Development and Validation of a Computational Method for Assessment of Missense Variants in Hypertrophic Cardiomyopathy
Development and Validation of a Computational Method for Assessment of Missense Variants in Hypertrophic Cardiomyopathy
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DOI：
10.1016/j.ajhg.2011.01.011
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发表时间：
2011-02-11
影响因子：
9.8
通讯作者：
Sunyaev, Shamil R.
中科院分区：
文献类型：
--
作者：
Jordan, Daniel M.;Kiezun, Adam;Sunyaev, Shamil R.
评估DNA测序揭示的新遗传变异的意义是基因组技术与医学实践相结合的一个重大挑战。许多变异仍然难以通过传统的遗传学方法进行分类。已经开发了有助于对这些变体进行分类的计算方法，但它们尚未得到适当的验证，并且通常被认为不够成熟，无法在临床环境中有效使用。我们开发了一种计算方法，用于预测肥厚型心肌病（HCM）患者中检测到的错义变体的影响。我们使用了与HCM相关的六个基因中的74个错义变体的策划临床数据集来训练和验证自动预测器。该预测器是基于支持向量回归，并使用特定的HCM参与基因的系统发育和结构特征。十重交叉验证估计我们的预测的敏感性为94%（95%置信区间：83%-98%）和特异性为89%（95%置信区间：72%-100%）。这对应于预测致病性的比值比为10（95%置信区间：4.0无穷大），或预测良性的比值比为9.9（95%置信区间：4.6-21）。覆盖率（预测的变体比例）为57%（95%置信区间：49%-64%）。这种性能超过了现有的方法，不是专门为HCM设计的。该预测因子的准确性为临床使用自动预测以及家族分离和人口频率数据解释新的错义变异提供了支持，并建议未来开发用于其他疾病的类似工具。
Assessing the significance of novel genetic variants revealed by DNA sequencing is a major challenge to the integration of genomic techniques with medical practice. Many variants remain difficult to classify by traditional genetic methods. Computational methods have been developed that could contribute to classifying these variants, but they have not been properly validated and are generally not considered mature enough to be used effectively in a clinical setting. We developed a computational method for predicting the effects of missense variants detected in patients with hypertrophic cardiomyopathy (HCM). We used a curated clinical data set of 74 missense variants in six genes associated with HCM to train and validate an automated predictor. The predictor is based on support vector regression and uses phylogenetic and structural features specific to genes involved in HCM. Ten-fold cross validation estimated our predictor's sensitivity at 94% (95% confidence interval: 83%-98%) and specificity at 89% (95% confidence interval: 72%-100%). This corresponds to an odds ratio of 10 for a prediction of pathogenic (95% confidence interval: 4.0 infinity), or an odds ratio of 9.9 for a prediction of benign (95% confidence interval: 4.6-21). Coverage (proportion of variants for which a prediction was made) was 57% (95% confidence interval: 49%-64%). This performance exceeds that of existing methods that are not specifically designed for HCM. The accuracy of this predictor provides support for the clinical use of automated predictions alongside family segregation and population frequency data in the interpretation of new missense variants and suggests future development of similar tools for other diseases.