Leveraging Clinical Data for Phenotyping and Predictive Modelling of Alzheimer’s Disease

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PROJECT SUMMARY/ABSTRACT Alzheimer’s Disease (AD) is a complex and heterogeneous neurodegenerative disorder, with numerous molecular and phenotypic features (e.g., sex) that have been identified as modifiers of disease risk, resilience, and progression. While single-omic (e.g. genomic or transcriptomics) contributions to the variability observed in AD have been studied, there have not been many integrative approaches to holistically understand precise mechanisms that link molecular pathways with clinical manifestations. With the abundance of longitudinal multi- modal clinical data (e.g., UCSF electronic medical records) and the development of integrative knowledge networks that link known relationships across multi-omic modalities (e.g., Scalable Precision Medicine Oriented Knowledge Engine), there is an untapped opportunity to derive further insights into the disease. I hypothesize that by utilizing integrative knowledge network representations on clinical datasets, I can characterize AD heterogeneity and apply predictive modelling to identify potential clinical and molecular features associated with AD risk, subtypes, and sex-specific differences. In Aim 1, I will characterize Alzheimer’s Disease heterogeneity through association analysis and utilization of unsupervised machine learning approaches. In Aim 2, I will develop predictive modelling approaches for identifying clinical and molecular features associated with AD progression. With this approach, I will aim to elucidate potential disease mechanisms underlying heterogeneous clinical manifestations, allowing for improved patient stratification and personalized therapeutic approaches. To pursue this project, I have the support of my sponsor Dr. Marina Sirota, an expert in integrative computational approaches and machine learning methods on clinical and omics data. I will also receive mentorship and support from my collaborators Dr. Sergio Baranzini, an expert in integrative networks and multi-omics integration, Dr. Kate Rankin, an exceptional and leading expert in neurodegeneration characterization, and Dr. Dena Dubal, an exceptional physician-scientist and expert in neurodegeneration sex-differences and resilience. Through this work, I will develop a variety of expertise across integrative computational and multi-disciplinary approaches that will allow for meaningful contributions to improve AD diagnosis and treatment and ultimately strengthen my training as an aspiring physician-scientist.