JP2016133486A - Chromatographic data processing system and method for searching chromatogram - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a system and method for efficiently and rationally comparing a measured chromatogram with a plurality of reference chromatograms for search.SOLUTION: The data processing system includes: chromatogram display means for selecting chromatographic data from chromatographic data storage means for acquiring and storing chromatographic data, and for displaying the chromatographic data as a chromatogram on a screen; pointing means for designating one or more holding time for the chromatogram displayed on the screen; index data storage means for storing one or more holding time designated by the pointing means as index data for each chromatogram; and search and display means for using one or more holding time designated by the pointing means as a search key, and for searching the chromatogram associated with the search key from the index data storage means, and for displaying a search key on the screen.SELECTED DRAWING: Figure 4

Description

  The present invention relates to a data processing system that can be connected to a chromatographic apparatus and can be used for data processing of chromatograms, and a method for retrieving related chromatograms from a reference chromatogram.

  Chromatography can identify chemical components by the retention values (retention time, retention volume, retention coefficient, etc.) of peaks in the chromatogram. However, for samples that contain various phenotypic proteins with similar structures, such as biological samples, or where there is an interaction between components, each component in the sample is separated and developed into a one-dimensional index. That is generally difficult. Therefore, in liquid chromatography used for medical diagnosis, diagnosis is performed by capturing a unique peak shape derived from a metabolite having a phenotype peculiar to a disease or a disease state even if separation into component peaks is incomplete. It has been carried out. For example, the Bio-Rad hemoglobin analyzer can use a library in which chromatograms of various phenotype hemoglobins based on known hemoglobin abnormalities are collected (Non-patent Document 1). The user can call up a reference chromatogram having a shape similar to the acquired sample chromatogram from the library on the display and compare it visually. Moreover, in order to quantitatively grasp the similarity between the shape of the sample program and the standard chromatogram, an invention (Patent Document 1) is disclosed in which a correlation coefficient between both waveform signals corresponding to the same holding time is obtained. .

Japanese Patent Laid-Open No. 9-25016

Philippe Joy et al., Ann Biol Clin 2010; 68 (2) 254-256.

  When trying to identify or estimate the composition information of a sample from the peak shape of the chromatogram, the reference chromatogram library as in Non-Patent Document 1 is visually referenced even if the sample chromatogram and the reference chromatogram are the same. Even if they can be arranged or displayed on the screen, if there are many similar reference chromatograms, an excessive burden is placed on the operator.

  In addition, as in Patent Document 1, when calculating the correlation coefficient between chromatograms to be compared, it is necessary to examine the range of retention times including characteristic peaks in advance for each of many reference chromatograms. . Otherwise, even if the characteristic peaks appear to be similar to each other by visual inspection, taking a correlation coefficient may determine that the correlation is low due to shoulder peaks, tailing, artifacts, etc. is there. In addition, it is not preferable in terms of time and memory resources to calculate the correlation coefficient for every reference chromatogram every time.

  Efficient and rational comparison of measured chromatograms with a large number of reference chromatograms without requiring complex visual comparisons to the operator or conversely inefficient automation that ignores user proficiency New systems and methods are needed to do this.

  In order to solve the above-mentioned problems, the present inventors have completed the invention described below by paying attention to extracting a retention time that can represent waveform characteristics from each reference chromatogram and using it as a search index.

That is, the data processing system according to the first aspect of the present invention is:
A data processing system for a chromatograph,
A chromatographic data storage means for acquiring and storing chromatographic data measured by the chromatograph;
Selecting chromatograph data from the chromatograph data storage means and displaying the chromatogram on the screen as a chromatogram;
A pointing means for designating one or more holding times for the chromatogram displayed on the screen;
Index data storage means for storing one or more holding times designated by the pointing means for each chromatogram as index data;
Search display means for searching a chromatogram associated with the search key from the index data storage means and displaying a search result on the screen using one or more holding times specified by the pointing means as a search key;
It is provided with.

