MicroArray Facility, VIB, Leuven, Belgium.
BMC Bioinformatics. 2009 Nov 19;10:380. doi: 10.1186/1471-2105-10-380.
Comparative genomic hybridization microarrays for the detection of constitutional chromosomal aberrations is the application of microarray technology coming fastest into routine clinical application. Through genotype-phenotype association, it is also an important technique towards the discovery of disease causing genes and genomewide functional annotation in human. When using a two-channel microarray of genomic DNA probes for array CGH, the basic setup consists in hybridizing a patient against a normal reference sample. Two major disadvantages of this setup are (1) the use of half of the resources to measure a (little informative) reference sample and (2) the possibility that deviating signals are caused by benign copy number variation in the "normal" reference instead of a patient aberration. Instead, we apply an experimental loop design that compares three patients in three hybridizations.
We develop and compare two statistical methods (linear models of log ratios and mixed models of absolute measurements). In an analysis of 27 patients seen at our genetics center, we observed that the linear models of the log ratios are advantageous over the mixed models of the absolute intensities.
The loop design and the performance of the statistical analysis contribute to the quick adoption of array CGH as a routine diagnostic tool. They lower the detection limit of mosaicisms and improve the assignment of copy number variation for genetic association studies.
用于检测染色体结构畸变的比较基因组杂交微阵列是微阵列技术在临床常规应用中最快的应用之一。通过基因型-表型关联，它也是发现致病基因和人类全基因组功能注释的重要技术。当使用双通道基因组 DNA 探针微阵列进行 array CGH 时，基本设置包括将患者与正常参考样本杂交。这种设置有两个主要缺点：（1）使用一半的资源来测量信息量较少的参考样本；（2）可能偏离的信号是由“正常”参考中的良性拷贝数变异引起的，而不是患者的异常。相反，我们应用了一种实验循环设计，在三个杂交中比较了三个患者。
我们开发并比较了两种统计方法（对数比的线性模型和绝对测量的混合模型）。在对我们遗传学中心的 27 名患者的分析中，我们观察到对数比的线性模型优于绝对强度的混合模型。
循环设计和统计分析的性能有助于将 array CGH 快速作为常规诊断工具采用。它们降低了嵌合体的检测限，并提高了遗传关联研究中拷贝数变异的分配。
