CN105044108B - Micro-array chip arraying quality automatization judgement system and judgment method - Google Patents
Micro-array chip arraying quality automatization judgement system and judgment method Download PDFInfo
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Abstract
The present invention provides a kind of micro-array chip arraying quality automatization judgement system and judgment methods.The judgement system includes micro-array chip, and scanner, computer software digitalizer and software compare device, according to the detection of the difference of institute's point probe and different probe the relative position information realization sample biological information on basement membrane.The judgement system has detection efficiency high, and the examining report of 936 parts of microarrays can be provided in 15 minutes；As a result objective, it is consistent with the multiple judging result of portion microarray；Of low cost, a work position can realize the significant advantages such as traditional 8 16 operations that manually can be done.
Description
Technical field
The invention belongs to field of biological technology detection, more particularly to micro-array chip arraying quality automatization judgement system and sentence
Disconnected method.
Background technology
Micro-array chip refer to array way be set on substrate can parallel processing and analysis sample in biology or change
Learn the microdevice of information.Note：Dot matrix arrangement point diameter is within 500 μm, and adjacent two dot center spacing minimum range is not to generate
(GB/T 27990-2011 subject to signal cross《Biochip basic terms》).
Because micro-array chip is small, point diameter is micron level, and in order to realize that high density point sample, point spacing are frequently less than
Point diameter, naked eyes are difficult the micro-array chip quality for judging production.
It is mostly artificial judgment that enterprise, which carries out arraying quality judgement, at present, by scanning or camera installation, by microarray images
Amplification several times are shown on a display screen, by manually recognizing or using measurer manual measurement on a display screen.This method detects
Efficiency is low, and subjective factor is big, and missing inspection false retrieval happens occasionally.
Biochip point sample process real-time detection system and analysis of the prior art CN101839688A based on machine vision
Method, including：One image picking-up apparatus, the image picking-up apparatus follow the sampling head of point sample equipment to synchronize three-dimensional motion simultaneously
Spotted area is shot to obtain spotted area image；One image capture device, the image capture device and described image
Capture apparatus signal connects, and is acquired to the image of image picking-up apparatus shooting and completes the digital-to-analogue conversion of image；One image
Processing equipment, the image processing equipment are connect with described image collecting device signal, the point sample acquired to image capture device
Area image is handled, is analyzed, and exports handling result.But during actual implementation, since technology needs are adopted in real time
Collect and analyze image, extend biochip point sample process, reduces the service efficiency of biochip point sample instrument.Meanwhile in order to
The requirement of data is analyzed in cooperation in real time, needs to set to apply every biochip point sample instrument outfit Image Acquisition of the technology
Standby, image processing equipment causes the increase of production cost.Moreover, the technology by biochip point sample and biochip test with
Analysis merges, and constitutes an increasingly complex new system, reduces the stability of system, and during actual implementation, point sample is steady
It is qualitative to be affected.
Invention content
Low, the of high cost and poor stability problem in view of efficiency of the existing technology, the present invention provides microarray cores
Piece arraying quality automatization judgement system and judgment method.The present invention can automate batch detection biochip quality, and
It can be performed simultaneously with multitask, execution efficiency is high.Since the present invention is only by scanner and computer digital device and point sample instrument
It is vertical, it is practical to execute stability height.
The micro-array chip arraying quality automatization judgement system includes：Micro-array chip, scanner, computer software
Digitalizer and software compare device.
The composition of the micro-array chip includes substrate, and point and DNA probe, surface chemistry Quality Control are arranged on substrate
Point probe and blank control probe, each probe is corresponding with point and blank spot.
The DNA probe of micro-array chip setting 26 kinds of HPV viruse different genotypes of detection, and it is reserved 8 it is expansible
Point.
4 " vertex " label of the substrate draws 1 isolated area, which is a micro-array chip, is divided into
A-f rows and g-l row.
The expansible point is located at c row l row points, e row k row points, f row h row points.
