Fig. 1

Proposed composite reference method (C-RM) for ID-NGS diagnostics. Panel a illustrates a walkthrough of the C-RM. Here, we show in silico target sequence comparison with FDA-ARGOS reference genomes in combination with representative clinical testing to understand the performance of ID-NGS diagnostic tests. Using raw sequence data from the ID-NGS diagnostic test device, in silico comparison of results obtained with the assay in-house database to results when using FDA-ARGOS will evaluate device bioinformatic analysis pipelines and report generation while eliminating the need for additional sample testing with a gold standard comparator (current FDA benchmarks). Overall, we anticipate the use of the C-RM based on assay-specific subsets of clinical samples and/or microbial reference materials (MRMs) for clinical validation in combination with FDA-ARGOS in silico target sequence comparison to generate scientifically valid evidence for understanding the performance of ID NGS diagnostic tests. Panel b lists the required quality control metrics for passing the regulatory-grade reference genome criteria. At a minimum, an FDA-ARGOS regulatory-grade reference genome adheres to six metrics (a–f). Specifically, category f details the minimum data requirements that are further described in (c). In addition, panel d lists the 10 critical metadata that need to be ascribed to a genome to meet the regulatory-grade criteria