School of Informatics, Indiana University, 535 W. Michigan Street, Indianapolis, IN 46202, USA.
Artif Intell Med. 2010 Feb-Mar;48(2-3):75-82. doi: 10.1016/j.artmed.2009.07.006. Epub 2009 Dec 8.
OBJECTIVE: The limitation of small sample size of functional genomics experiments has made it necessary to integrate DNA microarray experimental data from different sources. However, experimentation noises and biases of different microarray platforms have made integrated data analysis challenging. In this work, we propose an integrative computational framework to identify candidate biomarker genes from publicly available functional genomics studies. METHODS: We developed a new framework, Gaussian Mixture Modeling-Coupled Information Gain (GMM-IG). In this framework, we first apply a two-component Gaussian mixture model (GMM) to estimate the conditional probability distributions of gene expression data between two different types of samples, for example, normal versus cancer. An expectation-maximization algorithm is then used to estimate the maximum likelihood parameters of a mixture of two Gaussian models in the feature space and determine the underlying expression levels of genes. Gene expression results from different studies are discretized, based on GMM estimations and then unified. Significantly differentially-expressed genes are filtered and assessed with information gain (IG) measures. RESULTS: DNA microarray experimental data for lung cancers from three different prior studies was processed using the new GMM-IG method. Target gene markers from a gene expression panel were selected and compared with several conventional computational biomarker data analysis methods. GMM-IG showed consistently high accuracy for several classification assessments. A high reproducibility of gene selection results was also determined from statistical validations. Our study shows that the GMM-IG framework can overcome poor reliability issues from single-study DNA microarray experiment while maintaining high accuracies by combining true signals from multiple studies. CONCLUSIONS: We present a conceptually simple framework that enables reliable integration of true differential gene expression signals from multiple microarray experiments. This novel computational method has been shown to generate interesting biomarker panels for lung cancer studies. It is promising as a general strategy for future panel biomarker development, especially for applications that requires integrating experimental results generated from different research centers or with different technology platforms.
目的:功能基因组学实验的样本量小的局限性使得有必要整合来自不同来源的 DNA 微阵列实验数据。然而,不同微阵列平台的实验噪声和偏差使得集成数据分析具有挑战性。在这项工作中,我们提出了一种综合计算框架,从公开的功能基因组学研究中识别候选生物标志物基因。
方法:我们开发了一种新的框架,即高斯混合模型-耦合信息增益(GMM-IG)。在该框架中,我们首先应用双成分高斯混合模型(GMM)来估计两种不同类型样本(例如,正常与癌症)之间的基因表达数据的条件概率分布。然后使用期望最大化算法在特征空间中估计两个高斯模型混合的最大似然参数,并确定基因的潜在表达水平。基于 GMM 估计,对来自不同研究的基因表达结果进行离散化,然后统一。使用信息增益(IG)度量筛选和评估差异表达基因。
结果:使用新的 GMM-IG 方法处理来自三个先前研究的肺癌 DNA 微阵列实验数据。选择基因表达面板中的靶基因标记,并与几种常规计算生物标志物数据分析方法进行比较。GMM-IG 在几个分类评估中表现出一致的高精度。从统计验证中还确定了基因选择结果的高度可重复性。我们的研究表明,GMM-IG 框架可以克服单个研究 DNA 微阵列实验的可靠性问题,同时通过结合来自多个研究的真实信号来保持高精度。
结论:我们提出了一个概念上简单的框架,该框架能够可靠地整合来自多个微阵列实验的真实差异基因表达信号。这种新的计算方法已被证明可用于肺癌研究产生有趣的生物标志物面板。它有望成为未来面板生物标志物开发的一般策略,特别是在需要整合来自不同研究中心或使用不同技术平台的实验结果的应用中。
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