Robust Replication of Genotype-Phenotype Associations across Multiple Diseases in an Electronic Medical Record
Robust Replication of Genotype-Phenotype Associations across Multiple Diseases in an Electronic Medical Record
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DOI：
10.1016/j.ajhg.2010.03.003
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发表时间：
2010-04-09
影响因子：
9.8
通讯作者：
Roden, Dan M.
中科院分区：
文献类型：
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作者：
Ritchie, Marylyn D.;Denny, Joshua C.;Roden, Dan M.
与电子病历(EMR)系统相关联的大规模DNA数据库已被提议作为一种快速生成用于发现和复制基因-表型关联的大型、多样化队列的方法。然而，这种资源在多大程度上能够兑现这一承诺尚不清楚。我们研究了EMR连接的DNA生物信息库是否可以用来检测五种疾病的已知基因-表型关联。此前被认为是房颤、克罗恩病、多发性硬化症、类风湿性关节炎或2型糖尿病的常见变异的21个SNP在4mo内成功地对9483个样本进行了基因分型，这些样本进入了Vanderbilt大学医学中心DNA生物库。此前报道的优势比(ORPR)在1.14至2.36之间。对于每种表型，使用自然语言处理技术和帐单代码查询从已确定的健康记录中识别病例(n=70-698)和对照(n=808-3818)。21项关联性测试中的每一项都给出了预期方向的点数估计。在ORPR为1.25的14例患者中，有8例(ORPR较低的0/7例)复制了先前的基因-表型关联(P<；0.05)。在所有有充分证据的分析中，都检测到了具有统计学意义的相关性。在所研究的五种疾病中的每一种中，至少有一种先前报告的关联被重复。这些数据表明，代表临床诊断的表型可以从电子病历系统中提取出来，它们支持将与电子病历系统耦合的DNA资源用作快速生成大型数据集的工具，这些数据集是复制研究队列中发现的关联和在基因组科学中发现所需的。
Large-scale DNA databanks linked to electronic medical record (EMR) systems have been proposed as an approach for rapidly generating large, diverse cohorts for discovery and replication of genotype-phenotype associations. However, the extent to which such resources are capable of delivering on this promise is unknown. We studied whether an EMR-linked DNA biorepository can be used to detect known genotype-phenotype associations for five diseases. Twenty-one SNPs previously implicated as common variants predisposing to atrial fibrillation, Crohn disease, multiple sclerosis, rheumatoid arthritis, or type 2 diabetes were successfully genotyped in 9483 samples accrued over 4 mo into BioVU, the Vanderbilt University Medical Center DNA biobank. Previously reported odds ratios (ORPR) ranged from 1.14 to 2.36. For each phenotype, natural language processing techniques and billing-code queries were used to identify cases (n = 70-698) and controls (n = 808-3818) from deidentified health records. Each of the 21 tests of association yielded point estimates in the expected direction. Previous genotype-phenotype associations were replicated (p < 0.05) in 8/14 cases when the ORPR( was > 1.25, and in 0/7 with lower ORPR). Statistically significant associations were detected in all analyses that were adequately powered. In each of the five diseases studied, at least one previously reported association was replicated. These data demonstrate that phenotypes representing clinical diagnoses can be extracted from EMR systems, and they support the use of DNA resources coupled to EMR systems as tools for rapid generation of large data sets required for replication of associations found in research cohorts and for discovery in genome science.