使用多路复用功能数据来减少代表性不足人群中的变体分类不平等。

IF 10.4 1区 生物学 Q1 GENETICS & HEREDITY
Moez Dawood, Shawn Fayer, Sriram Pendyala, Mason Post, Divya Kalra, Karynne Patterson, Eric Venner, Lara A Muffley, Douglas M Fowler, Alan F Rubin, Jennifer E Posey, Sharon E Plon, James R Lupski, Richard A Gibbs, Lea M Starita, Carla Daniela Robles-Espinoza, Willow Coyote-Maestas, Irene Gallego Romero
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引用次数: 0

摘要

背景:多重变异效应测定法(Multiplexed Assays of Variant Effects, MAVEs)可以检测感兴趣基因中所有可能的单一变异。由此产生的饱和式功能数据可能有助于解决种群之间的变异分类差异,特别是对于不确定显著性变异(VUS)。方法:我们分析了来自All of Us和基因组聚集数据库的213,663名欧洲样遗传祖先个体与206,975名非欧洲样遗传祖先个体的临床意义分类。然后,我们将临床校准的MAVE数据纳入临床基因组资源的变异管理专家小组规则,以自动对BRCA1, TP53和PTEN进行VUS重新分类。结果:使用两种正交统计方法,我们显示在所有三个数据库中评估的所有医学专业中,非欧洲类遗传血统个体的VUS患病率较高(p≤5.95e - 06)。此外,在非欧洲样遗传祖先组中,在许多医学专业中发现了更高的良性或可能良性和无临床命名的变异(p≤2.5e - 05),而在欧洲样遗传祖先个体中,致病性或可能致病性分配增加(p≤2.5e - 05)。使用MAVE数据,我们对非欧洲人遗传祖先的VUS进行重新分类的比率明显高于对欧洲人遗传祖先的VUS进行重新分类的比率(p = 9.1e - 03),有效地补偿了VUS差异。此外,基本代码分析显示,对于非欧洲血统的个体,MAVE证据代码的影响是公平的,而等位基因频率(p = 7.47e - 06)和计算预测因子(p = 6.92e - 05)证据代码的影响是不公平的。结论:生成饱和式MAVE数据应该是减少VUS差异和为未来的计算预测器生成公平的训练数据的优先事项。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Using multiplexed functional data to reduce variant classification inequities in underrepresented populations.

Background: Multiplexed Assays of Variant Effects (MAVEs) can test all possible single variants in a gene of interest. The resulting saturation-style functional data may help resolve variant classification disparities between populations, especially for Variants of Uncertain Significance (VUS).

Methods: We analyzed clinical significance classifications in 213,663 individuals of European-like genetic ancestry versus 206,975 individuals of non-European-like genetic ancestry from All of Us and the Genome Aggregation Database. Then, we incorporated clinically calibrated MAVE data into the Clinical Genome Resource's Variant Curation Expert Panel rules to automate VUS reclassification for BRCA1, TP53, and PTEN.

Results: Using two orthogonal statistical approaches, we show a higher prevalence (p ≤ 5.95e - 06) of VUS in individuals of non-European-like genetic ancestry across all medical specialties assessed in all three databases. Further, in the non-European-like genetic ancestry group, higher rates of Benign or Likely Benign and variants with no clinical designation (p ≤ 2.5e - 05) were found across many medical specialties, whereas Pathogenic or Likely Pathogenic assignments were increased in individuals of European-like genetic ancestry (p ≤ 2.5e - 05). Using MAVE data, we reclassified VUS in individuals of non-European-like genetic ancestry at a significantly higher rate in comparison to reclassified VUS from European-like genetic ancestry (p = 9.1e - 03) effectively compensating for the VUS disparity. Further, essential code analysis showed equitable impact of MAVE evidence codes but inequitable impact of allele frequency (p = 7.47e - 06) and computational predictor (p = 6.92e - 05) evidence codes for individuals of non-European-like genetic ancestry.

Conclusions: Generation of saturation-style MAVE data should be a priority to reduce VUS disparities and produce equitable training data for future computational predictors.

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来源期刊
Genome Medicine
Genome Medicine GENETICS & HEREDITY-
CiteScore
20.80
自引率
0.80%
发文量
128
审稿时长
6-12 weeks
期刊介绍: Genome Medicine is an open access journal that publishes outstanding research applying genetics, genomics, and multi-omics to understand, diagnose, and treat disease. Bridging basic science and clinical research, it covers areas such as cancer genomics, immuno-oncology, immunogenomics, infectious disease, microbiome, neurogenomics, systems medicine, clinical genomics, gene therapies, precision medicine, and clinical trials. The journal publishes original research, methods, software, and reviews to serve authors and promote broad interest and importance in the field.
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