  Here, the term “retention time” can be rephrased as an elution time and an elution time used in liquid chromatography. Furthermore, a retention value or a retention parameter including a retention volume, a retention capacity, and a retention coefficient, which are technical terms in the field. Used interchangeably. The retention time expressed in a relative amount with respect to that of the reference standard, that is, the relative retention time is also included in the retention time in the present application. Usually, the retention time means the time axis component at the peak apex on the chromatogram, but in the present invention, it represents the time axis component of an arbitrary waveform portion constituting the chromatogram. For example, when a normal sample is characterized by the absence of a peak at a position on the time axis that is supposed to be a characteristic of the waveform of an abnormal sample, the location where there is no peak is stored in the index data storage means as an index of retention time Can do.

  In the present invention, “search” does not necessarily mean identification of an analysis target. For example, it is sufficient if the target can be narrowed down to a number that can be easily handled by the operator from a database or library of hundreds of reference chromatograms.

  Note that using the retention time as a search key determines whether the retention time (numerical data) specified on the sample chromatogram matches the index data (numerical data) of one or more reference chromatograms. Means that. For this purpose, one numerical data to be compared has an allowable width, and it is determined whether the other numerical data falls within this allowable width. In the present invention, it is advantageous to provide an allowable range for the holding time as a search key.

  Thus, in order to use the retention time as a search key, it is preferable that the chromatograph apparatus has sufficient reproducibility. Today, it has become possible to systematically manage validation information by connecting multiple chromatographs via a network, as well as automating daily inspection operations, sampling, and calibration curve creation. It is never difficult to satisfy sufficient reproducibility. Not that. However, although there may be situations where strict reproducibility of the retention time cannot be achieved, it is possible to substantially reproduce the retention time by using a well-known technique related to a method for correcting and aligning the retention time within the same device or between different devices. It is also preferable in the present invention to use the corrected holding time if the property is ensured.

  In the present invention, the operator who stores the index data in the index data storage means may be a manufacturer who supplies a data processing system for chromatograph or a customer service providing department thereof, or a user who performs chromatographic analysis. There may be. For example, a manufacturer provides a data processing system including a typical chromatogram (reference chromatogram) and index data storage means preinstalled with the index data, and a chromatogram (reference) of a known sample measured by the user himself / herself. In general, an embodiment in which the chromatogram) and the index data are additionally stored in the index data storage unit as needed. At this time, the data preinstalled as a reference chromatogram and the data added by the user may be merged and stored in the index data storage means, or the preinstalled part and the added part can be managed separately.

  In the present invention, the chromatographic data storage means acquires / stores chromatographic data measured by a chromatograph, and stores a reference chromatogram and a sample chromatogram obtained by measuring a sample.

The search display means in the present invention searches for a chromatogram associated with the search key, and particularly preferably searches for a reference chromatogram similar to the search key. As a search result, the number of search hits, a list of identification names of corresponding reference chromatograms, and the like can be displayed on the screen. On the display screen, one or more pointer cursors indicating the set position of the search key (holding time), the chromatogram set with the search key, and one or more chromatograms selected from the search results are displayed in an overlaid manner. Is preferred. As a result, the operator can immediately recognize how the waveform portion (holding time) designated for the search is related to the suitability of the search. Therefore, the operator who designates the search key learns how to designate the search key more accurately as he gains experience. This is also true for manufacturers and users who store index data. That is, if the index data does not accurately represent the characteristics of the reference chromatogram, the search will not be successful, and the relevance search using the search key can be improved by reviewing and correcting the index data.
By searching for chromatogram similarity using only the retention time as a search key, the index data storage means stores waveform characteristics corresponding to each retention time in case it takes too much time or narrowing down does not proceed. It is conceivable that the index is used for searching together with the holding time. That is, the data processing system according to the second aspect of the present invention is the data processing system according to the first aspect of the present invention,
-Pointing means can input waveform characteristics corresponding to each holding time,
The index data storage means stores the characteristics of the input waveform as index data for each chromatogram,
The search display means searches for the characteristics of the input waveform as a search key and displays the search result on the screen.

