Identifying and quantifying heterogeneity in high content analysis: application of heterogeneity indices to drug discovery.
Identifying and quantifying heterogeneity in high content analysis: application of heterogeneity indices to drug discovery.
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DOI：
10.1371/journal.pone.0102678
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Taylor DL
中科院分区：
文献类型：
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作者：
Gough AH;Chen N;Shun TY;Lezon TR;Boltz RC;Reese CE;Wagner J;Vernetti LA;Grandis JR;Lee AV;Stern AM;Schurdak ME;Taylor DL
生物医学研究、药物发现和诊断中最大的挑战之一是了解看似相同的细胞如何对干扰因素（包括疾病治疗药物）产生不同的反应。尽管异质性已成为细胞群的公认特征，但在药物发现中，异质性并未被常规评估或报告。基于细胞的高含量测定的标准做法是假设正态分布并报告带有标准差的孔间平均值。为了解决这个重要问题，我们试图定义一种可以轻松实现的方法，用于识别、量化和表征细胞和小生物体检测中的异质性，以指导药物发现和实验细胞/组织分析过程中的决策。我们的研究表明，可以通过指示多样性、非正态性和异常值百分比的三个指数来有效地识别和量化异质性。使用五种细胞系中 STAT3 激活的诱导和抑制来评估这些指数，其中系统响应（包括样品制备和仪器性能）得到了很好的表征和控制。这些异质性指数提供了一种标准化方法，可以轻松集成到小型和大型筛选或分析项目中，以指导生物学的解释以及治疗和诊断的开发。了解对扰动因素反应的异质性将成为设计治疗药物开发策略（包括靶向多药理学）的关键因素。
One of the greatest challenges in biomedical research, drug discovery and diagnostics is understanding how seemingly identical cells can respond differently to perturbagens including drugs for disease treatment. Although heterogeneity has become an accepted characteristic of a population of cells, in drug discovery it is not routinely evaluated or reported. The standard practice for cell-based, high content assays has been to assume a normal distribution and to report a well-to-well average value with a standard deviation. To address this important issue we sought to define a method that could be readily implemented to identify, quantify and characterize heterogeneity in cellular and small organism assays to guide decisions during drug discovery and experimental cell/tissue profiling. Our study revealed that heterogeneity can be effectively identified and quantified with three indices that indicate diversity, non-normality and percent outliers. The indices were evaluated using the induction and inhibition of STAT3 activation in five cell lines where the systems response including sample preparation and instrument performance were well characterized and controlled. These heterogeneity indices provide a standardized method that can easily be integrated into small and large scale screening or profiling projects to guide interpretation of the biology, as well as the development of therapeutics and diagnostics. Understanding the heterogeneity in the response to perturbagens will become a critical factor in designing strategies for the development of therapeutics including targeted polypharmacology.
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影响因子：
12.3
作者：
Auffray C;Chen Z;Hood L
通讯作者：
Hood L
影响因子：
64.5
作者：
Azam, M;Latek, RR;Daley, GQ
通讯作者：
Daley, GQ
影响因子：
64.5
作者：
Altschuler SJ;Wu LF
通讯作者：
Wu LF
影响因子：
5.8
作者：
Boland, MV;Murphy, RF
通讯作者：
Murphy, RF
DOI：
10.1038/nrg2918
发表时间：
2011-01
期刊：
Nature reviews. Genetics
影响因子：
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作者：
通讯作者：
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