RATIONALE Lung quantitative computed tomographic (qCT) severe asthma clusters have been reported, but their replication and underlying disease mechanisms are unknown. We identified and replicated qCT clusters of severe asthma in two independent asthma cohorts and determined their association with molecular pathways. METHODS We used consensus clustering on qCT measurements of airway and lung CT scans, performed in 105 severe asthmatic adults from the U-BIOPRED cohort. The same qCT measurements were used to replicate qCT clusters in a subsample of the ATLANTIS asthma cohort (n=97). We performed integrated enrichment analysis using blood, sputum, bronchial biopsies, bronchial brushings and nasal brushings transcriptomics and blood and sputum proteomics to characterize radiomultiomic-associated clusters (RACs). RESULTS qCT clusters and clinical features in U-BIOPRED were replicated in the matched ATLANTIS cohort. In the U-BIOPRED cohort, RAC1 (n=30) was predominantly female with elevated BMI, mild airflow limitation, normal qCT parameters and upregulation of the complement pathway. RAC2 (n=34) subjects had a lower degree of airflow limitation, airway wall thickness and dilatation, with upregulation of proliferative pathways, including neurotrophic receptor tyrosine kinase 2/tyrosine kinase receptor B (NTRK2/TRKB), and down-regulation of semaphorin pathways. RAC3 (n=41) showed increased lung attenuation area and air trapping, severe airflow limitation, hyperinflation, and upregulation of cytokine signaling and signaling by interleukin pathways, and matrix metallopeptidase 1, 2 and 9. CONCLUSIONS U-BIOPRED severe asthma qCT clusters were replicated in a matched independent asthmatic cohort and associated with specific molecular pathways. Radiomultiomics might represent anovel strategy to identify new molecular pathways in asthma pathobiology.

中文翻译：

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放射多组学：与多组学相关的严重哮喘的定量 CT 集群。


基本原理 肺定量计算机断层扫描 （qCT） 严重哮喘集群已有报道，但其复制和潜在疾病机制尚不清楚。我们在两个独立的哮喘队列中识别并复制了严重哮喘的 qCT 集群，并确定了它们与分子途径的关联。方法 我们对来自 U-BIOPRED 队列的 105 名严重哮喘成人进行的气道和肺部 CT 扫描的 qCT 测量使用了共识聚类。相同的 qCT 测量值用于复制 ATLANTIS 哮喘队列 （n=97） 亚样本中的 qCT 集群。我们使用血液、痰液、支气管活检、支气管刷牙和鼻刷转录组学以及血液和痰液蛋白质组学进行了综合富集分析，以表征放射多组学相关集群 （RAC）。结果 U-BIOPRED 中的 qCT 集群和临床特征在匹配的 ATLANTIS 队列中复制。在 U-BIOPRED 队列中，RAC1 （n=30） 以女性为主，BMI 升高，轻度气流受限，qCT 参数正常，补体途径上调。RAC2 （n=34） 受试者气流受限程度、气道壁厚度和扩张程度较低，增殖途径上调，包括神经营养受体酪氨酸激酶 2/酪氨酸激酶受体 B （NTRK2/TRKB），以及信号素途径下调。RAC3 （n=41） 显示肺衰减面积和空气潴留增加、严重的气流受限、过度充气以及细胞因子信号传导和白细胞介素途径以及基质金属肽酶 1、2 和 9 的信号传导上调。结论 U-BIOPRED 严重哮喘 qCT 集群在匹配的独立哮喘队列中复制，并与特定分子通路相关。 放射性多组学可能代表了在哮喘病理生物学中识别新分子途径的新策略。