Glossary · Laboratory techniques
Clinical metagenomics
In one sentence
Clinical metagenomics (mNGS) is the untargeted sequencing of the genetic material in a patient sample to detect bacteria, viruses, fungi or parasites without choosing the pathogen in advance. It complements culture and susceptibility testing rather than replacing them.
Also known as: mNGS · metagenomic next-generation sequencing · clinical metagenomic sequencing · diagnostic metagenomics · metagenómica clínica
What is clinical metagenomics?
It is the diagnostic use of shotgun metagenomics. Instead of ordering one test per suspicion (a culture, a specific PCR, a serology), all the genetic material in the sample is sequenced and analysed to see which organisms appear. Chiu and Miller reviewed the field in Nature Reviews Genetics in 2019, highlighting its value in infections of unknown cause and the challenges of running it in a clinical laboratory: contamination, interpretation, choice of database and prediction of antimicrobial susceptibility.
How it works
- DNA (and, depending on the assay, RNA) is extracted from the sample: blood, cerebrospinal fluid, urine, bronchoalveolar lavage, tissue.
- Human DNA, which dominates, is often depleted to enrich the microbial signal.
- The library is sequenced by NGS, using short reads or nanopore sequencing.
- Bioinformatics classifies the reads, compares them with negative controls and applies thresholds so that only relevant findings are reported.
What the evidence shows
A prospective study in The New England Journal of Medicine (Wilson et al., 2019) enrolled 204 patients with suspected meningitis or encephalitis. Metagenomic sequencing of cerebrospinal fluid identified 13 of the 58 infections diagnosed (22%) that the hospitals’ routine testing had missed, and 8 of those had a likely clinical impact. Equally, mNGS did not pick up every infection found by conventional methods, which is why it is positioned as an additional tool.
Limitations
- Variable sensitivity, driven by microbial load, host DNA and sequencing depth; a negative result does not rule out infection.
- Contamination and flora: in low-biomass samples, reagent or skin DNA can surface in the report.
- DNA is not viability: material from treated or dead organisms can still be detected.
- Resistance: detected antimicrobial resistance genes are not a substitute for susceptibility testing.
Example
An immunocompromised inpatient has a persistent fever and negative blood cultures after starting antibiotics. While the conventional work-up continues, the team also requests a metagenomic blood analysis. The report shows DNA from a fungus that had not been specifically sought, and the clinicians confirm it with further tests before adjusting treatment.
Clinical metagenomics at Xenogene
Xenogene’s AMC panels apply metagenomic nanopore sequencing to different sample types. AMC in Blood looks for bacteria, viruses, fungi, parasites and mycobacteria in venous blood, together with resistance and virulence genes, and is aimed at settings such as sepsis, bacteraemia in immunocompromised patients and fever of unknown origin. The product sheet states that a negative result does not exclude infection, that possible contamination must be considered and that interpretation rests with the clinical team.
Frequently asked questions
Can metagenomic sequencing replace culture?
No. Culture isolates the living organism and allows antimicrobial susceptibility testing, which measures how it actually responds to antibiotics. Metagenomics can find organisms that are hard to grow or that are missed after antibiotics, but it is used alongside culture and interpreted with the clinical picture.
Does mNGS detect antibiotic resistance?
It can detect genes associated with resistance, but carrying a gene does not always mean the organism is resistant, and its absence does not prove susceptibility. In mixed samples it is not always clear which organism a gene belongs to. Phenotypic susceptibility testing remains the reference.
Does a positive mNGS result mean there is an infection?
Not necessarily. The test detects DNA or RNA, which may come from dead organisms, skin or normal flora, or reagent contamination. The clinician decides whether the finding fits the clinical picture and whether it needs confirming with another test.
Related terms
- Shotgun metagenomics
Shotgun metagenomics sequences all the DNA in a sample in an untargeted way, without amplifying a single marker gene. It can identify bacteria, DNA viruses, fungi and parasites, often to species level, and reveal their functional and resistance genes.
- Blood culture
A blood culture incubates a blood sample in bottles of nutrient broth to find out whether live bacteria or fungi are circulating in the bloodstream. If anything grows, it is identified and tested against antibiotics to guide treatment.
- Nanopore sequencing
Nanopore sequencing is a third-generation technique that reads single DNA or RNA molecules as they pass through a nanometre-scale pore, by measuring changes in electrical current. It produces long reads and data in real time.
- Antimicrobial resistance
Antimicrobial resistance (AMR) is the ability of bacteria, viruses, fungi or parasites to stop responding to medicines that used to control them, making infections harder to treat.
- Sepsis
Sepsis is life-threatening organ dysfunction caused by a dysregulated host response to infection (Sepsis-3 definition, 2016). It is a medical emergency that needs immediate treatment.
Educational content for healthcare professionals and the general public. It does not replace assessment by a healthcare professional: ordering and interpreting any test is the responsibility of the requesting clinician.
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