Wang Shirley V, Kulldorff Martin, Poor Stephen, Rice Dennis S, Banks Angela, Li Ning, Lii Joyce, Gagne Joshua J
Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
Ophthalmology. 2021 Feb;128(2):248-255. doi: 10.1016/j.ophtha.2020.08.004. Epub 2020 Aug 7.
There is an urgent need for treatments that prevent or delay development to advanced age-related macular degeneration (AMD). Drugs already on the market for other conditions could affect progression to neovascular AMD (nAMD). If identified, these drugs could provide insights for drug development targets. The objective of this study was to use a novel data mining method that can simultaneously evaluate thousands of correlated hypotheses, while adjusting for multiple testing, to screen for associations between drugs and delayed progression to nAMD.
We applied a nested case-control study to administrative insurance claims data to identify cases with nAMD and risk-set sampled controls that were 1:4 variable ratio matched on age, gender, and recent healthcare use.
The study population included cases with nAMD and risk set matched controls.
We used a tree-based scanning method to evaluate associations between hierarchical classifications of drugs that patients were exposed to within 6 months, 7 to 24 months, or ever before their index date. The index date was the date of first nAMD diagnosis in cases. Risk-set sampled controls were assigned the same index date as the case to which they were matched. The study was implemented using Medicare data from New Jersey and Pennsylvania, and national data from IBM MarketScan Research Database. We set an a priori threshold for statistical alerting at P ≤ 0.01 and focused on associations with large magnitude (relative risks ≥ 2.0).
Progression to nAMD.
Of approximately 4000 generic drugs and drug classes evaluated, the method detected 19 distinct drug exposures with statistically significant, large relative risks indicating that cases were less frequently exposed than controls. These included (1) drugs with prior evidence for a causal relationship (e.g., megestrol); (2) drugs without prior evidence for a causal relationship, but potentially worth further exploration (e.g., donepezil, epoetin alfa); (3) drugs with alternative biologic explanations for the association (e.g., sevelamer); and (4) drugs that may have resulted in statistical alerts due to their correlation with drugs that alerted for other reasons.
This exploratory drug-screening study identified several potential targets for follow-up studies to further evaluate and determine if they may prevent or delay progression to advanced AMD.
迫切需要能够预防或延缓发展为晚期年龄相关性黄斑变性（AMD）的治疗方法。已上市用于其他病症的药物可能会影响向新生血管性AMD（nAMD）的进展。如果能够识别出这些药物，可为药物开发靶点提供思路。本研究的目的是使用一种新颖的数据挖掘方法，该方法可以在调整多重检验的同时，对数千个相关假设进行同步评估，以筛选药物与延缓进展至nAMD之间的关联。
我们对行政保险理赔数据应用了巢式病例对照研究，以识别nAMD病例以及在年龄、性别和近期医疗使用情况方面按1:4可变比例匹配的风险集抽样对照。
研究人群包括nAMD病例和风险集匹配对照。
我们使用基于树的扫描方法来评估患者在其索引日期前6个月、7至24个月或既往任何时间接触的药物分层分类之间的关联。索引日期为病例首次诊断为nAMD的日期。风险集抽样对照被分配与其匹配病例相同的索引日期。该研究使用来自新泽西州和宾夕法尼亚州的医疗保险数据以及来自IBM MarketScan研究数据库的全国数据实施。我们设定了P≤0.01的统计警示先验阈值，并关注具有较大效应量（相对风险≥2.0）的关联。
进展至nAMD。
在评估的约4000种通用药物和药物类别中，该方法检测到19种不同的药物暴露具有统计学显著的、较大的相对风险，表明病例接触这些药物的频率低于对照。这些包括：（1）先前有因果关系证据的药物（如甲地孕酮）；（2）先前无因果关系证据但可能值得进一步探索的药物（如多奈哌齐、促红细胞生成素）；（3）对该关联有其他生物学解释的药物（如司维拉姆）；（4）可能由于与因其他原因发出警示的药物相关而导致统计警示的药物。
这项探索性药物筛选研究确定了几个潜在靶点，有待后续研究进一步评估并确定它们是否可以预防或延缓进展至晚期AMD。
