Recommendations from the EGAPP Working Group: Genomic profiling to assess cardiovascular risk to improve cardiovascular health
Recommendations from the EGAPP Working Group: Genomic profiling to assess cardiovascular risk to improve cardiovascular health
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DOI：
10.1097/gim.0b013e3181f872c0
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发表时间：
2010-12-01
影响因子：
8.8
通讯作者：
Veenstra, David L.
中科院分区：
文献类型：
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作者：
Berg, Alfred O.;Botkin, Jeffrey;Veenstra, David L.
建议摘要：基因组实践应用评估和预防工作组 (EWG) 发现没有足够的证据建议对 9p21 遗传变异或 28 个基因中的 57 个其他变异（表 1 所列）进行检测，以评估普通人群心血管疾病 (CVD) 的风险，特别是心脏病和中风。专家工作组发现，单独或组合使用任何这些测试所带来的净健康效益的大小可以忽略不计。除非有进一步的证据支持改善临床结果，否则 EWG 不鼓励临床使用。根据现有证据，净健康效益的总体确定性被视为“低”。理由：有人认为，CVD 风险分类的改进（将 CVD 的中等风险调整为高风险或低风险类别）可能会导致管理变革（例如，更早开始或更高的医疗干预率，或有针对性的行为改变建议），从而改善 CVD 结果。在缺乏直接证据支持这种可能性的情况下，本综述寻求间接证据，旨在记录基因组分析单独或与传统风险因素结合改变 CVD 风险评估的程度，以及风险重新分类改善健康结果的程度。分析有效性：现有基因组分析测试的检测相关证据被认为是不充分的。然而，根据已经使用或可能使用的现有技术以及进行此类测试的两家公司的数据，单个基因变体测试的分析灵敏度和特异性可能至少令人满意。临床有效性：评估了 29 个候选基因，其中涉及 58 种不同的基因变异/疾病关联。其中 34 个协会 (59%) 的临床有效性证据被评为不充分，23 个协会 (40%) 的临床有效性证据被评定为充分。评分不足是由于证据有限、重复性差、可能存在偏差或这些因素的组合。对于心脏病（25 个组合关联）和中风（13 个组合关联），分析提供的接收者操作特征曲线下面积分别为 66% 和 57%。只有 9p21 变异与心脏病的关联具有令人信服的证据，表明每个等位基因的比值比在 1.2 到 1.3 之间；这是任何具有至少足够证据的变异/疾病组合的最高效应量。尽管 9p21 关联似乎独立于传统风险因素，但有足够的证据表明，风险预测的改善充其量也很小。临床实用性：迄今为止报告的任何研究（包括 9p21）均未正式评估临床实用性。因此，没有证据表明利益和危害之间的平衡。此外，没有直接证据来评估将这些标记添加到传统风险因素（例如弗雷明汉风险评分）中的健康益处和危害。然而，在传统风险因素中添加基因组标记所带来的额外收益估计可以忽略不计。背景问题：预防心血管疾病是公共卫生的首要任务。与基因组分析相关的结果的改善可能会产生重要影响。弗雷明汉风险评分中使用的传统风险因素在临床筛查和风险评估策略中具有优势，因为它们测量了治疗的实际目标（例如血脂水平和血压）。为了增加价值，基因组测试应该比单独评估和治疗传统风险因素能带来更好的结果。一些对临床实用性重要的问题仍然未知，例如最令人信服的标记物 (9p21) 与 CVD 关联的生物学机制；改变干预措施的风险水平；长期疾病结果是否会改善；直接向消费者订购测试的个人将如何理解/响应测试结果并与医疗保健系统互动；直接面向消费者的测试是否会促使行为改变或放大潜在危害。基因医学 2010:12(12):839-843。
The Summary of Recommendations: The Evaluation of Genomic Applications in Practice and Prevention Working Group (EWG) found insufficient evidence to recommend testing for the 9p21 genetic variant or 57 other variants in 28 genes (listed in Table 1) to assess risk for cardiovascular disease (CVD) in the general population, specifically heart disease and stroke. The EWG found that the magnitude of net health benefit from use of any of these tests alone or in combination is negligible. The EWG discourages clinical use unless further evidence supports improved clinical outcomes. Based on the available evidence, the overall certainty of net health benefit is deemed "Low." Rationale: It has been suggested that an improvement in CVD risk classification (adjusting intermediate risk of CVD into high-or low-risk categories) might lead to management changes (e. g., earlier initiation or higher rates of medical interventions, or targeted recommendations for behavioral change) that improve CVD outcomes. In the absence of direct evidence to support this possibility, this review sought indirect evidence aimed at documenting the extent to which genomic profiling alters CVD risk estimation, alone and in combination with traditional risk factors, and the extent to which risk reclassification improves health outcomes. Analytic validity: Assay-related evidence on available genomic profiling tests was deemed inadequate. However, based on existing technologies that have been or may be used and on data from two of the companies performing such testing, the analytic sensitivity and specificity of tests for individual gene variants might be at least satisfactory. Clinical validity: Twenty-nine gene candidates were evaluated, with 58 different gene variant/disease associations. Evidence on clinical validity was rated inadequate for 34 of these associations (59%) and adequate for 23 (40%). Inadequate grades were based on limited evidence, poor replication, existence of possible biases, or combinations of these factors. For heart disease (25 combined associations) and stroke (13 combined associations), profiling provided areas under the receiver operator characteristics curve of 66% and 57%, respectively. Only the association of 9p21 variants with heart disease had convincing evidence of a per-allele odds ratio of between 1.2 and 1.3; this was the highest effect size for any variant/disease combination with at least adequate evidence. Although the 9p21 association seems to be independent of traditional risk factors, there is adequate evidence that the improvement in risk prediction is, at best, small. Clinical utility: Clinical utility was not formally evaluated in any of the studies reported to date, including for 9p21. As a result, no evidence was available on the balance of benefits and harms. Also, there was no direct evidence available to assess the health benefits and harms of adding these markers to traditional risk factors (e. g., Framingham Risk Score). However, the estimated additional benefit from adding genomic markers to traditional risk factors was found to be negligible. Contextual Issues: Prevention of CVD is a public health priority. Improvements in outcomes associated with genomic profiling could have important impacts. Traditional risk factors such as those used in the Framingham Risk Scores have an advantage in clinical screening and risk assessment strategies because they measure the actual targets for therapy (e. g., lipid levels and blood pressure).To add value, genomic testing should lead to better outcomes than those achievable by assesment and treatment of traditional risk factors alone. Some issues important for clinical utility remain unknown, such as the biological mechanism underlying the most convincing marker's (9p21) association with CVD; the level of risk that changes intervention; whether long-term disease outcomes will improve; how individuals ordering direct to consumer tests will understand/ respond to test results and interact with the health care system; and whether direct to consumer testing will motivate behavior change or amplify potential harms. Genet Med 2010:12(12):839-843.