Diagnostics
metagenomic sequencing market is predicted to hit the $4.3bn mark by the end of the decade, along the way enjoying a remarkable CAGR of 17.6%. All the same, it’d be wrong to imagine mNGS as a panacea. While it can helpfully pinpoint relevant pathogens, doctors can’t ignore a patient’s symptoms and biological signs either. No wonder Jamet notes that after the reads have been analysed by bioinformatics software, clinical microbiologists must still interpret the results – before passing on their findings to clinicians. “In clinical practice,” she stresses, “diagnosing an infection is a real team effort.”
Metagenomic next- generation sequencing has the potential to revolutionise medical diagnostics and uncover new paths in the fight against emerging infectious diseases.
clinical metagenomic next-generation sequencing differs significantly from older forms of pathogen detection. Rather than growing the organism in a lab, a testing sample can instead be taken directly from a patient’s stool or urine. From there, scientists extract the relevant genetic material, in a process called library preparation, before testing it in a sequencing machine. Just a few hours later, millions of sequences (or ‘reads’) are available for analysis, something typically done by specialised bioinformatics software.
“This is important for rare, and novel pathogens with new aetiology.” Dr Jessica Galloway-Peña
700+
The number of samples taken for mNGS analysis by Jamet and her team.
Institut Pasteur $2,250
The average cost of a single mNGS test.
ADLM 10
Certainly, that’s far quicker and simpler than cultivating a sample – but what makes mNGS special is its flexibility. Rather than needing prior knowledge about what to look for, the technology allows researchers to examine all the microbial genomes present in any given sample – both familiar examples and totally new arrivals. As Galloway-Peña says: “This is important for rare, and novel pathogens with new aetiology.” Jamet, for her part, has proof of this in practice. Over three years from 2019, in partnership with colleagues at the Institut Pasteur’s Pathogen Discovery Laboratory, she used mNGS technology to analyse over 700 samples. The first comprehensive study of its kind in France, it involved subjects from various backgrounds. The results were striking. Proving what Jamet calls the “high positivity rate” of tissue analysis, the study underlined the strengths of mNGS’s non-targeted approach – especially among immunocompromised patients suffering otherwise mysterious ailments. The rising popularity of mNGS is clear financially too. As research by CoherentMI found, the global
A needle in a haystack Other limitations of mNGS can’t be solved by collaboration. Some are technological. Though it’s adept at analysing the genetic material present in a sample, for example, that encompasses both pathogens and regular human DNA. “The problem,” Jamet says, “is that the patient’s genetic material can be much more abundant than that of the pathogens, so it can be difficult to find a needle in a haystack.” In a similar vein, mNGS can struggle to detect mycobacteria and fungi, while it also risks missing low-abundance pathogens. Other factors, from how human nucleic acids are extracted to which sequencing reagents are chosen, can potentially distort the results of metagenomics too. As Galloway-Peña adds, different referencing databases can impact outcomes too. Bolstering the technology’s standardisation is therefore a must, as is ensuring platforms are accessible. Though she concedes that sequencing instruments are “widely available” across medical life, Jamet notes that “there are as yet no standardised, user-friendly solutions for adopting mNGS in clinical laboratories lacking local bioinformatics expertise.” Cost is undoubtedly another problem: a single test can cost $2,000–2,500.
Not that the situation is hopeless. For one thing, wider adoption promises to nudge prices down, with resource pooling one obvious tactic. More generally, both Jamet and Galloway-Peña are confident that the scientific foibles of mNGS could soon be ironed out. As the French expert says, the “continuing refinement of bioinformatics techniques and algorithms” may shortly allow researchers to identify fungi alongside viruses and other pathogens. Galloway-Peña seems similarly optimistic, especially when it comes to standardisation. “If,” she says, “we can actually figure out a way to decrease the high variability, and have FDA-approved platforms with use and reporting guidelines,” then she believes mNGS could be an excellent tool to diagnose patients, and identify new threats. Considering how revolutionary metagenomics could soon be, you have to hope she’s right.
Practical Patient Care /
www.practical-patient-care.com
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Shutterstock.com
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