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WO1999045366A1 - Systeme d'imagerie optique pour diagnostics - Google Patents

Systeme d'imagerie optique pour diagnostics Download PDF

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Publication number
WO1999045366A1
WO1999045366A1 PCT/US1999/005012 US9905012W WO9945366A1 WO 1999045366 A1 WO1999045366 A1 WO 1999045366A1 US 9905012 W US9905012 W US 9905012W WO 9945366 A1 WO9945366 A1 WO 9945366A1
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WIPO (PCT)
Prior art keywords
field
computer
test
imaging
machine
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Application number
PCT/US1999/005012
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English (en)
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WO1999045366A9 (fr
Inventor
Ajoy K. Prabhu
William P. Trainor
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Universal Healthwatch, Inc.
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Filing date
Publication date
Application filed by Universal Healthwatch, Inc. filed Critical Universal Healthwatch, Inc.
Priority to AU28995/99A priority Critical patent/AU2899599A/en
Publication of WO1999045366A1 publication Critical patent/WO1999045366A1/fr
Publication of WO1999045366A9 publication Critical patent/WO1999045366A9/fr

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
    • G01N21/25—Colour; Spectral properties, i.e. comparison of effect of material on the light at two or more different wavelengths or wavelength bands
    • G01N21/251—Colorimeters; Construction thereof
    • G01N21/253—Colorimeters; Construction thereof for batch operation, i.e. multisample apparatus

