences Ab | Method for determining a size of biomolecules |
CN107787452A (en) * | 2015-07-01 | 2018-03-09 | 通用电气健康护理生物科学股份公司 | For the method for the size for determining biomolecule |
CN113916964A (en) * | 2015-07-01 | 2022-01-11 | 思拓凡瑞典有限公司 | Method for determining the size of a biomolecule |
US11237130B2 (en) | 2015-07-01 | 2022-02-01 | Cytiva Sweden Ab | Method for determining a size of biomolecules |
Also Published As
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AU2001283003B2 (en) | 2004-04-08 |
AU8300301A (en) | 2002-02-05 |
JP2004505254A (en) | 2004-02-19 |
WO2002008949A3 (en) | 2003-07-31 |
EP1350179A2 (en) | 2003-10-08 |
CA2416611A1 (en) | 2002-01-31 |
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