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We compared HTS with the conventional assays using the same sample preparation of CHO cell harvest spiked with human respiratory syncytial virus (RSV) and mammalian orthoreovirus (Reo1). The viruses were selected with the expectation that one would produce a positive result in each test. The study results indicated both RSV and Reo1 were detected by HTS and in vitro assays, albeit with inter-assay and intra-lab differences in sensitivity of virus detection, and only Reo1 was detected by the in vivo assays. The results support using HTS to replace the in vivo assays. Additionally, based on capabilities of HTS for non-targeted virus detection, it may supplement or replace the in vitro assays. 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