JP6515548B2 - Chromatographic data processing system and method for searching chromatograms - Google Patents

Description

  The present invention relates to a data processing system which can be connected to a chromatograph apparatus and used for processing data of chromatograms, and to a method of searching for a relevant chromatogram from among reference chromatograms.

  In chromatography, chemical components can be identified by retention values (retention time, retention volume, retention coefficient, etc.) of peaks in a chromatogram. However, for samples that contain proteins of various phenotypes that are similar in structure, such as biological samples, and there may also be interaction between components, each component in the sample is separated and developed into a one-dimensional index. Things are 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 specific to a disease or condition even though the separation into component peaks is incomplete. It is being offered to For example, Bio-Rad's hemoglobin analyzer has made available a library of collected chromatograms of various phenotypic hemoglobins based on known hemoglobinopathies (Non-patent Document 1). The user can call a reference chromatogram of a shape similar to the acquired sample chromatogram from the library and visually compare it on the display. In addition, an invention (Patent Document 1) is disclosed in which the correlation coefficient between both waveform signals corresponding to the same holding time is obtained in order to quantitatively grasp the similarity between the shape of the sample program and the standard chromatogram. .

JP-A-9-251016

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

  When trying to identify or estimate composition information of a sample from the peak shape of a chromatogram, it is better to visually refer to a library of known chromatograms like Non-patent document 1 even if the sample chromatogram and the reference chromatogram are identical. Even if they can be arranged or overlaid on the screen, if there are many reference chromatograms with similar shapes, the operator will be overloaded.

  When calculating the correlation coefficient between chromatograms to be compared as in Patent Document 1, it is necessary to examine in advance the range of retention time including characteristic peaks for each of many reference chromatograms. . Otherwise, even if the characteristic peaks look similar to each other visually, it may be determined that the correlation is low due to shoulder peaks, tailing, artifacts, etc. is there. Also, it is not preferable in terms of time and memory resources to calculate the correlation coefficient for every reference chromatogram every time.

  Measured chromatograms can be efficiently and rationally compared with a large number of reference chromatograms without requiring a complicated visual comparison from the operator, or without performing inefficient automation ignoring the user's familiarity. There is a need for new systems and methods for

  In order to solve the above problems, the present inventors completed the following invention focusing on the fact that the retention time that can represent the feature of the waveform is extracted from each reference chromatogram and used as the index for the search.

That is, the data processing system according to the first aspect of the present invention is
A data processing system for chromatographs,
· Chromatograph data storage means for acquiring and storing chromatograph data measured by chromatograph,
· Chromatogram display means for selecting chromatograph data from the chromatograph data storage means and displaying the screen as a chromatogram;
Pointing means for specifying one or more holding times for the chromatogram displayed on the screen;
An index data storage unit that stores one or more holding times designated by the pointing unit as index data for each chromatogram;
Search display means for searching a chromatogram associated with the search key from the index data storage means using one or more holding times designated by the pointing means as a search key, and displaying a search result on the screen;
It is characterized by having.

  Here, the term retention time can be rephrased as elution time and elution time used in liquid chromatography, and further is a scientific term of the art, such as retention volume, retention volume, retention value or retention parameter including retention coefficient, and the like. It is used in the same sense. The retention time or relative retention time expressed in relative amount to that of the reference standard is also included in the retention time in the present application. In general, the retention time means the time-axis component at the peak of the peak on the chromatogram, but in the present invention, it is assumed to represent the time-axis component of any waveform site constituting the chromatogram. For example, when it is a feature of the waveform of an abnormal sample that there is no peak at a position on the time axis that should normally be a normal sample, the location without the peak is stored in the index data storage means as a retention time index. Can.

  Further, in the present invention, "to 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 or does not match index data (numerical data) of one or more reference chromatograms. It means that. For this purpose, one numerical data to be compared may have an allowance, and it may be determined whether the other numerical data falls within the allowance. In the present invention, it is convenient to allow an allowance for the retention time as a search key.

  Thus, in order to use the retention time as a search key, it is preferable that the chromatography device has sufficient reproducibility. In addition to the automation of routine inspection operations, sample collection and calibration curve creation, it became possible to connect multiple chromatographs via a network to perform system management of validation information, and it is difficult to satisfy sufficient reproducibility today. It is not a thing. However, although there may be situations where exact repeatability of the retention time can not be achieved, substantial reproduction of the retention time can be achieved by using known techniques relating to the method of correcting and matching the retention time in the same device or between different devices. It is also preferred in the present invention to use a corrected holding time, as long as the property is ensured.

