Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York.
Department of Biostatistics and Bioinformatics, Duke University, Durham, North Carolina.
Ophthalmology. 2018 Mar;125(3):391-397. doi: 10.1016/j.ophtha.2017.09.008. Epub 2017 Oct 9.
Considerable controversy has erupted in recent years regarding whether genotyping should be part of standard care for patients with age-related macular degeneration (AMD) who are being considered for treatment with antioxidants and zinc. We aimed to determine whether genotype predicts response to supplements in AMD.
Three separate statistical teams reanalyzed data derived from the Age-Related Eye Disease Study (AREDS), receiving data prepared by the AREDS investigators and, separately, data from investigators reporting findings that support the use of genotyping.
The population of interest was AREDS participants with AMD worse than category 1 and genotyping data available. Data from the 2 groups overlap imperfectly with respect to measurements made: the largest common set involved 879 participants for whom the same CFH and ARMS2 single nucleotide polymorphisms were measured by both groups.
Each team took a separate but complementary approach. One team focused on data concordance between conflicting studies. A second team focused on replicating the key claim of an interaction between genotype and treatment. The third team took a blank slate approach in attempting to find baseline predictors of treatment response.
Progression to advanced AMD.
We found errors in the data used to support the initial claim of genotype-treatment interaction. Although we found evidence that high-risk patients had more to gain from treatment, we were unable to replicate any genotype-treatment interactions after adjusting for multiple testing. We tested 1 genotype claim on an independent set of data, with negative results. Even if we assumed that interactions in fact did exist, we did not find evidence to support the claim that supplementation leads to a large increase in the risk of advanced AMD in some genotype subgroups.
Patients who meet criteria for supplements to prevent AMD progression should be offered zinc and antioxidants without consideration of genotype.
近年来，关于是否应该将基因分型作为接受抗氧化剂和锌治疗的年龄相关性黄斑变性（AMD）患者标准治疗的一部分，存在相当大的争议。我们旨在确定基因型是否可以预测 AMD 对补充剂的反应。
三个独立的统计团队重新分析了来自年龄相关性眼病研究（AREDS）的数据，这些团队分别收到了 AREDS 研究人员准备的数据，以及支持基因分型使用的研究人员报告的研究结果的数据。
感兴趣的人群是患有比 1 类更严重的 AMD 且有基因分型数据的 AREDS 参与者。两组数据在测量方面存在不完全重叠：最大的共同数据集涉及 879 名参与者，两组均对这些参与者的 CFH 和 ARMS2 单核苷酸多态性进行了测量。
每个团队都采取了单独但互补的方法。一个团队专注于相互矛盾的研究之间的数据一致性。第二个团队专注于复制基因型与治疗之间相互作用的关键主张。第三个团队在试图寻找治疗反应的基线预测因素方面采取了空白方案。
进展为晚期 AMD。
我们发现了支持最初基因型-治疗相互作用主张的数据错误。尽管我们发现高风险患者从治疗中获益更多，但在进行多次检验调整后，我们无法复制任何基因型-治疗相互作用。我们在一组独立的数据上测试了一个基因型主张，结果为阴性。即使我们假设相互作用实际上确实存在，我们也没有发现证据支持补充剂会导致某些基因型亚组中晚期 AMD 风险增加的主张。
符合预防 AMD 进展补充剂标准的患者应在不考虑基因型的情况下接受锌和抗氧化剂治疗。
