WO2004013627A1 - Systeme et procede d'analyse de signaux dans une puce proteique a marqueurs multiples - Google Patents

Systeme et procede d'analyse de signaux dans une puce proteique a marqueurs multiples Download PDF

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Publication number
WO2004013627A1
WO2004013627A1 PCT/CN2003/000123 CN0300123W WO2004013627A1 WO 2004013627 A1 WO2004013627 A1 WO 2004013627A1 CN 0300123 W CN0300123 W CN 0300123W WO 2004013627 A1 WO2004013627 A1 WO 2004013627A1
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standard
signal
concentration
curve
camera device
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PCT/CN2003/000123
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English (en)
Chinese (zh)
Inventor
Gengxi Hu
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Shanghai Health Digit Co.Ltd
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Priority to AU2003211848A priority Critical patent/AU2003211848A1/en
Publication of WO2004013627A1 publication Critical patent/WO2004013627A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C40—COMBINATORIAL TECHNOLOGY
    • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
    • C40B30/00—Methods of screening libraries
    • C40B30/04—Methods of screening libraries by measuring the ability to specifically bind a target molecule, e.g. antibody-antigen binding, receptor-ligand binding
    • 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
    • G16B25/00—ICT specially adapted for hybridisation; ICT specially adapted for gene or protein expression
    • G16B25/10—Gene or protein expression profiling; Expression-ratio estimation or normalisation
    • 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
    • G16B25/00—ICT specially adapted for hybridisation; ICT specially adapted for gene or protein expression

