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Principal Investigator  
Principal Investigator's Name: Feixiong Cheng
Institution: Cleveland Clinic
Department: Genomic Medicine
Proposed Analysis: We propose to develop capable and intelligent computer-based toolboxes that enable searching, sharing, visualizing, querying, and analyzing genetics, genomics, multi-omics, and clinical data for Alzheimer's disease (AD). The central unifying hypothesis of this project (1U01AG073323-01 [pending for Council meeting at May/2021) is that a genome-wide, multimodal artificial intelligence (AI) framework to identify novel risk genes and networks from human WGS/WES and multi-omics findings will offer drug targets for targeted therapeutic development in AD. Aim 1 will identify rare coding variant-based risk genes using a sequence and structure-based deep learning model. Aim 2 will identify rare non-coding variant-based risk genes using a multiple kernel learning approach. Aim 3 will test whether GWAS common variants linked to AD pathobiology and endophenotypes are enriched in gene regulatory networks in a cell-type specific manner using a Bayesian framework. These analyses will leverage variants from ethnically diverse WGS/WES and clinical data (i.e., imaging, biomarkers, and cognitive measures) from Alzheimer's Disease Sequencing Project (ADSP, approval DAR ID: 10373), deep phenotyping data (including imaging data) from Alzheimer's Disease Neuroimaging Initiative (ADNI), and publicly available chromatin interactomic data from NIH RoadMap, FANTOM5, and NIH 4D Nucleome. We will validate our findings using WGS/WES data and protein expression data from our existing cohorts: The Cleveland Clinic Lou Ruvo Center for Brain Health Aging and Neurodegenerative Disease Biobank (CBH-Biobank) and the Cleveland Alzheimer's Disease Research Center (CADRC). We will compile information for clinical data harmonization, including functional imaging, AD biomarkers, and cognitive measures for all integrative analyses.
Additional Investigators  
Investigator's Name: Yadi Zhou
Proposed Analysis: Dr. Zhou is a senior data scientist at Dr. Feixiong Cheng's lab who will manage all data and perform bioinformatics and multi-omics data analysis.