Pathological tissue mapping

This application claims priority under 35 U.S.C. §119(e) of U.S. patent application Ser. No. 60/520,815, filed Nov. 17, 2003, the entire disclosure of which is herein incorporated by reference in its entirety.

This invention relates to molecular biology, histology, and clinical diagnostics. Clinical, micro-anatomic and molecular profiles of disease are integrated to create a system for tissue analysis which, in a preferred embodiment, comprises a pathological mapping of a tissue image to determine a pathological status or condition of the tissue in the image. The file of this patent contains at least one figure executed in color. Copies of this patent with color figures will be provided by the Office upon request and payment of the necessary fee.

Pathology is the medical science and specialty practice that deals with all aspects of disease, but with special reference to the essential nature, causes, and development of abnormal conditions. This generally includes analysis of the structural and functional changes that result from diseases.

To determine the causes of a disease, a pathologist may study: how various internal and external injuries affect cells and tissues, how a disease progresses (pathogenesis), and how a disease manifests in a tissue (i.e., its clinical expression and the lesions produced). In other words, pathology provides a scientific foundation for clinical medicine and serves as a bridge between the basic sciences and patient care.

Accordingly, accurate and repeatable quantitative analysis of tissue is important to characterize a disease and evaluate effects that new therapies might have. To date, little if any reliable structural information exists at the tissue level (e.g., 1-1000 microns, in the range of microscopic to mesoscopic). It is believed that if reliable, multi-dimensional structural tissue information (including, for example, clinical, molecular and genetic information) existed in readily accessible databases. Such information would enhance and accelerate new advances in tissue engineering, drug design, gene discovery, proteomics, and genomics research.

In order to facilitate the study and diagnosis of disease, investigators have developed a variety of systems and methods. Generally, prior art methods and systems relating to the study of disease are slow, difficult and prone to error. Accordingly, there exists a need for a system and/or method to quickly, efficiently, and/or automatically quantify tissue for determining a condition of a tissue.

The present invention presents methods and systems for processing and analyzing a tissue image(s), and moreover, with regard to some embodiments of the invention, for automating object/feature extraction from tissue and/or determining quantitative definition of tissue features. Embodiments of the present invention produce a pathological tissue map (PTM) of the tissue, which comprises a modified version of an image of the tissue. The PTM classifies objects of the tissue into visible indicators which may be analyzed quickly by a user (e.g., pathologist) and/or an algorithm, to more quickly determine a tissue condition (e.g., normal versus abnormal). For example, a PTM may be generated by quantifying a variety of micro-anatomic and/or molecular data and associating a color grade with a range for that particular data. Accordingly, the data may be rendered in a format where areas of abnormality are identified in a specific color (red for example), which may be easily identifiable to a viewer (e.g., pathologists, scientists or physicians).

In one embodiment of the invention, an automated tissue processing system is disclosed, for advanced tissue image classification of (for example) hematoxylin and eosin (H&E)-stained tissue sections. Using such a system, tissue images may be segmented then analyzed. Furthermore, using neural network or support vector regression (“SVR”), the segmented images may be used to train a biostatistical model to determine tissue condition (e.g., normal versus abnormal).

In particular, such a system may facilitate distinguishing and visualizing an object in a tissue image using predetermined criteria. When an object is found, boundaries of the object may be constructed using (for example) modified object extraction algorithms used in the art.

Criteria for locating tissue objects may include, for example, object color, color intensity, object morphology (including material composition), object size and shape (e.g., dimensions, round, oval, etc.), arrangement of objects, or any combination thereof. For example, with regard to color, a tissue may be stained to highlight certain objects. To detect tissue objects in an image, existing mathematical feature detection algorithms may be used, or modified versions thereof, such as those available with the Cellenger software product marketed by Definiens A.G. Such algorithms may include, for example, dilation (adding pixels to the boundary of an object), erosion (removing pixels on the object boundaries), and thresholding. In addition, the detection of background intensity is useful for object determination and is required in some feature extraction algorithms.

One can also apply one or more morphological filters to enhance certain objects and suppress others. Such enhancements may change the shape of an object contained within an image. Morphological filters are preferably used prior to applying character/shape recognition algorithms since these filters can highlight the contour of objects which aid the recognition. For example, a morphological filter may be used to enhance certain objects of a particular size and the dilation and/or erosion algorithms may be used to bring out the enhanced objects.

Embodiments of the invention may further include quantitative determination of object geometry. One or more found objects may be quantified (e.g., measured), and a modified tissue image established with visual indicators indicating the quantified objects. The modified image represents the PTM for pathological analysis.

Still other embodiments of the present invention are directed to databases, which may be used in conjunction with other embodiments of the invention. Specifically, such databases may include characterization data and/or associated images (“tissue information”) representative of a tissue population, and/or an automated method to create such database and use of the database for classification and evaluation of tissue specimens. For example, samples of normal tissue specimens obtained from a subset of a population of subjects with shared characteristics may be profiled (e.g., objects extracted and classified as normal) in order to generate a plurality of structural indices that correspond to statistically significant representations of tissue associated with the population.

The database may also include information from profiled tissue images from samples of specimens of a particular tissue obtained from a subset of a population with respect to certain structural or other indicia, that correspond to a particular clinical condition associated with that tissue. Such information may be used to provide a comparison with information obtained from additional specimens of the tissue, including specimens which may have been previously profiled by other means or for other purposes. Indicia may include at least one of cell density, matrix density, blood vessel density, layer thickness or geometry, and the like.

Embodiments of the invention may be used to identify a toxic effect or response, immunological reactions, morphological lesions caused by, for example, hepatitis (acute, subacute and chronic), cholestasis (with and without inflammation or necrosis), fibrosis, granulomatous hepatitis, steatosis (macro and microvesicular), vascular lesions, and hepatic tumors. Further yet, embodiments of the invention may be used to characterize pathological objects, for example, Kupffer cell hyperplasia, cholangitis, cholangiolitis, necrotizing angitis, sinusoidal dilatation, hepatoportal sclerosis and venous thromboses.