Novel Quantitative Emphysema Subtypes in MESA and SPIROMICS

MESA 和 SPIROMICS 中新的定量肺气肿亚型

• 批准号: 10225220
• 负责人: R Graham BARR
• 金额: $ 80.63万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10225220
• 关键词: Algorithms; Angiography; Apical; Bayesian learning; Biological; Blood Vessels; Cause of Death; Characteristics; Chronic Obstructive Airway Disease; Clinic; Clinical; Computed Tomography Scanners; Data; Diffuse; Disease; Dose; Endothelium; Fibrosis; Funding; Genetic; Genotype; Histologic; Histology; Image; Impairment; Learning; Lung; Machine Learning; Malignant neoplasm of lung; Molecular; Molecular Target; Morbidity - disease rate; Participant; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Phenotype; Physiology; Pulmonary Emphysema; Pulmonary Fibrosis; Rare Diseases; Reproducibility; Research; Scanning; Smoker; Smoking; Structure; Symptoms; Techniques; Testing; Text; Translating; X-Ray Computed Tomography; c new; clinical care; clinical practice; computed tomography screening; contrast enhanced; deep learning; disorder control; follow-up; genetic variant; genome sequencing; genome wide association study; genome-wide; improved; innovation; lung cancer screening; microCT; mortality; novel; population based; recruit; success; symptomatology; unsupervised learning; whole genome

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.

慢性阻塞性肺病（COPD）和肺气肿是第四大死因 在美国和全球。数十年的研究尚未发现除 a1 以外的缓解疾病的疗法 抗胰蛋白酶缺乏症，一种通过改善表型发现的罕见疾病，其特征是特定的肺气肿 亚型并由 SERPINA1 基因变异引起。此次更新建立在成功发现六个 新的定量肺气肿亚型（QES），与更严重的症状独立相关， 除了几个基因组范围内的显着关联外，功能受损和死亡率增加 变种。在更新中，我们建议利用 5-7 年随访中获得的 27,000 多个 CT 4,500 名高度表型和基因型的参与者来测试深度和无监督学习是否能适应新的状态 最先进的 CT 和 CT 血管造影将揭示额外的深度学习和分子 QES，表明 治疗的机械途径。此外，我们将收集 60 个摘除的肺部并使用最先进的技术 microCT 测试 QES 是否具有独特的组织学和结构。最后，我们将招募100名接受治疗的患者 肺癌 CT 筛查，以测试 QES 是否可转化为临床低剂量肺癌筛查 CT 在当代扫描仪上获得的扫描。成功完成这些目标将发现新的深度 QES 和分子 QES，并验证和转化 QES 以进一步确定肺气肿亚表型并促进测试 个性化分子疗法，并有望复制α1-抗胰蛋白酶缺乏症治疗的成功 对于更常见的肺气肿亚型。