Future of mNGS Diagnostics: Expert Panel on Barriers
The technology behind metagenomic next-generation sequencing (mNGS) is proven — it detects more pathogens, across more organism classes, than any single conventional method. Yet the future of mNGS in clinical diagnostics hinges on solving non-technical problems: cost, regulation, reporting complexity, and workforce training. In this symposium panel discussion, moderated by Dr. Mengchu Wu, CEO of Micronbrane Medical, four experts from public health labs, academic medical centers, and clinical genomics facilities across the UK, Israel, Turkey, and the United States shared their firsthand experience with mNGS clinical adoption and the practical strategies emerging to overcome implementation barriers.
Key Takeaways
- Pandemic preparedness and novel pathogen detection are immediate high-impact applications for mNGS, but combined microbial identification and antimicrobial resistance (AMR) characterization represents the strongest long-term value proposition over syndromic PCR.
- Multi-loading flow cells with diverse pathogen types (viral, bacterial, mycobacterial) in a single run is an operationally proven strategy for reducing per-sample sequencing cost.
- FDA and European regulatory frameworks remain significant barriers — laboratory-developed test (LDT) classification in the US and ISO accreditation requirements in Europe add friction to every workflow change.
- Clinical interpretation requires multidisciplinary diagnostic boards analogous to tumor boards — but reimbursement for this expertise remains unresolved.
- Education and workforce development are not keeping pace with the technology; pathogen genomics lacks dedicated training curricula for both laboratory scientists and clinicians.
Where mNGS Can Make the Biggest Clinical Impact Today
The panelists identified several immediate use cases where mNGS provides value that existing methods cannot match.
Joanne Watkins (Public Health Wales) pointed to pandemic preparedness and novel pathogen identification as the clearest near-term application. Detecting unknown organisms in undiagnosed patients — before specific assays exist — is something only unbiased sequencing can do. She also predicted that mNGS will eventually replace syndromic PCR for surveillance, particularly when additional data (outbreak linkage, resistance profiling, vaccine strain monitoring) is needed from the same specimen.
Dr. Amos Adler (Israel) emphasized that the strongest added value of mNGS over syndromic testing lies in concurrent AMR gene detection — not just pathogen identification. He cited Helicobacter pylori as an example: an extremely common infection with serious resistance problems where mNGS could simultaneously identify the organism and characterize its resistance profile from a single sample. For rare CNS pathogens, mNGS fills a real but narrow niche; for AMR characterization of common infections, the addressable population is far larger.
Dr. Wayne Wong (Grady Memorial Hospital, Atlanta) identified three practical clinical scenarios: growing organisms that MALDI-TOF cannot identify after repeated attempts, tissue specimens from surgical infections that reference labs reject due to gauze contamination, and streptococcal typing for vaccine coverage assessment — all situations where conventional methods fail or are unavailable.
Cost Reduction Strategies — Beyond Cheaper Reagents
Every panelist identified cost as the primary barrier to wider mNGS adoption. Practical strategies for reducing mNGS costs per sample complement the operational approaches discussed here. The discussion moved beyond hoping for cheaper sequencing chemistry to operational strategies laboratories can implement now.
Multi-Loading Flow Cells Across Pathogen Types
Watkins described the approach at Public Health Wales: pooling COVID, HIV, mycobacteria, AMR, and C. difficile samples onto the same flow cell, balanced by genome size and quantification. This ensures flow cells are never under-loaded, keeping per-sample costs down regardless of individual pathogen volume. The downstream bioinformatics pipeline routes each sample to the appropriate organism-specific analysis automatically.
A panelist from Turkey described a similar approach at Intergen Genetic Disease Center, where human genomics exome sequencing runs (processing 15,000+ patients per year) share sequencing platforms with metagenomics samples, leveraging existing infrastructure and capacity.
Host Depletion as a Cost Control Lever
Dr. Wu noted that host DNA depletion using the Devin filter serves a dual purpose: improving sensitivity and reducing cost. By removing human reads before sequencing, laboratories spend their sequencing capacity on microbial signal rather than wasting it on host background. For sample types with high human DNA content (blood, respiratory specimens, tissue biopsies), effective host depletion can mean the difference between needing an entire flow cell for one sample versus multiplexing it alongside others.
Dr. Adler confirmed this from his clinical experience: tissue biopsies without host depletion consume tens of millions of reads — making them impractical to include in pooled runs. Solving the high-human-DNA sample problem is essential for mNGS to expand beyond CSF and sterile fluids into broader clinical use.
Regulatory Pathways and Standardization Challenges
The regulatory landscape varies dramatically by country. In the US, Dr. Wong described the FDA’s pending framework for next-generation sequencing-based diagnostics as a significant source of uncertainty. Even routine molecular tests face LDT classification challenges when used outside FDA-approved specimen types. In Israel, Dr. Adler noted that LDT regulations are relatively flexible, which enables faster clinical implementation but places greater responsibility on individual institutions for validation and quality control.
In the UK, Watkins described the dual regulatory burden of European in-vitro diagnostic directives and ISO laboratory accreditation. Any process change — even adding a single filtration step — triggers a formal audit cycle. International standardization of bioinformatics pipelines, quality metrics, and reporting formats remains absent, creating risks for both clinical decision-making and global surveillance data comparability.
Multiple panelists noted that erroneous bioinformatic results from insufficiently validated pipelines have already caused problems. During COVID surveillance, inadequately developed wastewater sequencing pipelines at some UK universities reported false variant calls to government authorities — demonstrating that standardization is not an academic concern but an operational safety issue.
Diagnostic Stewardship and Workforce Development
The panel converged on a critical insight: mNGS results cannot simply be released to clinicians like a culture report. Dr. Adler described his institution’s multidisciplinary diagnostic board — comprising clinical microbiologists, infectious disease physicians, neurologists, and ophthalmologists — that selects patients for testing, reviews every result, and makes joint treatment recommendations. He was blunt: “We can’t just report what you get. You review results, you consider — does it make sense, does it correspond with other diagnostic modalities?”
Dr. Wong drew a parallel to tumor boards in oncology but noted a fundamental problem: reimbursement structures in the US do not support professional fees for microbiology board participation, creating a financial barrier to implementing the very interpretive framework that mNGS requires.
Watkins raised workforce development as perhaps the most urgent challenge. Education in pathogen genomics is not part of standard biomedical science or clinical microbiology curricula. Public Health Wales is actively developing training modules with Portsmouth University, creating laboratory training videos, and working with government to incorporate genomics into professional education pathways. Clinician training is equally deficient — FRCPath curricula include minimal sequencing content, leaving physicians unprepared to interpret reads-per-million data or RPMR thresholds. The consensus was clear: until reporting is standardized and made “user-friendly” for clinicians, mNGS results require expert mediation through analytical platforms like PaRTI-Seq and institutional review boards.
About the Panelists
- Dr. Mengchu Wu (moderator), CEO, Micronbrane Medical
- Joanne Watkins, Deputy Head, Pathogen Genomics Unit, Public Health Wales
- Dr. Amos Adler, Director of Clinical Microbiology, Tel Aviv, Israel
- Dr. Wayne Wong, Director of Microbiology, Grady Memorial Hospital, Atlanta, USA
- Panelist from Intergen Genetic Disease Center, Turkey (head of R&D, human genomics)