Definitions

  • the present invention relates to imaging methods for diagnostic assay of multiple analytes and to automated instrumentation.
  • Tests for sexually transmitted disease for example, ideally should subject a sample to a small battery of tests to detect exposure to various organisms such as HIV, syphilis and chlamydia.
  • the best technology for conducting such tests uses separate reaction containers wherein antibody binding reactions occur, followed by a signal development step whereby presence of the analyte (or an antibody made in response to infection) is detected by the formation of a visual signal.
  • an HIV confirmation test should include test results for p24, gp41, gpl20 and gpl ⁇ O polypeptides.
  • a Western blot test can provide this information as a series of spots along an electrophoresed image field.
  • no corresponding system, machine or method is available for obtaining multiple reactivity information from a small mmunometric assay binding reaction.
  • the invention meets the need for diagnostic tests that provide more information by combining dot-blot technology with new imaging techniques.
  • the invention allows multiple antigen-antibody binding reactions to occur in one test reagent system, using two-dimensional optic imaging to simultaneously detect the rich information provided by, for example, multiple dot-blots, or other diagnostic test results that cause an optical change in a single optical field.
  • Embodiments of the invention also solve the poor resolution problem by focusing the optics onto a single field of about 0.5 to about 5 mm in diameter, and also by using frame grabbing image processing software.
  • Frame grabbing software is software that, using data obtained from multiple two dimensional images (each of which is said to have been grabbed), compares the images and outputs an improved resolution image of an imaged field. Output in this context means to place the higher resolution image into memory and/or print or make a hard copy permanent record.
  • the invention also simplifies manufacture and packaging of diagnostic test devices by using software to compensate for variability in the placement of control and/or test spot signals in a diagnostic test. This is particularly helpful when the test signals are very small. For example, if a test device surface (that produces an imaging field for a single test sample analysis) has a 3 mm diameter and a test spot within the field is 0.1 mm in diameter then a shift in the plate or holder that contains the test device of only 0.1 mm can omit the test spot signal entirely.
  • the invention prevents this problem by converting the problem of reproducibility in placement and movement of (1) reagents in the diagnostic test device (2) the diagnostic test device into a holder of multiple devices and (3) the holder itself within a reader, into a software issue that is more easily and quickly resolved by a computer.
  • One embodiment of the invention is a machine that accepts a multiple sample reaction container plate, and that images one or more diagnostic test device images ("imaging fields.")
  • a test device image is a two-dimensional field with color and/or light intensity information pertaining to control and test spot results.
  • Each sample reagent well from a plate of a plurality of wells (for example, a 96 well plate) is used to test for the presence of at least two, and preferably three or more analytes at the same time.
  • the machine further comprises a two dimensional charge coupled device to obtain an image, and memory for storing the test image.
  • the machine uses software to enhance the image obtained by multiple imaging measurements, determines areas of the image that correspond to background, signal control region(s), and test spot region(s), and outputs a result to the user concerning the presence, absence and/or amount of multiple analytes.
  • an imaging system comprises an electronic two dimensional imager that produces electrical information and a computer that analyses the electrical information wherein the two dimensional imager obtains two dimensional visual information from an imaging field after liquid is dispensed onto the field by the liquid dispense unit, and the computer determines the position of a control signal and a test signal (which optionally is a dot blot) from the two dimensional information in order to create a test result.
  • the computer determines the position of the control signal by comparing the visual information with a predetermined pattern by a lookup table or by an algorithm that searches for the pattern within the visual information.
  • the invention is a computer program for use in obtaining at least one test result from a single imaging field, the computer program being run on a computer, the computer program comprising: a first computer readable program code for determining a location of a non test- signal background region of the imaging field based on sensed signals provided to the computer by a two-dimensional imaging sensor, the sensed signals including a dark border region around the field and a lighter region of the field, the field including a dark control mark; a second computer readable program code for processing pixel information obtained from a predetermined number of pixels that are located at the non test-signal background region, the pixel information being provided to the computer by the two-dimensional imaging sensor; a third computer readable program code for processing pixel information obtained from a predetermined number of pixels that are located at a test signal region, the pixel information being provided to the computer by the two-dimensional imaging sensor and corresponding to information obtained from a corresponding test spot located at a test spot region; and a fourth computer readable program code for determining
  • Figure 1 is a picture of a 96 well disposable multi-sample plate.
  • Figure 2 shows an advantageous embodiment of the invention using a modification of a commercially available liquid handling robotic instrument.
  • Figure 3 shows a preferred image field with one darkened control region and 3 darkened test spots.
  • the inventors discovered an instrument platform that provides multiple simultaneous assays by integrating: (1) the convenience and economy of individual specific (i.e. based on specific binding reactions) assays in a disposable plate form, each assay having an imaging field; (2) liquid handling robotics; and (3) high resolution imaging for simultaneous detection (i.e. determination of presence or absence, and optional quantitation) of multiple analytes within each imaging field and optional simultaneous detection from multiple fields.
