Grouping 34 Chemicals Based on Mode of Action Using Connectivity Mapping

Abstract

Connectivity mapping is a method used in the pharmaceutical industry to find connections between small molecules, disease states, and genes. The concept can be applied to a predictive toxicology paradigm to find connections between chemicals, adverse events, and genes. In order to assess the applicability of the technique for predictive toxicology purposes, we performed gene array experiments on 34 different chemicals: bisphenol A, genistein, ethinyl-estradiol, tamoxifen, clofibrate, dehydorepiandrosterone, troglitazone, diethylhexyl phthalate, flutamide, trenbolone, phenobarbital, retinoic acid, thyroxine, 1α,25-dihydroxyvitamin D3, clobetasol, farnesol, chenodeoxycholic acid, progesterone, RU486, ketoconazole, valproic acid, desferrioxamine, amoxicillin, 6-aminonicotinamide, metformin, phenformin, methotrexate, vinblastine, ANIT (1-naphthyl isothiocyanate), griseofulvin, nicotine, imidacloprid, vorinostat, 2,3,7,8-tetrachloro-dibenzo-p-dioxin (TCDD) at the 6-, 24-, and 48-hour time points for 3 different concentrations in the 4 cell lines: MCF7, Ishikawa, HepaRG, and HepG2 GEO (super series accession no.: GSE69851). The 34 chemicals were grouped in to predefined mode of action (MOA)-based chemical classes based on current literature. Connectivity mapping was used to find linkages between each chemical and between chemical classes. Cell line-specific linkages were compared with each other and to test whether the method was platform and user independent, a similar analysis was performed against publicly available data. The study showed that the method can group chemicals based on MOAs and the inter-chemical class comparison alluded to connections between MOAs that were not predefined. Comparison to the publicly available data showed that the method is user and platform independent. The results provide an example of an alternate data analysis process for high-content data, beneficial for predictive toxicology, especially when grouping chemicals for read across purposes.

Evaluation of Connectivity Map shows limited reproducibility in drug repositioning

“…The data for the GEO record corresponding to De Abrew et al (De Abrew et al, 2016), GSE69845, was loaded into the Gemma platform (http://tinyurl.com/Gemma-GSE69845). The raw data was reprocessed from CEL files using the "RMA" algorithm and differential expression analysis was performed for each treatment versus control using a linear model.…”

“…On the other hand, there are also anecdotal reports of positive results, in which researchers have experimentally verified the biological effects of candidate drugs recommended by CMap 1 (Braconi et al, 2009;Brum et al, 2015Brum et al, , 2018Byun et al, 2019;Johnstone et al, 2012;Luo et al, 2019;Schanstra et al, 2019;Wang et al, 2019;Wu et al, 2019) or CMap 2 (Ferguson et al, 2018;Leung et al, 2019;Manzotti et al, 2019;Ryals et al, 2018). An attempt to address the reproducibility question was presented by De Abrew et al, in which they generated an independent CMap-style dataset for 34 compounds in four cell lines (De Abrew et al, 2016). They compared compound retrieval performance to CMap 1 for the 17 compounds shared with their study (their work predates CMap 2).…”

A transcriptomics data-driven gene space accurately predicts liver cytopathology and drug-induced liver injury

“…The US Broad Institute Connectivity Map (CMap) data set has thousands of gene expression profiles of mostly FDA approved drugs and has been used to connect small molecules, genes and diseases (‘connectivity mapping’) to define biologically similar compounds, including for the purpose of identifying toxic modes of action11152526272829. The US National Cancer Institute (NCI) 60 tumour cell line screen includes results on GI 50 (50% growth inhibition), total growth inhibition (TGI), and LC 50 (50% lethal concentration) for many compounds tested in the major CMap cell lines30.…”

Analysis of gene expression profiles of multiple skin diseases identifies a conserved signature of disrupted homeostasis

“…Biopsies for studies 9‐12 were processed for Laser Capture Microdissection of the epidermis and RNA analysis and were placed into plastic cryomolds containing Optimal Cutting Temperature (Sukura Fintek, USA) compound as described . In Study #8, epidermis was separated from the dermis using ammonium thiocyanate .…”