Improving variant prioritization in exome analysis by entropy-weighted ensemble of multiple tools
Improving variant prioritization in exome analysis by entropy-weighted ensemble of multiple tools
复制标题
通过多种工具的熵加权集成改进外显子组分析中的变异优先顺序
DOI：
10.1111/cge.14257
复制
发表时间：
2022-11-01
影响因子：
3.5
通讯作者：
Yu, Yongguo
中科院分区：
文献类型：
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作者：
Fan, Yanjie;Zhou, Ying;Yu, Yongguo
变体优先排序是外显子组分析和基因组测序中的关键步骤。已经开发了多个表型驱动的工具来自动化变体优先化过程，但是这些工具在具有模糊表型信息的临床环境中的功效以及这些工具的集合是否能够优于单个算法仍有待评估。招募了一个具有异质表型信息的大型罕见疾病队列，包括1614例患者的主要队列和1904例患者的复制队列（参考外显子组测序），以评估变体优先化及其整体的疗效。三个免费提供的工具-Exomiser，Xrare和DeepPVP-及其集成进行了评估。所有三种工具的性能都受到表型输入属性的影响。当通过加权和熵方法（EWE 3）组合这三种工具时，集成优于任何单一算法，在前3名中实现了78%的诊断变体率（与当前最佳表现者相比，Exomiser：63%，Xrare：65%，DeepPVP：51%），前10名中为88%，前30名中为96%。结果在另一个独立的队列中重复。我们的研究支持使用多种工具的熵加权集成来改善变体优先级并加速外显子组/基因组测序中的分子诊断。
Variant prioritization is a crucial step in the analysis of exome and genome sequencing. Multiple phenotype-driven tools have been developed to automate the variant prioritization process, but the efficacy of these tools in clinical setting with fuzzy phenotypic information and whether ensemble of these tools could outperform single algorithm remains to be assessed. A large rare disease cohort with heterogeneous phenotypic information, including a primary cohort of 1614 patients and a replication cohort of 1904 patients referred to exome sequencing, were recruited to assess the efficacy of variant prioritization and their ensemble. Three freely available tools-Exomiser, Xrare, and DeepPVP-and their ensemble were evaluated. The performance of all three tools was influenced by the attributes of phenotypic input. When combining these three tools by weighted-sum entropy method (EWE3), the ensemble outperformed any single algorithm, achieving a rate of 78% diagnostic variants in top 3 (13% improvement over current best performer, compared to Exomiser: 63%, Xrare: 65%, and DeepPVP: 51%), 88% in top 10 and 96% in top 30. The results were replicated in another independent cohort. Our study supports using entropy-weighted ensemble of multiple tools to improve variant prioritization and accelerate molecular diagnosis in exome/genome sequencing.