Representing high throughput expression profiles via perturbation barcodes reveals compound targets.
High throughput mRNA expression profiling can be used to characterize the response of cell culture models to perturbations such as pharmacologic modulators and genetic perturbations. As profiling campaigns expand in scope, it is important to homogenize, summarize, and analyze the resulting data in a manner that captures significant biological signals in spite of various noise sources such as batch effects and stochastic variation. We used the L1000 platform for large-scale profiling of 978 representative genes across thousands of compound treatments. Here, a method is described that uses deep learning techniques to convert the expression changes of the landmark genes into a perturbation barcode that reveals important features of the underlying data, performing better than the raw data in revealing important biological insights. The barcode captures compound structure and target information, and predicts a compound's high throughput screening promiscuity, to a higher degree than the original data measurements, indicating that the approach uncovers underlying factors of the expression data that are otherwise entangled or masked by noise. Furthermore, we demonstrate that visualizations derived from the perturbation barcode can be used to more sensitively assign functions to unknown compounds through a guilt-by-association approach, which we use to predict and experimentally validate the activity of compounds on the MAPK pathway. The demonstrated application of deep metric learning to large-scale chemical genetics projects highlights the utility of this and related approaches to the extraction of insights and testable hypotheses from big, sometimes noisy data.
Medical Writing, Merck Research Laboratories, Upper Gwynedd, Pennsylvania, United States of America.
Tracey M
0000-0001-9276-9279
TM
Filzen
Informatics, Merck Research Laboratories, Boston, Massachusetts, United States of America.
Peter S
PS
Kutchukian
Screening & Protein Sciences, Merck Research Laboratories, North Wales, Pennsylvania, United States of America.
Jeffrey D
0000-0001-7360-8322
JD
Hermes
Screening and Compound Profiling, Merck Research Laboratories, Kenilworth, New Jersey, United States of America.
Jing
J
Li
Informatics, Merck Research Laboratories, West Point, Pennsylvania, United States of America.
Matthew
M
Tudor
D000818:Animals; D002468:Cell Physiological Phenomena / Q000187:drug effects*; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics*; D020869:Gene Expression Profiling / Q000379:methods*; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D006801:Humans; D058990:Molecular Targeted Therapy / Q000379:methods*; D004364:Pharmaceutical Preparations / Q000008:administration & dosage*
D004364:Pharmaceutical Preparations