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Metagenomic sequencing is frequently claimed to have the potential to revolutionize microbiology through rapid species identification and antimicrobial resistance (AMR) prediction. We assess the progress toward these developments. We perform a systematic review and meta-analysis of all published literature on culture-independent metagenomic sequencing for pathogen-agnostic infectious disease diagnostics up to 12 August 2020. Methodologic bias and applicability were assessed using the tool Quadas-2. (Prospero CRD42020163777). A total of 2,023 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% (95% confidence interval [CI], 78% to 96%) and 86% (45% to 98%) for blood, 75% (54% to 89%) and 96% (72% to 100%) for cerebrospinal fluid (CSF), and 84% (79% to 88%) and 67% (38% to 87%) for orthopedic samples, respectively. We identified a limited use of controls, especially negative controls which were used in only 62% (13/21) of studies. AMR prediction and comparison to phenotypic results were undertaken in four studies; categorical agreement was 88%(80% to 97%), and very major and major error rates were 24% (8% to 40%) and 5% (0% to 12%), respectively. Better human DNA depletion methods are required; a median 91% (interquartile range [IQR], 82% to 98%; range, 76% to 98%) of sequences was classified as human. The median (IQR; range) time from sample to result was 29 hours (24 to 94; 4 to 144 hours). The reported consumable cost per sample ranged from $130 to $685. 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 practices may improve performance in the future.

Original publication

DOI

10.1128/jcm.02916-20

Type

Journal article

Journal

Journal of clinical microbiology

Publication Date

18/08/2021

Volume

59

Addresses

Nuffield Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom.

Keywords

Humans, Communicable Diseases, Diagnostic Tests, Routine, Sensitivity and Specificity, Metagenome, Metagenomics