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  • 1.
    Azar, Jimmy
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computerized Image Analysis and Human-Computer Interaction. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Division of Visual Information and Interaction.
    Automated Tissue Image Analysis Using Pattern Recognition2014Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Automated tissue image analysis aims to develop algorithms for a variety of histological applications. This has important implications in the diagnostic grading of cancer such as in breast and prostate tissue, as well as in the quantification of prognostic and predictive biomarkers that may help assess the risk of recurrence and the responsiveness of tumors to endocrine therapy.

    In this thesis, we use pattern recognition and image analysis techniques to solve several problems relating to histopathology and immunohistochemistry applications. In particular, we present a new method for the detection and localization of tissue microarray cores in an automated manner and compare it against conventional approaches.

    We also present an unsupervised method for color decomposition based on modeling the image formation process while taking into account acquisition noise. The method is unsupervised and is able to overcome the limitation of specifying absorption spectra for the stains that require separation. This is done by estimating reference colors through fitting a Gaussian mixture model trained using expectation-maximization.

    Another important factor in histopathology is the choice of stain, though it often goes unnoticed. Stain color combinations determine the extent of overlap between chromaticity clusters in color space, and this intrinsic overlap sets a main limitation on the performance of classification methods, regardless of their nature or complexity. In this thesis, we present a framework for optimizing the selection of histological stains in a manner that is aligned with the final objective of automation, rather than visual analysis.

    Immunohistochemistry can facilitate the quantification of biomarkers such as estrogen, progesterone, and the human epidermal growth factor 2 receptors, in addition to Ki-67 proteins that are associated with cell growth and proliferation. As an application, we propose a method for the identification of paired antibodies based on correlating probability maps of immunostaining patterns across adjacent tissue sections.

    Finally, we present a new feature descriptor for characterizing glandular structure and tissue architecture, which form an important component of Gleason and tubule-based Elston grading. The method is based on defining shape-preserving, neighborhood annuli around lumen regions and gathering quantitative and spatial data concerning the various tissue-types.

    List of papers
    1. Microarray Core Detection by Geometric Restoration
    Open this publication in new window or tab >>Microarray Core Detection by Geometric Restoration
    2012 (English)In: Analytical Cellular Pathology, ISSN 0921-8912, E-ISSN 1878-3651, Vol. 35, no 5-6, p. 381-393Article in journal (Refereed) Published
    Abstract [en]

    Whole-slide imaging of tissue microarrays (TMAs) holds the promise of automated image analysis of a large number of histopathological samples from a single slide. This demands high-throughput image processing to enable analysis of these tissue samples for diagnosis of cancer and other conditions. In this paper, we present a completely automated method for the accurate detection and localization of tissue cores that is based on geometric restoration of the core shapes without placing any assumptions on grid geometry. The method relies on hierarchical clustering in conjunction with the Davies-Bouldin index for cluster validation in order to estimate the number of cores in the image wherefrom we estimate the core radius and refine this estimate using morphological granulometry. The final stage of the algorithm reconstructs circular discs from core sections such that these discs cover the entire region of each core regardless of the precise shape of the core. The results show that the proposed method is able to reconstruct core locations without any evidence of localization error. Furthermore, the algorithm is more efficient than existing methods based on the Hough transform for circle detection. The algorithm's simplicity, accuracy, and computational efficiency allow for automated high-throughput analysis of microarray images.

    National Category
    Medical Image Processing
    Identifiers
    urn:nbn:se:uu:diva-183618 (URN)10.3233/ACP-2012-0067 (DOI)000311675800005 ()22684152 (PubMedID)
    Available from: 2012-10-30 Created: 2012-10-30 Last updated: 2017-12-07Bibliographically approved
    2. Blind Color Decomposition of Histological Images
    Open this publication in new window or tab >>Blind Color Decomposition of Histological Images
    Show others...
    2013 (English)In: IEEE Transactions on Medical Imaging, ISSN 0278-0062, E-ISSN 1558-254X, Vol. 32, no 6, p. 983-994Article in journal (Refereed) Published
    Abstract [en]

    Cancer diagnosis is based on visual examination under a microscope of tissue sections from biopsies. But whereas pathologists rely on tissue stains to identify morphological features, automated tissue recognition using color is fraught with problems that stem from image intensity variations due to variations in tissue preparation, variations in spectral signatures of the stained tissue, spectral overlap and spatial aliasing in acquisition, and noise at image acquisition. We present a blind method for color decomposition of histological images. The method decouples intensity from color information and bases the decomposition only on the tissue absorption characteristics of each stain. By modeling the charge-coupled device sensor noise, we improve the method accuracy. We extend current linear decomposition methods to include stained tissues where one spectral signature cannot be separated from all combinations of the other tissues' spectral signatures. We demonstrate both qualitatively and quantitatively that our method results in more accurate decompositions than methods based on non-negative matrix factorization and independent component analysis. The result is one density map for each stained tissue type that classifies portions of pixels into the correct stained tissue allowing accurate identification of morphological features that may be linked to cancer.

