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Bridging Histology and Bioinformatics: Computational analysis of spatially resolved transcriptomics
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, 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.
Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, S-17165 Stockholm, Sweden..
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.ORCID iD: 0000-0002-4139-7003
2017 (English)In: Proceedings of the IEEE, ISSN 0018-9219, E-ISSN 1558-2256, Vol. 105, no 3, 530-541 p.Article in journal (Refereed) Published
Abstract [en]

It is well known that cells in tissue display a large heterogeneity in gene expression due to differences in cell lineage origin and variation in the local environment. Traditional methods that analyze gene expression from bulk RNA extracts fail to accurately describe this heterogeneity because of their intrinsic limitation in cellular and spatial resolution. Also, information on histology in the form of tissue architecture and organization is lost in the process. Recently, new transcriptome-wide analysis technologies have enabled the study of RNA molecules directly in tissue samples, thus maintaining spatial resolution and complementing histological information with molecular information important for the understanding of many biological processes and potentially relevant for the clinical management of cancer patients. These new methods generally comprise three levels of analysis. At the first level, biochemical techniques are used to generate signals that can be imaged by different means of fluorescence microscopy. At the second level, images are subject to digital image processing and analysis in order to detect and identify the aforementioned signals. At the third level, the collected data are analyzed and transformed into interpretable information by statistical methods and visualization techniques relating them to each other, to spatial distribution, and to tissue morphology. In this review, we describe state-of-the-art techniques used at all three levels of analysis. Finally, we discuss future perspective in this fast-growing field of spatially resolved transcriptomics.

Place, publisher, year, edition, pages
2017. Vol. 105, no 3, 530-541 p.
Keyword [en]
Biomedical image processing, biomedical signal analysis, computer-aided analysis, genetics, image analysis, image processing
National Category
Medical Image Processing
Research subject
Computerized Image Processing
Identifiers
URN: urn:nbn:se:uu:diva-283723DOI: 10.1109/JPROC.2016.2538562ISI: 000395894900011OAI: oai:DiVA.org:uu-283723DiVA: diva2:919582
Funder
Science for Life Laboratory - a national resource center for high-throughput molecular bioscienceeSSENCE - An eScience CollaborationSwedish Research Council, 2012-4968 2014-00599
Available from: 2016-04-06 Created: 2016-04-14 Last updated: 2017-04-27Bibliographically approved
In thesis
1. Image Analysis and Deep Learning for Applications in Microscopy
Open this publication in new window or tab >>Image Analysis and Deep Learning for Applications in Microscopy
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Quantitative microscopy deals with the extraction of quantitative measurements from samples observed under a microscope. Recent developments in microscopy systems, sample preparation and handling techniques have enabled high throughput biological experiments resulting in large amounts of image data, at biological scales ranging from subcellular structures such as fluorescently tagged nucleic acid sequences to whole organisms such as zebrafish embryos. Consequently, methods and algorithms for automated quantitative analysis of these images have become increasingly important. These methods range from traditional image analysis techniques to use of deep learning architectures.

Many biomedical microscopy assays result in fluorescent spots. Robust detection and precise localization of these spots are two important, albeit sometimes overlapping, areas for application of quantitative image analysis. We demonstrate the use of popular deep learning architectures for spot detection and compare them against more traditional parametric model-based approaches. Moreover, we quantify the effect of pre-training and change in the size of training sets on detection performance. Thereafter, we determine the potential of training deep networks on synthetic and semi-synthetic datasets and their comparison with networks trained on manually annotated real data. In addition, we present a two-alternative forced-choice based tool for assisting in manual annotation of real image data. On a spot localization track, we parallelize a popular compressed sensing based localization method and evaluate its performance in conjunction with different optimizers, noise conditions and spot densities. We investigate its sensitivity to different point spread function estimates.

Zebrafish is an important model organism, attractive for whole-organism image-based assays for drug discovery campaigns. The effect of drug-induced neuronal damage may be expressed in the form of zebrafish shape deformation. First, we present an automated method for accurate quantification of tail deformations in multi-fish micro-plate wells using image analysis techniques such as illumination correction, segmentation, generation of branch-free skeletons of partial tail-segments and their fusion to generate complete tails. Later, we demonstrate the use of a deep learning-based pipeline for classifying micro-plate wells as either drug-affected or negative controls, resulting in competitive performance, and compare the performance from deep learning against that from traditional image analysis approaches. 

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2016. 76 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 1371
Keyword
Machine learning, Deep learning, Image analysis, Quantitative microscopy, Bioimaging
National Category
Signal Processing
Research subject
Computerized Image Processing
Identifiers
urn:nbn:se:uu:diva-283846 (URN)978-91-554-9567-1 (ISBN)
Public defence
2016-06-09, 2446, ITC, Lägerhyddsvägen 2, Hus 2, Uppsala, 10:15 (English)
Opponent
Supervisors
Available from: 2016-05-18 Created: 2016-04-14 Last updated: 2016-06-01Bibliographically approved

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Mignardi, MarcoIshaq, OmerWählby, Carolina

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