Science unlocked: publication picks from October 2025

In this monthly series, we share a selection of recent publications in which Oxford Nanopore sequencing was used to unlock novel insights. Spanning somatic variant discovery, microbial metagenomics, and paediatric cancer profiling, these studies showcase the advances in scientific research made possible by Oxford Nanopore sequencing.

Featured in this edition:

1. Identify severe respiratory infections in just one day
2. Fast-track respiratory infection detection in children
3. Classify paediatric cancers with one assay
4. Pinpoint somatic small variants with confidence
5. From many assays to one: simplify clinical genetics workflows
6. Is the diagnostic odyssey within reach?

Infectious disease

1. Rapid pan-microbial metagenomics for pathogen detection and personalised therapy in the intensive care unit: a single-centre prospective observational study (Lancet Microbe)

Severe respiratory infections in patients in intensive care units are often difficult to diagnose quickly because current clinical tests rely on slow culture methods, delaying effective treatment plans. Here, researchers investigated the use of metagenomics to detect pathogens from research samples without the need for culturing. Using Oxford Nanopore sequencing, they identified bacteria, fungi, and viruses from respiratory samples in a single assay, delivering results within 24 hours. This approach detected pathogens that were missed by standard methods and demonstrates the future potential of metagenomic nanopore sequencing to guide antimicrobial therapy and enhance public health surveillance.

Key points:

• Preliminary results were delivered within two hours and final reports within 24 hours for 94% of samples, showing it could potentially be integrated into real-time critical care decisions
• Across 107 research samples, metagenomic sequencing identified 42 additional pathogens missed by standard tests in 32 samples, including clinically significant organisms, such as Mycobacterium tuberculosis, HIV-1, and Group A Streptococcus
• The results suggested changes to antimicrobial therapy in 28% of cases and immunomodulation therapy in 20% of samples
• These findings highlight the potential for Oxford Nanopore-based respiratory metagenomic sequencing to deliver personalised therapy and population-level surveillance

Figure 1. The additional pathogens detected by metagenomic sequencing compared with routine testing. Figure redistributed from Alcolea-Medina and Snell et al.¹ under the Creative Commons Attribution License CC by 4.0.

Download the workflow overview for metagenomic sequencing.

2. Implementing rapid pan-microbial metagenomics in paediatric intensive care (medRxiv)

Lower respiratory tract infections cause an estimated 502,000 deaths in children under five globally, but current routine testing is time-consuming and suffers from culture bias. Replicating the method used by Alcolea-Medina and Snell et al.¹, researchers successfully adapted the method for research samples from paediatric patients. Within 24 hours, causative pathogens were identified with a high specificity of >99%, alongside an additional 50 pathogens previously missed by standard methods. This study demonstrates that this metagenomic Oxford Nanopore sequencing is replicable and has the potential to provide faster and more comprehensive results than current methods. Furthermore, it has the potential to positively impact patient outcomes and improve antimicrobial stewardship.

Key points:

• Adapted a rapid pan-microbial respiratory metagenomic sequencing protocol, previously validated on adults, to a paediatric population
• In 174 research samples from 122 patients, after 16 hours, sensitivity reached 89% for bacteria, 100% for fungi, and 87% for viruses, with specificities ≥99% across all organism kingdoms
• Metagenomic sequencing detected 50 additional pathogens missed by standard clinical methods, which were all confirmed by PCR, and showed clinical impact for 29% of cases
• This observational prospective study is the first to show adaptation of a same-day metagenomic sequencing protocol to detect bacteria, fungi, and DNA and RNA viruses in a paediatric population

Watch the Knowledge Exchange about metagenomic sequencing for pathogen surveillance.

Cancer research

3. Single-workflow nanopore whole-genome sequencing with adaptive sampling for accelerated and comprehensive paediatric cancer profiling (medRxiv)

Paediatric cancers feature a broad range of genomic and epigenomic changes, which are difficult and time-consuming to identify because they require multiple genetic tests, delaying crucial treatment decisions. Here, the authors used Oxford Nanopore sequencing to detect all major genomic and epigenomic alterations across the whole genome of research samples, in real time and within a single workflow. In addition, the team used adaptive sampling, a targeted sequencing method, to enrich genomic regions, enabling them to identify key mutations, fusions, and methylation patterns within hours. This study shows the potential of nanopore sequencing with adaptive sampling to streamline future paediatric cancer diagnoses into one rapid and affordable assay.

Key points:

• Targeted 380 genes relevant to paediatric oncology, including 23 specifically covering alterations in acute myeloid leukaemias
• High on-target coverage (~165x) was achieved across 31 research samples, capturing 95% of known fusions, 94% of single nucleotide variants and indels, and nearly all copy number changes with potential clinical relevance
• Potentially clinically actionable results, such as information on fusions and large copy number variations, were identifiable within hours, with most findings emerging in under 24 hours
• The integrated, open-source nf-core-oncoseq pipeline enables real-time data analysis, including methylation profiling.
• Classifiers such as MARLIN and ALMA correctly predicted cancer lineage and subtype using data available after just 10 minutes of sequencing.

