Longitudinal, computer assisted analysis in IPF

描述（由申请人提供）： 特发性肺纤维化（IPF）是最常见的特发性间质性肺炎，其特征是进行性纤维化，导致残疾和死亡增加。 IPF 无法治愈。死亡率是新型治疗药物临床试验中最重要且最容易定义的终点。不幸的是，以死亡率为依据的试验的规模、持续时间和成本都令人望而却步。这一事实促使研究人员积极寻找易于测量的替代终点来预测未来的死亡率。我们证明，用力肺活量 (FVC) 下降 6 个月和 12 个月与随后死亡风险增加相关。不幸的是，生理机能的下降无法正确预测所有患者的死亡率，因为许多患者在出现用力肺活量下降之前就急性死亡，而其他患者尽管肺功能大量丧失，但仍能存活较长时间。这些数据强调需要新的替代终点，可用于有效评估 IPF 患者的治疗药物。高分辨率计算机断层扫描（HRCT）在 IPF 的诊断中发挥着关键作用。 HRCT 特征的基线定性和半定量评分一致地预测长期预后；纵向变化的研究不太一致。使用半定量 HRCT 评分系统的困难包括医师时间、评估者之间的分歧以及影响半定量评分所需的相当大的变化。自适应多特征方法 (AMFM) 是一种基于计算机化纹理的方法，用于表征肺部 HRCT 特征。该应用的总体假设是计算机辅助 AMFM 可以被训练来识别 IPF 的 3D 特征（蜂窝图案、磨砂玻璃不透明度）。此外，与半定量方法相比，AMFM 的定量评分与用力肺活量 (FVC) 和死亡率的纵向变化具有更好的相关性。本研究将利用肺组织研究联盟和 IPF 网络 (IPFnet) 的案例来获取不同的 IPF 患者群体来训练 AMFM。纵向目标将利用 IPFnet 的多中心、随机、双盲安慰剂对照试验，对 IPF 患者单独使用泼尼松硫唑嘌呤 N-乙酰半胱氨酸或 N-乙酰半胱氨酸与安慰剂进行对比（PANTHER 研究）。从 2008 年 3 月开始，PANTHER 将在每个治疗组中招募 130 名患者，并进行为期 60 周的随访。该应用程序将提供一种获取纵向 HRCT 扫描的机制，这不是 PANTHER 方案的一部分。该应用程序将利用 IPFnet 开发包含基线和纵向数据的 HRCT 数据库。通过该奖项，我们将 1) 测试计算机辅助分析是否可以识别和量化 IPF 的 HRCT 特征 2) 比较 HRCT 特征基线和纵向变化的半定量（放射科医生）和定量 (AMFM) 测量的一致性 3) 通过与肺功能、生活质量和死亡率变化的相关性，评估 HRCT 的纵向变化是否可以作为临床试验中的替代终点。相关性声明：特发性肺纤维化是一种病因不明的无法治愈的疾病，其特征是肺实质进行性纤维化，导致残疾增加和最终死亡。研究影响这种疾病的新药物对于了解对生活数量和质量的潜在影响至关重要。不幸的是，以死亡率为依据的试验的规模、持续时间和成本都令人望而却步。本研究将评估计算机辅助分析高分辨率计算机断层扫描纵向变化是否与 IPF 患者的生理、生活质量和生存变化相关。如果属实，高分辨率计算机断层扫描的变化可以作为治疗这种毁灭性疾病的新药研究中的非侵入性替代终点。 （摘要完）

DESCRIPTION (provided by applicant): Idiopathic pulmonary fibrosis (IPF), the most common idiopathic interstitial pneumonia, is characterized by progressive fibrosis leading to increased disability and death. There is no cure for IPF. Mortality is the most important and easily definable endpoint for clinical trials of novel therapeutic agents. Unfortunately the size, duration, and cost of mortality-powered trials are prohibitive. This fact has led investigators to actively pursue identification of easily-measurable surrogate endpoints that predict future mortality. We demonstrated that six and 12 month decline in forced vital capacity (FVC) is associated with an increased risk of subsequent mortality. Unfortunately decline in physiology is unable to correctly predict mortality in all patients as many patients die acutely prior to demonstrating a decline in FVC while others can survive for extended periods of time despite large losses of lung function. These data highlight the need for novel surrogate endpoints that can be used to efficiently evaluate therapeutic agents for patients with IPF. High resolution computed tomography (HRCT) plays a pivotal role in the diagnosis of IPF. Baseline qualitative and semi- quantitative scoring of HRCT features consistently predicts long-term prognosis; longitudinal change has been studied less consistently. Difficulties in utilizing semi-quantitative HRCT scoring systems include physician time, inter-rater disagreement, and the rather large changes required to impact semi-quantitative scores. The Adaptive Multiple Feature Method (AMFM) is a computerized texture-based method for characterizing lung HRCT features. The overall hypothesis of this application is that the computer aided AMFM can be trained to recognize 3D features of IPF (honeycomb pattern, ground glass opacity). Furthermore, quantitative scoring by the AMFM will have better correlation with longitudinal change in forced vital capacity (FVC) & mortality compared to semi-quantitative methodology. This study will utilize cases from the Lung Tissue Research Consortium and the IPF network (IPFnet) to obtain a diverse group of patients with IPF for training the AMFM. Longitudinal aims will utilize the IPFnet's multi-center, randomized, double-blind placebo controlled trial of prednisone + azathioprine + N-acetylcysteine or N-acetylcysteine alone versus placebo in IPF patients (PANTHER study). PANTHER will enroll 130 patients, followed for 60 weeks, into each treatment arm beginning March, 2008. This application will provide a mechanism for obtaining longitudinal HRCT scans which are not part of the PANTHER protocol. This application will take advantage of the IPFnet to develop a HRCT database with baseline and longitudinal data. Through this award we will 1) test if computer aided analysis can recognize and quantify HRCT features of IPF 2) compare the agreement of semi- quantitative (radiologist) and quantitative (AMFM) measures of baseline and longitudinal changes in HRCT features 3) evaluate if longitudinal changes in HRCT can function as surrogate endpoints in clinical trials through correlations with changes in pulmonary function, quality of life, and mortality. Statement of Relevance: Idiopathic pulmonary fibrosis is an incurable disease of unknown etiology characterized by progressive fibrosis of the lung parenchyma leading to increased disability and eventual death. The study of novel agents to impact this disease is critical to access for potential impact on quantity and quality of life. Unfortunately the size, duration, and cost of mortality-powered trials are prohibitive. This study will evaluate if computer aided analysis of longitudinal changes in high resolution computed tomography scans correlates with changes in physiology, quality of life, and survival in patients with IPF. If true, changes in high resolution computed tomography could serve as a non-invasive surrogate endpoint in the study of novel agents to treat this devastating disease. (End of Abstract)