Title: Improving pressure ulcer prevention trial design and analysis using multi-state modelling of existing data
Funder: Department of Health and Social Care

Abstract: Background: Pressure ulcers (PUs) are defined as localized injury to the skin and/or underlying tissue usually over a bony prominence, as a result of pressure, or pressure in combination with shear'. PUs are a burden to patients, represent a significant cost burden to the NHS,and are a key quality indicator. PUs are categorised using the International PU Classification System which is a semi-ordered scale based on the clinical appearance of skin. Classification of PUs requires clinical judgement and misclassification can occur through non-specialist staff, particularly for early skin changes. For PU research, investigators assess multiple skin sites at multiple time points, recording whether skin is healthy or not and, the classification if there is pressure damage. During analysis repeated assessments of skin sites are combined for each patient to identify whether they develop at least one PU during study participation so considerable data is not utilised. The current approach requires large sample sizes to answer intervention effectiveness questions and trials are not feasible to deliver. Multi-state models have the potential to address these problems and will be explored throughout this fellowship. Aim: to transform the design and analysis of PU trials by making better use of all data collected during repeated skin assessments. Objectives:Develop a better understanding of PU onset and development through statistical models that make full use of longitudinal assessment of skin site level data.Assess the level of misclassification of PU categoriesInvestigate methods for dealing with missing data within this modelling framework.Explore whether alternative endpoints could be used in order to lead to more efficient phase II and III trials (including reduced sample sizes) of PU interventions.Plan of Investigation: Two Literature reviews: An updated systematic review of published PU prevention trials will be conducted to identify endpoints used to evaluate PU incidence, and corresponding results. A structured literature review will identify the state of the art of multi-state model methodology to develop knowledge of the statistical features. Work Package 1: Datasets available within the Leeds Institute of Clinical trials Research (LICTR), including data which have previously been unused/crudely aggregated, will be analysed using multi-state model methodology. A model will be developed for each skin site to explore factors related to specific sites. Thereafter a model including all skin sites will be developed including patient as a random effect, to capitalise on the natural correlation between skin sites within the same patient. Work Package 2: The extent of misclassification and the effect of this on assessment of treatment effects will be assessed using hidden Markov models within the multi-state model framework. Work Package 3: Methods for dealing with missing data in these models will be explored. These methods will consider a range of assumptions about the missing data. Work Package 4: Sections of the models will be investigated to explore how the models link early skin changes to endpoints for trials of PU interventions. The models will be explored for potential phase III trial outcomes in order to better use the data collected in PU research and subsequently reduce required sample sizes. Summary of potential benefits to patients and the NHS: The key benefit of this research will be its application to future clinical trials of PU prevention interventions, the potential for reducing sample size requirements, informing phase II trial design and increasing the number of interventions which can feasibly be evaluated using robust trials. This will mean patients will benefit from improved care provided by the NHS and other healthcare providers. This methodology will be applicable to other conditions with correlated disease processes (e.g. hand eczema).

Lay abstract: Aim of Research: The aim of this doctoral fellowship is to understand how pressure ulcers develop so that the information provided by patients during research is used in a better way. Objectives of the research in order to achieve this aim are to:Improve understanding of how and why pressure ulcers develop using data collected in previous researchUnderstand how pressure ulcers are assessed by research staff and ward staffExplore how to handle missing information in pressure ulcer researchExplore whether pressure ulcer prevention trials could be more efficient (including using fewer patients)Background: Pressure ulcers (sometimes called bedsores or pressure sores) are areas of damaged skin and tissue. They are usually caused by limited mobility and often occur as a complication of another illness or injury. They are a significant cost to the NHS, can lead to longer hospital stays, confinement to bed, reduced quality of life and, rarely, death. Accurate skin assessments (i.e. looking at someone's skin to see there is any damage) are a vital part of pressure ulcer research. The ways that skin assessments are reported and analysed are also really important. Data that are collected in pressure ulcer studies are often combined in a way that means that important information can be missed. This is because separate skin sites (e.g. the buttocks and heels) and changes in skin condition over time are not explored. There are also problems with staff assessing pressure ulcers incorrectly, this is called misclassification. This means that trials use more severe pressure ulcers as an outcome for pressure ulcer research because misclassification is less likely to happen. However, earlier skin changes are a sign of a pressure ulcer developing. If we are able to take misclassification into account then we could use these earlier skin changes as a way to evaluate pressure ulcer prevention methods. This will mean that we would require fewer patients to take part in pressure ulcer prevention trials. Assessments of skin may also be missed because patients are too poorly or unavailable. However, we do not use this important information in the analysis of pressure ulcer trials at the moment. We also do not consider whether patients are re-admitted to hospital after discharge or transferred to another facility. We would like to tackle all of these problems using sophisticated statistical methods called multi-state models'. These methods estimate how quickly patients move through different stages of pressure ulcer development, and can identify the characteristics that increase or decrease development and recovery of pressure ulcers. Methods: A systematic review of the literature will be conducted to understand how data are currently collected and analysed on pressure ulcer trials. A second literature review will identify the current best methods of analysis using multi-state models and how they have been used in other disease areas. Lots of information is available from previous pressure ulcer research for use throughout this research. These data will be used to apply and develop existing multi-state modelling methods for pressure ulcer data. This will take into account that each patient can have lots of skin sites that are at risk of developing pressure ulcers and that each skin site can go through lots of skin changes before a pressure ulcer develops. The research will also explore how to handle both misclassification and missing data. Finally, the research will use methods developed in the fellowship to identify whether early skin changes can be used as outcomes in pressure ulcer trials. The models will also be used to design and analyse pressure ulcer trials in a better way. Patient and public involvement(PPI): The established Pressure Ulcer Research Service User Network (PURSUN: http://medhealth.leeds.ac.uk/info/2660/pressure_ulcer_research_service_user_network//) initiated and now hosted by the Leeds Institute for Clinical Trials Research, has been involved in the development of this application. Regular(6-monthly) meetings (facilitated by a PPI officer) will be held with PURSUN members, throughout the fellowship, to ensure that patient/service user voices are embedded throughout the research at key milestones. Dissemination: The research will be presented to PURSUN and at clinical and statistical conferences throughout the fellowship and after completion. Publications will be submitted to high impact journals aimed at clinical, statistical and trial methodology audiences. Contribution from PURSUN members will be fully acknowledged. Conclusion: By completing this doctoral fellowship a better understanding of pressure ulcer development will be obtained. The design and analysis of pressure ulcer trials will be improved to ensure that fewer patients are required, costs are reduced and more reliable results for pressure ulcer prevention and treatment strategies become available.

Research activity codes: 2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: SKIN