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Predicting Low Dose Effects for Chemicals in High Through-Put Studies

机译:在高通量研究中预测化学品的低剂量效应

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High through-put studies commonly use automated systems with 96-well plates in which multiple chemicals are tested at multiple doses using log-2 dose increments after a suitable incubation period. There are typically multiple (ranging from five to eleven) doses on each chemical, and occasionally plate replications of the dose-response studies. The target endpoint for such studies is typically the LC50, but for some chemicals, there may be multiple doses below a benchmark dose where there is no apparent adverse response relative to control response. We show how an estimation approach can lead to clearly interpretable results about response in the low dose region using data from a high throughput study of 2189 chemicals on yeast. Accurate estimates can be obtained of response for study chemicals by using best linear unbiased predictors (BLUPs) in a mixed model, and summarized via plots with expected response (assuming no low-dose effect) with confidence intervals for response below the benchmark dose for each chemical, providing an informative summary of response at low doses. We conclude that this approach can provide valuable insights that would be missed if the observational data were only considered through the lens of statistical methods appropriate for experimental studies.
机译:高通量研究通常使用带有96孔板的自动化系统,其中在适当的孵育时间后,使用log-2剂量增量以多种剂量测试多种化学物质。每种化学品通常有多个剂量(从五到十一),并且偶尔会重复进行剂量反应研究。此类研究的目标终点通常是LC50,但对于某些化学品,可能会在低于基准剂量的情况下出现多个剂量,在这些剂量下,相对于对照反应,没有明显的不良反应。我们使用来自酵母上2189种化学物质的高通量研究数据,展示了一种估计方法如何能够导致有关低剂量区域响应的清晰可解释的结果。通过在混合模型中使用最佳线性无偏预测因子(BLUP),可以获得对研究化学药品的准确估算,并通过具有预期响应(假设无低剂量效应)的图进行汇总,并在每个剂量均低于基准剂量的情况下置信区间化学药品,提供低剂量反应的信息摘要。我们得出的结论是,如果仅通过适用于实验研究的统计方法来考虑观测数据,则该方法可以提供有价值的见解,而这些见解将被忽略。

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