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Background: Metagenomic sequencing is frequently claimed to have the potential to revolutionise microbiology through rapid species identification and antimicrobial resistance (AMR) prediction. We assess progress towards this.Methods: We perform a systematic review and meta-analysis of all published literature on culture-independent metagenomic sequencing for pathogen-agnostic infectious disease diagnostics to August 12, 2020. Methodologic bias and applicability were assessed using QUADAS-2. (PROSPERO CRD42020163777)Results: A total of 2023 clinical samples from 13/21 eligible diagnostic test accuracy studies were included in the meta-analysis. Reference standards were culture, molecular testing, clinical decision or a composite measure. Sensitivity and specificity in the most widely investigated sample types were 90%(78-96%) and 86%(45-98%) for blood, 75%(95%CI, 54-89%) and 96%(72-100%) for CSF, and 84%(79-88%) and 67%(38-87%) for orthopaedic samples respectively. We identified limited use of controls, especially negative controls which were used in only 62%(13/21) studies. AMR prediction and comparison to phenotypic results was undertaken in four studies: categorical agreement was 88%(80%-97%), very major and major error rates were 24%(8-40%) and 5%(0-12%) respectively. Better human DNA depletion methods are required: a median 91%(IQR 82-98%)[range 76-98%] of sequences were classified as human. The median(IQR)[range] time from sample to result was 29(24-94)[4-144] hours. The reported consumables cost per sample ranged from $130-$685.Conclusions: There is scope for improving the quality of reporting in clinical metagenomic studies. Although our results are limited by the heterogeneity displayed, our results reflect a promising outlook for clinical metagenomics. Methodological improvements, and convergence around protocols and best practises may improve performance in future.

Original publication




Journal article


Journal of clinical microbiology

Publication Date



Nuffield Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK