Differentiation and visualization of diverse cellular phenotypic responses in primary high-content screening

J Biomol Screen. 2012 Jul;17(6):843-9. doi: 10.1177/1087057112439324. Epub 2012 Mar 6.

Abstract

High-throughput screening, based on subcellular imaging, has become a powerful tool in lead discovery. Through the generation of high-quality images, not only the specific target signal can be analyzed but also phenotypic changes of the whole cell are recorded. Yet analysis strategies for the exploration of high-content screening results, in a manner that is independent from predefined control phenotypes, are largely missing. The approach presented here is based on a well-established modeling technique, self-organizing maps (SOMs), which uses multiparametric results to group treatments that create similar morphological effects. This report describes a novel visualization of the SOM clustering by using an image of the cells from each node, with the most representative cell highlighted to deploy the phenotype described by each node. The approach has the potential to identify both expected hits and novel cellular phenotypes. Moreover, different chemotypes, which cause the same phenotypic effects, are identified, thus facilitating "scaffold hopping."

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CHO Cells
  • Cluster Analysis
  • Cricetinae
  • Cricetulus
  • Cystic Fibrosis Transmembrane Conductance Regulator / agonists
  • Cystic Fibrosis Transmembrane Conductance Regulator / metabolism
  • Drug Evaluation, Preclinical / methods*
  • High-Throughput Screening Assays / methods*
  • Image Processing, Computer-Assisted / methods*
  • Laser Scanning Cytometry / instrumentation
  • Laser Scanning Cytometry / methods*
  • Multivariate Analysis
  • Phenotype
  • Principal Component Analysis

Substances

  • CFTR protein, human
  • Cystic Fibrosis Transmembrane Conductance Regulator