  • This combination provides advantages of speed, throughput and other improvements to previous technology as will be evident upon a more detailed review of the invention presented here.
  • binding reactions refers to detection systems that employ specific binding reaction(s) to detect an analyte from a sample.
  • a binding reaction may be, for example, between an antibody, or antibody-fragment and an antigen.
  • other, non-antibody based specific binding reactions also are contemplated, such as nucleic acid hybridization reactions, and are useful in various embodiments of the invention.
  • the term "specific” reflects the broader meaning of specific binding between molecules, be they antibody- antigen, enzyme-substrate, lectin-hapten, or nucleic acid with nucleic acid and the like. In a test, such binding leads eventually to an optical signal, which may be proportional to the amount of the specific analyte.
  • Advantageous binding reactions include those described in co-pending patent applications 08/933,943 entitled “Diagnostic Devices with Improved Fluid Movement and Resistance to Interferences” filed September 19, 1997, 09/069,935 entitled “Multiple Readout Immunoassay with Improved Resistance to Interferences” filed April 30, 1998, and “Multi- Analyte test for Multiple Blood-borne Diseases” filed March 4, 1999 (Attorney docket 073294/0214).
  • Such reactions are advantageously combined to allow testing of, for example 3 analytes, such as used for confirmation tests, or for panels of tests, within a single reaction container having a "field” or surface where results can be determined optically, as described in those co-pending patent applications.
  • a preferred reaction container in this context is a 96 well disposable plate having 12 rows of 8 containers each, as shown in Figure 1.
  • the inventors constructed and tested this embodiment, and realized that they could, for example, combine 3 tests or more in each sample well, along with one or more controls.
  • Figure 1 represents a small disposable plate embodiment that contains 288 tests and 96 controls, and which accepts up to 96 different individual samples for testing.
  • sample wells are possible, such as, for example a 4x8, 2x4, 4x4, 6x6, 2x10, or 10x10 array of wells in a common form such as a plate shown in Figure 1.
  • a disposable plate form as exemplified here, preferably is between about 3 cm to about 35 cm in its longest dimension. More preferable is a plate that is about 8-10 cm in its longest dimension.
  • the individual samples, and optional wash or reagent fluids advantageously are added by a robotic mechanism.
  • An example of this is an adapted Tecan Genesis 150/8 RSP (TM) instrument with standard, non-disposable tips, logic software, a right manipulator arm, RCS software, strip rack for 16mm tubes, reagent racks, reagent troughs and fixed strip adapters.
  • This instrument is adapted to seat the multi-well device shown in Figure 1 by modifying the right manipulator arm to increase its jaw size, thus, enabling the arm to grasp the multi-well plate.
  • the Tecan Logic for Windows software is adjusted to allow dispense of fluid and detection of signals by reflectance, in accordance with instructions given in the operating manual for using the software.
  • the Tecan model system for example, is modified to hold a camera system such as the Chemilmager, manufactured by Alpha Innotech, Corp.
  • This camera includes a thermoelectrically cooled CCD camera, software "AlphaEase," a computer, color printer and a zoom lens with a close-up diopter lens.
  • the software Upon robotic dispensing of fluid and optical signal generation in one or more imaging fields of the plate, the software, via dynamic data exchange, or other means such as control through an interface, signals imaging software to start the image analysis.
  • the imaging software begins by taking a high- resolution image of the entire plate. This resolution should provide at least 4 pixels per dot-blot analyte signal detection region, wherein at least one, and preferably more than one signal detection region exists within each imaging field (corresponding to a test device), and multiple test devices are present within the plate.
  • the “signal detection region” is defined as the area of optical signal development for one analyte determination and corresponds to one "dot-blot. " This area roughly is determined by the area on a test device (typically a reagent membrane such as nitrocellulose, sitting on top of an absorbent pad made from, for example, ethyl cellulose, or a top layer of the pad) that has an immobilized binding pair member such as antigen or antibody, as described in the co-pending applications referenced above.
  • the signal detection region also is characterized by the absence of binding pair member in the surrounding area of the field. This blank surround area represents background, and normally does not contain a detectable optic signal.
  • the signal detection region is created by dispensing the immobilized binding pair member onto the test device surface.
  • the size of a test spot and the size and shape of the control is determined by how much fluid is applied to each respective area and how it is applied during manufacture, as described in the co-pending applications and which is known to the skilled artisan.
  • a dot-blot dispensing mechanism as is known in the art, dispenses a small volume, for example, 0.5, 1, 2, 3, or 5 microliters of peptide or protein in water solution onto a reagent layer such as nitrocellulose.
  • the peptide or protein adheres to the reagent layer and later binds other reagent(s) that can form color, fluorescence, or light, to indicate the presence, absence or concentration of an analyte from an aqueous solution.
  • the signal detection region is round.
  • a "control mark,” typically a line, is provided as a negative control, as described in the above-referenced applications.
  • the software looks for the presence of this control mark, using an algorithm that exploits the a difference between optic signal between the control mark (low light signal pixels recorded in computer memory) and the surrounding background (high light signal pixels recorded in computer memory.
