We consider the problem of automated cancer diagnosis in the context of breast tissues. We present graph theoretical techniques that identify and compute quantitative metrics for tissue characterization and classification. We segment digital images of histopatological tissue samples using k-means algorithm. For each segmented image we generate different cell-graphs using positional coordinates of cells and surrounding matrix components. These cell-graphs have 500-2000 cells(nodes) with 1000-10000 links depending on the tissue and the type of cell-graph being used. We calculate a set of global metrics from cell-graphs and use them as the feature set for learning. We compare our technique, hierarchical cell graphs, with other techniques based on intensity values of images, Delaunay triangulation of the cells, the previous technique we proposed for brain tissue images and with the hybrid approach that we introduce in this paper. Among the compared techniques, hierarchical-graph approach gives 81.8% accuracy whereas we obtain 61.0%, 54.1% and 75.9% accuracy with intensity-based features, Delaunay triangulation and our previous technique, respectively.
Pathological examination of a biopsy is the most reliable and widely used technique to diagnose bone cancer. However, it suffers from both inter-and intra-observer subjectivity. Techniques for automated tissue modeling and classification can reduce this subjectivity and increases the accuracy of bone cancer diagnosis. This paper presents a graph theoretical method, called extracellular matrix (ECM)-aware cell-graph mining, that combines the ECM formation with the distribution of cells in hematoxylin and eosin (H&E) stained histopathological images of bone tissues samples. This method can identify different types of cells that coexist in the same tissue as a result of its functional state. Thus, it models the structure-function relationships more precisely and classifies bone tissue samples accurately for cancer diagnosis. The tissue images are segmented, using the eigenvalues of the Hessian matrix, to compute spatial coordinates of cell nuclei as the nodes of corresponding cellgraph. Upon segmentation a color code is assigned to each node based on the composition of its surrounding ECM. An edge is hypothesized (and established) between a pair of nodes if the corresponding cell membranes are in physical contact and if they share the same color. Hence, multiple colored-cell-graphs coexist in a tissue each modeling a different cell-type organization. Both topological and spectral features of ECM-aware cell-graphs are computed to quantify the structural properties of tissue samples and classify their different functional states as healthy, fractured, or cancerous using support vector machines. Classification accuracy comparison to related work shows that ECM-aware cell-graph approach yields 90.0% whereas Delaunay triangulation and simple cellgraph approach achieves 75.0% and 81.1% accuracy, respectively.
Motivation: Our goal is to develop a screening platform for quantitative profiling of colony organizations in 3D cell culture models. The 3D cell culture models, which are also imaged in 3D, are functional assays that mimic the in vivo characteristics of the tissue architecture more faithfully than the 2D cultures. However, they also introduce significant computational challenges, with the main barriers being the effects of growth conditions, fixations and inherent complexities in segmentation that need to be resolved in the 3D volume.Results: A segmentation strategy has been developed to delineate each nucleus in a colony that overcomes (i) the effects of growth conditions, (ii) variations in chromatin distribution and (iii) ambiguities formed by perceptual boundaries from adjacent nuclei. The strategy uses a cascade of geometric filters that are insensitive to spatial non-uniformity and partitions a clump of nuclei based on the grouping of points of maximum curvature at the interface of two neighboring nuclei. These points of maximum curvature are clustered together based on their coplanarity and proximity to define dissecting planes that separate the touching nuclei. The proposed curvature-based partitioning method is validated with both synthetic and real data, and is shown to have a superior performance against previous techniques. Validation and sensitivity analysis are coupled with the experimental design that includes a non-transformed cell line and three tumorigenic cell lines, which covers a wide range of phenotypic diversity in breast cancer. Colony profiling, derived from nuclear segmentation, reveals distinct indices for the morphogenesis of each cell line.Availability: All software are developed in ITK/VTK and are available at https://vision.lbl.gov/Software/3DMorphometry.Contact: b_parvin@lbl.gov or hchang@lbl.govSupplementary information: Supplementary data are available at Bioinformatics online.
BioSig3D is a computational platform for high-content screening of three-dimensional (3D) cell culture models that are imaged in full 3D volume. It provides an end-to-end solution for designing high content screening assays, based on colony organization that is derived from segmentation of nuclei in each colony. BioSig3D also enables visualization of raw and processed 3D volumetric data for quality control, and integrates advanced bioinformatics analysis. The system consists of multiple computational and annotation modules that are coupled together with a strong use of controlled vocabularies to reduce ambiguities between different users. It is a web-based system that allows users to: design an experiment by defining experimental variables, upload a large set of volumetric images into the system, analyze and visualize the dataset, and either display computed indices as a heatmap, or phenotypic subtypes for heterogeneity analysis, or download computed indices for statistical analysis or integrative biology. BioSig3D has been used to profile baseline colony formations with two experiments: (i) morphogenesis of a panel of human mammary epithelial cell lines (HMEC), and (ii) heterogeneity in colony formation using an immortalized non-transformed cell line. These experiments reveal intrinsic growth properties of well-characterized cell lines that are routinely used for biological studies. BioSig3D is being released with seed datasets and video-based documentation.
Pattern formation in developing tissues involves dynamic spatio-temporal changes in cellular organization and subsequent evolution of functional adult structures. Branching morphogenesis is a developmental mechanism by which patterns are generated in many developing organs, which is controlled by underlying molecular pathways. Understanding the relationship between molecular signaling, cellular behavior and resulting morphological change requires quantification and categorization of the cellular behavior. In this study, tissue-level and cellular changes in developing salivary gland in response to disruption of ROCK-mediated signaling by are modeled by building cell-graphs to compute mathematical features capturing structural properties at multiple scales. These features were used to generate multiscale cell-graph signatures of untreated and ROCK signaling disrupted salivary gland organ explants. From confocal images of mouse submandibular salivary gland organ explants in which epithelial and mesenchymal nuclei were marked, a multiscale feature set capturing global structural properties, local structural properties, spectral, and morphological properties of the tissues was derived. Six feature selection algorithms and multiway modeling of the data was performed to identify distinct subsets of cell graph features that can uniquely classify and differentiate between different cell populations. Multiscale cell-graph analysis was most effective in classification of the tissue state. Cellular and tissue organization, as defined by a multiscale subset of cell-graph features, are both quantitatively distinct in epithelial and mesenchymal cell types both in the presence and absence of ROCK inhibitors. Whereas tensor analysis demonstrate that epithelial tissue was affected the most by inhibition of ROCK signaling, significant multiscale changes in mesenchymal tissue organization were identified with this analysis that were not identified in previous biological studies. We here show how to define and calculate a multiscale feature set as an effective computational approach to identify and quantify changes at multiple biological scales and to distinguish between different states in developing tissues.
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