Definitions

  • Multi-marker protein chip signal analysis system and method thereof Multi-marker protein chip signal analysis system and method thereof
  • the present invention relates to a biochip signal analysis system and method, and in particular, to a signal analysis system and method for a protein chip for detecting multiple markers, particularly multiple tumor markers. Background technique
  • Biochip technology is a high-tech developed rapidly in the field of life sciences in the past 10 years. It mainly refers to the construction of a miniature biochemical analysis system on the surface of a solid chip through micromachining and microelectronic technology to achieve accurate, fast and large information on the tissues, cells, proteins, nucleic acids, sugars and other biological components of living organisms. Amount of detection.
  • the common biochips are divided into three categories: gene chips (Genechip, DNAchip, DNAmicroarray), protein chips (Label on-a-chip), and so on.
  • Gene chips are very similar to the computer chips we call everyday, except that highly integrated are not semiconductor tubes, but thousands of grid-shaped densely arranged gene probes, through DNA fragments of known base sequence. Single-stranded DNA with complementary base sequences is combined to determine the corresponding sequence. In this way, abnormal genes or their products can be identified.
  • the principle of a protein chip is similar to that of a gene chip. The difference is that one is that the molecules fixed on the chip are proteins such as antigens or antibodies. Second, the detection principle is based on the interaction between protein molecules, proteins and nucleic acids, and proteins and other molecules. The protein chip technology appeared relatively late and is still in the development stage.
  • the lab of chips is the ultimate goal of the development of biochip technology. It intensifies the entire process of sample preparation, biochemical reaction, and detection and analysis into a micro-analysis system. Now there are chip laboratories consisting of heaters, micropumps, microvalves, microflow controllers, microelectrodes, electrochemistry and electroluminescence detectors, etc., and biochemical reactions, sample preparation, detection and analysis have appeared. And other partially integrated biochips.
  • the gene chip is the first commercialized product in biochip technology, many products have appeared as signal analysis systems for the gene chip.
  • the most commonly used gene chip signal analysis system is to place the chip in a chip scanner, collect the fluorescence intensity and fluorescence position of each reaction point, and analyze it by related software. Image to obtain biological information.
  • the fluorescence signal analysis system is roughly divided into two types according to different principles: laser confocal fluorescence microscopy and CCD fluorescence microscopy detection. The former has higher detection sensitivity and resolution, but has a longer scan time; the latter has a shorter scan time, but the sensitivity and resolution are not as good as the former.
  • An object of the present invention is to provide an analysis system mainly for detecting a multi-marker protein chip signal of a protein chip for clinical use in the case that an existing chip signal analysis system is mainly used for signal analysis of a gene chip.
  • the object of the present invention is also to provide a multi-marker protein chip analysis method that can simultaneously detect multiple markers, particularly multiple tumor marker protein chip signals, and perform fast, accurate, simple, and quantitative detection.
  • a multi-marker protein chip signal analysis system includes: a base plate, a cassette disposed on the base plate, a skin cavity located on the cassette and communicating with the skin cavity, and a skin cavity tightly arranged on the skin cavity and connected to the skin cavity.
  • Camera device its features are also: a light-tight X- ⁇ -Z- ⁇ positioning adjustment device and a computer analysis processor;
  • the X- ⁇ -Z- ⁇ positioning adjustment device includes: a camera device connector, the camera device connector is fastened to the lower part of the camera device; an XY direction adjusting frame, one end of which is connected to the camera device; a Z direction One end of the adjusting frame is connected with the XY direction adjusting frame, and the other end is fixed on the bottom plate; a triangular supporting frame is used for supporting the XY direction adjusting frame and the z direction adjusting frame;
  • the computer analysis processor has a data acquisition card, in which a corresponding image analysis application program is stored, which is used to store the image data signals collected by the camera device and analyze and process the image data signals.
  • the bottom plate is provided with two horizontal adjustment screws capable of adjusting the horizontal position of the bottom plate on the front side thereof; and a cassette guide bar is provided at an appropriate position on the bottom plate.
  • the cassette is fixed inside the cassette rail.
  • the connector includes a connector body which is gripped and surrounds the lower part of the camera device.
  • a camera device connection block is provided on the connector body.
  • a camera device connection screw is provided on the camera device connection block to connect the camera device. The device is fastened to the lower part of the camera device;
  • the X-Y direction adjusting frame includes an X-axis adjusting piece frame and an X-axis adjusting handle thereof, a Y-axis adjusting frame and a Y-axis adjusting handle thereof;
  • the z-direction adjusting frame includes a Z-axis base plate, a Z-axis adjusting knob provided on the Z-axis base plate, a Z moving plate connected to the X-Y direction adjusting frame, and a Z-axis set knob;
  • the X-Y-Z- ⁇ positioning adjustment device further includes a triangular support frame, which is supported under the X-Y direction adjustment frame and inside the Z-axis substrate of the z-direction adjustment frame.
  • a sample stage is provided in the cassette, and a sample stage level adjustment button capable of adjusting the angle of the sample stage is provided on the casing of the cassette.
  • An analysis method for quantitatively detecting a multi-marker protein chip signal by using the above-mentioned multi-marker protein chip signal analysis system which is characterized in that the analysis method includes the following steps:
  • Step 1 setting parameters on the computer analysis processor, including setting the exposure time of the camera in the signal analysis system and setting the temperature of the camera itself;
  • Step 2 After the required parameters are set, the camera device in the analysis system collects multiple light signals on the protein chip on the sample stage and captures image signals;
  • step three the image signals collected by the camera device are converted into digital signals and sent to a computer analysis processor
  • Step 4 After receiving the image data signal, the computer analysis processor 60 performs the following quantitative detection and analysis processing steps:
  • the fitting manner of the standard curve of "signal-concentration" of each marker may be It is a quadratic curve, a hyperbola, a logarithmic curve, or a combination of various quadratic curves.
  • Standard 1 If the conditions of 1 are not satisfied, remove Standard 1, and Standard 2 respectively.
  • Standard n-1 Standard n performs n-point fitting to obtain three sets of R values and curve monotonicity. The best one set of fit is selected as the output of this fitting.
  • the standard curve uses a signal value and a standard sample concentration as variables.