    National Category
    Medical Image Processing
    Research subject
    Computerized Image Processing
    Identifiers
    urn:nbn:se:uu:diva-160312 (URN)10.1109/TMI.2013.2239655 (DOI)000319701800002 ()
    Available from: 2011-10-21 Created: 2011-10-21 Last updated: 2018-12-02
    3. Histological Stain Evaluation for Machine Learning Applications
    Open this publication in new window or tab >>Histological Stain Evaluation for Machine Learning Applications
    2012 (English)In: Proceedings of the International Conference on Medical Image Computing and Computer Assisted Intervention, 2012Conference paper, Published paper (Refereed)
    National Category
    Medical Image Processing
    Identifiers
    urn:nbn:se:uu:diva-183619 (URN)
    Conference
    MICCAI 2012, the 15th International Conference on Medical Image Computing and Computer Assisted Intervention, October 1-5, 2012, Nice, France
    Available from: 2012-10-30 Created: 2012-10-30 Last updated: 2015-01-23
    4. Image segmentation and identification of paired antibodies in breast tissue
    Open this publication in new window or tab >>Image segmentation and identification of paired antibodies in breast tissue
    2014 (English)In: Computational & Mathematical Methods in Medicine, ISSN 1748-670X, E-ISSN 1748-6718, p. 647273:1-11Article in journal (Refereed) Published
    Abstract [en]

    Comparing staining patterns of paired antibodies designed towards a specific protein but toward different epitopes of the protein provides quality control over the binding and the antibodies' ability to identify the target protein correctly and exclusively. We present a method for automated quantification of immunostaining patterns for antibodies in breast tissue using the Human Protein Atlas database. In such tissue, dark brown dye 3,3'-diaminobenzidine is used as an antibody-specific stain whereas the blue dye hematoxylin is used as a counterstain. The proposed method is based on clustering and relative scaling of features following principal component analysis. Our method is able (1) to accurately segment and identify staining patterns and quantify the amount of staining and (2) to detect paired antibodies by correlating the segmentation results among different cases. Moreover, the method is simple, operating in a low-dimensional feature space, and computationally efficient which makes it suitable for high-throughput processing of tissue microarrays.

    National Category
    Medical Image Processing
    Identifiers
    urn:nbn:se:uu:diva-229978 (URN)10.1155/2014/647273 (DOI)000338856800001 ()25061472 (PubMedID)
    Projects
    eSSENCE
    Available from: 2014-07-01 Created: 2014-08-18 Last updated: 2017-12-05Bibliographically approved
    5. Automated Classification of Glandular Tissue by Statistical Proximity Sampling
    Open this publication in new window or tab >>Automated Classification of Glandular Tissue by Statistical Proximity Sampling
    2015 (English)In: International Journal of Biomedical Imaging, ISSN 1687-4188, E-ISSN 1687-4196, article id 943104Article in journal (Refereed) Published
    Abstract [en]

    Due to the complexity of biological tissue and variations in staining procedures, features that are based on the explicit extraction of properties from subglandular structures in tissue images may have difficulty generalizing well over an unrestricted set of images and staining variations. We circumvent this problem by an implicit representation that is both robust and highly descriptive, especially when combined with a multiple instance learning approach to image classification. The new feature method is able to describe tissue architecture based on glandular structure. It is based on statistically representing the relative distribution of tissue components around lumen regions, while preserving spatial and quantitative information, as a basis for diagnosing and analyzing different areas within an image. We demonstrate the efficacy of the method in extracting discriminative features for obtaining high classification rates for tubular formation in both healthy and cancerous tissue, which is an important component in Gleason and tubule-based Elston grading. The proposed method may be used for glandular classification, also in other tissue types, in addition to general applicability as a region-based feature descriptor in image analysis where the image represents a bag with a certain label (or grade) and the region-based feature vectors represent instances.

