Analysis of variability in high throughput screening data

Applications to melanoma cell lines and drug responses

Kuan Fu Ding, Darren Finlay, Hongwei Yin, William P.D. Hendricks, Chris Sereduk, Jeffrey Kiefer, Aleksandar D Sekulic, Patricia M. LoRusso, Kristiina Vuori, Jeffrey M. Trent, Nicholas J. Schork

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

High-throughput screening (HTS) strategies and protocols have undergone significant development in the last decade. It is now possible to screen hundreds of thousands of compounds, each exploring multiple biological phenotypes and parameters, against various cell lines or model systems in a single setting. However, given the vast amount of data such studies generate, the fact that they use multiple reagents, and are often technician-intensive, questions have been raised about the variability, reliability and reproducibility of HTS results. Assessments of the impact of the multiple factors in HTS studies could arguably lead to more compelling insights into the robustness of the results of a particular screen, as well as the overall quality of the study. We leveraged classical, yet highly flexible, analysis of variance (ANOVA)- based linear models to explore how different factors contribute to the variation observed in a screening study of four different melanoma cell lines and 120 drugs over nine dosages studied in two independent academic laboratories. We find that factors such as plate effects, appropriate dosing ranges, and to a lesser extent, the laboratory performing the screen, are significant predictors of variation in drug responses across the cell lines. Further, we show that when sources of variation are quantified and controlled for, they contextualize claims of inconsistencies and reveal the overall quality of the HTS studies performed at each participating laboratory. In the context of the broader screening study, we show that our analysis can also elucidate the robust effects of drugs, even those within specific cell lines.

Original languageEnglish (US)
Pages (from-to)27786-27799
Number of pages14
JournalOncotarget
Volume8
Issue number17
DOIs
StatePublished - 2017
Externally publishedYes

Fingerprint

Melanoma
Cell Line
Pharmaceutical Preparations
Linear Models
Analysis of Variance
Phenotype

Keywords

  • Computational modeling
  • Drug screens
  • High-throughput screening
  • Melanoma
  • Variability

ASJC Scopus subject areas

  • Oncology

Cite this

Ding, K. F., Finlay, D., Yin, H., Hendricks, W. P. D., Sereduk, C., Kiefer, J., ... Schork, N. J. (2017). Analysis of variability in high throughput screening data: Applications to melanoma cell lines and drug responses. Oncotarget, 8(17), 27786-27799. https://doi.org/10.18632/oncotarget.15347

Analysis of variability in high throughput screening data : Applications to melanoma cell lines and drug responses. / Ding, Kuan Fu; Finlay, Darren; Yin, Hongwei; Hendricks, William P.D.; Sereduk, Chris; Kiefer, Jeffrey; Sekulic, Aleksandar D; LoRusso, Patricia M.; Vuori, Kristiina; Trent, Jeffrey M.; Schork, Nicholas J.

In: Oncotarget, Vol. 8, No. 17, 2017, p. 27786-27799.

Research output: Contribution to journalArticle

Ding, KF, Finlay, D, Yin, H, Hendricks, WPD, Sereduk, C, Kiefer, J, Sekulic, AD, LoRusso, PM, Vuori, K, Trent, JM & Schork, NJ 2017, 'Analysis of variability in high throughput screening data: Applications to melanoma cell lines and drug responses', Oncotarget, vol. 8, no. 17, pp. 27786-27799. https://doi.org/10.18632/oncotarget.15347
Ding, Kuan Fu ; Finlay, Darren ; Yin, Hongwei ; Hendricks, William P.D. ; Sereduk, Chris ; Kiefer, Jeffrey ; Sekulic, Aleksandar D ; LoRusso, Patricia M. ; Vuori, Kristiina ; Trent, Jeffrey M. ; Schork, Nicholas J. / Analysis of variability in high throughput screening data : Applications to melanoma cell lines and drug responses. In: Oncotarget. 2017 ; Vol. 8, No. 17. pp. 27786-27799.
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