Leveraging Medicare Linkages to Identify New Associations: Prescription Drugs and Digestive Cancer Risk

项目总结 近90%的65岁及以上的美国成年人使用处方药；然而，令人惊讶的是，人们对此知之甚少 这些药物的长期健康影响超出了它们所指示的条件。是这样的 不可预见的风险和好处，特别是对癌症等潜伏期较长的疾病，情况并不乐观。 适合于临床试验中的检测，因为此类试验在规模和后续时间方面不够充分 检测药物与癌症之间的联系。多条证据表明，使用普通处方药可能会 影响各种消化系统癌症的发展。然而，以前的研究主要集中在广泛的， 常见的药物类别，而不是个别药物。医疗保险联系的可用性-特点是 非常庞大的不同老年人群体，详细的处方药数据，以及癌症的随访 结果--能够全面扫描个别药物和癌症风险之间的关联。vt.给出 老年人使用处方药的高流行率和这一群体患癌症的风险增加， 对于了解处方药在老龄化人口中的长期影响尤为关键。 我们将利用来自国家癌症研究所监测、流行病学和最终结果计划的数据 (SEER)-Medicare链接数据库，以发现和跟踪处方药之间的新关联 和消化道癌的风险，总体上和特定于五个最常见的消化部位(结直肠， 胰腺、胃、口咽和肝脏)。首先，我们将进行一项全药物协会的研究(‘Drugwas’) 确定处方药与消化系统癌症风险之间的关联，使用自举纠正 进行多次测试。其次，我们将通过评估来评估潜在混杂的影响。 当直接与因相同适应症而服用的药物进行比较时，这种联系是否成立。对于协会 在应用上述步骤后，我们将使用其他数据执行倾向分数校准 来自联邦医疗保险当前受益人调查(MCBS)；这将使我们能够在 说明了混淆的其他来源。 我们建议的混合方法-将无假设的框架与对多个 测试和混淆-将在老年人中识别新的药物信号，并进一步提炼这些信号以 经得起多次检验校正和混杂调整的。这项探索性研究将 提出新的药物-癌症关联的假设，并为资源-癌症的后续行动提供动力 密集设置。此外，我们将提供多阶段方法的原则证明，该方法利用 通过美国国立卫生研究院几十年的投资创建的公开可用的数据集，以识别新的和有意义的癌症 协会；这一方法可用于长期监测药物对健康的影响。

PROJECT SUMMARY Nearly 90% of US adults ages 65 and older use prescription drugs; however, surprisingly little is known about the long-term health effects of these drugs beyond the conditions for which they are indicated. Such unforeseen risks and benefits, particularly for diseases with a long latency period, such as cancer, are not well suited to detection in clinical trials, given that such trials are inadequate in size and duration of follow-up to detect drug-cancer associations. Multiple lines of evidence suggest that use of common prescription drugs may influence the development of various digestive cancers. However, prior studies have largely focused on broad, common classes of drugs, rather than individual drugs. The availability of Medicare linkages—featuring an extremely large diverse population of older adults, detailed prescription drug data, and follow-up for cancer outcomes—enables the comprehensive scan of associations between individual drugs and cancer risk. Given the high prevalence of prescription drug use among older adults and increased risk of cancer in this group, it is especially critical to understand the long-term effects of prescription drugs in aging populations. We will leverage data from the National Cancer Institute Surveillance, Epidemiology, and End Results Program (SEER)-Medicare linked database to discover and follow-up novel associations between prescription drugs and risk of digestive cancer, both overall and specific to the five most common digestive sites (colorectum, pancreas, stomach, oropharynx, and liver). First, we will conduct a Drug-Wide Association Study (‘DrugWAS’) to identify associations between prescription drugs and risk of digestive cancers, using bootstrapping to correct for multiple testing. Second, we will assess the influence of potential confounding by indication by evaluating whether the associations hold when compared directly to drugs taken for the same indication. For associations that remain after applying the steps above, we will perform propensity score calibration using additional data from the Medicare Current Beneficiary Survey (MCBS); this will allow us to estimate associations after accounting for additional sources of confounding. Our proposed hybrid approach—integrating a hypothesis-free framework with careful adjustment for multiple testing and confounding—will identify novel drug signals in older adults and further refine these signals to those that withstand correction for multiple testing and adjustment for confounding. This exploratory study will generate hypotheses of novel drug-cancer associations as well as provide impetus for follow-up in resource- intensive settings. Moreover, we will provide proof of principle for a multi-phased approach that leverages large publicly available datasets created through decades of NIH investment to identify novel and meaningful cancer associations; this approach can be applied in long-term surveillance efforts of drug effects on health.