  • This difference in optic signal typically is a difference in signal obtained by the camera (in two-dimensional imaging) from reflectance light intensity, although chemiluminescence light, reflectance color or another parameter may be used.
  • the software looks for the presence of an optic signal at the known "dot-blot" locations for analyte tests, as reviewed in the referenced co-pending applications.
  • the presence or absence of analyte, or optionally, the concentration of analyte is determined by the relative strength and/or area of an optic signal associated with the dot- blot for the analyte, from the stored optical image.
  • the signal intensity of the pixels is relatively constant (less than 25 % change) with increasing analyte but the number of pixels having less light signal (typically less than 5 % of background) increases, as the visual spot from the chemical reaction(s) becomes larger.
  • a background signal is subtracted before making this determination.
  • the background advantageously is determined from an average optical reading over an area of the field that always does not contain a control mark or analyte dot-blot.
  • an area of the visual field that is known to lack control or test spot is used for the background determination and preferably, after making this determination, the software compares the background from this spot to a predetermined value as a quality control measure. If the background is too low (too dark, low recorded pixel value compared to a stored value as determined by computer) then the software outputs an error signal.
  • a manufacturing process is used that always avoids the center of the imaging field (no dot-blotting at the exact center of the reagent membrane) and always places control and test spots elsewhere.
  • the software looks at a (preferably round) group of pixels (typically about 3-25 but even more if a suitably large number of pixels are generated by the imager) at the exact center of the imaging field.
  • the exact center of the field is determined by looking for a demarcation between the dark perimeter of the visual field and the white reflected visual field.
  • the highly reflective visual field chemistry surface (typically membrane on top of absorbent or top surface of absorbent with immobilized chemistry reagent such as antigen or antibody) is packaged within a black or other colored dark plastic container that provides a dark surround to the visual field.
  • Multiple visual fields are packaged together in a plate with consistent spacing between visual fields as exemplified in Figure 1.
  • the plate in the preferred embodiment, appears as a dark rectangular area with 96 white and round visual fields.
  • the preferred embodiments utilize reflectance measurements wherein a light source irradiates the surface of the fields to be imaged and the imager collects information by virtue of light intensity across the visual field.
  • the light is chemiluminescence light from a chemiluminescence reaction.
  • fluorescence light is detected.
  • a disposable plate contains 96 sample wells.
  • one sample such as a blood sample, (whole blood, serum or plasma) ideally may be added to a small group of wells such as a row of 8 wells.
  • the first well may yield blood type information
  • the second well may yield HIV test results, etc.
  • other chemistries besides dot-blot systems can be used, such as blood typing, in which particles aggregate to form a denser optical region toward the center of a test spot that is imaged.
  • the invention is useful for these other reactions and software used to locate the center of test spot(s) such as those is particularly desirable in combination with analysis software that determines a positive test result by detecting an increase in darkness of pixels towards the center portion of a determined test spot region.
  • a positive test result can be determined when, for example, the center 10% of a test spot area is more than twice the darkness of the remainder of the test spot region.
  • the optimum size of the entire imaged test spot region ideally is somewhat less (for example 50% less) than the actual corresponding size of the chemistry spot, to help correct for imprecisions in the chemistry.
  • one embodiment is to replace a dot-blot test and analysis with such a test.
  • the invention images each field of the plate simultaneously.
  • the size of a field preferably is between 0.1 cm (centimeters) and 1.5 cm (centimeters) in diameter.
  • 0.1 cm now is a lower limit of this size according to the embodiment, advances in the field will allow smaller field sizes in the future, such as 0.01 to 0.1 cm.
  • the most preferred diameter of images to be sized is 0.3 cm and devices made by the inventors having such field sizes give good clinical results, including test results for 3 different HIV antigens, along with a control line in the same field. Fewer and also more than 3 tests, of course, can be conducted in one field.
  • the instrument images each field having a diameter as described above separately and processes the image data separately for each field, as reviewed above.
  • the separate imaging of each field is preferred in some circumstances where, for example, a lower cost imaging device and optics are desired.
  • Many robotic plate-handling systems are designed to move either the plate or the optics (such as a fiber optic cable or a lens system attached to a CCD imaging device) in a step-wise fashion to allow such individual reading.
  • the machine optics advantageously focus on a field with a diameter of between 0.5 to 5 mm in diameter. More advantageous is a diameter of between 1 and 1.5 mm.
  • the plate of multiple fields is moved in step-wise fashion under the imaging camera or the camera itself is moved step-wise above the plate.
  • a higher resolution image is obtained by analysis of multiple images using software developed to increase resolution by comparing multiple images.
  • "frame grabber” software is exemplified by a product called “Snappy” from Play Incorporated. The inventors found this software to improve resolution of an instrument in the context of the present invention.
  • Other image analysis techniques are known and are contemplated as part of the operation of embodiments of the invention, such as for example that described in U.S. Nos. 5,078,496, 5,740,266, 4,020,463, 5,528,703, 5,101,445, 5,023,714, 5,740,266, and 5,668,887, all of which are explicitly incorporated by reference in their entireties.
  • FIG. 2 An example of an instrument that can be modified for the invention, showing the basic parts needed is displayed in Figure 2.
