Abstract
Though whole exome sequencing (WES) is the gold-standard for measuring tumor mutational burden (TMB), the development of gene-targeted panels enables cost-effective TMB estimation. With the growing number of panels in clinical trials, developing a statistical method to effectively evaluate and compare the performance of different panels is necessary. The mainstream method uses R-squared value to measure the correlation between the panel-based TMB and WES-based TMB. However, the performance of a panel is usually overestimated via R-squared value based on the long-tailed TMB distribution of the dataset. Herein, we propose angular distance, a measurement used to compute the extent of the estimated bias. Our extensive in silico analysis indicates that the R-squared value reaches a plateau after the panel size reaches 0.5 Mb, which does not adequately characterize the performance of the panels. In contrast, the angular distance is still sensitive to the changes in panel sizes when the panel size reaches 6 Mb. In particular, R-squared values between the hypermutation-included dataset and the non-hypermutation dataset differ widely across many cancer types, whereas the angular distances are highly consistent. Therefore, the angular distance is more objective and logical than R-squared value for evaluating the accuracy of TMB estimation for gene-targeted panels.
Highlights
Though whole exome sequencing (WES) is the gold-standard for measuring tumor mutational burden (TMB), the development of gene-targeted panels enables cost-effective TMB estimation
By comprehensive comparison of the two measurements, we have demonstrated that angular distance is a more logical and efficient solution
Our simulation has demonstrated that panel size is an important factor that affects the accuracy of TMB estimation[28]
Summary
Though whole exome sequencing (WES) is the gold-standard for measuring tumor mutational burden (TMB), the development of gene-targeted panels enables cost-effective TMB estimation. It is impossible for all patients to use WES to estimate their TMBs due to the high cost of the large genomic space sequenced To this end, the development of gene-targeted panels enables cost-effective TMB estimation for more patients. The generation sequencing (NGS) panel FoundationOne CDx (F1CDx) developed by Foundation Medicine, counting both synonymous mutations and nonsynonymous mutations (not included in dbSNP or COSMIC database) from 324 genes (1.2 Mb), has proven highly consistent with the estimation from WES21–23 Another panel MSK-IMPACT, targeting only nonsynonymous mutations from 468 genes (1.22 Mb), shows a high correlation with the results from W ES24. We used angular distance as opposed to R-squared, which performs a more veritable, objective and logical measurement when evaluating the performance of a panel
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