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Chunk #4 — Results and discussion

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Use of >100,000 NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium whole genome sequences improves imputation quality and detection of rare variant associations in admixed African and Hispanic/Latino populations.
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Compared with the 1000G Phase 3 reference panel [9], we were able to increase the number of well-imputed variants from ~28 and ~35 million to ~51 and ~58 million in JHS and HCHS/SOL, respectively (see S3 Table for genome-wide distribution of well-imputed variants). We defined well-imputed variants based on our previous work [1, 2, 4], using MAF-specific estimated R2 thresholds to ensure an average R2 ≥ 0.8 in each imputed cohort separately. For all rare variants with MAF < 0.5%, we observed ~4.2X (2.3X) and ~6.1X (3.3X) increases in the number of well-imputed variants in JHS (HCHS/SOL), compared with 1000G and HRC, respectively. We also observed 22% (11%) and 34% (20%) increases in imputation information content (as measured by average true R2, which is the squared Pearson correlation between imputed and true genotypes) (Fig 1 and S1 Fig, Table 1). For very rare variants with MAF <0.05%, we observed ~22.1X (5.8X) and ~11.8X (10.7X) increases in the number of well-imputed variants, with 6% (5%) and 13% (11%) increases in average true R2, in JHS (HCHS/SOL), compared with 1000G and HRC