Novel Quantitative Emphysema Subtypes in MESA and SPIROMICS

慢性阻塞性肺疾病(COPD)和肺气肿并列第四大死因 在美国和全球。几十年的研究还没有发现除A1以外的治疗疾病的方法 抗胰蛋白酶缺乏症是一种通过改进表型发现的罕见疾病，其特征是一种特殊的肺气肿。 亚型，由SERPINA1基因变异引起。这一更新建立在成功发现六个 新的定量肺气肿亚型(QE)，它们独立地与更严重的症状相关， 功能受损和死亡率增加，此外还有几个全基因组范围的显著基因关联 变种。在续订中，我们建议利用在5-7年内通过以下方式获得的27,000多个CT 4,500名高度表型和基因分型的参与者，以测试是否在新的状态下进行深度和非监督学习 最先进的CT和CT血管成像将揭示更多的深入学习和分子QE，提示 治疗的机械化途径。此外，我们将收集60个移植的肺，并使用最先进的 MicroCT检查QES是否具有清晰的组织学和结构。最后，我们将招募100名接受治疗的患者 肺癌CT筛查QES能否移植到临床低剂量肺癌筛查CT 在当代扫描仪上获取的扫描。成功完成这些目标将发现新的深层次量化宽松 和分子QES，并验证和翻译QES以进一步亚型肺气肿和促进检测 个性化的分子疗法，并有望复制A1-抗胰蛋白酶缺乏症治疗的成功 更常见的肺气肿亚型。

Chronic obstructive pulmonary disease (COPD) and emphysema, jointly, are the fourth leading cause of death in the US and globally. Decades of research have not found disease-modifying therapies except for a1 antitrypsin deficiency, a rare disease found by improved phenotyping, characterized by a specific emphysema subtype and caused by gene variants in SERPINA1. This renewal builds on the successful discovery of six new quantitative emphysema subtypes (QES), which were associated independently with greater symptoms, impaired function and increased mortality in addition to several genome-wide significant associations for gene variants. In the renewal, we propose to leverage over 27,000 CTs acquired over 5-7 years of follow-up from 4,500 highly phenotyped and genotyped participants to test if deep and unsupervised learning on new state-of- the-art CTs and CT angiograms will reveal additional deep-learned and molecular QES that suggest mechanistic pathways to treatment. Further, we will collect 60 explanted lungs and use state-of-the art microCT to test if QES have distinct histology and structure. Finally, we will recruit 100 patients undergoing lung cancer CT screening to test if QES will be translatable to clinical low-dose lung cancer screening CT scans acquired on contemporary scanners. Successful completion of these aims will discover new deep QES and molecular QES and validate and translate QES to further subphenotype emphysema and facilitate testing of personalize molecular therapies and, hopefully, replicate the success of therapy for a1-antitrypsin deficiency for more common emphysema subtypes.