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. 2020 Apr 2;9:e54558. doi: 10.7554/eLife.54558

Figure 1. Schematic of method.

Figure 1.

An overview of the method using the example given in Appendix 1 Supplementary Methods ‘Worked example of the Fraction Shared’. More details can be found in the Materials and methods and Appendix 1 Supplementary Methods. (i) Consider the example of investigating the mechanism underlying the association between HLA-A*02:07 and reduced risk of disease (HAM/TSP) in the context of HTLV-1 infection. (ii) Take the HTLV-I cohort and for each individual calculate their nearness to A*02:07 in ‘CD8 T cell recognition space’ (i.e. calculate TCR.FS). (iii) The graph shows the similarity to A*02:07 (TCR.FS) for each HLA allele in the cohort ranked from most similar on the left to least similar on the right. Individual 1 is homozygous at both their HLA-B and HLA-C loci so they have 4 unique alleles (A*11:01, A*24:02, B*07:02, C*07:02). We calculate the similarity of A*02:07 to each of these HLA alleles, they are marked on the graph as red dots. The most similar allele to A*02:07 in terms of CD8 recognition carried by individual 1 is C*07:02 with a TCR.FS = 0.273. Individual 1 thus has a TCR.FS with A*02:07 of 0.273. (iv) This is repeated for all individuals in the cohort and all 5 metrics and the cohort table completed. The table relates only to nearness to A*02:07 for the HTLV-1 proteome, for another index allele (or another proteome) the process will need to be repeated to complete the table (v) multiple regression is then performed on the cohort. Each metric is included in turn as a predictor variable. To investigate the independence or relative importance of different predictors they should be included in the regression model together (vi) Results of the regression are then interpreted. In this case the index A*02:07 is protective; other HLA class I alleles with similar TCR-HLA:peptide binding to the index allele are also protective that is, TCR.FS is a significant (protective) predictor of outcome; whereas HLA class I alleles with similar iKIR-HLA:peptide and LILRB1-HLA binding show no protective associations. Only three dimensions are sketched; similarity in aKIR and LILRB2 binding-space are also computed (and near alleles were not protective). We conclude that A*02:07-associated protection is most likely to be attributable to its TCR binding properties.

Figure 1—source data 1. Data underlying Figure 1.