  In the present invention, an operator who stores index data in index data storage means may be a manufacturer supplying a data processing system for chromatograph or its customer service providing department, or a user who performs chromatograph analysis It may be. For example, a manufacturer provides a data processing system having a typical chromatogram (reference chromatogram) and index data storage means pre-installed with its index data, and the user operates on a chromatogram related to a known sample (see reference) An embodiment is general in which the chromatogram) and the index data are additionally stored in the index data storage means as needed. At this time, the data pre-installed as a reference chromatogram and the data added by the user may be merged and stored in the index data storage means, or the pre-installed portion and the additional portion may be separately managed.

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

Although the search display means in the present invention searches for chromatograms associated with the search key, it is preferable to search a reference chromatogram that is particularly similar to the search key. Then, as a search result, the number of search hits, a list of identification names of corresponding reference chromatograms, etc. can be displayed on the screen. On the display screen, one or more pointer cursors indicating the setting position of the search key (holding time), a chromatogram in which the search key is set, and one or more chromatograms selected from the search results are superimposed and displayed. Is preferred. As a result, the operator can immediately recognize how the waveform part (retention time) designated for the search is linked to the propriety of the search. Therefore, the operator specifying the search key learns how to specify the search key more accurately as experience is gained. This holds true for manufacturers and users who store index data. That is, if the index data does not accurately represent the features of the reference chromatogram, the search will not be successful, and the relevancy search by the search key can be improved by reviewing and correcting the index data.
Now, searching for similarities of chromatograms using only the retention time as a search key is an index data storage means for waveform features corresponding to the respective retention times in preparation for cases where it takes too long or narrowing-down does not proceed. It is possible to record in and to make it a search index together with the retention time. That is, a data processing system according to a second aspect of the present invention is the data processing system according to the first aspect of the present invention,
The pointing means can input waveform features corresponding to the respective holding times,
The index data storage means stores the features of the input waveform as index data for each chromatogram,
The search display means searches 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, around 10 in order to reduce the time and effort of inputting and to speed up the search speed. Are preferred.

The method according to the third aspect of the present invention is a method of searching a chromatogram related to a sample chromatogram obtained by measuring an analysis sample from among reference chromatograms,
(1) For each of the reference chromatograms, one or more holding times for providing a search are recorded as index data,
(2) Specify one or more holding times for subjecting the sample chromatogram to search and use as a search key, search all or part of the index data recorded in step 1 as a search target, and 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 at one or more different retention times for the same sample chromatogram. It features.

  In the present invention, the reference chromatogram may be a typical chromatogram pre-installed as described above, or may be one obtained by adding such a chromatogram from a known sample as needed. Also, to search for "related" chromatograms to the sample chromatogram from among the reference chromatograms, it is preferable to search for "similar" chromatograms as described in the first invention.

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

  Although it is also within the technical scope of the present invention that only the retention time of the reference chromatogram is recorded in Step 1 above, 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 better to search the waveform characteristics at the holding time together rather than searching the relationship of the chromatogram using the holding time only as the search key. This is because it is considered that quick and accurate search results can be obtained. 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 waveform features corresponding to the respective holding times are also recorded as index data in step 1; Is a method in which the feature of the waveform corresponding to is also used as a search key.

  The third and fourth inventions can be used according to the use situation and the level of familiarity of the operator. For example, if there are few reference chromatograms from the beginning, satisfying search results will be obtained just by specifying the retention time, but if there are many chromatograms to be referred to, it is better to search the waveform characteristics together It is thought that efficient search is possible. In addition, it is expected that it will be difficult or unsuccessful to specify the waveform characteristics accurately for the sample chromatogram if the operator's skill level and knowledge about the analysis method and object of analysis are at the basic stage. Be done. On the other hand, for a skilled operator who can grasp waveform characteristics instantaneously, it is more efficient to search by combining waveform characteristics from the beginning. In addition, it is also possible to obtain satisfactory search results at once by specifying a plurality of retention times that are targeted from the beginning.

  In the third and fourth inventions, step 2 can be repeatedly executed to narrow down the search results. In the third invention, the search is repeated specifying at least the holding time, and in the fourth invention, the search is repeated specifying the holding time and the waveform feature.

On the other hand, a method may be considered in which it is left to the operator's judgment whether or not to specify and search the waveform feature for each repetition of the search operation. This is the fifth invention. That is, the fifth aspect of the present invention is a method of searching a chromatogram related to a sample chromatogram obtained by measuring an analysis sample from among reference chromatograms,
(1) For each of the reference chromatograms, one or more holding times for providing a search, and waveform features corresponding to the holding times are recorded as index data,
(2) Specify one or more holding times for subjecting the sample chromatogram to search and use as a search key, search all or part of the index data recorded in step 1 as a search target, and search Obtaining the search results of the reference chromatogram associated with the key,
Alternatively, one or more holding times for subjecting the sample chromatogram to the search, and waveform features corresponding to the holding times are designated as search keys, and all the index data recorded in step 1 are recorded. Or a step of searching for a part as a search target, and acquiring a search result of a reference chromatogram associated with the search key,
Including and
(3) Further, in the above method, if it is necessary to narrow down the search results acquired in step 2, step 2 is performed on the same sample chromatogram at one or more different retention times.

