A simple and robust method for connecting small-molecule drugs using gene-expression signatures.
BACKGROUND
Interaction of a drug or chemical with a biological system can result in a gene-expression profile or signature characteristic of the event. Using a suitably robust algorithm these signatures can potentially be used to connect molecules with similar pharmacological or toxicological properties by gene expression profile. Lamb et al first proposed the Connectivity Map [Lamb et al (2006), Science 313, 1929-1935] to make successful connections among small molecules, genes, and diseases using genomic signatures.


RESULTS
Here we have built on the principles of the Connectivity Map to present a simpler and more robust method for the construction of reference gene-expression profiles and for the connection scoring scheme, which importantly allows the valuation of statistical significance of all the connections observed. We tested the new method with two randomly generated gene signatures and three experimentally derived gene signatures (for HDAC inhibitors, estrogens, and immunosuppressive drugs, respectively). Our testing with this method indicates that it achieves a higher level of specificity and sensitivity and so advances the original method.


CONCLUSIONS
The method presented here not only offers more principled statistical procedures for testing connections, but more importantly it provides effective safeguard against false connections at the same time achieving increased sensitivity. With its robust performance, the method has potential use in the drug development pipeline for the early recognition of pharmacological and toxicological properties in chemicals and new drug candidates, and also more broadly in other 'omics sciences.
MRC Toxicology Unit, Hodgkin Building, Lancaster Road, University of Leicester, Leicester, UK. sdz1@le.ac.uk
Shu-Dong
SD
Zhang
Timothy W
TW
Gant
D000465:Algorithms; D002460:Cell Line; D030541:Databases, Genetic; D004967:Estrogens / Q000235:genetics / Q000494:pharmacology; D020869:Gene Expression Profiling / Q000706:statistics & numerical data; D023281:Genomics / Q000379:methods; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D016571:Neural Networks, Computer; D020411:Oligonucleotide Array Sequence Analysis; D010363:Pattern Recognition, Automated / Q000379:methods; D004364:Pharmaceutical Preparations / Q000145:classification* / Q000378:metabolism; D010600:Pharmacology / Q000379:methods*; D012015:Reference Standards; D012107:Research Design / Q000706:statistics & numerical data; D012680:Sensitivity and Specificity
D004967:Estrogens; D056572:Histone Deacetylase Inhibitors; D007166:Immunosuppressive Agents; D004364:Pharmaceutical Preparations