    National Category
    Medical Image Processing
    Identifiers
    urn:nbn:se:uu:diva-230871 (URN)10.1155/2015/943104 (DOI)000362067400001 ()
    Available from: 2014-09-01 Created: 2014-09-01 Last updated: 2017-12-05Bibliographically approved
  • 2.
    Azar, Jimmy
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computerized Image Analysis and Human-Computer Interaction.
    Busch, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Carlbom, Ingrid
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computerized Image Analysis and Human-Computer Interaction.
    Histological Stain Evaluation for Machine Learning Applications2012In: Proceedings of the International Conference on Medical Image Computing and Computer Assisted Intervention, 2012Conference paper (Refereed)
  • 3.
    Azar, Jimmy
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computerized Image Analysis and Human-Computer Interaction.
    Busch, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Carlbom, Ingrid
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computerized Image Analysis and Human-Computer Interaction.
    Microarray Core Detection by Geometric Restoration2012In: Analytical Cellular Pathology, ISSN 0921-8912, E-ISSN 1878-3651, Vol. 35, no 5-6, p. 381-393Article in journal (Refereed)
    Abstract [en]

    Whole-slide imaging of tissue microarrays (TMAs) holds the promise of automated image analysis of a large number of histopathological samples from a single slide. This demands high-throughput image processing to enable analysis of these tissue samples for diagnosis of cancer and other conditions. In this paper, we present a completely automated method for the accurate detection and localization of tissue cores that is based on geometric restoration of the core shapes without placing any assumptions on grid geometry. The method relies on hierarchical clustering in conjunction with the Davies-Bouldin index for cluster validation in order to estimate the number of cores in the image wherefrom we estimate the core radius and refine this estimate using morphological granulometry. The final stage of the algorithm reconstructs circular discs from core sections such that these discs cover the entire region of each core regardless of the precise shape of the core. The results show that the proposed method is able to reconstruct core locations without any evidence of localization error. Furthermore, the algorithm is more efficient than existing methods based on the Hough transform for circle detection. The algorithm's simplicity, accuracy, and computational efficiency allow for automated high-throughput analysis of microarray images.

  • 4.
    Azar, Jimmy C.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Division of Visual Information and Interaction. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computerized Image Analysis and Human-Computer Interaction.
    Simonsson, Martin
    Bengtsson, Ewert
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Division of Visual Information and Interaction. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computerized Image Analysis and Human-Computer Interaction.
    Hast, Anders
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Division of Visual Information and Interaction. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computerized Image Analysis and Human-Computer Interaction.
    Image segmentation and identification of paired antibodies in breast tissue2014In: Computational & Mathematical Methods in Medicine, ISSN 1748-670X, E-ISSN 1748-6718, p. 647273:1-11Article in journal (Refereed)
    Abstract [en]

    Comparing staining patterns of paired antibodies designed towards a specific protein but toward different epitopes of the protein provides quality control over the binding and the antibodies' ability to identify the target protein correctly and exclusively. We present a method for automated quantification of immunostaining patterns for antibodies in breast tissue using the Human Protein Atlas database. In such tissue, dark brown dye 3,3'-diaminobenzidine is used as an antibody-specific stain whereas the blue dye hematoxylin is used as a counterstain. The proposed method is based on clustering and relative scaling of features following principal component analysis. Our method is able (1) to accurately segment and identify staining patterns and quantify the amount of staining and (2) to detect paired antibodies by correlating the segmentation results among different cases. Moreover, the method is simple, operating in a low-dimensional feature space, and computationally efficient which makes it suitable for high-throughput processing of tissue microarrays.

  • 5.
    Azar, Jimmy
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computerized Image Analysis and Human-Computer Interaction.
    Simonsson, Martin
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computerized Image Analysis and Human-Computer Interaction.
    Bengtsson, Ewert
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computerized Image Analysis and Human-Computer Interaction.
    Hast, Anders
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computerized Image Analysis and Human-Computer Interaction.
    Automated Classification of Glandular Tissue by Statistical Proximity Sampling2015In: International Journal of Biomedical Imaging, ISSN 1687-4188, E-ISSN 1687-4196, article id 943104Article in journal (Refereed)
    Abstract [en]

