Figure 13. Detectable HLA association and complementarity determining region (CDR)3 probability of generation.
We evaluated 1831 meta-clonotypes from 17 MIRA sets in a cohort of 694 COVID-19 patients for their association with predicted HLA-restricting alleles. Statistical evidence of the HLA association for each meta-clonotype (RADIUS or RADIUS + MOTIF) and the centroid alone (EXACT) is indicated by the associated false discovery rate (FDR; y-axis) in beta-binomial regressions (see Methods for model details). The probability of generation (pgen) of each centroid’s CDR3-β was estimated using the software OLGA (x-axis). Using exact matching, only associations with high probability of generation (pgen) antigen-specific T-cell receptors (TCRs) are likely to be detected reliably. However, using meta-clonotypes, tcrdist3 revealed strong evidence of HLA-restriction for TCRs with both high and low probability of generation. Meta-clonotype radii were engineered using synthesized backgrounds developed for each MIRA set. Each background contained 100,000 Optimized Likelihood estimate of Immunoglobulin Amino acid sequences (OLGA)-generated TCRs and 100,000 TCRs subsampled from umbilical cord blood; OLGA-generated TCRs were sampled to match to the V–J gene frequency in each MIRA receptor set with weighting to account for the sampling bias (see Methods for details).