The internal reference probe is located at f row i points, f row j row points；The surface chemistry Quality Control point probe is located at a rows g
Row point, a row l row point, f row l row points；The blank control probe is located at f row k row points；Blank spot is located at f rows g row
Point, DNA probe are located at remaining point.
Wherein, micro-array chip is made of substrate, probe.Substrate is used to carry probe, has certain mechanical strength,
The effect of acquisition target target can be realized with supporting probe.It is keyed by chemistry between probe and substrate, during acquisition target target
Realization is stably connected with.Substrate is mostly to have the material of certain mechanical strength for glass, nylon membrane, silicon chip, plastics or ceramics etc.
It makes, and has profile pattern and chemical modification, it is living to have specific biology mostly based on large biological molecule for two probes
Property, target specific can be captured, the conversion of target organisms information is realized according to location information of the probe in micro-array chip
With identification.Micro-array chip realizes that function must be premised on the ordered microarray that probe particular arrangement is formed, i.e. microarray core
The order of piece is to realize the premise necessary condition of micro-array chip.
Scanner is made of plate glass, light source, photosensitive element, driver, mainboard, USB port, and micro-array chip is placed on
On plate glass, the surface of probe is combined with towards light source and photosensitive element, driver drives light source and photosensitive element are by micro- battle array
The top of row chip is moved to bottom end, and during which light source sends out visible light, threw glass and is radiated on micro-array chip, microarray core
The reflected light of piece enters photosensitive element, realizes that the collection of image, photosensitive information carry out digital conversion through mainboard, and through USB port
It is sent to computer software digitalizer.Scanner may be implemented 36 × 26 the disposable of total 936 micro-array chips and sweep
It retouches.
The group of computer software digitalizer becomes USB port, display, processor, memory, and USB port reception is swept
The digitized video that instrument is sent is retouched, and is kept in memory, software transfer digitized video, and the choice box delimited according to user
Logarithm image is split, binary picture, and the dimension information of the position of each target spot, long axis, short axle is temporarily stored in memory
In.
And software comparison device calls the dimension information of each target spot of 936 chips and mark set by user in memory
Quasi- dimension information is compared, and the target spot for complying with standard setting is judged as qualification, otherwise as unqualified, and will determine that result
It is output on display with Excel formats.
The judgment method includes：Using aforementioned micro-array chip arraying quality automatization judgement system, (1) analyzes picture
In the color of each pixel constitute, red pixel is more than 200 in the color of pixel is constituted and red pixel is more than blue picture
When element+40, then the pixel will be construed to target spot, otherwise will be considered for background, and rake pixel is switched to white, background pixel
Switch to black；(2) according to binary picture, the corresponding position of each rake point and size are found out by Contour extraction, for rake
Point is directly ignored less than minimum dimension；(3) if the height of rake point or width are more than rake point full-size, judge the rake point
Strictly two rake points are bonded together, and the rake point being bonded together is carried out and is split；(4) according to the rake point detected
It sets, size, the information such as length-width ratio be compared with the standard value of setting, generate examining report.
Present case realizes micro-array chip arraying quality automatization judgement system, which has to micro-array chip certainly
The dynamic function of judging quality, can arrange feature according to the dot matrix of chip, by setting array line number, array line space, array
Columns, array column pitch, target spot line number, target spot line space, target spot columns, target spot column pitch, target spot diameter, target spot are maximum straight
The parameters such as diameter, target spot minimum diameter, target spot aspect ratio maximum value, target spot maximum displacement, and software comparison device voluntarily with setting
Parameter is compared to determine the quality condition per chips and provide report.
Term in the present invention：HB-internal reference the probes；+ VE-surface chemistry Quality Control point probes；- VE-blank controls
Probe.
Human papilloma virus (HPV), HPV viruse have more than 130 a gene types, chip of the present invention wherein 26 kinds detectable
HPV viruse type (be respectively HPV 16,18,31,33,35,39,45,51,52,56,58,59,68,6,11,40,42,43,
44,53,54,55,57,66,67,73 type).