  An advantage of the fifth invention is that it allows the freedom to search using waveform features as needed in addition to the holding time. That is, in the step 2 of specifying the holding time, whether or not to specify the characteristics of the waveform together can be arbitrarily selected each time it is repeated. In the present invention, as the number of search targets (reference chromatograms) increases, the number of required search repetitions increases. In addition, since the search key specification is left to the judgment of the operator, if the search key is specified in an inappropriate place (holding time), it is expected that the search will take time against the intention of the operator Be done. Therefore, for example, while executing a search operation in which only the holding time is the search key in the third invention, there may be a demand for speeding up the search by adding waveform features. In addition, while the search is repeatedly executed in the fourth invention, there may be a demand that the search is desired only by the holding time without specifying the feature of the waveform so as not to be narrowed down at once. The fifth invention can meet such needs.

  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 water in the environment. In the third to fifth inventions, it is preferable that the reference chromatogram shows a phenotype of hemoglobin.

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

  In the present invention, since the search display means for displaying the search results is provided on the screen, the operator immediately recognizes on the screen how the waveform part (holding time) designated for the search is connected to the suitability of the search. be able to. If the search result is unintended, the specified search key can be corrected 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 retention time is adopted as the search index. Even in the case where it is impossible to represent the waveform feature 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 similarities of chromatograms using only the holding time as a search key, the features of the waveform corresponding to each holding time are recorded in the index data storage means, and combined with the holding time to search for the search. 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 the chromatogram related to the sample chromatogram obtained by measuring the analysis sample from the reference chromatogram performs the search using the retention time as the search key, and the obtained search result is On the other hand, the squeeze search can be repeated. According to the present invention, even when the number of results searched by the search key specified first is too large, the search can be narrowed down by adding the search key. There are innumerable ways of specifying search keys, that is, search paths, in the process of specifying the search key from the first specification to the narrowing process, but by repeating the search, the finally obtained search results are almost the same regardless of the skill of the search Is expected to be Therefore, even for an analyst who has little knowledge and experience of the object of analysis and chromatography, even when the user starts from the waveform position (retention time) intuitively selected from the chromatogram, a search that should be satisfactory by several search operations Expected to get results.

It is a block diagram which shows the basic composition of this invention. FIG. 5 shows a flowchart of a registration operation in the method of the present invention. FIG. 5 shows a flowchart of a search operation in the method of the present invention. It is a figure which shows the screen which shows the registration operation which inputs the kind of characteristic 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 the 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 an arithmetic function for receiving measurement data from the chromatography apparatus 2, and a chromatograph A chromatogram display means 12 for selecting chromatographic data from the data storage means 11 and the chromatographic data storage means 11 and displaying the chromatogram as a screen, and one or more holding times for the chromatogram displayed on the screen Pointing means 13 for specifying, index data storage means 14 for storing one or more holding times specified by the pointing means 13 as index data for each chromatogram, and one or more holding times specified by the pointing means 13 Search for 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 chromatographic 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, the holding time to be registered is designated, and the feature of the waveform in the holding time is designated. The appearance 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 one of hemoglobin variants. Here, a screen for registering the holding time of 0.66 minutes by the pointing device capable of operating the vertical line cursor 20 perpendicular to the time axis on the chromatogram to the left and right is shown. At this time, it is possible to select and enter 10 types of features: large or clear peaks, small or unclear peaks, thick peaks, poor separation, front shoulder, back shoulder, leading, tailing, no peaks and unclassifiable features. it can. In this reference program, two retention times of retention time 0.48 minutes (type of feature: tailing) and retention time 0.66 minutes (type of feature: large or clear peak) are set. Hb Riccarton is input in the upper right of FIG. 4 as the registered name of the library (data) corresponding to step S15 of FIG.

