 From Cellular Characteristics to Disease Diagnosis: Uncovering Phenotypes with SupercellsJulián Candia, Ryan Maunu, Meghan Driscoll, Angélique Biancotto, Pradeep Dagur, J Philip McCoy, H Nida Sen, Lai Wei, Amos Maritan, Kan Cao, Robert B Nussenblatt, Jayanth R Banavar and Wolfgang Losert PLOS Computational Biology, 2013, vol. 9, issue 9, 1-10 Abstract: Cell heterogeneity and the inherent complexity due to the interplay of multiple molecular processes within the cell pose difficult challenges for current single-cell biology. We introduce an approach that identifies a disease phenotype from multiparameter single-cell measurements, which is based on the concept of “supercell statistics”, a single-cell-based averaging procedure followed by a machine learning classification scheme. We are able to assess the optimal tradeoff between the number of single cells averaged and the number of measurements needed to capture phenotypic differences between healthy and diseased patients, as well as between different diseases that are difficult to diagnose otherwise. We apply our approach to two kinds of single-cell datasets, addressing the diagnosis of a premature aging disorder using images of cell nuclei, as well as the phenotypes of two non-infectious uveitides (the ocular manifestations of Behçet's disease and sarcoidosis) based on multicolor flow cytometry. In the former case, one nuclear shape measurement taken over a group of 30 cells is sufficient to classify samples as healthy or diseased, in agreement with usual laboratory practice. In the latter, our method is able to identify a minimal set of 5 markers that accurately predict Behçet's disease and sarcoidosis. This is the first time that a quantitative phenotypic distinction between these two diseases has been achieved. To obtain this clear phenotypic signature, about one hundred CD8+ T cells need to be measured. Although the molecular markers identified have been reported to be important players in autoimmune disorders, this is the first report pointing out that CD8+ T cells can be used to distinguish two systemic inflammatory diseases. Beyond these specific cases, the approach proposed here is applicable to datasets generated by other kinds of state-of-the-art and forthcoming single-cell technologies, such as multidimensional mass cytometry, single-cell gene expression, and single-cell full genome sequencing techniques.Author Summary: The behavior of organisms is based on the concerted action occurring on an astonishing range of scales from the molecular to the organismal level. Molecular properties control the function of a cell, while cell ensembles form tissues and organs, which work together as an organism. In order to understand and characterize the molecular nature of the emergent properties of a cell, it is essential that multiple components of the cell are measured simultaneously in the same cell. Similarly, multiple cells must be measured in order to understand health and disease in the organism. In this work, we develop an approach that is able to determine how many cells, how many measurements per cell, and which measurements are needed to reliably diagnose disease. We apply this method to two different problems: the diagnosis of a premature aging disorder using images of cell nuclei, and the distinction between two similar autoimmune eye diseases using stained cells from patients' blood samples. Our findings shed new light on the role of specific kinds of immune system cells in systemic inflammatory diseases and may lead to improved diagnosis and treatment. Date: 2013 Downloads: (external link) Related works: Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text Persistent link: https://EconPapers.repec.org/RePEc:plo:pcbi00:1003215 DOI: 10.1371/journal.pcbi.1003215 Access Statistics for this article More articles in PLOS Computational Biology from Public Library of Science |
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