Traditional artificial judgement system has significant advantage to automatization judgement system of the present invention compared to the prior art, is described in detail
It is as follows：
1. detection efficiency is high
Coordinate high-performance computer, automatization judgement system that can provide the examining report of 936 parts of microarrays in 15 minutes,
And multi-core parallel parsing may be implemented, may be implemented on multi-core CPU computer 4~8 detection simultaneously it is parallel, go out report
It is constant to accuse the time.And traditional artificial judgement system judge 936 parts of microarrays need 30~60 minutes (array complexity is different,
Judge that time difference is very big).
2. result is objective
Automatization judgement system is judged chip image by image digitizing system, and when image passes through high-resolution
Rate scanner obtains, and is identical with material object, and image is formed according to color and Color Range forms numerical value, and logarithm is compared
Analysis, thus it is consistent with the multiple judging result of a microarray.And traditional artificial judgement system judges according to personal experience,
Judging result is difficult to be consistent under the different conditions of different people and people.
3. of low cost
A set of micro-array chip arraying quality automatization judgement system can group comprising scanner, computer and software kit
Build implementation.The Quality estimation of micro-array chip can be realized by simple training and according to operating instruction manipulation software by personnel.One
A work position can realize the traditional 8-16 operations that manually can be done.Greatly reduce the employment cost of enterprise.
Description of the drawings
Fig. 1 micro-array chip arraying quality automatization judgement working-flow figures of the present invention.
A kind of micro-array chip structure chart of Fig. 2 present invention
A kind of microarray chip analysis figure of Fig. 3 present invention, wherein pictorial diagram before Fig. 3 (A) chip binaryzations to be checked, Fig. 3
(B) chip binaryzation post analysis figure to be checked.
A kind of binaryzation micro-array chip dot matrix marginal texture figure of Fig. 4 present invention, converts to obtain by Contour extraction.
A kind of judgement parameter list figure of Fig. 5 present invention.
A kind of 26 × 36 chip row matrix column distribution schematic diagrames of single-point chip of Fig. 6 present invention
A kind of single-point chip chamber Quality Control parameter schematic diagram of Fig. 7 present invention
Quality Control parameter schematic diagram in a kind of single-point chip of Fig. 8 present invention.
A kind of parameter judging result list of Fig. 9 present invention.
Specific implementation mode
In order to explain the present invention, the invention will be further described with embodiment with reference to the accompanying drawings of the specification, but this hair
It is bright without being limited thereto.
Specific implementation mode one：
As shown in Figure 1, the micro-array chip arraying quality automatization judgement system includes：Micro-array chip, scanner,
Computer software digitalizer and software compare device.
Wherein, micro-array chip with lower component by being formed：
Nylon film substrate：Nylon membrane has certain mechanical strength and DNA combination biological activities, can be in specific item
It is combined with DNA probe under part and carries DNA probe and complete Biological Detection.4 " vertex " label draws nylon membrane in wherein Fig. 2
Go out 1 isolated area, which is a micro-array chip, is divided into a-f rows and g-l row.
Human papilloma virus (HPV) different genotype viral DNA probe：Different digital represents different HPV genes in Fig. 2
Type amounts to 26 kinds of HPV viruse different genotypes of detection, and (" undetermined " point, c rows l are arranged reserved 3 expansible points in Fig. 2
Point, e row k row points, f row h row point).
Internal reference probe：" HB " point (f row i points, f row j row point) in Fig. 2, synthetic gene sequence is in gene core
The point of sample of on piece has the ability of specific binding with related gene in human genome, judges whether success during the test
Whether the extraction efficiency for obtaining cell and cell DNA is up to standard.
Surface chemistry Quality Control point："+VE " point (a row g row point, a row l row point, f row l row point) in Fig. 2, containing special
Point of sample of the synthetic gene sequence of property substance that show color on genetic chip, can be not against PCR product to process color
Carry out Quality Control.
Blank control："-VE " point (f row k row point) in Fig. 2 is free of the sampling liquid of bioactive molecule, for verifying core
Whether piece deposition process occurs point sample mistake.
