Title: Diagnosis of OsteoMyelitis: INvestigation Optimisation in Diabetic Foot Ulcers (DOMINO-DFU)
Funder: Department of Health and Social Care

Abstract: Diabetes affects 4.5million UK adults, of whom 25% will develop a diabetic foot ulcer (DFU). DFU treatment costs the NHS 1billion annually. 20% of DFUs will develop osteomyelitis (DFO) by contiguous spread of infection from the ulcer, with detrimental outcomes. Guidelines suggest bone biopsy to aid diagnosis and target antibiotic management, but the proposed route (through-the-wound versus remote biopsy) is discrepant. Current diagnosis is based on clinical features, leading to over-diagnosis in 30% of patients, unnecessary and prolonged antibiotics, associated risk of antimicrobial resistance and health-care associated infections. The aims of this fellowship are to: Describe the current clinical standard for diagnosis of DFO. Quantify the concordance of 'though-the-wound' and 'remote' bone biopsies for microbiology and histology to identify a gold-standard diagnostic test for DFO. Using the gold-standard test, develop and validate a diagnostic prediction model to improve diagnostic and therapeutic yield compared to current clinical standard.Workpackage 1 I will conduct a 3-centre observational prospective cohort of patients presenting with DFUs. All new patients (~4550) will be invited to enter the cohort requiring minimal data collection for most. Amongst these patients will be a subgroup with high-risk features for DFO. Additional data in these patients will be collected in 3 phases: Phase 1 (225 patients; 6 months): To define current clinical standard for diagnosis of DFO, data on diagnostic criteria, antibiotic utilisation, clinical outcomes to 52-weeks and if consenting, quality-of-life and health resource utilisation will be collected. Phase 2 (192 patients; 18 months): To identify gold-standard bone biopsy technique, patients providing second-level consent will have remote and through-the-wound bone trephine biopsies (Workpackage 1b). Outcomes: histology; presence and number of pathogens; estimated concordance and diagnostic yield; complications; clinical outcomes as for Phase 1. Biochemical markers and X-ray will be performed in all patients. Phase 3 (450 patients; 18 months): To develop a diagnostic prediction model for DFO, patients will be investigated using optimal bone biopsy technique, biochemical markers and X-rays. Clinical outcomes are as for Phase 1.Workpackage 2 A national audit of healthcare professionals managing DFO to ensure cohort centre practice as determined in WP1 Phase 1 is reflective of national practice, and to identify information clinicians require of a new diagnostic pathway to maximise NHS adoption. Workpackage 3 Using data from WP1 Phase 2 and 3, a diagnostic prediction model for DFO using clinical, biochemical and X-ray criteria against a gold-standard of optimised bone biopsy will be modelled (642 patients) and validated internally. External validation will use a Dutch dataset. Clinical- and cost-effectiveness will be compared to current practice. I have involved patients in the development of this Fellowship. Five Leeds DFU PPI group members felt this was an important question, and that the proposed design encouraged patient engagement. Two participants will fulfil Fellowship project management roles.The project will be delivered over 60 months. Results will be disseminated in peer review journals, national/international conferences, and will inform national/international guidelines. The Fellowship will inform design of a Phase III cluster-randomised trial comparing the diagnostic model with standard practice.

Lay abstract: Diabetes affects 4.5million adults in the UK, one in four of whom will develop a diabetic foot ulcer (foot wound; DFU). Treating DFUs costs the NHS 1billion per year due to costs of dressings, treating infection, and for some people amputations. One in five people with a DFU will develop infection in the bone underlying the wound (osteomyelitis; DFO). The treatment for this is usually 6 weeks of antibiotics, but in some it needs an operation to remove the infected bone, often with a toe amputation. Guidelines state that we should take a sample of the infected bone to test for bugs, and to look under the microscope for evidence of infection. Whether this should be taken through the wound, or through normal skin near the wound (remote), has not been tested. It is likely that the results are not the same for each of these sampling methods. For this and other reasons, clinicians choose to diagnose DFO based on the clinical appearances of the wound. These may over-diagnose DFO in up to one third of people, meaning unnecessary prolonged course of antibiotics. In this fellowship I will answer 3 questions to try and improve the diagnosis of DFO: What is the current clinical standard for diagnosis of DFO? Which of the 2 bone sampling methods gives the best results for diagnosis of DFO? Can we produce a better way of diagnosing DFO using a combination of wound appearance, blood tests and X-ray?I will do this by setting up a trial that collects data from all new patients with a DFU attending a specialist clinic in 3 hospitals over 3 years. After consent, for most patients (~4550) I would merely collect information from their clinical notes. This will tell me what the risk of developing DFO in low-risk patients is over time. There will be a proportion of patients who have wounds with high-risk features for DFO. In these patients we will obtain extra information in 3 phases: Phase 1 (225 patients, 6 months): Information on: whether clinicians have diagnosed DFO, and if so, how; how much antibiotic was used; was treatment successful? In those that agree, questionnaires on quality of life, healthcare resource use, and out-of-pocket expenses. Phase 2 (192 patients, 18 months): I will ask people to provide extra consent to have bone samples taken, both through-the-wound and remote, so that we can compare what bugs we grow, and what the bone looks like under the microscope. This will determine the 'gold-standard' technique. Their clinical information will give us information about how this relates to treatment outcomes. Phase 3 (450 patients, 18 months): Patients will have 'gold-standard' bone sample technique, blood tests and X-rays. Using bone sample results, I will develop a guide for clinicians on how to best diagnose DFO based on wound appearance, blood test and X-ray results, to reduce overtreatment.I will also perform a national survey of people treating DFO to check that how things are diagnosed in our 3 hospitals is the same as in the rest of the country. I will ask these people what information they need to have from my guide to ensure it is used throughout the NHS. Patients agree that this is an important question to answer. They feel that there isn't anything in how I have designed the study that would stop people participating. Two of these patients will be involved in helping run the project. The results will be published in journals and at presented at conferences. They should also lead to a change in national/international guidelines.

Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: METABOLIC AND ENDOCRINE;INFECTION;SKIN