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确定的终点。不幸的是，死亡率试验的规模、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求确定易于测量的替代终点，以预测未来的死亡率。我们证明了6个月和12个月用力肺活量（FVC）下降与随后死亡风险增加相关。不幸的是，生理学下降无法正确预测所有患者的死亡率，因为许多患者在FVC下降之前急性死亡，而其他患者尽管肺功能大量丧失，但仍能存活较长时间。这些数据突出表明需要新的替代终点，可用于有效评价IPF患者的治疗药物。高分辨率计算机断层扫描（HRCT）在IPF的诊断中起着关键作用。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生时间、评分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）是一种基于纹理的计算机化方法，用于表征肺部HRCT特征。本申请的总体假设是，计算机辅助AMFM可以被训练以识别IPF的3D特征（蜂窝状图案、毛玻璃不透明度）。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。本研究将利用来自肺组织研究联盟和IPF网络（IPFnet）的病例，以获得不同的IPF患者组，用于培训AMFM。纵向目标将利用IPFnet的多中心、随机、双盲安慰剂对照试验，在IPF患者中比较泼尼松+硫唑嘌呤+N-乙酰半胱氨酸或N-乙酰半胱氨酸单药治疗与安慰剂治疗（PANTHER研究）。从2008年3月开始，PANTHER将招募130名患者进入每个治疗组，随访60周。该应用程序将提供一种机制，用于获得纵向HRCT扫描，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）比较半定量分析的一致性，HRCT特征的基线和纵向变化的（放射科医生）和定量（AMFM）测量3）通过与肺功能、生活质量、and mortality.相关性声明：特发性肺纤维化是一种病因不明的不治之症，其特征在于肺实质的进行性纤维化，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获得对生活数量和质量的潜在影响至关重要。不幸的是，死亡率试验的规模、持续时间和成本都令人望而却步。本研究将评价高分辨率计算机断层扫描纵向变化的计算机辅助分析是否与IPF患者的生理学、生活质量和生存期变化相关。如果是真的，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物研究的非侵入性替代终点。(End摘要）

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)