Evaluation of connectivity map shows limited reproducibility in drug repositioning

Abstract The Connectivity Map (CMap) is a popular resource designed for data-driven drug repositioning using a large transcriptomic compendium. However, evaluations of its performance are limited. We used two iterations of CMap (CMap 1 and 2) to assess their comparability and reliability. We queried...

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Autores principales:	Nathaniel Lim, Paul Pavlidis
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/9e2c9782c48e4f3c8dd4b0ba6b14221c
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spelling	oai:doaj.org-article:9e2c9782c48e4f3c8dd4b0ba6b14221c2021-12-02T19:04:36ZEvaluation of connectivity map shows limited reproducibility in drug repositioning10.1038/s41598-021-97005-z2045-2322https://doaj.org/article/9e2c9782c48e4f3c8dd4b0ba6b14221c2021-09-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-97005-zhttps://doaj.org/toc/2045-2322Abstract The Connectivity Map (CMap) is a popular resource designed for data-driven drug repositioning using a large transcriptomic compendium. However, evaluations of its performance are limited. We used two iterations of CMap (CMap 1 and 2) to assess their comparability and reliability. We queried CMap 2 with CMap 1-derived signatures, expecting CMap 2 would highly prioritize the queried compounds; the success rate was 17%. Analysis of previously published prioritizations yielded similar results. Low recall is caused by low differential expression (DE) reproducibility both between CMaps and within each CMap. DE strength was predictive of reproducibility, and is influenced by compound concentration and cell-line responsiveness. Reproducibility of CMap 2 sample expression levels was also lower than expected. We attempted to identify the “better” CMap by comparison with a third dataset, but they were mutually discordant. Our findings have implications for CMap usage and we suggest steps for investigators to limit false positives.Nathaniel LimPaul PavlidisNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-14 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Nathaniel Lim Paul Pavlidis Evaluation of connectivity map shows limited reproducibility in drug repositioning
description	Abstract The Connectivity Map (CMap) is a popular resource designed for data-driven drug repositioning using a large transcriptomic compendium. However, evaluations of its performance are limited. We used two iterations of CMap (CMap 1 and 2) to assess their comparability and reliability. We queried CMap 2 with CMap 1-derived signatures, expecting CMap 2 would highly prioritize the queried compounds; the success rate was 17%. Analysis of previously published prioritizations yielded similar results. Low recall is caused by low differential expression (DE) reproducibility both between CMaps and within each CMap. DE strength was predictive of reproducibility, and is influenced by compound concentration and cell-line responsiveness. Reproducibility of CMap 2 sample expression levels was also lower than expected. We attempted to identify the “better” CMap by comparison with a third dataset, but they were mutually discordant. Our findings have implications for CMap usage and we suggest steps for investigators to limit false positives.
format	article
author	Nathaniel Lim Paul Pavlidis
author_facet	Nathaniel Lim Paul Pavlidis
author_sort	Nathaniel Lim
title	Evaluation of connectivity map shows limited reproducibility in drug repositioning
title_short	Evaluation of connectivity map shows limited reproducibility in drug repositioning
title_full	Evaluation of connectivity map shows limited reproducibility in drug repositioning
title_fullStr	Evaluation of connectivity map shows limited reproducibility in drug repositioning
title_full_unstemmed	Evaluation of connectivity map shows limited reproducibility in drug repositioning
title_sort	evaluation of connectivity map shows limited reproducibility in drug repositioning
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/9e2c9782c48e4f3c8dd4b0ba6b14221c
work_keys_str_mv	AT nathaniellim evaluationofconnectivitymapshowslimitedreproducibilityindrugrepositioning AT paulpavlidis evaluationofconnectivitymapshowslimitedreproducibilityindrugrepositioning
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Evaluation of connectivity map shows limited reproducibility in drug repositioning

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