  When inputting waveform features, pointing means and index data storage means can be selected and input from a limited number of pre-registered options, for example, about 10 items, in order to reduce the input effort and increase the search speed. It is preferable to constitute.

A method according to a third aspect of the present invention is a method for searching a chromatogram related to a sample chromatogram obtained by measuring an analytical sample from a reference chromatogram,
(1) For each of the reference chromatograms, one or more holding times for use in the search are recorded as index data,
(2) Specify one or more holding times to be used for the search for the sample chromatogram and use it as a search key to search all or part of the index data recorded in step 1 as a search target, and the search Obtaining a search result of a reference chromatogram associated with the key,
(3) Further, if it is necessary to narrow down the search result acquired in step 2, the search result is set as a new search target, and step 2 is executed for the same sample chromatogram at one or more different holding times. Features.

  In the present invention, the reference chromatogram may be a typical chromatogram preinstalled as described above, or may be a chromatogram added to a known sample as needed. Searching for a chromatogram “related” to the sample chromatogram from the reference chromatogram is preferably performed by searching for a “similar” chromatogram as described in the first aspect of the present invention.

  In Step 3 above, “if it is necessary to narrow down the search result” means that the operator who performs this method appropriately determines the necessity of narrowing down in a given situation. It suffices to obtain a search result with a sufficient number of hits necessary to obtain qualitative information on the analysis sample by comparing the similarity with many reference chromatograms. The operator can increase the accuracy of analysis using other analysis techniques such as mass spectrometry, spectroscopic techniques, electrophoresis, nucleic acid analysis, etc. in addition to chromatographic judgment depending on the purpose of analysis. If the purpose is medical analysis of a biological sample containing abnormal hemoglobin, there is an example in which the type of abnormal hemoglobin estimated by the present invention is determined by DNA analysis.

  In Step 1, it is within the technical scope of the present invention that only the retention time of the reference chromatogram is recorded, but it is preferable that the characteristics of the waveform are also recorded. As described above with respect to the data processing system according to the second aspect of the present invention, it is more preferable to search the characteristics of the waveform at the holding time than to search the relevance of the chromatogram using only the holding time as a search key. This is because an accurate search result can be obtained quickly. That is, in the method according to the fourth aspect of the present invention, in the method according to the third aspect of the present invention, the characteristics of the waveform corresponding to each of the retention times are recorded as index data in step 1, and each of the retention times is recorded in step 2. The feature of the waveform corresponding to is also used as a search key.

  The third and fourth aspects of the present invention can be used in accordance with the situation of use and the proficiency level of the operator. For example, if the number of reference chromatograms is small from the beginning, you will be able to obtain a satisfactory search result simply by specifying the retention time. However, if there are many chromatograms to be referenced, it is better to search the waveform characteristics together. It is thought that efficient search can be performed. In addition, when the operator's proficiency level and knowledge about the analysis method and analysis target are in the elementary stage, it is expected that it will be difficult or unsuccessful to accurately specify the waveform characteristics for the sample chromatogram. Is done. On the other hand, for an experienced operator who can grasp the characteristics of the waveform instantaneously, it is more efficient to retrieve the characteristics of the waveform from the beginning. In addition, by specifying a plurality of holding times that are targeted from the beginning, it becomes possible to obtain search results that are satisfactory at once.

  In the third and fourth aspects of the present invention, Step 2 can be repeatedly executed to narrow down the search results. In the third invention, the search is repeated by specifying at least the holding time, and in the fourth invention, the search is repeated by specifying at least the holding time and the waveform characteristics.