Blank spot：" no point " point (f row h row point) in Fig. 2, the point is without point sample, due to that will not develop the color, according to the position
The relative position with three certain colour developing points of+VE is set, realizes and the direction of rotation in chip process color is confirmed.
The above probe specificity captures bioactivity target, is realized according to the difference of position of the probe in micro-array chip
The other differentiation of HPV different genotypes and the judgement of detection test validity.
Scanner：Canoscan 9000F Mark II, 36 × 26 amount to the one-off scanning of 936 micro-array chips.
Computer software digitalizer：Desktop computer, Windows 7 (64) system, can install software program, and
The operation of arraying quality automatization judgement system program is provided.
Specific implementation mode two：
As shown in Fig. 3,4,5,6,7,8 and 9, the judgment method includes：Using the micro-array chip of previous embodiment one,
Scanner, computer software digitalizer install point sample quality automatic judgement system in computer software digitalizer
Chip scanning figure is opened using program, position is pinpointed to it by system program, and program is automatically performed following comparative analysis：
(1) color for analyzing each pixel in picture is constituted, in the color of pixel is constituted red pixel be more than 200 and
When red pixel is more than blue pixel+40, then the pixel will be construed to target spot, otherwise will be considered for background, rake pixel
Point switchs to white, and background pixel switchs to black (shown in Fig. 3)；
(2) according to binary picture, the corresponding position of each rake point and size are found out by Contour extraction, for harrowing point
Less than minimum dimension, directly ignore；
(3) if the height of rake point or width are more than rake point full-size, judge that the rake point is two rake point bondings in fact
Together, the rake point being bonded together is carried out and is split (first row shown in Fig. 4 is crosslinked point and splits)；
(4) according to the rake point position detected, size, the information such as length-width ratio carry out and the standard value of setting (ginseng shown in Fig. 9
Number is standard value range) it is compared, generate examining report.
Judge that parameter selection is as shown in Figure 8,9.
K and L parameters are less than " target spot maximum displacement " 30 in Fig. 9 in Fig. 8, for qualification.
N parameters have maximum value and minimum value two, wherein maximum value to should be less than in Fig. 9 " target spot maximum gauge " 40 in Fig. 8
It is otherwise excessive for target spot for qualification, it is unqualified；And it is qualification that minimum value, which should be less than " target spot minimum diameter " 23, is otherwise target spot
Missing, it is unqualified；Simultaneously maxima and minima ratio should be less than " target spot aspect ratio maximum value " 1.5 be qualification, otherwise for
Target spot is in irregular shape, unqualified.
Performance summary：
1, detection efficiency is high
Coordinate high-performance computer, automatization judgement system that can provide the examining report of 936 parts of microarrays in 15 minutes,
And multi-core parallel parsing may be implemented, may be implemented on multi-core CPU computer 4~8 detection simultaneously it is parallel, go out
Report time is constant.And traditional artificial judgement system judges that 936 parts of microarrays need that (array complexity was or not 30~60 minutes
Together, judge that time difference is very big).
2, result is objective
Automatization judgement system is judged chip image by image digitizing system, and when image passes through high-resolution
Rate scanner obtains, and is identical with material object, and image is formed according to color and Color Range forms numerical value, and logarithm is compared
Analysis, thus it is consistent with the multiple judging result of a microarray.And traditional artificial judgement system judges according to personal experience,
Judging result is difficult to be consistent under the different conditions of different people and people.
3, of low cost
A set of micro-array chip arraying quality automatization judgement system can group comprising scanner, computer and software kit
Build implementation.The Quality estimation of micro-array chip can be realized by simple training and according to operating instruction manipulation software by personnel.One
A work position can realize the traditional 8-16 operations that manually can be done.Greatly reduce the employment cost of enterprise.
The above content is a further detailed description of the present invention in conjunction with specific preferred embodiments, and it cannot be said that
The specific implementation of the present invention is confined to these explanations.For those of ordinary skill in the art to which the present invention belongs, exist
Under the premise of not departing from present inventive concept, a number of simple deductions or replacements can also be made, all shall be regarded as belonging to the present invention's
Protection domain.
