Enrichment Analysis for Discovering Biological Associations in Phenotypic Screens

A phenotypic screen (PS) is used
to identify compounds causing a desired phenotype in a complex biological
system where mechanisms and targets are largely unknown. Deconvoluting
the mechanism of action of actives and identification of relevant
targets and pathways remains a formidable challenge. Current methods
fail to use the rich information available regarding compounds and
their targets in a systematic way for this deconvolution. We have
developed an enrichment analysis algorithm to identify targets associated
with the desired phenotype in a rigorous data-driven manner using
actives and hundreds of thousands of inactives in a PS, as well as
results of thousands of available legacy target-based screens in an
institution. Our method quantifies association between the PS and
targets while reducing sampling bias, which leads to identification
of novel targets, additional chemical matter, and appropriate assays.
Its use is illustrated using two examples from our laboratories: TRAIL
and DNA fragmentation. Enrichment analysis of these PSs is discussed
using both biological pathway analysis and known cell biology to demonstrate
the value of our method. We believe this enrichment analysis method
is an indispensable tool for the analysis of PSs.