Department of Statistics, North Carolina State University, Raleigh, NC, USA.
BioData Min. 2012 Dec 12;5(1):21. doi: 10.1186/1756-0381-5-21.
The large sample sizes, freedom of ethical restrictions and ease of repeated measurements make cytotoxicity assays of immortalized lymphoblastoid cell lines a powerful new in vitro method in pharmacogenomics research. However, previous studies may have over-simplified the complex differences in dose-response profiles between genotypes, resulting in a loss of power.
The current study investigates four previously studied methods, plus one new method based on a multivariate analysis of variance (MANOVA) design. A simulation study was performed using differences in cancer drug response between genotypes for biologically meaningful loci. These loci also showed significance in separate genome-wide association studies. This manuscript builds upon a previous study, where differences in dose-response curves between genotypes were constructed using the hill slope equation.
Overall, MANOVA was found to be the most powerful method for detecting real signals, and was also the most robust method for detection using alternatives generated with the previous simulation study. This method is also attractive because test statistics follow their expected distributions under the null hypothesis for both simulated and real data. The success of this method inspired the creation of the software program MAGWAS. MAGWAS is a computationally efficient, user-friendly, open source software tool that works on most platforms and performs GWASs for individuals having multivariate responses using standard file formats.
大样本量、不受伦理限制的自由以及易于重复测量，使得永生化淋巴母细胞系的细胞毒性测定成为药物基因组学研究中的一种强大的新体外方法。然而，先前的研究可能过于简化了基因型之间剂量反应曲线的复杂差异，从而导致效力降低。
本研究调查了四种先前研究过的方法，外加一种基于方差分析（MANOVA）设计的新方法。使用具有生物学意义的基因座之间的癌症药物反应差异进行了模拟研究。这些基因座在单独的全基因组关联研究中也具有显著性。本研究建立在前一项研究的基础上，该研究使用Hill 斜率方程构建了基因型之间的剂量反应曲线差异。
总体而言，MANOVA 被发现是检测真实信号最有力的方法，也是使用以前的模拟研究生成的替代方法进行检测最稳健的方法。这种方法也很有吸引力，因为检验统计量在模拟数据和真实数据下的零假设下都遵循其预期分布。该方法的成功促使 MAGWAS 软件程序的创建。MAGWAS 是一种计算效率高、用户友好、开源的软件工具，可在大多数平台上运行，并且使用标准文件格式为具有多元反应的个体执行 GWAS。
