Evaluation of the Ultima Genomics UG 100 sequencer for low-cost, high-sensitivity metagenomic pathogen detection from cerebrospinal fluid

Clinical metagenomic next-generation sequencing (mNGS) is a diagnostic tool allowing near-universal pathogen detection directly from clinical specimens. Despite promising clinical data, broad adoption of mNGS has been hindered by high cost and reduced sensitivity relative to targeted nucleic acid amplification tests (NAATs). Recently, Ultima Genomics introduced the UG 100 NGS platform which advertises 10 billion reads per $2,400 sequencing wafer. By lowering costs and improving sequencing depth, the historical value proposition of mNGS may be improved. This study evaluates the UG 100 sequencer's ability to generate reads for metagenomic pathogen detection from cerebrospinal fluid specimens. Ultima reads demonstrated 93% (26/28) positive agreement with orthogonal test results and 63% (10/16) negative agreement against a syndromic panel for meningitis and encephalitis. Near full-length genomes were recovered for three organisms (human herpesvirus-1 [HSV-1], <i>Streptococcus pneumoniae</i>, and <i>Haemophilus influenzae</i>), with the ability to detect putative antimicrobial resistance genes for <i>H. influenzae</i>. Recovery of <i>Borrelia burgdorferi</i> reads (6.1 reads per million [RPM] and 9.03 RPM) was achieved from clinical samples with late cycle threshold values (39.7 and 43.0, respectively). Limit of detection (LoD) studies demonstrated detection of HSV-1 and <i>S. pneumoniae</i> reads at concentrations of 50 genomes/mL each, which is below the reported LoD for the orthogonal NAATs used in this study. Reducing sequencing costs and improving the analytical sensitivity remove two major hurdles for mNGS adoption by clinical laboratories. While these results are preliminary, they demonstrate a future in which mNGS may be more widely implemented.IMPORTANCEClinical metagenomic next-generation sequencing has struggled to gain wider adoption for nearly a decade, due in part to its high cost and reduced performance versus targeted molecular assays. This study demonstrates the ability of the UG100 sequencing platform to reduce per-base metagenomic sequencing costs while producing reads that maintain high positive agreement with existing molecular assays. Further improvements to cost and analytical performance may shift clinical metagenomics from an expensive test of last resort to a front-line diagnostic for identifying infections.