  • This figure shows an imaging camera, a work area, where disposable multi-well plate(s) can be kept and an imaging area where a plate is positioned for imaging of multiple optic signals from one or more fields.
  • a computer CPU
  • robotic arm and sample rack (to hold, for example, blood samples) also are shown.
  • a CCD camera having a visual field of at least 1000 pixels by at least 1000 pixels is used to image a 96 well plate (with 96 sample fields).
  • Each well of the plate has a surface that is an imaging field that represents a small portion of the total two-dimensional visual field of the CCD camera.
  • a preferred well imaging field is shown in Figure 3.
  • the imaging field 310 is about 3 mm in diameter and has within it control line 320, and three test spots 330. Imaging field 310 in advantageous embodiments is about 1 mm, 2 mm, 4 mm, 5 mm, 7 mm and 10 mm in diameter.
  • Control line 32 is about 0.3mm high by about 1.5 mm long and each test spot is about 0.3 mm in diameter.
  • the term "about” as used here means that an average spot is within 20% of this value, and it is recognized that in most applications, the test result obtained is a yes or no answer, and the simple presence of a visual signal at a test spot position is sufficient to make a determination.
  • the software for finding the position of the test spot based on the location of the control spot looks for the basic shape of the control and in many embodiments, already knows the border of the visual field. In these embodiments, the software has to determine where among known possible positions the test spots are. In order to make this determination, it is important that during manufacture, the center of each control and test spot be accurately placed with respect to the edge of the visual field.
  • the dot-blot machine that places dots onto a membrane should place them at the same spot of a reagent layer (preferably round) but the reagent layer itself can be placed into a diagnostic device, and the device can be assembled into a plate of multiple devices in a random orientation.
  • a tradeoff is made between some precision in manufacturing (need to place dots reproducibly but relaxed requirements at later stages) and software (need to determine dot placement from a limited set of possible locations that differ in rotation about the center of the visual field).
  • less computer processing is needed because a limited number of sites are possible.
  • a specific preferred embodiment of the invention is that (1) the computer determine the location of a control mark (preferably a line as shown in Figure 3), (2) the computer then determines the center of the test spot(s) based on the known positional relationship between the control mark and the test spot, the positional relationship having been loaded into the computer, (3) the computer selects a small group (preferably round) of between, preferably 4 and 100 pixels at the center of the test spot location ("pixel” in this context is the light intensity value stored for that pixel in computer memory) and (preferably) averages them to obtain a test result value, (4) the computer compares the average test value for the test spot and decides whether the test result is positive, negative or indeterminate, and (5) the computer signals the test result, for example by a computer display or paper output.
  • pixel in this context is the light intensity value stored for that pixel in computer memory
  • step 4 may differ depending on the chemistry used and the cutoff values used for this determination are readily determined by an artisan and even preferably are modified for a given manufacturing run of test plates, for which calibrators may be used to input variables to the computer program.
  • the group of pixels chosen for step 3 cover (correspond to the 2 dimensional image of) less than the test spot size.
  • the test spot size determined by the total size of surface that is blotted with reagent such as antigen or antibody during manufacture
  • reagent such as antigen or antibody during manufacture
  • fewer than 200 most centrally located pixels
  • fewer than 80%, 70%, 50% , and fewer than 33 % of the pixels are used, and the unused pixels are those that are most peripheral from the center. This method provides greater precision and immunity from manufacturing variability by selecting the most reliable pixel information and is highly preferred.
  • the two dimensional image is stored in an electronic array and the software averages the signal within the pre-selected pixel group associated with a test spot.
  • a pre-selected pixel group preferably is a round block of between 1 and 100 pixels, and may be between 1 and 10 pixels.
  • a 96 well plate is imaged with 1,000,000 pixels and each visual field is imaged with approximately between 500 and 3000 pixels of the field and preferably 1500 pixels. Of the 1500 pixels, at least 25 may be associated with a given test spot and of these only the central half, and preferably less than one-fourth, are used to make a determination.
  • the software knows which 1500 pixels are associated with a given field based on (1) absolute position in the field and also by comparing light and dark areas.
  • each visual field typically a white membrane surface
  • black plastic which is easily distinguished in the field by the absence of recorded light in the associated pixels.
  • a preferred control signal is an oblong shape, which can be easily perceived by the software.
  • the software can look for a minimum sized block of 16 "dark" pixels (having a below- threshold degree of reflected light, for example less than 10% of the mean light in the entire sample visual field or less than 5% of a determined background value) and, upon finding a multitude of such blocks, can select that block which is furthest away from the edge of the sample visual field. This block is the center of the control line as seen in the figures.
  • the software looks to the right and left to determine whether other contiguous blocks of dark pixels exist along that vector. If so, then the program has discovered the control line and knows where to look for blocks of pixels corresponding to the first, the second and to the third test spots shown in the figures. Of course, the actual number of pixels and the positioning of the control and test spots is determined for a given system configuration of sample plate, optics and control/test spot pattern.

