Improved estimation of cancer dependencies from large-scale RNAi screens using model-based normalization and data integration.
Improved estimation of cancer dependencies from large-scale RNAi screens using model-based normalization and data integration.
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DOI：
10.1038/s41467-018-06916-5
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发表时间：
2018-11-02
影响因子：
16.6
通讯作者：
Tsherniak A
中科院分区：
文献类型：
--
作者：
McFarland JM;Ho ZV;Kugener G;Dempster JM;Montgomery PG;Bryan JG;Krill-Burger JM;Green TM;Vazquez F;Boehm JS;Golub TR;Hahn WC;Root DE;Tsherniak A
在数百种不同的癌细胞系中，包括基因组规模的RNAi活力筛选的多个数据集的可用性为理解癌症脆弱性提供了新的机会。这些数据的综合分析，以评估跨基因和细胞系的差异依赖性是具有挑战性的，由于混杂因素，如批次效应和可变的筛选质量，以及难以评估基因依赖性的绝对规模。为了解决这些问题，我们将细胞系筛选质量参数和分层贝叶斯推理纳入DEMETER 2，这是一种用于分析RNAi筛选的分析框架（https：//depmap.org/R2-D2）。该模型大大提高了对一系列性能指标的基因依赖性的估计，包括鉴定金标准必需基因以及与基于CRISPR/Cas9的活力筛选的一致性。它还允许我们整合三个大型RNAi筛选数据集的信息，提供一个统一的资源，代表迄今为止最广泛的癌细胞系遗传依赖性汇编。多个大规模筛选的综合分析可能会因批量效应和技术人为因素而变得复杂。麦克法兰等人介绍了DEMETER 2，这是一种与基于模型的标准化相结合的分层模型，可以评估基因和细胞系之间的差异依赖性。
The availability of multiple datasets comprising genome-scale RNAi viability screens in hundreds of diverse cancer cell lines presents new opportunities for understanding cancer vulnerabilities. Integrated analyses of these data to assess differential dependency across genes and cell lines are challenging due to confounding factors such as batch effects and variable screen quality, as well as difficulty assessing gene dependency on an absolute scale. To address these issues, we incorporated cell line screen-quality parameters and hierarchical Bayesian inference into DEMETER2, an analytical framework for analyzing RNAi screens (https://depmap.org/R2-D2). This model substantially improves estimates of gene dependency across a range of performance measures, including identification of gold-standard essential genes and agreement with CRISPR/Cas9-based viability screens. It also allows us to integrate information across three large RNAi screening datasets, providing a unified resource representing the most extensive compilation of cancer cell line genetic dependencies to date. Integrated analyses of multiple large-scale screenings can be complicated by batch effects and technical artefacts. McFarland et al. introduce DEMETER2, a hierarchical model coupled with model-based normalization, which allows the assessment of differential dependencies across genes and cell lines.
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影响因子：
48
作者：
Li T;Wernersson R;Hansen RB;Horn H;Mercer J;Slodkowicz G;Workman CT;Rigina O;Rapacki K;Stærfeldt HH;Brunak S;Jensen TS;Lage K
通讯作者：
Lage K
影响因子：
64.5
作者：
McDonald, E. Robert, III;de Weck, Antoine;Sellers, William R.
通讯作者：
Sellers, William R.
降低的AGO2表达水平导致哺乳动物细胞中的siRNA竞争增加。
影响因子：
14.9
作者：
Vickers, Timothy A.;Lima, Walt F.;Nichols, Josh G.;Crooke, Stanley T.
通讯作者：
Crooke, Stanley T.
影响因子：
5.8
作者：
Yu, Jiyang;Silva, Jose;Califano, Andrea
通讯作者：
Califano, Andrea
影响因子：
48
作者：
Birmingham, A;Anderson, EM;Khvorova, A
通讯作者：
Khvorova, A