Statistical Methods For Quantitative Immunohistochemistry Biomarkers

项目摘要 免疫组织化学（IHC）被广泛用于癌症分类和指导患者的临床管理。一 IHC的主要功能是在肿瘤组织的空间分辨背景下检测标志物，包括 癌和基质成分、单个细胞类型和亚细胞区室。定量 免疫荧光（QIF）越来越多地用于蛋白质的IHC定量， 用于特定癌症治疗的生物标志物或靶标。QIF的一个常见应用是基于同步幻灯片的 使用组织微阵列（TMAs）分析某些蛋白质表达，所述组织微阵列（TMAs）结合来自以下的肿瘤组织： 大量患者。这项技术与机器阅读器相结合，可以实现高通量的分子检测。 肿瘤组织分析以及新的预后和预测癌症的快速开发和验证 生物标志物。 我们提案的总体目标是开发一个新的IHC发现的分析框架。 生物标志物，以改善诊断和药物反应预测。新的统计方法将 定制以使用关于细胞水平蛋白质表达水平的丰富且未开发的信息。新型QIF IHC 生物标志物将被优化为基于细胞水平蛋白质分布函数的灵活指标， 表达或对IHC信号的空间定位的影响，这些信号被视为空间点模式的标记， 癌细胞拟议的研究将产生广泛适用的方法，用于开发新的生物标志物， 癌改进的生物标志物将支持合理招募复发风险升高的患者 进入生物标志物驱动的临床试验，有可能对临床研究产生重大的近期影响， 降低癌症死亡率。

PROJECT SUMMARY Immunohistochemistry (IHC) is widely used to classify cancer and guide clinical management of patients. A major power of IHC is the detection of markers in the spatially resolved context of tumor tissue, including cancerous and stromal elements, individual cell types, and subcellular compartments. Quantitative Immunofluorescence (QIF) is used increasingly for IHC quantification of proteins that may serve as prognostic biomarkers or targets for specific cancer therapies. A common application of QIF is simultaneous slide-based analysis of certain protein expression using tissue microarrays (TMAs), which incorporate tumor tissues from large cohorts of patients. This technology combined with machine readers allows for high-throughput molecular profiling of tumor tissues and rapid development and validation of new prognostic and predictive cancer biomarkers. The overall goal of our proposal is to develop an analytical framework of for discovery of new IHC biomarkers to improve prognostication and drug response prediction. The new statistical methods will be tailored to use the rich and untapped information on cell-level protein expression levels. Novel QIF IHC biomarkers will be optimized as flexible indices based either on distribution functions of cell-level protein expressions or on the spatial localization of the IHC signals viewed as marks of the spatial point pattern of cancer cells. The proposed studies will yield broadly applicable methods for development of new biomarkers in cancer. The improved biomarkers would support rational recruitment of patients at elevated risk of recurrence into biomarker-driven clinical trials, with a potential to have major near-term impact on clinical research and reduce mortality from cancer.