  • step 3 of the data analysis described above a large template is first used to locate multiple sub-arrays on the chip, and then a small template is used. Position the sample to be tested for each sub-array, position multiple sub-arrays on the chip, locate each signal point, and identify the gray level of the bright point by a computer analysis processor, and convert it into an electrical signal value.
  • the multi-marker protein chip signal analysis system and its analysis method adopt the above technical solution, so that compared with the prior art, it has the following advantages and positive effects:
  • the multi-marker protein chip signal analysis system of the present invention adopts the X-y-z-0 four-dimensional positioning adjustment device and a cooled charge-coupled camera device, which can accurately capture and capture multiple optical signals on the protein chip for images.
  • the multi-marker protein chip signal analysis system of the present invention can accurately analyze and detect the concentration of multiple target proteins in multiple generation samples in the protein chip due to the application of the above-mentioned quantitative analysis method.
  • the protein chip signal analysis system of the present invention has good reproducibility, stability and reliability, simple and intuitive operation, and can simultaneously perform the signals of multiple protein chips (each protein chip has signals of multiple test substances). Read and calculate, saving data analysis time. Brief description of the drawings.
  • FIG. 1 is a block diagram of a multi-marker protein chip signal analysis system in the present invention
  • FIG. 2 is a schematic structural diagram of a multi-marker protein chip signal analysis system in the present invention
  • FIG. 3 is a flowchart of a multi-marker protein chip signal analysis method in the present invention
  • FIG. 4 is an exposure of the chip signal analysis processing in the present invention Time setting dialog;
  • FIG. 5 is a dialog box of temperature setting in the chip signal analysis processing of the present invention.
  • FIG. 6 is a working interface diagram of a computer analysis processor in the present invention.
  • FIG. 7 is a chip signal image before contrast adjustment in chip signal analysis processing of the present invention
  • FIG. 8 is a chip signal image after contrast adjustment in chip signal analysis processing of the present invention
  • FIG. 9 is a secondary standard in chip signal analysis processing of the present invention Flow diagram of curve fitting
  • FIG. 10 is a standard curve diagram after fitting in the chip signal analysis processing of the present invention
  • FIG. 11 is a view of positioning a large template of a corresponding protein chip array in a chip signal analysis process according to the present invention.
  • FIG. 12 is a view of positioning a small template of a corresponding protein chip array in a chip signal analysis process according to the present invention.
  • FIG. 13 is a dialog box of positioning information in the chip signal analysis processing of the present invention.
  • FIG. 14 is a contrast transformation curve diagram of the chip signal analysis processing of the present invention.
  • FIG. 15 is a detection result report sheet output in a report form in the chip signal analysis processing of the present invention.
  • Fig. 16 is a standard signal value limitation table in the process of performing quadratic standard curve fitting on the chip signal analysis processing of the present invention. detailed description:
  • FIG. 1 and FIG. 2 are block diagrams and structure diagrams of a multi-marker protein chip signal analysis system in the present invention.
  • the invention relates to a multi-marker protein chip signal analysis system for providing a signal analysis system that captures a light signal generated by a chemical reaction on a protein chip and emits light.
  • the system includes a base plate 10, a cassette 20, a skin cavity 30, and a camera device. 40.
  • the bottom plate 10 is in the shape of a flat plate.
  • a horizontal adjustment screw 11 capable of adjusting the horizontal position of the bottom plate 10 is respectively provided at both ends of the front side of the bottom plate 10.
  • the cassette 20 is disposed on the bottom plate 10.
  • a cassette guide bar 21 is provided at an appropriate position on the bottom plate 10, and the cassette 20
  • a sample stage is provided, and a sample stage horizontal adjustment knob for adjusting the angle of the sample stage ⁇ is provided on the casing of the cassette 20, and the setting of the ⁇ angle rotation adjustment device for the subject is because the signal direction system of the biochip is Simultaneous shooting and analysis of a large number of signals, and if the location of each signal is not accurate, it will make analysis very difficult.
  • the present invention provides a device for adjusting the angle rotation of the subject on the horizontal plane by ⁇ angle to The angle adjustment function of the sample stage is realized.
  • the ⁇ angle rotation adjustment and positioning device is formed by simplifying the principle of a worm gear, so that an adjustment range of -5 degrees to +5 degrees can be achieved.
  • the leather cavity 30 is fixedly disposed on the cassette 20.
  • the leather cavity 30 communicates with the cassette 20, and a leather cavity tight frame 31 is provided on the leather cavity 30 for connecting with the upper object.
  • the camera device 40 is disposed on the skin cavity 30, and is fixedly connected and communicated with the skin cavity 30 through the skin cavity tight frame 31.
  • the camera device 40 uses a High-resolution cooled CCD camera system (COOL CCD camera); Cooled CCD camera system has higher sensitivity and is used to achieve low-light and very low-light to the conventional CCD camera system is difficult to achieve
  • the camera can be used under low temperature conditions.
  • the cooled CCD camera system can work at a low temperature below 0 ° C. This can reduce the dark current noise, make the captured image noise lower, and improve the image quality. ⁇
  • the optically sealed X-Y-Z- ⁇ positioning adjustment device 50 is composed of a camera device connector 51, an X-Y direction adjustment frame 52, a Z direction adjustment frame 53 and a triangular support frame 54;
  • the camera device connector 51 is fastened to the lower part of the camera device 50;
  • the camera device connector 51 includes a connector body 511, which is in the shape of a grip, which surrounds the lower part of the camera device 50, and
  • the body 511 is provided with a camera device connection block 512, and the connection surface of the camera device connection block 512 is an arc surface adapted to the camera device 50, so that it can be fit outside the camera device 50, and is provided on the camera device connection block 512
  • There is a camera device connection screw 513 and the camera device connector 51 can be fastened to the lower part of the camera device 50 by tightening the connection screw 513;
  • the upper end of the X-Y direction adjusting frame 52 is connected to the camera device 50;
  • the adjusting frame 52 includes an X-axis adjusting piece frame 521 and its X-axis adjusting handle 522, a Y-axis adjusting frame 523 and its Y-axis adjusting handle 524;
  • the Z-direction adjusting frame 53 includes a Z-axis substrate 531, which is fixed on the bottom plate 10, a Z-axis adjustment knob 532 is provided on the Z-axis substrate 531, and an upper end of the Z-axis substrate 531 is connected and provided with a Z moving plate 533 connected to the XY direction adjusting frame 52, and the Z axis is fixed Knob 534.
  • the triangular support frame 54 is disposed on the side of the XY direction adjustment frame 52 and the Z direction adjustment frame 53.
