Novel Quantitative Emphysema Subtypes in MESA and SPIROMICS

MESA 和 SPIROMICS 中新的定量肺气肿亚型

• 批准号: 9927683
• 负责人: R Graham BARR
• 金额: $ 72.59万
• 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 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9927683
• 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.

慢性阻塞性肺疾病（COPD）和肺气肿是第四大死亡原因 在美国和全球。几十年的研究还没有发现除了a1以外的疾病改善疗法 抗胰蛋白酶缺乏症，一种通过改进表型发现的罕见疾病，以特异性肺气肿为特征 亚型和SERPINA 1基因变异引起的。这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， 功能受损和死亡率增加，以及几个基因组范围内的基因相关性， 变体。在更新中，我们建议利用在5-7年随访期间获得的27，000多个CT， 4，500名高度表型和基因型的参与者，以测试深度和无监督学习是否对新的 最先进的CT和CT血管造影将揭示更多的深层学习和分子QES， 治疗的机械途径。此外，我们将收集60个移植的肺， microCT以测试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 现代扫描仪上获得的扫描。成功完成这些目标将发现新的深层QES 和分子QES，并验证和翻译QES，以进一步亚表型肺气肿，并促进测试 个性化的分子治疗，并有希望复制治疗a1-抗胰蛋白酶缺乏症的成功， 更常见的肺气肿亚型。