Inverse Mapping of Spatial-Temporal Molecular Heterogeneity from Imaging Phenotype

治疗一些侵袭性癌症和神经系统疾病的一个重大挑战是缺乏对病变组织/器官的时空分子异质性的了解。分子特征和相互作用在组织/器官的不同空间亚单位上显著不同。随着疾病的发展，空间模式也会随着时间的推移而变化。绘制出分子生物标志物的时空模式的能力对于阐明疾病形成、发展和治疗耐药的生物基础是有用的。然而，这种映射具有极大的挑战性，因为它需要通过高侵入性活组织检查对活人的病变组织/器官进行密集采样，这是不可行的。现实中，只能采集几个样本，留下了大量未知的空白区域。另一方面，近年来见证了生物医学成像技术的快速发展，它可以生成各种形式的结构和功能图像。多模式图像可以非侵入性地对整个病变组织/器官进行拍摄；重要的是，它们提供了潜在分子特征的互补表型呈现。这创造了一个前所未有的机会，可以从图像中产生潜在的时空分子特征的反向估计，以填补“空白区域”。一旦实现，这种反向估计将有助于破译疾病组织/器官的复杂生物系统，并以适应时空分子异质性的无与伦比的精度提供新的有效治疗方法。该项目的目标是开发一套新的统计模型，用于从多模式图像表型反向映射/估计分子生物标记物的时空异质性。研究人员提出了一种新的建模框架，该框架集成了数据驱动和生物原理驱动的机制模型，同时融合了全球范围的图像数据和稀疏采样的局部活检测量。这一框架包含了描述疾病的空间异质性和时间动力学的建模方法。此外，为了考虑患者的相似性和特异性，研究人员提出了一个稳健的迁移学习模型，将每个患者的S数据与从其他患者选择性转移的信息进行整合，以避免负迁移。此外，该项目还解决了生物标记物小组的联合建模，以表征时空生物标记物的相互作用。建议的模型将在两个应用中得到验证：胶质母细胞瘤和阿尔茨海默病。该项目有望为揭开这些疾病背后的复杂生物系统提供重要的洞察力，并为新的治疗干预措施奠定基础。此外，提出的建模框架集成了统计模型和生物力学模型，将两个传统上分离的研究领域连接在一起。该研究团队致力于培养具有跨学科技能的下一代统计学家和生物医学研究人员，招募少数族裔和女性学生，并在统计和生物/生物医学界传播研究成果。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

A significant challenge in treating some aggressive cancers and neurological diseases is the lack of understanding regarding the spatial-temporal molecular heterogeneity of the diseased tissue/organ. Molecular characteristics and interaction vary significantly across different spatial sub-units of the tissue/organ. The spatial pattern also changes over time as the disease progresses. The capability of mapping out the spatial-temporal patterns of molecular biomarkers is instrumental for elucidating the biological underpinning of disease formation, progression, and treatment resistance. This mapping, however, is extremely challenging, because it would require dense sampling of the diseased tissue/organ of a living person by highly invasive biopsy, which is infeasible. In reality, only a few samples can be taken, leaving a vast amount of unknown blank regions. On the other hand, recent years have witnessed the rapid advances of biomedical imaging technologies, which create structural and functional images of various modalities. Multimodality images can be taken non-invasively and for the entire diseased tissue/organ; importantly, they provide a complementary phenotypic presentation of underlying molecular characteristics. This creates an unprecedented opportunity to generate inverse-estimates of the underlying spatial-temporal molecular characteristics from the images to fill in the "blank regions." Once achieved, such inverse-estimates would help decipher the complex biological system of the diseased tissue/organ and inform new effective treatments with unparalleled precision adapted to spatial-temporal molecular heterogeneity. The objective of this project is to develop a suite of new statistical models for inverse mapping/estimation of the spatial-temporal heterogeneity of molecular biomarkers from multimodality image phenotype. The investigators propose a novel modeling framework that integrates data-driven and biological-principle-driven mechanistic models, and meanwhile fuses global-scale image data and sparsely-sampled local biopsy measurements. This framework embraces modeling approaches to characterize both spatial heterogeneity and temporal dynamics of the disease. Furthermore, to account for patient similarity and specificity, the investigators propose a robust transfer learning model for integrating each patient?s data with information selectively transferred from other patients to avoid the negative transfer. Also, the project tackles joint modeling of a biomarker panel for characterizing spatial-temporal biomarker interaction. The proposed models will be validated in two applications: glioblastoma and Alzheimer's Disease. This project is expected to generate significant insight for unraveling the complex biological systems underlying these diseases and provide the groundwork for new treatment intervention. Additionally, the proposed modeling framework integrates statistical and bio-mechanistic models, which bridges two traditionally separate research fields together. The research team is committed to educating the next generation statisticians and biomedical researchers with cross-disciplinary skills, recruiting minority and women students, and disseminating research results in both statistical and bio/biomedical communities.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.