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进展性纤维化性间质性肺疾病的蛋白质组学生物标志物：一项多中心队列分析
Proteomic biomarkers of progressive fibrosing interstitial lung disease: a multicentre cohort analysis
作者：JWillis S Bowman, et al.
翻译：北京协和医院呼吸与危重症医学科 张东明
文献来源：DOI: 10.1016/S2213-2600(21)00503-8
背景
具有进行性表型的纤维化性间质性肺疾病（PF-ILD）特征表现为肺实质瘢痕形成，其发病率和死亡率高。目前对此表型预测困难，研究者对PF-ILD进行了蛋白质组学分析以确定新的血浆生物标志物，并开发蛋白组学特征来预测这一表型。
方法
使用半定量、靶向蛋白质组学平台测定结缔组织病相关ILD、慢性过敏性肺炎或无法分类ILD（均来自加利福尼亚大学【探索队列】或德克萨斯大学【验证队列】）患者外周血中368种生物标记物的相对血浆浓度。用单因素logistic回归确定与1年ILD进展（指死亡、肺移植或相对用力肺活量【FVC】下降≥10%）相关的个体生物标志物。用机器学习在加利福尼亚大学队列中分析PF-ILD的蛋白质组学特征，并在德克萨斯大学队列中验证。
表1：探索队列和验证队列的基线特征和结果
结果
探索队列中包括385名患者（平均年龄63.6岁，女性占59%），验证队列包括204名患者（平均年龄60.7岁，女性占61%）。在探索队列中，共31个生物标志物与PF-ILD相关，其中17个在验证队列中得到验证。经验证的生物标志物均与PF-ILD相关。通过机器学习获得12个生物标记物组成的蛋白质组特征，并在验证队列中得到验证，其敏感性为0.90，阴性预测值为0.91。这表明约10%具有低风险蛋白质组特征的患者在采血后一年内发生ILD进展。具有低风险蛋白质组特征的患者 FVC 变化为 +85·7 mL（95% CI 6·9 至 164·4），具有高风险特征的患者 FVC 变化为 –227·1 mL（95% CI – 286·7 至 –167·5)。，相比于不考虑纳入患者蛋白质组特征的临床试验，仅纳入具有高风险蛋白质组特征患者的试验所需患者数量理论上可减少80%。
表2：不同ILD亚型中生物标志物与PF-ILD的关系
图1：高风险和低风险蛋白组学特征患者的1年FVC变化的纵向图
A-衍生队列 B-验证队列 C-组合队列 D-寻常型间质性肺炎E-非特异性间质性肺炎F-其他高分辨CT模式
意义
该研究确定了17种与PF-ILD相关的血浆生物标志物，在各ILD亚型之间具有一致性。PF-ILD的蛋白质组学特征可以丰富临床试验队列，并有助于避免在PF-ILD临床试验入组定义PF-ILD时对入组前ILD进展这一条件的需求。
参考文献
Summary
Background Progressive fibrosing interstitial lung disease (ILD) is characterised by parenchymal scar formation, leading to high morbidity and mortality. The ability to predict this phenotype remains elusive. We conducted a proteomic analysis to identify novel plasma biomarkers of progressive fibrosing ILD and developed a proteomic signature to predict this phenotype.
Methods Relative plasma concentrations for 368 biomarkers were determined with use of a semi-quantitative, targeted proteomic platform in patients with connective tissue disease-associated ILD, chronic hypersensitivity pneumonitis, or unclassifiable ILD who provided research blood draws at the University of California (discovery cohort) and the University of Texas (validation cohort). Univariable logistic regression was used to identify individual biomarkers associated with 1-year ILD progression, defined as death, lung transplant, or 10% or greater relative forced vital capacity (FVC) decline. A proteomic signature of progressive fibrosing ILD was then derived with use of machine learning in the University of California cohort and validated in the University of Texas cohort.
Findings The discovery cohort comprised 385 patients (mean age 63.6 years, 59% female) and the validation cohort comprised 204 patients (mean age 60.7 years, 61% female). 31 biomarkers were associated with progressive fibrosing ILD in the discovery cohort, with 17 maintaining an association in the validation cohort. Validated biomarkers showed a consistent association with progressive fibrosing ILD irrespective of ILD clinical diagnosis. A proteomic signature comprising 12 biomarkers was derived by machine learning and validated in the University of Texas cohort, in which it had a sensitivity of 0.90 and corresponding negative predictive value of 0.91, suggesting that approximately 10% of patients with a low-risk proteomic signature would experience ILD progression in the year after blood draw. Those with a low-risk proteomic signature experienced an FVC change of +85.7 mL (95% CI 6.9 to 164.4) and those with a high-risk signature experienced an FVC change of –227.1 mL (–286.7 to –167.5). A theoretical clinical trial restricted to patients with a high-risk proteomic signature would require 80% fewer patients than one designed without regard to proteomic signature.
Interpretation 17 plasma biomarkers of progressive fibrosing ILD were identified and showed consistent associations across ILD subtypes. A proteomic signature of progressive fibrosing ILD could enrich clinical trial cohorts and avoid the need for antecedent progression when defining progressive fibrosing ILD for clinical trial enrolment.
译者
张东明
内科学博士；北京协和医院呼吸内科2021级博士研究生，师从王孟昭教授，所在课题组主要从事肺部肿瘤的临床和基础研究。
审核
王平
医学博士 主治医师；主要从事间质性肺疾病、肺部疑难罕见病、肺部特殊感染的诊疗及研究。UCSF呼吸内科间质性肺疾病中心国家公派访问学者。中国老年医学学会呼吸分会青年委员，北京中西医结合学会呼吸分会委员。主持北京自然科学基金项目1项，参加国家自然科学基金多项和国家重点研发计划1项，参加多项肺纤维化新药研究，以第一作者在国内外核心期刊发表论文多篇。
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原链接戳：进展性纤维化性间质性肺疾病的蛋白质组学生物标志物：一项多中心队列分析 | 引经据典[109] · 协和呼吸