Advancing diagnostics for precision medicine in severe infection
Lead supervisor: Prof. Julian Knight
Co-supervisor: Dr Alexander Mentzer
Commercial partner: Danaher
This project aims to advance precision medicine for severe infections by identifying informative biomarkers that may indicate when the normally protective immune response to infection becomes maladaptive, leading to life-threatening organ dysfunction and the clinical syndrome of sepsis.
The academic supervisors Knight and Mentzer have established deeply phenotyped longitudinal cohorts of patients with severe infection and identified patient subgroups (or endotypes) using white blood cell transcriptomics and plasma proteomics that are informative for immune state, outcome and drug response (refs 1-5). Specifically, they have identified an endotype with features of immunosuppression and bone marrow dysfunction that may be targetable for personalized therapy.
An academic-industry partnership has been established through a Danaher Beacon (https://www.ndm.ox.ac.uk/news/partnership-with-danaher-to-pave-the-way-for-precision-medicine-tests-for-sepsis) to develop a point-of-care diagnostic (POCD) for this immunosuppressed endotype. This will use a multiplex reverse-transcriptase PCR assay for a specific sepsis response signature (SRS) of blood transcribed genes originally identified by the Oxford team.
The proposed project will build on these findings and resources to investigate
(1) clinical use cases for the SRS POCD including implementation in predicting patient trajectories in patients presenting to the emergency department, or acutely deteriorating with hospital-acquired infections, and subsequent actioning on these results
(2) how combinations of other biomarkers (for example clinical, transcriptomic, proteomic, immunological) in sepsis patients, or those at risk of developing sepsis, may be informative for interrogating the response to infection and informing clinical decision-making
(3) identifying pharmacological interventions that could be tested in the sepsis endotypes following POCT identification, laying the foundation for potential future clinical trials
Prospective data collection will be complemented by large in-house datasets available for data mining such as the UK Genomic Advances in Sepsis (GAinS) study. The project will involve big data approaches including artificial intelligence, developing innovative ways to combine molecular phenotyping with data from the electronic health care record and physiological monitoring, and how this can be most effectively translated to patient care.
For the student, the project will provide an outstanding opportunity to gain training in and advance precision medicine, diagnostic and data analytics, aligning with the MRC’s remit and Strategic Delivery Plan. This includes advanced data science methods for data analytics and machine learning using complex high dimensional datasets spanning human health and biology.
The project is highly collaborative, building on strong existing relationships between the proposed supervisors in academia and industry settings, and will help promote innovation and researcher mobility between sectors. The supervisors Knight, Mentzer and Tsalik are clinician scientists with established expertise and track records of research outputs in this field, and Tsalik brings significant industry expertise. The project will accelerate development and application of a POCD for patient benefit, advance understanding of pathophysiology, and provide a paradigm for precision medicine in this field.
1. Mi, et al. Science Translational Medicine 16, eadh0185 (2024).
2. Kwok et al. Nat Immunol 24, 767-779 (2023).
3. Cano-Gamez. Sci Transl Med 14, eabq4433 (2022).
4. Davenport et al. Lancet Respir Med 4, 259-71 (2016).
5. Antcliffe et al. Am J Respir Crit Care Med 199, 980-986 (2019).
Apply using course: DPhil in Clinical Medicine
