Our findings showcase the power of the large, ancestrally diverse TOPMed WGS data set as an imputation reference panel for admixed populations, in terms of both imputation quality and accuracy (especially for rare variants) and subsequent association studies for complex traits. Specifically, we identified two rare variants associated with hematological traits in AA and Hispanic/Latino populations and were able to validate our initial HBB association with WBC in an independent replication sample of sequenced individuals. In our study, we used EAGLE and minimac4 for imputation. We anticipate that the advantages of TOPMed as a reference panel also manifest when using alternative imputation methods. However, making TOPMed available as a reference panel compatible with each imputation method (e.g., corresponding recombination rate information) would be essential. In addition, computing time and memory usage should be taken into consideration as not all existing methods can scale to ~100 million markers in populations containing over thousands of individuals. TOPMed freeze 5b imputation is slightly more computationally intensive than use of the HRC reference panel (and takes nearly eight times longer than 1000G based imputation
