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Cytometry A. 2016 Jul;89(7):633-43. doi: 10.1002/cyto.a.22873. Epub 2016 Jun 21.

Point process models for localization and interdependence of punctate cellular structures.

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State Key Laboratory of Information Engineering in Surveying, Mapping, and Remote Sensing, Wuhan University, Wuhan, 430079, China.
Computational Biology Department, Carnegie Mellon University, Pittsburgh, Pennsylvania, 15213.
Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, Pennsylvania, 15213.
Departments of Biomedical Engineering and Machine Learning, Carnegie Mellon University, Pittsburgh, Pennsylvania, 15213.
Freiburg Institute for Advanced Studies and Faculty of Biology, Albert Ludwig University of Freiburg, Albertstrasse 19, 79104 Freiburg Im Breisgau, Germany.


Accurate representations of cellular organization for multiple eukaryotic cell types are required for creating predictive models of dynamic cellular function. To this end, we have previously developed the CellOrganizer platform, an open source system for generative modeling of cellular components from microscopy images. CellOrganizer models capture the inherent heterogeneity in the spatial distribution, size, and quantity of different components among a cell population. Furthermore, CellOrganizer can generate quantitatively realistic synthetic images that reflect the underlying cell population. A current focus of the project is to model the complex, interdependent nature of organelle localization. We built upon previous work on developing multiple non-parametric models of organelles or structures that show punctate patterns. The previous models described the relationships between the subcellular localization of puncta and the positions of cell and nuclear membranes and microtubules. We extend these models to consider the relationship to the endoplasmic reticulum (ER), and to consider the relationship between the positions of different puncta of the same type. Our results do not suggest that the punctate patterns we examined are dependent on ER position or inter- and intra-class proximity. With these results, we built classifiers to update previous assignments of proteins to one of 11 patterns in three distinct cell lines. Our generative models demonstrate the ability to construct statistically accurate representations of puncta localization from simple cellular markers in distinct cell types, capturing the complex phenomena of cellular structure interaction with little human input. This protocol represents a novel approach to vesicular protein annotation, a field that is often neglected in high-throughput microscopy. These results suggest that spatial point process models provide useful insight with respect to the spatial dependence between cellular structures.


generative models; pattern recognition; spatial point processes; subcellular location; systems biology

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