    Due to the complexity of biological tissue and variations in staining procedures, features that are based on the explicit extraction of properties from subglandular structures in tissue images may have difficulty generalizing well over an unrestricted set of images and staining variations. We circumvent this problem by an implicit representation that is both robust and highly descriptive, especially when combined with a multiple instance learning approach to image classification. The new feature method is able to describe tissue architecture based on glandular structure. It is based on statistically representing the relative distribution of tissue components around lumen regions, while preserving spatial and quantitative information, as a basis for diagnosing and analyzing different areas within an image. We demonstrate the efficacy of the method in extracting discriminative features for obtaining high classification rates for tubular formation in both healthy and cancerous tissue, which is an important component in Gleason and tubule-based Elston grading. The proposed method may be used for glandular classification, also in other tissue types, in addition to general applicability as a region-based feature descriptor in image analysis where the image represents a bag with a certain label (or grade) and the region-based feature vectors represent instances.

  • 6.
    Gavrilovic, Milan
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computerized Image Analysis and Human-Computer Interaction. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Division of Visual Information and Interaction.
    Azar, Jimmy
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Division of Visual Information and Interaction. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computerized Image Analysis and Human-Computer Interaction.
    Lindblad, Joakim
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computerized Image Analysis and Human-Computer Interaction. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Division of Visual Information and Interaction.
    Wählby, Carolina
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Division of Visual Information and Interaction. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computerized Image Analysis and Human-Computer Interaction. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Bengtsson, Ewert
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Division of Visual Information and Interaction. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computerized Image Analysis and Human-Computer Interaction.
    Busch, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Carlbom, Ingrid
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computerized Image Analysis and Human-Computer Interaction.
    Blind Color Decomposition of Histological Images2013In: IEEE Transactions on Medical Imaging, ISSN 0278-0062, E-ISSN 1558-254X, Vol. 32, no 6, p. 983-994Article in journal (Refereed)
    Abstract [en]

    Cancer diagnosis is based on visual examination under a microscope of tissue sections from biopsies. But whereas pathologists rely on tissue stains to identify morphological features, automated tissue recognition using color is fraught with problems that stem from image intensity variations due to variations in tissue preparation, variations in spectral signatures of the stained tissue, spectral overlap and spatial aliasing in acquisition, and noise at image acquisition. We present a blind method for color decomposition of histological images. The method decouples intensity from color information and bases the decomposition only on the tissue absorption characteristics of each stain. By modeling the charge-coupled device sensor noise, we improve the method accuracy. We extend current linear decomposition methods to include stained tissues where one spectral signature cannot be separated from all combinations of the other tissues' spectral signatures. We demonstrate both qualitatively and quantitatively that our method results in more accurate decompositions than methods based on non-negative matrix factorization and independent component analysis. The result is one density map for each stained tissue type that classifies portions of pixels into the correct stained tissue allowing accurate identification of morphological features that may be linked to cancer.

  • 7.
    Hamid Muhammed, Hamed
    et al.
    School of Technology and Health (STH), Royal Institute of Technology (KTH), Alfred Nobels Alle 10, SE-141 52 Huddinge, Sweden.
    Azar, Jimmy C
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computerized Image Analysis and Human-Computer Interaction.
    Automatic Characterization of the Physiological Condition of the Carotid Artery in 2D Ultrasound Image Sequences Using Spatiotemporal and Spatiospectral 2D Maps.2014In: International Journal of Biomedical Imaging, ISSN 1687-4188, E-ISSN 1687-4196, Vol. 2014, article id 876267Article in journal (Refereed)
    Abstract [en]

    A novel method for characterizing and visualizing the progression of waves along the walls of the carotid artery is presented. The new approach is noninvasive and able to simultaneously capture the spatial and the temporal propagation of wavy patterns along the walls of the carotid artery in a completely automated manner. Spatiotemporal and spatiospectral 2D maps describing these patterns (in both the spatial and the frequency domains, resp.) were generated and analyzed by visual inspection as well as automatic feature extraction and classification. Three categories of cases were considered: pathological elderly, healthy elderly, and healthy young cases. Automatic differentiation, between cases of these three categories, was achieved with a sensitivity of 97.1% and a specificity of 74.5%. Two features were proposed and computed to measure the homogeneity of the spatiospectral 2D map which presents the spectral characteristics of the carotid artery wall's wavy motion pattern which are related to the physical, mechanical (e.g., elasticity), and physiological properties and conditions along the artery. These results are promising and confirm the potential of the proposed method in providing useful information which can help in revealing the physiological condition of the cardiovascular system.

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