On the other hand, a method is conceivable in which it is left to the operator to decide whether or not to search by specifying the waveform characteristics for each repetition of the search operation. This is the fifth aspect of the present invention. That is, the fifth aspect of the present invention is a method for searching a chromatogram related to a sample chromatogram obtained by measuring an analytical sample from a reference chromatogram,
(1) For each of the reference chromatograms, one or more holding times for use in the search, and waveform characteristics corresponding to each of the holding times are recorded as index data,
(2) Specify one or more holding times to be used for the search for the sample chromatogram and use it as a search key to search all or part of the index data recorded in step 1 as a search target, and the search Obtaining a reference chromatogram search result associated with the key;
Alternatively, all of the index data recorded in step 1 can be designated by specifying one or more holding times to be used for searching the sample chromatogram and the waveform characteristics corresponding to each of the holding times. Or searching a part as a search target and obtaining a search result of a reference chromatogram associated with the search key;
Including
(3) Furthermore, if it is necessary to narrow down the search results obtained in step 2, step 2 is executed for the same sample chromatogram at one or more different holding times.

  An advantage of the fifth invention resides in that the degree of freedom of whether to search using the waveform feature in addition to the holding time is increased as necessary. That is, in step 2 for designating the holding time, whether or not the waveform characteristics are designated together can be arbitrarily selected at each repetition. In the present invention, as the number of search objects (reference chromatograms) increases, the number of necessary search repetitions increases. Also, because the search key specification is left to the operator's judgment, if the search key is specified at an inappropriate location (holding time), it is expected that the search will take time against the operator's will. Is done. Therefore, for example, in the third aspect of the invention, there may be a desire to speed up the search by adding a waveform feature during the execution of a search operation using only the holding time as a search key. Further, in the fourth aspect of the present invention, there may be a demand for performing a search only by holding time without specifying a waveform feature so that the search is not excessively narrowed down during the repeated search. The fifth invention can meet such a demand.

  In the first to fifth inventions, the sample to which the chromatograph is applied is not particularly limited, and examples thereof include body fluids such as blood, plasma, and serum, tap water, sewage, and environmental water. In the third to fifth inventions, the reference chromatogram preferably shows a phenotype of hemoglobin.

  The data processing system according to the present invention uses the retention time as an index for relevance search such as chromatogram similarity search. The holding time is one piece of numerical data, and even if a plurality of holding times are specified, for example, it is about several tens at most per chromatogram. Even if a range is specified, it is sufficient to specify a lower limit and an upper limit. In any case, the data is very simple and easy to handle as a search index. Therefore, it is very advantageous in terms of saving of memory resources of the computer and calculation speed. In addition, the method for designating the holding time can be easily implemented because the feature of the waveform is simply designated by pointing means on the screen.

  In the present invention, since the search display means for displaying the search result on the screen is provided, the operator immediately recognizes on the screen how the waveform part (holding time) designated for the search is related to the suitability of the search. be able to. If the search result is not what you want, you can modify the specified search key immediately or from the next time. The index data storage means can also be corrected or added by learning from the search results. The reason why the operator's experience can be maximized in this way is that the holding time is adopted as the search index. Even if it is impossible to represent the characteristics of the waveform by one holding time, a powerful search index can be configured by combining a plurality of holding times.

  On the other hand, instead of searching for chromatogram similarity using only the retention time as a search key, the characteristics of the waveform corresponding to each retention time are recorded in the index data storage means, and the search time is stored together with the retention time. In the case of an index, satisfactory search results can be obtained with a small number of searches.

  The method according to the present invention for searching for a chromatogram related to a sample chromatogram obtained by measuring an analytical sample from a reference chromatogram performs a search using the retention time as a search key, On the other hand, the narrowing search can be repeated. According to the present invention, even when the number of results searched by the initially specified search key is too large, the search can be narrowed down by adding the search key. In the process of narrowing down from the initial specification of the search key, there are innumerable ways of specifying the search key, that is, search paths, but by repeating the search, the final search result is almost the same regardless of the skill of the search. Is expected to be. Therefore, even for analysts with little knowledge and experience in analysis and chromatography, even when starting from a waveform position (holding time) intuitively selected from the chromatogram, a search that can be satisfied by several search operations Expect to get results.

