Image analysis – Applications – Biomedical applications
Reexamination Certificate
2001-06-11
2004-12-07
Boudreau, Leo (Department: 2621)
Image analysis
Applications
Biomedical applications
C702S019000
Reexamination Certificate
active
06829376
ABSTRACT:
BACKGROUND OF INVENTION
1. Field of the Invention
The present invention relates to the field of computerized image alignment. In particular, the present invention relates to computer systems, methods, and products for aligning grids on scanned images of high-density arrays of biological materials.
2. Related Art
A variety of systems are known for synthesizing or depositing dense arrays of biological materials, sometimes referred to as probes, on a substrate or support. Labeled targets in hybridized probe-target pairs may be detected using various commercial devices, referred to for convenience hereafter as scanners. Scanners image the targets by detecting fluorescent or other emissions from the labels. Data representing the detected emissions are stored in a memory device for processing. The processed images may be presented to a user on a video monitor or other device, and/or operated upon by various data processing products or systems. Some techniques are known for identifying the data representing detected emissions and separating them from background information. For example, U.S. Pat. No. 6,090,555 to Fiekowsky, et al. describes various of these techniques.
SUMMARY OF INVENTION
The present invention is directed in one embodiment to a method for adjusting the alignment of a grid with an image. Generally speaking, this method seeks an alignment that provides maximum contrast between bright and dim features rather than seeking to identify boundaries, per se, between bright and dim features. The grid in accordance with this method includes grid elements, such as grid squares in an example illustrated below. The image includes image features made up of pixels. For example, the image may include a checkerboard pattern in which the image features are alternating bright and dim squares. Each of the squares is made up of a number of pixels. It will be understood, however, that the pattern is not limited to a checkerboard, and that the image features may be any shape or combination of shapes.
The method includes the step of (1) determining an initial position of the grid. This determination may be made in some implementations such that the grid elements are at least approximately aligned with the plurality of image features. The term approximately is used broadly in this context to mean that, in a typical application, a significant portion of the grid elements are not out of alignment in a particular dimension with respect to image features by more than half the length of the features in that direction. Thus, the grid elements may be significantly out of alignment in one or both dimensions of, for example, a planar grid, but yet be approximately aligned as the term is used herein. It will be understood that although the examples described herein are drawn for convenience to two-dimensional images, the invention is not so limited. Rather, the images and alignment grids may be employed in three or more dimensions.
Additional steps in the method include the following. (2) One or more additional positions of the grid are determined so that each additional position is offset from the initial position and from other additional positions. (3) For each of two or more test grid elements of the two or more grid elements, a set of intensity scores is determined. Each member of this set is based, at least in part, on intensities of pixels of one or more image features within the test grid element in one of the initial or additional positions. (4) For each of the test grid elements, the set of intensity scores is ranked with respect to each other to generate a set of rank scores for the test grid element. (5) For each of the initial and additional grid positions, the members of the sets of rank scores corresponding to the grid position are combined to generate a combined rank score for the grid position. (6) The alignment of the grid is adjusted based, at least in part, on a comparison among the combined rank scores of the initial and additional grid positions.
The first step in this method may be accomplished in accordance with any of variety of known, or yet to be developed, techniques for aligning grids with images. For example, a technique described in U.S. Pat. No. 6,090,555, may be used. The '555 patent is hereby incorporated by reference herein in its entirety for all purposes. In accordance with one method of the '555 patent, the image includes a first pattern. Steps in that method include (a) convolving the image with a filter to generate a second image having a second pattern, (b) identifying the second pattern, (c) aligning the grid over the image according to a position of the second pattern, and (d) adjusting the position of the grid to minimize a sum of the intensities of pixels along a direction in the grid. Thus, in this example, steps (a) through (c) implement step (1) of the method described with respect to the present invention.
In some implementations of the method of the present invention, step (2) includes moving the grid from the first grid position in a positive or negative X direction by a value substantially equal to a span of one or more pixels, moving the grid from the first grid position in a positive or negative Y direction by a value substantially equal to a span of one or more pixels, or both. In aspects of these implementations, the test grid elements each have a first length in the X direction and a second length in the Y direction. Step (2) in these aspects further includes moving the grid from the first grid position in the positive or negative X direction by a value no greater than approximately half the first length, moving the grid from the first grid position in the positive or negative Y direction by a value no greater than approximately half the second length, or both.
Step (3) may include determining, for at least one member of the set of intensity scores, a mean of intensity values of pixels within the test grid element. Also, step (3) may include the following two steps: (a) based on the initial grid position, identifying each of the plurality of grid elements as either a dim grid element or, in the alternative, a bright grid element; and (b) selecting the test grid elements based, at least in part, on including dim grid elements when they are bordered on all sides by a bright grid element. In other implementations, the dim grid elements may be including among the test grid elements if they are bordered on fewer than all sides, or on no side, by a bright grid element. Some bright grid elements may also not be included among the test grid elements in some implementations.
In some aspects of the preceding method, step (3)(a) may include the further steps of (i) based on a determined pattern (such as, for example, a checkerboard), associating each of the plurality of grid elements with one of either a first element group or a second element group; (ii) determining a first intensity of one or more of the grid elements in the first element group and a second intensity of one or more of the grid elements in the second element group; (iii) comparing the first and second intensities; (iv) designating the grid elements in the first element group as dim grid elements when the first intensity is less than the second intensity and as bright grid elements when the first intensity is greater than the second intensity; and (v) designating the grid elements in the second element group as dim grid elements when the second intensity is less than the first intensity and as bright grid elements when the second intensity is greater than the first intensity. Step (3) (a)(ii) may include determining a median of intensities of three or more pixels, or every pixel, within each of the one or more grid elements in the first and second element groups. Similarly, in other aspects, step (
3
)(a)(ii) may include determining a median of intensities of three or more pixels, or every pixel, within each grid element in the first and second element groups. The first intensity may include a first overall median of the medians of intensities of pixels within each grid element
Affymetrix Inc.
Boudreau Leo
Lu Tom Y.
McCarthy III William R.
McGarrigle Philip L.
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