TY - JOUR
T1 - Analysis of variability in high throughput screening data
T2 - Applications to melanoma cell lines and drug responses
AU - Ding, Kuan Fu
AU - Finlay, Darren
AU - Yin, Hongwei
AU - Hendricks, William P.D.
AU - Sereduk, Chris
AU - Kiefer, Jeffrey
AU - Sekulic, Aleksandar
AU - LoRusso, Patricia M.
AU - Vuori, Kristiina
AU - Trent, Jeffrey M.
AU - Schork, Nicholas J.
PY - 2017
Y1 - 2017
N2 - 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.
AB - 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.
KW - Computational modeling
KW - Drug screens
KW - High-throughput screening
KW - Melanoma
KW - Variability
UR - http://www.scopus.com/inward/record.url?scp=85018447771&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85018447771&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.15347
DO - 10.18632/oncotarget.15347
M3 - Article
C2 - 28212541
AN - SCOPUS:85018447771
SN - 1949-2553
VL - 8
SP - 27786
EP - 27799
JO - Oncotarget
JF - Oncotarget
IS - 17
ER -