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Principal Investigator  
Principal Investigator's Name: Corinne Engelman
Institution: University of Wisconsin-Madison
Department: Population Health Sciences
Country:
Proposed Analysis: We will leverage sequencing and array genotyping data from the Discovery, Discovery Extension, and, when available, the Augmentation and Follow Up phases of the ADSP, including ADNI (our study is contributing 1,531 samples to the Follow Up phase). We will generate a common variant polygenic score (PGS) by calculating a weighted sum of 39 variants previously associated with AD and use their effect sizes from a large meta-analysis as the weights (de Rojas et al., 2020; Kunkle et al., 2019; Lambert et al., 2013). To generate a PGS comprised of all frequencies, we will add rare and low frequency variants associated with AD, weighted by their effect sizes, to the common variant polygenic score. The effect sizes for these variants will come from the individual studies that identified their association with AD or, if sample size allows, from a subset of the ADSP samples that will then be held out from downstream analyses. Prediction of AD case-control status for both the common variant and full frequency PGS will be characterized with an empirical receiver operating characteristic (ROC) curve, which summarizes the sensitivity in relationship to the specificity of a PGS at multiple thresholds that separate AD cases and controls. Discovery and Discovery Extension phase samples will be separately analyzed because the case and control definitions were different for the two phases (Crane et al., 2017) and because the two phases have different genetic data available. The statistical software R will be used to perform regression analyses and to evaluate the AUC.
Additional Investigators  
Investigator's Name: Eva Vasiljevic
Proposed Analysis: Eva will be doing the bulk of the analyses already described.
Investigator's Name: Yuetiva Robles
Proposed Analysis: Yuetiva will assist with the analyses already described.
Investigator's Name: Diandra Denier Fields
Proposed Analysis: Diandra will assist with the analyses already described.
Investigator's Name: Qiongshi Lu
Proposed Analysis: Qiongshi will advise Eva on the analyses already described.
Investigator's Name: Yuexuan Xu
Proposed Analysis: Yuexuan will perform the newly proposed APOE * polygenic risk score interaction analyses.