Method and apparatus for automated assay of biological specimens

A method of analysis of biological specimens on each of a plurality of slides having large specimen areas with a specimen occupying only a small fraction of the specimen area, said method comprising the steps of:

• providing a plurality of specimen locating stations at which an operator locates the small specimen in the large specimen area;
• providing a specimen carrier at each station for the operator to handle a plurality of slides associated with the carrier;
• the operator at each station viewing a specimen slide at low resolution and the operator storing the location of the specimen on a storage media;
• transferring the slides and their carrier to an automated analysis station;
• transferring the stored locations of the addresses of the specimens to the analysis station;
• initiating scanning of the specimens at a substantially higher resolution than the low resolution at the location address previously established by the operator;
• and
• automatically positioning each of the slides beneath the microscope of a digital imaging apparatus for an automated analysis thereof using the previously applied addresses to avoid scanning large areas empty of the specimen to be scanned.

An interactive method of specifying one or more action points on each of a group of microscope slides mounted in a carrier for subsequent automatic image analysis comprising:

• positioning a slide mounted in the carrier before an operator who visually inspects the slide to select the coordinate locations of one or more action points on the slide;
• entering into storage the coordinate address of at least one action point;
• selecting and entering into storage one or more appropriate actions for subsequent automatic image analysis at said at least one action point;
• providing a group of slides in the carrier;
• proceeding to each of the group of slides in the carrier and having the operator visually inspect each slide to select one or more action points and having the operator enter the coordinate location for each action point into storage;
• forming an enlarged image on a monitor related to the location of the action point and the operator entering from the enlarged image a more finely defined coordinate address for a given action point into storage;
• displaying on a monitor an image of a microscope slide having a coordinate grid pattern of rectangles thereon;
• and
• forming a coordinate grid on at least one of the microscope slides and the operator using a display cursor to locate the action point on the monitor grid related to the location of the action point on the slide.

A method of assaying with a microscope and an image analysis means of biological specimens on each of a group of microscope slides mounted in a carrier comprising:

• positioning a slide before an operator who visually inspects the slide for one or more action points on the slide with a first microscope at a first resolution and selects a coordinate address on the slide for the action point;
• entering into storage the address for the action point and a selected function from one of several functions performable at the various action points;
• proceeding to each of the slides of the group of slides in the carrier and having the operator view each of the slides, the operator entering the coordinate address and selected analysis action for each action point into storage;
• positioning the carrier with the slides therein into an operative position with respect to a second microscope at the image analysis means and at a higher resolution;
• and
• reading each of the stored addresses for each of the slides and automatically moving the carrier relative to the second microscope to position each stored address on each slide at the microscope for performing automatically the action for that action point by the image analysis means.

An apparatus for interactively specifying one or more action points on each of a group of microscope slides, said apparatus comprising:

• means for holding the group of slides in a side-by-side relationship before an operator who visually inspects the slides for one or more action points on each slide;
• means for providing an associated visible coordinate system for the slide to allow an operator to select a coordinate address on the slide for each action point;
• a monitor to display the visible coordinate system with respect to a slide at the operative position;
• a storage means for storing addresses of selected action points on the slide;
• means for displaying an enlarged image on the monitor related to the location of the action point at a resolution substantially lower than the resolution at which said action point is subsequently analyzed;
• and
• means for generating a spot on the enlarged image and thereby to produce a more finely defined coordinate address for a given action point;
• wherein said visible coordinate system is provided by means for generating a grid pattern on the slide for viewing by the operator, and wherein said apparatus includes a monitor having a grid displayed from storage, a monitor cursor to locate the address point on the grid on the monitor related to the location of the action point on the slide.

An apparatus for assaying biological specimens on each of a group of microscope slides, said apparatus comprising:

• means for holding a slide before an operator who visually inspects the slide for one or more action points on the slide;
• means providing an associated coordinate system for the slide to allow an operator to select a coordinate address on the slide for the action point;
• a storage means for storing in the storage means address and associated analysis action for each slide;
• means for entering into storage the address and a selected analysis action from one of several analysis actions performable at the various action points;
• said means for holding slide, holding the next slide of the group of slides in the carrier for viewing the next slide and an associated coordinate system provided therewith and selecting an action point thereon, said means for entering being operable by the operator to enter the coordinate address and selected analysis action for each action point into storage;
• an image analysis means for receiving a carrier with the slides therein into an operative position;
• a microscope in the image analysis means for viewing a slide at the operative position;
• means for automatically moving the carrier relative to the microscope to position each stored address on each slide at the microscope operative position for performing the associated stored analysis action for that action point by the image analysis means;
• a monitor to display the coordinate system with respect to a slide at the operative position;
• means for forming an enlarged image on the monitor related to the location of the action point;
• means for generating a spot on the enlarged image and thereby to produce a more finely defined coordinate address for a given point;
• and
• means for generating a grid pattern on the slide for viewing by the operator, said monitor having a grid displayed from storage, and a cursor to locate the address point on the grid on the monitor related to the location of the action point on the slide.

An apparatus for automated assay of biological specimens positioned on microscope slides comprising:

• a first microscope of a first resolution for viewing action points on a microscope slide;
• specifying means actuated by an operator for specifying at least one action point on a microscope slide by an operator;
• selecting means operated by an operator for selecting an analysis action from one of several actions performable by said automated apparatus to be performed at each action point specified by the specifying means;
• means operable by said specifying means and selecting means for storing associated representations of the location of each specified action point and each defined action to be performed at the specified action point for subsequent automatic analysis;
• means for reading a specified action point representation and the defined action representation associated therewith from the storage means;
• and
• automatic analysis means including a second microscope having a microscope objective at a higher resolution, for aligning said microscope objective with each action point represented by the action point representation read from said storage means and for performing the action represented by the action representation associated therewith.

An automated apparatus for identifying action points for the performance of analysis functions on biological specimens positioned on microscope slides comprising;

• means operable manually by an operator for specifying by operator interaction at least one action point address on a microscope slide;
• means operable manually by an operator for selecting an analysis action from one of several actions performable by said automated apparatus to be performed at each action point address specified by the operator operating said means for specifying;
• means for storing in a data file associated representations of each specified action point address and each defined action to be performed at the specified action point;
• means for transmitting to a separate image analysis apparatus said data file for performance of said specified actions;
• means responsive to operator interaction for moving a cursor on said displayed visual image;
• means for selecting an action point identified by said cursor;
• wherein said display means displays location reference markings on the displayed visual image;
• and
• means for forming on the microscope slide a visual pattern of location reference markings substantially identical to the pattern of reference markings on said displayed visual image.

An automated apparatus for identifying action points for the performance of analysis functions on biological specimens positioned on microscope slides comprising:

• means operable manually by an operator for specifying by operator interaction at least one action point address on a microscope slide;
• means operable manually by an operator for selecting an analysis action from one of several actions performable by said automated apparatus to be performed at each action point address specified by the operator operating said means for selecting;
• means for storing in a data file associated representations of each specified action point address and each defined action to be performed at the specified action point;
• means for transmitting separate image analysis apparatus said data file for performance of said specified actions;
• means responsive to operator interaction for moving a cursor on said displayed visual image;
• means for selecting an action point identified by said cursor;
• wherein said display means displays a pattern of grid markings defining a plurality of rectangles on said displayed visual image, and said means for specifying comprises means for specifying one of said rectangles;
• and
• means for forming on the microscope slide a pattern of grid markings substantially identical to the grid markings presented on said displayed visual image.