Read the case study about MARLIN.

4. Accurate somatic small variant discovery for multiple sequencing technologies with DeepSomatic (Nature Biotechnology)

Cancer is a highly heterogeneous disease, with thousands of somatic variants across different cells, requiring accurate characterisation. Typically, cancer research relies on short-read sequencing, but limitations of this approach include the inability to resolve repetitive or complex regions. With Oxford Nanopore sequencing, any length of DNA can be sequenced and analysed, revealing areas that were previously inaccessible. Here, the authors present DeepSomatic, a somatic small variant caller that combines long- and short-read data to accurately detect somatic small nucleotide variants and indels. They found that this bioinformatic tool outperformed other somatic variant callers, achieving consistently high F1-scores.

Key points:

• DeepSomatic, a deep-learning method, achieved consistently higher F1-scores than existing somatic variant callers such as ClairS and Strelka2
• Researchers developed the open Cancer Standards Long-Read Evaluation (CASTLE) dataset, featuring six matched tumour–normal cell line pairs sequenced with Illumina, PacBio HiFi, and Oxford Nanopore Technologies, providing a new benchmark for somatic variant detection
• The multi-cancer models of DeepSomatic delivered consistently high F1-scores across different sequencing depths, tumour purities, and contamination levels
• The method includes dedicated modes for whole-genome and whole-exome sequencing of tumour-normal, tumour-only, and FFPE samples

Human genetics

5. Nanopore long-read sequencing for the critically ill facilitates ultrarapid diagnostics and urgent clinical decision-making (European Journal of Human Genetics)

Critically ill paediatric patients often have a genetic disorder that requires rapid diagnosis for the best outcomes. Current clinical genetic testing takes several weeks, but critical care decisions must be made within days, meaning patients will not be on optimal treatment from the beginning of their care. Here, researchers investigated the potential clinical utility of Oxford Nanopore sequencing to provide DNA analysis in real time. This method provided results in an average of 5 days for 26 research samples from critically ill patients and revealed the causative variant for 42% of samples. This single-test approach shows huge potential for directly informing urgent care decisions and could lead to immediate treatment changes and improved patient outcomes in the future.

Key points:

• Research samples from 26 critically ill patients, ranging from 3 days to 31.4 years in age, were sequenced using Oxford Nanopore technology alongside the standard clinical genetic testing
• Oxford Nanopore sequencing revealed causative variants in 42% of research samples in a single workflow, compared with 46% using standard clinical genetic testing, which requires multiple assays
• From sample receipt to result, the average turnaround time was 5.3 days for nanopore sequencing and 18.4 days for standard clinical genetic testing
• Oxford Nanopore sequencing also provided DNA methylation analysis in 3/26 cases

Figure 2. A) Overview of this study using research samples from 26 patients, sequencing using Oxford Nanopore ultra-rapid nanopore long-read genome sequencing and standard genomic care methods, before analysis and clinical decision making. B) Sunburst chart summarising the age group breakdown of the patients, the analysis type (single or trio analysis), and the variant classes identified. C) Comparison of the turnaround times for both sequencing methods alongside the overview of the results’ impact on clinical decision making. Figure redistributed from Smits, Ferraro, Drost, Rots, and Verhoeven et al.⁵ under the Creative Commons Attribution License CC by 4.0.

Download the workflow overview for rapid human whole-genome sequencing.

6. Enriching for answers in rare diseases (medRxiv)

Rare diseases affect one in 20 people globally, with many people remaining undiagnosed. For the best outcomes, rapid and accurate diagnosis of genetic variants is required; however, current methods are time-consuming and cannot access the entire genome. Here, the authors performed trio analysis with Oxford Nanopore sequencing and adaptive sampling on one flow cell. Analysing research samples from 13 patients with a rare disease, de novo and inherited variants were accurately detected, and causative variants were identified in 77% of cases. Furthermore, sequencing costs were halved by running three samples across one flow cell. These findings demonstrate a scalable and cost-effective sequencing method for rare disease research, potentially helping patients receive an accurate diagnosis for better care.

Key points:

• The authors developed Trio-barcoded ONT Adaptive Sampling (TBAS), which sequences rare disease trios together on one PromethION Flow Cell
• This method cut sequencing costs by 50% by running trio samples on one flow cell compared with running each sample separately
• All research samples had prior short-read testing, with eight remaining undiagnosed despite comprehensive genomic testing with current clinical methods
• The TBAS method using nanopore sequencing confirmed known variants in five cases and identified new or missed genetic causes in 62% of undiagnosed cases
• The study identified causative variants in 77% of cases, detecting a broad range of variant types, including repeat expansions and methylation changes

Download the getting started guide about targeted sequencing.

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