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Evaluating the analytical validity of circulating tumor DNA sequencing assays for precision oncology


Circulating tumor DNA (ctDNA) sequencing is being rapidly adopted in precision oncology, but the accuracy, sensitivity and reproducibility of ctDNA assays is poorly understood. Here we report the findings of a multi-site, cross-platform evaluation of the analytical performance of five industry-leading ctDNA assays. We evaluated each stage of the ctDNA sequencing workflow with simulations, synthetic DNA spike-in experiments and proficiency testing on standardized, cell-line-derived reference samples. Above 0.5% variant allele frequency, ctDNA mutations were detected with high sensitivity, precision and reproducibility by all five assays, whereas, below this limit, detection became unreliable and varied widely between assays, especially when input material was limited. Missed mutations (false negatives) were more common than erroneous candidates (false positives), indicating that the reliable sampling of rare ctDNA fragments is the key challenge for ctDNA assays. This comprehensive evaluation of the analytical performance of ctDNA assays serves to inform best practice guidelines and provides a resource for precision oncology.

Type Journal
ISBN 1546-1696 (Electronic) 1087-0156 (Linking)
Authors Deveson, I. W.; Gong, B.; Lai, K.; LoCoco, J. S.; Richmond, T. A.; Schageman, J.; Zhang, Z.; Novoradovskaya, N.; Willey, J. C.; Jones, W.; Kusko, R.; Chen, G.; Madala, B. S.; Blackburn, J.; Stevanovski, I.; Bhandari, A.; Close, D.; Conroy, J.; Hubank, M.; Marella, N.; Mieczkowski, P. A.; Qiu, F.; Sebra, R.; Stetson, D.; Sun, L.; Szankasi, P.; Tan, H.; Tang, L. Y.; Arib, H.; Best, H.; Burgher, B.; Bushel, P. R.; Casey, F.; Cawley, S.; Chang, C. J.; Choi, J.; Dinis, J.; Duncan, D.; Eterovic, A. K.; Feng, L.; Ghosal, A.; Giorda, K.; Glenn, S.; Happe, S.; Haseley, N.; Horvath, K.; Hung, L. Y.; Jarosz, M.; Kushwaha, G.; Li, D.; Li, Q. Z.; Li, Z.; Liu, L. C.; Liu, Z.; Ma, C.; Mason, C. E.; Megherbi, D. B.; Morrison, T.; Pabon-Pena, C.; Pirooznia, M.; Proszek, P. Z.; Raymond, A.; Rindler, P.; Ringler, R.; Scherer, A.; Shaknovich, R.; Shi, T.; Smith, M.; Song, P.; Strahl, M.; Thodima, V. J.; Tom, N.; Verma, S.; Wang, J.; Wu, L.; Xiao, W.; Xu, C.; Yang, M.; Zhang, G.; Zhang, S.; Zhang, Y.; Shi, L.; Tong, W.; Johann, D. J., Jr.; Mercer, T. R.; Xu, J.; Group, Seqc Oncopanel Sequencing Working
Responsible Garvan Author Dr Ira Deveson
Published Date 2021-09-30
Published Volume 39
Published Issue 9
Published Pages 1115-1128
Status Published in-print
DOI 10.1038/s41587-021-00857-z
URL link to publisher's version