  • the upper plane of the triangular support frame 54 is supported under the XY direction adjustment frame 52, and the side plane of the triangular support frame 54 is Z.
  • the direction adjusting frame 53 is supported on the inside of the Z-axis substrate 531 by the mountain.
  • the computer analysis processor 60 is used for quantitative detection and analysis of a variety of target proteins to be detected on a protein chip; a data acquisition card is set in the computer analysis processor 60, and corresponding images are stored in the data acquisition card
  • the analysis application program is used to store the image data signals collected by the imaging device 40 and analyze and process the image data signals.
  • FIG. 3 is a flowchart of a method for analyzing a signal of a multi-marker protein chip in the present invention.
  • the multi-marker protein chip signal analysis method of the present invention can analyze and detect gene chip signals and detect clinical protein chip signals, and can simultaneously detect multiple markers, especially protein chip signals of multiple tumor markers.
  • the above tumor markers may include AFP, PSA, free-PSA, HGH, ⁇ -hCG, CEA, NSE, CA19-9, CA242, CA15-3, CA125, Ferritin, and the like.
  • a method for analyzing a multi-marker protein chip signal includes the following steps:
  • Step 1 Setting parameters on the computer analysis processor includes setting the exposure time of the camera 40 in the signal analysis system, and setting the temperature of the camera 40 itself;
  • Step 2 After the required parameters are set, the camera device 40 in the analysis system collects multiple optical signals on the protein chip on the sample stage and captures image signals;
  • step three the image signal collected by the camera device 40 is converted into a digital signal and sent to a computer analysis processor;
  • Step 4 After receiving the image data signal, the computer analysis processor 60 performs the following quantitative detection and analysis processing steps:
  • image processing which enlarges the selected image area, increases the contrast of the image, and removes the noise points on the image.
  • Curve uses signal value and standard sample concentration as variables; and the standard curve fitting method may be a quadratic curve, a hyperbola, a logarithmic curve, or a variety of quadratic curves The combination;
  • the “signal-concentration” standard curve for each marker is a quadratic curve
  • the specific process of fitting the quadratic standard curve is:
  • the fitting result is used as the current fitting output.
  • the method for determining whether the curve is monotonic can be verified by a computer algorithm based on the characteristics of the quadratic curve. In this embodiment, The method to determine whether R> 0.98 and the curve is monotonic is:
  • the following is an example of a specific operation process of the computer analysis processor 60 in the present invention for performing quantitative detection and analysis on the signal of the multi-marker protein chip.
  • FIG. 4 and FIG. 5 are descriptions of images acquired by the multi-marker protein chip.
  • the invention can be used to detect 12 tumor markers: AFP, PSA, free-PSA, HGH, ⁇ -hCG, CEA, NSE, CA19-9, CA242, CA15-3, CA125, Ferritin.
  • the chemiluminescence-producing protein chip is placed on the sample stage in the cassette;
  • set the exposure time to a fixed value from 10 seconds to 5 minutes, such as 15 seconds or 60 seconds, as shown in the figure.
  • Settings The exposure time is 30 seconds.
  • the implementation method is as follows: Enter the exposure time m_ExpTime from the exposure time setting dialog shown in Figure 4 and pass it to the variable exposure_time.
  • the function PICM_SetExposure controls the exposure time. ;
  • Set the CCD temperature to any value from -10 ° C to -50 ° C, such as:-20 ° C; set the CCD temperature to -20 ⁇ in the figure; the implementation method is: input from the temperature setting dialog shown in Figure 5
  • the set temperature setTmp is controlled by the function PICM— Set— Temperature (setTmp); click on the “Image Acquisition” menu to obtain the chip image captured by the camera system, and store it in the computer.
  • FIG. 6 to FIG. 8 are working interface diagrams of the computer analysis processor and chip signal images before and after contrast adjustment in the present invention.
  • the computer analysis processor 60 performs image processing on the signal of the multi-marker protein chip, click the "Image Transformation” menu on the working interface of the computer analysis processor, and perform "enlargement", "contrast enhancement", etc. as required.
  • Processing, used to adjust the image display size, contrast, etc. can also use the "fill" function to remove noise in the chip image.
  • the implementation method is as follows: (1) Zoom in
  • Tx the width of the subwindow / the width of the selected image
  • ty the height of the subwindow / the height of the selected image
  • the magnification of the image m_Scale takes the smaller of ⁇ , ty;
  • the noise area with the mouse, and fill the area with the value SpotValue.
  • the calculation method of SpotValue is: outside the selected noise area (3 pixels width), find gray For pixels with a degree value between 40 and 150, take the average of these pixels as the SpotValue. If the number of points is 0, the SpotValue is 80.
  • FIG. 9 is a flow block diagram of the quadratic standard curve fitting in the chip signal analysis processing of the present invention.
  • FIGS. 10 to 15 are standard curve diagrams, protein chip array diagrams, and test result reports related to data analysis and output operations in chip signal analysis and processing of the present invention.
  • Data analysis and output operations are as follows;
  • the method is: use a small template to position each standard array, and adjust the array row, column number, row spacing, column spacing, template size, and template position of the template to make the positioning All the squares of the template are just fixed with all the signal points of a sub-array, and each small square contains only one signal point. Take the average value of the brightest 4 pixels in each small square as the signal value of each point StandardPixAve [i] [SD], and according to the concentration value and signal value, fit the x markers according to Example 3 respectively. standard curve line.
  • Various fitting methods can also be used. combination.
  • Figure 10 A legend of the quadratic standard curve of the CA125 marker in the protein chip, where the X-axis represents the concentration value and the y-axis represents the signal value.
  • a positioning information dialog box will appear, as shown in Figure 13. Click the "Position” button in the dialog box to save the coordinates of the upper left corner of the template as the actual coordinate position of the sub-array LS_ActualPoint [i] [j ], Calculate and search the nearest LS_IdealPoint [i] [j], set it to the array at that position (such as the A1 sub-array), hide the buttons corresponding to the array, and position each sub-array in turn according to this method .
  • the multi-marker protein chip signal analysis system and analysis method of the present invention adopts the above technical solutions and operation steps, which not only can obtain high-quality image resolution, but also can accurately detect the protein chip.
  • Multiple target proteins in multiple samples to be tested that is, the concentration of the marker;
  • the analytical data is reproducible, stable and reliable, and the operation is simple and intuitive;
  • multiple protein chips (each protein chip can be used)
  • the quantitative instrument can also be used in combination with other biochips, so it is extremely practical.

