Measuring the corticosteroid responsiveness endophenotype in asthmatic patients
Measuring the corticosteroid responsiveness endophenotype in asthmatic patients
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DOI：
10.1016/j.jaci.2015.03.029
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发表时间：
2015-08-01
影响因子：
14.2
通讯作者：
Weiss, Scott T.
中科院分区：
文献类型：
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作者：
Clemmer, George L.;Wu, Ann Chen;Weiss, Scott T.
背景资料：吸入性皮质类固醇是哮喘最常用的控制性治疗，在6种临床表型中产生治疗反应：肺功能、支气管扩张剂反应、气道反应性、症状、口服类固醇的需求以及急诊就诊和住院的频率。我们假设所有这些表型的治疗反应都是由一个单一的定量皮质类固醇反应性endophenotype.Objective：我们试图开发一种复合表型，结合多种临床表型来测量皮质类固醇反应性，具有高准确性，跨人群的稳定性和对缺失数据的鲁棒性。我们使用主成分分析，以确定一个复合皮质类固醇反应表型，我们在4个复制人群进行了测试。我们评估了复合表型和临床表型使用受试者工作特征曲线（AUC）下的治疗效应面积测量内表型的相对准确性。在研究人群中，复合表型测量的内表型AUC为0.74，显著超过6种单独临床表型的AUC，其范围为0.56（P <0.001）至0.67（P = 0.015）。在4个重复群体中，共有22个临床表型可用，复合表型AUC范围为0.69至0.73，显著超过14个表型的AUC，并没有显着超过任何单一phenotype.Conclusion：复合表型测量的内表型具有更高的准确性，更高的稳定性，更高的鲁棒性，以丢失数据比任何临床表型。这将提供模拟皮质类固醇药理学反应和耐药性的能力，具有更高的准确性和重现性。
Background: Inhaled corticosteroids are the most commonly used controller therapies for asthma, producing treatment responses in 6 clinical phenotypes: lung function, bronchodilator response, airway responsiveness, symptoms, need for oral steroids and frequency of emergency department visits and hospitalizations. We hypothesize that treatment response in all of these phenotypes is modulated by a single quantitative corticosteroid responsiveness endophenotype.Objective: We sought to develop a composite phenotype that combines multiple clinical phenotypes to measure corticosteroid responsiveness with high accuracy, stability across populations, and robustness to missing data.Methods: We used principal component analysis to determine a composite corticosteroid responsiveness phenotype that we tested in 4 replication populations. We evaluated the relative accuracy with which the composite and clinical phenotypes measure the endophenotype using treatment effect area under the receiver operating characteristic curve (AUC).Results: In the study population the composite phenotype measured the endophenotype with an AUC of 0.74, significantly exceeding the AUCs of the 6 individual clinical phenotypes, which ranged from 0.56 (P < .001) to 0.67 (P = .015). In 4 replication populations with a total of 22 clinical phenotypes available, the composite phenotype AUC ranged from 0.69 to 0.73, significantly exceeded the AUCs of 14 phenotypes, and was not significantly exceeded by any single phenotype.Conclusion: The composite phenotype measured the endophenotype with higher accuracy, higher stability across populations, and higher robustness to missing data than any clinical phenotype. This should provide the capability to model corticosteroid pharmacologic response and resistance with increased accuracy and reproducibility.