Novel Morphological Phenotypes Discovery in High-Content Screens Using Underused Features

Cell-based high-content screening (HCS) is a powerful high-throughput technology for studying cellular processes through the analysis of complex cellular morphology. A typical large-scale HCS screen can generate many novel morphological phenotypes. It is challenging to identify novel phenotypes due to the huge volume of data and the lack of domain knowledge. This paper presents a new strategy that discovers novel phenotypes using underused image features, which are defined as those not fully utilized by the existing phenotypes. Our approach was successfully applied to a data set generated in a genetic HCS of Drosophila BG-2 cells to discover novel phenotypes and make interesting predictions.

[1]  Anne E Carpenter Image-based chemical screening. , 2007, Nature chemical biology.

[2]  Michael Boutros,et al.  Identification of JAK/STAT signalling components by genome-wide RNA interference , 2005, Nature.

[3]  Robert F. Murphy,et al.  Towards a Systematics for Protein Subcellular Location: Quantitative Description of Protein Localization Patterns and Automated Analysis of Fluorescence Microscope Images , 2000, ISMB.

[4]  Hanchuan Peng,et al.  Bioimage informatics: a new area of engineering biology , 2008, Bioinform..

[5]  Norbert Perrimon,et al.  Parallel Chemical Genetic and Genome-Wide RNAi Screens Identify Cytokinesis Inhibitors and Targets , 2004, PLoS biology.

[6]  Don H. Johnson,et al.  Symmetrizing the Kullback-Leibler Distance , 2001 .

[7]  David G. Stork,et al.  Pattern Classification (2nd ed.) , 1999 .

[8]  Daniel Rauh,et al.  An Unbiased Cell Morphology–Based Screen for New, Biologically Active Small Molecules , 2005, PLoS biology.

[9]  Bianca Habermann,et al.  Genome-wide analysis of human kinases in clathrin- and caveolae/raft-mediated endocytosis , 2005, Nature.

[10]  Lani F. Wu,et al.  Characterizing heterogeneous cellular responses to perturbations , 2008, Proceedings of the National Academy of Sciences.

[11]  Cynthia L Adams,et al.  Compound classification using image-based cellular phenotypes. , 2006, Methods in enzymology.

[12]  C. Bakal,et al.  Quantitative Morphological Signatures Define Local Signaling Networks Regulating Cell Morphology , 2007, Science.

[13]  Anne E Carpenter,et al.  A Novel Small Molecule Regulator of Guanine Nucleotide Exchange Activity of the ADP-ribosylation Factor and Golgi Membrane Trafficking* , 2008, Journal of Biological Chemistry.

[14]  R. Saint,et al.  A RhoGEF and Rho family GTPase-activating protein complex links the contractile ring to cortical microtubules at the onset of cytokinesis. , 2003, Developmental cell.

[15]  Timothy J Mitchison,et al.  Small‐Molecule Screening and Profiling by Using Automated Microscopy , 2005, Chembiochem : a European journal of chemical biology.

[16]  Lani F. Wu,et al.  Multidimensional Drug Profiling By Automated Microscopy , 2004, Science.

[17]  M. Glotzer,et al.  Central spindle assembly and cytokinesis require a kinesin-like protein/RhoGAP complex with microtubule bundling activity. , 2002, Developmental cell.

[18]  M. Basseville Distance measures for signal processing and pattern recognition , 1989 .

[19]  Chen Lin,et al.  Intelligent Interfaces for Mining Large-Scale RNAi-HCS Image Databases , 2007, 2007 IEEE 7th International Symposium on BioInformatics and BioEngineering.

[20]  Robert F Murphy,et al.  Automated interpretation of protein subcellular location patterns. , 2006, International review of cytology.

[21]  John A. Tallarico,et al.  Integrating high-content screening and ligand-target prediction to identify mechanism of action. , 2008, Nature chemical biology.

[22]  Stephan R. Sain,et al.  Multi-dimensional Density Estimation , 2004 .

[23]  Robert Tibshirani,et al.  Estimating the number of clusters in a data set via the gap statistic , 2000 .

[24]  Anne E Carpenter,et al.  Cell microarrays and RNA interference chip away at gene function , 2005, Nature Genetics.

[25]  Stephen T. C. Wong,et al.  Cellular Phenotype Recognition for High-Content RNA Interference Genome-Wide Screening , 2008, Journal of biomolecular screening.

[26]  M V Boland,et al.  Automated analysis of patterns in fluorescence-microscope images. , 1999, Trends in cell biology.

[27]  Ian T. Jolliffe,et al.  Principal Component Analysis , 2002, International Encyclopedia of Statistical Science.

[28]  Robert F. Murphy,et al.  A neural network classifier capable of recognizing the patterns of all major subcellular structures in fluorescence microscope images of HeLa cells , 2001, Bioinform..

[29]  M V Boland,et al.  Automated recognition of patterns characteristic of subcellular structures in fluorescence microscopy images. , 1998, Cytometry.

[30]  R. Wollman,et al.  High throughput microscopy: from raw images to discoveries , 2007, Journal of Cell Science.

[31]  H. Erfle,et al.  High-throughput RNAi screening by time-lapse imaging of live human cells , 2006, Nature Methods.

[32]  J. Engel,et al.  Focal adhesion components are essential for mammalian cell cytokinesis , 2008, Cell cycle.

[33]  T. Heino,et al.  Drosophila α-actinin in ovarian follicle cells is regulated by EGFR and Dpp signalling and required for cytoskeletal remodelling , 2006, Mechanisms of Development.

[34]  Lani F. Wu,et al.  Image-based multivariate profiling of drug responses from single cells , 2007, Nature Methods.

[35]  R. A. Leibler,et al.  On Information and Sufficiency , 1951 .

[36]  Xiaobo Zhou,et al.  Using iterative cluster merging with improved gap statistics to perform online phenotype discovery in the context of high-throughput RNAi screens , 2008, BMC Bioinformatics.

[37]  A. Poustka,et al.  A microscope‐based screening platform for large‐scale functional protein analysis in intact cells , 2003, FEBS letters.

[38]  Paul Martin,et al.  The small GTPase Rac plays multiple roles in epithelial sheet fusion--dynamic studies of Drosophila dorsal closure. , 2005, Developmental biology.

[39]  Shigeo Abe DrEng Pattern Classification , 2001, Springer London.

[40]  A. Coulson,et al.  Full-genome RNAi profiling of early embryogenesis in Caenorhabditis elegans , 2005, Nature.

[41]  M. Glotzer,et al.  Animal cell cytokinesis. , 2001, Annual review of cell and developmental biology.