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Abstract

L'invention concerne un système et un procédé d'analyse de signaux dans une puce protéique à marqueurs multiples. Le système comprend une plaque de base, une cassette sur la plaque de base, une cavité de dépôt en communication avec la cassette, une caméra positionnée sur la cavité de dépôt, un dispositif de positionnement X-Y-Z-υ étanche à la lumière et un processeur analytique informatisé. Le dispositif de réglage de position X-Y-Z-υ comprend un connecteur de caméra, un cadre de réglage de direction X-Y dont une extrémité est connectée à la caméra, un cadre de réglage de la direction Z et un support en triangle. Le processeur analytique informatisé contient une carte d'acquisition de données dans laquelle est utilisé un programme d'application de stockage et d'analyse des signaux de données d'images prises par la caméra. Le procédé consiste (1) à régler les paramètres, (2) à acquérir les signaux, (3) à transformer les signaux, (4) à analyser et à traiter ces signaux, l'étape d'analyse et de traitement consistant à traiter les images, à réaliser une courbe standard, à analyser les données et à sortir des tables. Il est ainsi possible d'obtenir une très bonne résolution d'image permettant de détecter précisément la concentration des marqueurs et de les analyser.
PCT/CN2003/000123 2002-08-02 2003-02-08 Systeme et procede d'analyse de signaux dans une puce proteique a marqueurs multiples WO2004013627A1 (fr)

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AU2003211848A AU2003211848A1 (en) 2002-08-02 2003-02-08 System and method for analyzing signals in a multi-markers protein chip

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CNB021363706A CN1255671C (zh) 2002-08-02 2002-08-02 多标志物生物芯片信号分析方法
CN02136370.6 2002-08-02

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CN105548179A (zh) * 2015-12-04 2016-05-04 深圳市赛尔生物技术有限公司 一种基于透射光或自发光测定生物芯片的方法及系统
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CN1317692A (zh) * 2000-04-10 2001-10-17 财团法人工业技术研究院 生物芯片检测装置

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AU2006246751B2 (en) * 2005-05-20 2010-08-19 Fidia Farmaceutici S.P.A. Bioresorbable fillers constituted by phospholipid liposomes and hyaluronic acid and/or the derivatives thereof

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