It is a block diagram which shows the basic composition of this invention. It is a figure which shows the flowchart of registration operation in the method of this invention. It is a figure which shows the flowchart of search operation in the method of this invention. It is a figure which shows the screen which shows registration operation which inputs the kind of feature in this invention. It is a figure which shows the screen which shows the registration state of the library in this invention. It is a figure which shows the search result screen in this invention.

  FIG. 1 shows an example of a basic configuration of a data processing system according to the present invention. The data processing system 1 shown here can be configured using a computer system, and includes a processing unit 10 having an input / output function and a calculation function for receiving measurement data from the chromatograph apparatus 2, and a chromatograph. A data storage unit 11; a chromatogram display unit 12 for selecting chromatograph data from the chromatograph data storage unit 11 and displaying it on a screen as a chromatogram; and at least one holding time for the chromatogram displayed on the screen. Pointing means 13 for designating, index data storage means 14 for storing one or more holding times designated by the pointing means 13 for each chromatogram as index data, and one or more holding times designated by the pointing means 13 Search key As, a, a search display unit 15 to the search key on the display screen search to search result chromatogram associated from among the index data storage unit 14.

  FIG. 2 is a flowchart showing an example of an operation of acquiring / selecting a reference chromatogram and storing / registering one or more holding times and waveform features representing characteristic waveform portions as index data for each chromatogram. First, in step S11, reference chromatograph data obtained by measuring a known sample is acquired / selected, and in step S12, the reference chromatogram is displayed on the screen. In steps S13 and S14, a holding time to be registered is designated, and a waveform characteristic at the holding time is designated. The state of the screen at that time is shown in FIG. The chromatogram shown in FIG. 4 is obtained by measuring a known sample containing Hb Riccarton, which is a kind of hemoglobin mutant. Here, a screen is shown in which a holding time of 0.66 minutes is registered by pointing means capable of operating the vertical line cursor 20 perpendicular to the time axis on the chromatogram to the left and right. At this time, it is possible to select and input 10 types of features, that is, large or clear peak, small or unclear peak, thick peak, poor separation, front shoulder, back shoulder, leading, tailing, no peak, and unclassifiable features. it can. In this reference program, two holding times of a holding time of 0.48 minutes (feature type: tailing) and a holding time of 0.66 minutes (feature type: large or clear peak) are set. Corresponding to step S15 in FIG. 2, Hb Riccarton is entered in the upper right of FIG. 4 as the registered name of the library (data).

  FIG. 5 shows a library that is a collection of a plurality of reference chromatograms each having a characteristic retention time as described above, and here is a library of hemoglobin variants (also referred to as an abnormal hemoglobin library). This library is recorded in the index data storage means. There are 29 reference chromatograms constituting this library, and 18 library (data) names are displayed on the left side of the screen of FIG. The reference chromatogram Hb Iraq Halabja at the center of the screen shows the retention times of 0.29 minutes (Front Shoulder), 0.33 minutes (Large or Clear Peak) and 0.64 minutes (Large or Clear Peak) is registered.