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Abstract

Cette invention se rapporte à un système optique et à un logiciel qui améliorent la précision d'une multitude de tests de diagnostic effectués sur un échantillon et qui permettent d'assouplir les tolérances de fabrication nécessaires pour produire des plateaux jetables multipuits. Ce système utilise une caméra d'imagerie bidimensionnelle et un logiciel permet l'analyse d'une multitude de résultats à partir d'une seule image optique.
PCT/US1999/005012 1998-03-05 1999-03-05 Systeme d'imagerie optique pour diagnostics WO1999045366A1 (fr)

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AU28995/99A AU2899599A (en) 1998-03-05 1999-03-05 Optical imaging system for diagnostics

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US7693798P 1998-03-05 1998-03-05
US60/076,937 1998-03-05

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WO2002006854A1 (fr) * 2000-07-18 2002-01-24 Pamgene B.V. Procede pour localiser des zones de substrat presentant un interet
NL1019875C2 (nl) * 2001-11-28 2003-06-02 Ibis Technologies B V Drager voor gebruik bij het bepalen van deeltjes in een monster en werkwijze voor de vervaardiging van zo een drager, en werkwijze voor het bepalen van deeltjes in een monster.
WO2003045558A1 (fr) * 2001-11-28 2003-06-05 Ibis Technologies B.V. Support utilise dans le dosage de particules dans un echantillon et procede d'elaboration d'un tel support et methode de dosage de particules dans un echantillon
WO2003088123A1 (fr) * 2002-04-16 2003-10-23 Evotec Oai Ag Procede pour analyser des echantillons chimiques et/ou biologiques au moyen d'images particulaires
US7376256B2 (en) 2002-04-16 2008-05-20 Evotec Oai Ag Method for analyzing chemical and or biological samples by means of particle images
USRE44555E1 (en) 2002-04-16 2013-10-22 Evotec Ag Method for analyzing chemical and/or biological samples by means of particle images
EP2201373A1 (fr) * 2007-10-09 2010-06-30 Siemens Healthcare Diagnostics Inc. Imagerie à deux dimensions de zones ayant réagi sur un réactif
EP2201373A4 (fr) * 2007-10-09 2011-01-05 Siemens Healthcare Diagnostics Imagerie à deux dimensions de zones ayant réagi sur un réactif

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AU2899599A (en) 1999-09-20

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