Current ongoing genome-wide association (GWA) studies represent a powerful approach to uncover common unknown genetic variants causing common complex diseases. The discovery of these genetic variants offers an important opportunity for early disease prediction, prevention, and individualized treatment. We describe here a method of combining multiple genetic variants for early disease prediction, based on the optimality theory of the likelihood ratio (LR). Such theory simply shows that the receiver operating characteristic (ROC) curve based on the LR has maximum performance at each cutoff point and that the area under the ROC curve so obtained is highest among that of all approaches. Through simulations and a real data application, we compared it with the commonly used logistic regression and classification tree approaches. The three approaches show similar performance if we know the underlying disease model. However, for most common diseases we have little prior knowledge of the disease model and in this situation the new method has an advantage over logistic regression and classification tree approaches. We applied the new method to the type 1 diabetes GWA data from the Wellcome Trust Case Control Consortium. Based on five single nucleotide polymorphisms, the test reaches medium level classification accuracy. With more genetic findings to be discovered in the future, we believe a predictive genetic test for type 1 diabetes can be successfully constructed and eventually implemented for clinical use.

译文

:目前正在进行的全基因组关联(GWA)研究代表了一种强大的方法,可揭示导致常见复杂疾病的常见未知遗传变异。这些遗传变异的发现为疾病的早期预测,预防和个体化治疗提供了重要的机会。我们在这里描述一种基于似然比(LR)的最优性理论,将多种遗传变异结合起来进行早期疾病预测的方法。这种理论简单地表明,基于LR的接收机工作特性(ROC)曲线在每个截止点都具有最佳性能,并且在所有方法中,如此获得的ROC曲线下的面积最高。通过仿真和实际数据应用,我们将其与常用的逻辑回归和分类树方法进行了比较。如果我们知道潜在的疾病模型,则这三种方法显示出相似的性能。但是,对于大多数常见疾病,我们几乎没有疾病模型的先验知识,在这种情况下,新方法比逻辑回归和分类树方法更具优势。我们将新方法应用于来自Wellcome Trust病例对照协会的1型糖尿病GWA数据。基于五个单核苷酸多态性,该测试达到中等水平的分类准确性。随着将来发现更多的遗传发现,我们相信可以成功构建1型糖尿病的预测性遗传测试,并最终用于临床。

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