Claims (6)
1. micro-array chip arraying quality automatization judgement system, which is characterized in that including：Micro-array chip, scanner calculate
The makeup of machine software digital is set and software comparison device, and the composition of the micro-array chip includes substrate, set-point on substrate
Position and DNA probe, surface chemistry Quality Control point probe and blank control probe, internal reference probe, each probe is corresponding with point,
And part point is blank spot, software comparison device can simultaneously analyze 936 chips, and voluntarily with setting
Parameter is compared to determine the quality condition per chips and provide report, 26 kinds of HPV of the micro-array chip setting detection
The DNA probe of viral different genotype, and 8 expansible points are reserved, 4 " vertex " label of the substrate draws 1 solely
Vertical region, which is a micro-array chip, is divided into a-f rows and g-l row, the internal reference probe be located at f row i points,
F row j row points；The surface chemistry Quality Control point probe is located at a row g row point, a row l row point, f row l row points；The sky
White control probe is located at f row k row points；Blank spot is located at f row g row points, and DNA probe is located at remaining point.
2. micro-array chip arraying quality automatization judgement system according to claim 1, which is characterized in that described to expand
Machine plotting position is located at c row l row points, e row k row points, f row h row points.
3. micro-array chip arraying quality automatization judgement system according to claim 1, which is characterized in that each DNA
Probe is different, be followed successively by HPV 16,18,31,33,35,39,45,51,52,56,58,59,68,6,11,40,42,43,44,
53,54,55,57,66,67,73 type DNA probe.
4. micro-array chip arraying quality automatization judgement system according to claim 1, which is characterized in that the substrate
For glass, nylon membrane, silicon chip, plastics or ceramics.
5. a kind of micro-array chip arraying quality automatization judgement method, which is characterized in that including：Using preceding claims
Micro-array chip arraying quality automatization judgement system described in 1-4 any claims, according to the difference of institute's point probe, with
And different probe relative position information on substrate realizes the detection of sample biological information.
6. a kind of micro-array chip arraying quality automatization judgement method according to claim 5, which is characterized in that packet
It includes：It is as follows：
(1) color for analyzing each pixel in picture is constituted, and red pixel is more than 200 and red in the color of pixel is constituted
When pixel is more than blue pixel+40, then the pixel will be construed to target spot, otherwise will be considered for background, and rake pixel is turned
For white, background pixel switchs to black；
(2) according to binary picture, the corresponding position of each rake point and size are found out by Contour extraction, rake point is less than
Minimum dimension, directly ignore；
(3) if the height of rake point or width are more than rake point full-size, judge that the rake point is that two rake points are bonded in one in fact
It rises, the rake point being bonded together is carried out and is split；
(4) the rake point position that basis detects, size, the information such as length-width ratio be compared with the standard value of setting, are generated
Examining report.
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| CN105590079B (en) * | 2015-12-23 | 2018-02-16 | 上海百傲科技股份有限公司 | A kind of method and apparatus of multiple continuous automatically identifying and readings of biochip transmission signal |
| US11299783B2 (en) | 2016-05-27 | 2022-04-12 | Personalis, Inc. | Methods and systems for genetic analysis |
| CN106479880B (en) * | 2016-11-01 | 2019-06-04 | 上海市同仁医院 | A kind of human papilloma virus result interpretation device |
| US11814750B2 (en) | 2018-05-31 | 2023-11-14 | Personalis, Inc. | Compositions, methods and systems for processing or analyzing multi-species nucleic acid samples |
| CN113658209B (en) * | 2021-08-12 | 2023-06-16 | 山东省计算中心（国家超级计算济南中心） | Morphology-based excellent discriminating method for mounting position of slice tissue |
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| CN103409553A (en) * | 2013-02-01 | 2013-11-27 | 港龙生物技术（深圳）有限公司 | Gene chip, reagent and kit thereof for high-throughput typing detection of human papilloma virus |
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