Novel imaging genetic biomarkers for sporadic frontotemporal dementia through machine learning

项目摘要 这是Iris Broce-Diaz博士的K 01奖申请，他是神经影像遗传学博士后研究员， 加州大学圣地亚哥分校和加州大学弗朗西斯科分校。布鲁斯·迪亚兹医生正在建立 作为一名年轻的影像遗传学家，她对神经退行性疾病进行临床研究。K 01将 为博士提供必要的支持，以实现以下目标：（1）熟练掌握 机器学习和计算建模技术，（2）熟练掌握临床和遗传研究 认知老化和神经退行性疾病的复杂谱的方法学，包括临床 额颞叶痴呆（FTD）和其他阿尔茨海默病相关痴呆的特征， 鉴别诊断、风险预测和生物标志物开发，以及（3）开展独立的研究 事业为了实现这些目标，Broce-Diaz博士组建了一个专家指导团队，包括她的主要 导师：Anders Dale博士（著名的计算神经成像遗传学家）和共同主要导师 布鲁斯米勒（国际公认的行为神经学家和FTD的领导者），共同导师：Dr. Jennifer Yokoyama（FTD遗传学专家）和Chun Chieh Fan（流行病学/生物统计学专家），以及两名 合作者：Adam Boxer博士（FTD谱系障碍临床试验的领导者）和Wesley Thompson （高级统计学专家）。 该项目的目标是开发新的成像遗传学生物标志物，用于预测个体在 发生散发性（非家族性）FTD的风险，并提高散发性FTD的分类准确性。布鲁斯医生- 迪亚兹将通过以下具体目标实现这一目标：（1a）利用多基因危害方法， 并验证一种新的遗传生物标志物，用于预测散发性FTD的年龄特异性风险;（1b）利用多效性 用于提高遗传风险评分的准确性并导出基于生物学的遗传风险评分的信息;（2） 使用机器学习方法对FTD临床亚型进行可靠准确的分类， 从这些脑地图个性化萎缩评分;和（3）通过整合萎缩改善FTD分类 遗传风险评分。这项拟议的研究采用了高度创新的方法， 为FTD预后、诊断和最终临床试验设计提供信息。如果得到验证，这些生物标志物将使 通过协助临床医生识别散发性FTD风险升高的患者， 在早期阶段协助诊断散发性FTD，减少诊断延迟，加速 发现新的治疗方法，并提高临床试验中的招募准确性。K 01研究项目 将为博士提供受保护的研究时间和机会，以培训与领导人在该领域，她 需要掌握建立一个独立的，以病人为导向的，成像遗传学和生物标志物所需的技能 制定临床研究计划，为FTD的诊断、预后和指导治疗提供信息， 其他神经退行性疾病。

Project Summary This is an application for a K01 award for Dr. Iris Broce-Diaz, a neuroimaging genetics postdoctoral fellow at the University of California, San Diego and University of California, San Francisco. Dr. Broce-Diaz is establishing herself as a young imaging geneticist conducting clinical research on neurodegenerative disease. This K01 will provide Dr. Broce-Diaz with the support necessary to accomplish the following goals: (1) gain proficiency in machine learning and computational modeling techniques, (2) gain proficiency in clinical and genetic research methodology for cognitive aging and complex spectrum of neurodegenerative diseases, including clinical characterization of frontotemporal dementia (FTD) and other Alzheimer’s Disease-Related Dementias, differential diagnosis, risk prediction, and biomarker development, and (3) develop an independent research career. To achieve these goals, Dr. Broce-Diaz has assembled an expert mentoring team, including her primary mentors: Dr Anders Dale (renowned computational neuroimaging genetics scientist) and co-primary mentor Bruce Miller (internationally recognized behavioral neurologist and leader in FTD), co-mentors: Drs. Jennifer Yokoyama (expert in FTD genetics) and Chun Chieh Fan (expert in epidemiology/biostatistics), and two collaborators: Drs. Adam Boxer (leader in clinical trials for FTD-spectrum disorders) and Wesley Thompson (expert in advanced statistics). The goal of the proposed project is to develop novel imaging genetics biomarkers for predicting individuals at risk of developing sporadic (non-familial) FTD and improving classification accuracy of sporadic FTD. Dr. Broce- Diaz will achieve this goal through the following specific aims: (1a) utilize a polygenic hazard approach to develop and validate a novel genetic biomarker for predicting age-specific risk of sporadic FTD; (1b) leverage pleiotropic information to increase accuracy of the genetic risk scores and derive biologically-based genetic risk scores; (2) use machine learning approaches to reliably and accurately classify FTD clinical subtypes and obtain personalized atrophy scores from these brain maps; and (3) improve FTD classification by integrating atrophy scores with genetic risk scores. This proposed study uses highly innovative methodological approaches for informing FTD prognosis, diagnosis, and, ultimately, clinical trial design. If validated, these biomarkers will make significant contributions by assisting clinicians in identifying patients at elevated risk for sporadic FTD and assisting in diagnosing sporadic FTD in its earliest stages—reducing diagnostic delays, accelerating the discovery of novel treatments, and improving recruitment accuracy in clinical trials. This K01 research project will provide Dr. Broce-Diaz with the protected research time and opportunity to train with leaders in the field she needs to master the skills required to establish an independent, patient-oriented, imaging genetics and biomarker development clinical research program that will inform diagnosis, prognosis, and guide treatments of FTD and other neurodegenerative diseases.