  FIG. 3 is a flowchart showing an example of a method for searching a chromatogram related to a sample chromatogram obtained by measuring an analysis sample from a reference chromatogram. First, in step S21, sample chromatograph data obtained by measuring the analysis sample is acquired / selected, and the sample chromatogram is displayed on the screen in step S22. Next, in step S23, for the sample chromatogram, a holding time serving as a search key and a search condition including a search target are designated. Usually, the search target designates a group of reference chromatograms highly relevant to the sample chromatogram. In this example, the entire library of hemoglobin mutants is automatically designated as a search target at first. The retention time serving as a search key may be designated together with the types of waveform features as in FIG. 4 showing the reference chromatogram registration operation. An example of the display (S25) of the result of executing the search process (S24) is shown in FIG. A sample chromatogram as a search target is drawn at the top of the screen, and a reference chromatogram of one of the searched library data (Hb J-Bangkok) is drawn at the bottom of the screen. A vertical line cursor 21 in both the upper and lower chromatograms represents a holding time of 0.82 minutes as a search key. In this example, only the retention time of 0.82 minutes is specified as the search key, so there are 11 search results for the 29 reference chromatogram data that make up the library. 9 items are displayed in a scrollable manner. If the search result is satisfied (YES) in step S26, the search is terminated. On the other hand, if it is not satisfactory (NO), 11 reference chromatograms which are the search results obtained now are set as new search objects (S27), and the process returns to step S23 to the previous sample chromatogram. As a search key, a holding time (and a waveform characteristic if necessary) different from the previous search key is designated and the search is performed again (S24). A reference chromatogram similar to the sample chromatogram can be effectively extracted from the library by the above-described refinement search.

DESCRIPTION OF SYMBOLS 1 Data processing system 2 Chromatograph apparatus 10 Processing part 11 Chromatograph data storage means 12 Chromatogram display means 13 Pointing means 14 Index data storage means 15 Search display means 20 Vertical line cursor 21 for holding time designation Holding used for search key Vertical line cursor representing time

Claims (6)

A data processing system for a chromatograph,
A chromatographic data storage means for acquiring and storing chromatographic data measured by the chromatograph;
Selecting chromatograph data from the chromatograph data storage means and displaying the chromatogram on the screen as a chromatogram;
A pointing means for designating one or more holding times for the chromatogram displayed on the screen;
Index data storage means for storing one or more holding times designated by the pointing means for each chromatogram as index data;
Search display means for searching a chromatogram associated with the search key from the index data storage means and displaying a search result on the screen using one or more holding times specified by the pointing means as a search key;
The data processing system comprising: The data processing system of claim 1, wherein
-Pointing means can input waveform characteristics corresponding to each holding time,
The index data storage means stores the characteristics of the input waveform as index data for each chromatogram,
-The search display means searches the feature of the input waveform as a search key and displays the search result on the screen.
The data processing system. A method for retrieving a chromatogram related to a sample chromatogram obtained by measuring an analytical sample from a reference chromatogram,
(1) For each of the reference chromatograms, one or more holding times for use in the search are recorded as index data,
(2) Specify one or more holding times to be used for the search for the sample chromatogram and use it as a search key to search all or part of the index data recorded in step 1 as a search target, and the search Obtaining a search result of a reference chromatogram associated with the key,
(3) Further, if it is necessary to narrow down the search result acquired in step 2, the search result is set as a new search target, and step 2 is executed for the same sample chromatogram at one or more different holding times. Said method characterized.   4. The method according to claim 3, wherein the feature of the waveform corresponding to each of the holding times is recorded as index data in step 1, and the feature of the waveform corresponding to each of the holding times is also used as a search key in step 2. Method. A method for retrieving a chromatogram related to a sample chromatogram obtained by measuring an analytical sample from a reference chromatogram,
(1) For each of the reference chromatograms, one or more holding times for use in the search, and waveform characteristics corresponding to each of the holding times are recorded as index data,
(2) Specify one or more holding times to be used for the search for the sample chromatogram and use it as a search key to search all or part of the index data recorded in step 1 as a search target, and the search Obtaining a reference chromatogram search result associated with the key;
Alternatively, all of the index data recorded in step 1 can be designated by specifying one or more holding times to be used for searching the sample chromatogram and the waveform characteristics corresponding to each of the holding times. Or searching a part as a search target and obtaining a search result of a reference chromatogram associated with the search key;
Including
(3) Furthermore, if there is a need to narrow down the search results obtained in step 2, step 2 is executed for the same sample chromatogram at one or more different holding times.   6. The method according to any one of claims 3 to 5, wherein the reference chromatogram is indicative of a hemoglobin phenotype.

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