  A library which is a collection of a plurality of reference chromatograms in which characteristic retention times are registered as described above, that is, a library of hemoglobin variants (also referred to as abnormal hemoglobin library) is shown in FIG. This library is recorded in 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 of searching for a chromatogram related to a sample chromatogram obtained by measuring an analysis sample from among reference chromatograms. First, in step S21, sample chromatograph data obtained by measuring an analysis sample is acquired / selected, and the sample chromatogram is displayed on the screen in step S22. Next, in step S23, a retention time as a search key and a search condition including a search target are specified for the sample chromatogram. The search target usually designates a group of reference chromatograms that are closely related to the sample chromatograms. In the present embodiment, initially, the entire library of hemoglobin variants is automatically designated as a search target. The designation of the retention time as the search key may be designated together with the type of the waveform feature, as in FIG. 4 showing the registration operation of the reference chromatogram. An example of display (S25) of the result of execution of the search process (S24) is shown in FIG. A sample chromatogram as a search target is displayed at the top of the screen, and a reference chromatogram of one (Hb J-Bangkok) of library data searched for a search is drawn at the bottom of the screen. Vertical line cursors 21 in both upper and lower chromatograms represent a retention time of 0.82 minutes as a search key. In this example, since only the retention time of 0.82 is specified as the search key, 11 results of the search are hit against the 29 data numbers of the reference chromatograms constituting the library, and this screen is displayed. There are 9 items displayed scrollable. If the search result is satisfied (YES) in step S26, then the search ends. On the other hand, if not satisfactory (NO), 11 reference chromatograms, which are the search results obtained just now, are set as a new search target (S 27), and the process returns to step S 23 and the previous sample chromatogram As a search key, a retention time (also a waveform feature, if necessary) different from that of the previous search key is specified and the search is performed again (S24). The above narrowing search makes it possible to effectively extract a reference chromatogram similar to the sample chromatogram from the library.

DESCRIPTION OF SYMBOLS 1 data processing system 2 chromatograph apparatus 10 processing unit 11 chromatograph data storage means 12 chromatogram display means 13 pointing means 14 index data storage means 15 retrieval display means 20 vertical line cursor 21 for holding time designation 21 retention used for retrieval key Vertical line cursor representing time

Claims (6)

A data processing system for chromatographs,
· Chromatograph data storage means for acquiring and storing chromatograph data measured by chromatograph,
· Chromatogram display means for selecting chromatograph data from the chromatograph data storage means and displaying the screen as a chromatogram;
Pointing means for specifying a retention time other than one or more peak tops for the chromatogram displayed on the screen;
Index data storage means for storing, for each chromatogram , retention times other than one or more peak tops designated by the pointing means as index data;
Search for searching the chromatogram associated with the search key from the index data storage means using the retention time other than the peak top designated by the pointing means as a search key, and displaying the search result on the screen Display means,
Said data processing system comprising: In the data processing system according to claim 1,
The pointing means can input waveform features corresponding to the retention times other than the peak top ,
The index data storage means stores the features of the input waveform as index data for each chromatogram,
The search display means searches the characteristics of the input waveform as a search key and displays the search result on the screen.
Said data processing system. A method of searching for a chromatogram related to a sample chromatogram obtained by measuring an analysis sample from among reference chromatograms, comprising:
(1) For each of the reference chromatograms , retention times other than one or more peak tops to be provided for search are recorded as index data,
(2) A retention time other than one or more peak tops to be subjected to a search is specified for a sample chromatogram, a search key is designated, and all or a part of index data recorded in step 1 is searched as a search target Obtaining a search result of a reference chromatogram associated with the search key,
(3) Furthermore, if it is necessary to narrow down the search results acquired in step 2, the search results are set as new search targets, and step 2 is performed for retention times other than one or more different peak tops for the same sample chromatogram. Said method characterized in that it is carried out. In the method according to claim 3, waveform features corresponding to respective retention times other than peak top in step 1 are also recorded as index data, and waveforms corresponding to each retention time other than peak top in step 2 How to use as a search key also features of. A method of searching for a chromatogram related to a sample chromatogram obtained by measuring an analysis sample from among reference chromatograms, comprising:
(1) For each of the reference chromatograms , a retention time other than one or more peak tops to be subjected to a search, and a waveform feature corresponding to each retention time are recorded as index data,
(2) A retention time other than one or more peak tops to be subjected to a search is specified for a sample chromatogram, a search key is designated, and all or a part of index data recorded in step 1 is searched as a search target Obtaining a search result of a reference chromatogram associated with the search key,
Alternatively , a retention time other than one or more peak tops to be subjected to a search on the sample chromatogram, and a waveform feature corresponding to each of the retention times are designated and used as a search key, and recorded in step 1 Searching all or part of index data as a search target, and acquiring search results of a reference chromatogram associated with the search key;
Including and
(3) Further, if it is necessary to narrow down the search results acquired in Step 2, the above-mentioned method is characterized in that Step 2 is performed on the same sample chromatogram at retention times other than one or more different peak tops .   6. The method according to any of claims 3 to 5, wherein the reference chromatogram is indicative of a hemoglobin phenotype.

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