Title: The diagnostic utility of inflammatory markers in primary care: a mixed methods study.
Funder: Department of Health and Social Care

Abstract: Background Millions of inflammatory marker tests are performed in the UK annually and rates of testing are rising. It is not known whether it is appropriate to order so many inflammatory markers and what should be done with abnormal results. I have done qualitative interviews with clinicians, many of whom use inflammatory markers as a test of exclusion for patients with non-specific symptoms. They describe a tension between not wanting to miss anything' and, on the other hand, being wary of picking up borderline abnormalities which can lead to a cascade of further tests. These uncertainties stem from the fact that almost all previous studies, which I have reviewed in the BMJ, describe laboratory findings for a given disease, and most are based in secondary care. This fellowship sets out to describe the probability of various diseases given the test results in primary care. Patients' perspectives have also not been explored previously; given that inflammatory markers performed in low probability settings are likely to have high false positive rates this may be particularly concerning if this is associated with significant patient anxiety. Aims: The overall aim is to improve the use of inflammatory markers in primary care. Research questions: Phase 1: What is the predictive value of inflammatory markers in primary care for infections, autoimmune conditions and cancers? Phase 2: What are the benefits and harms of using inflammatory markers as a test of exclusion for patients with non-specific symptoms? Phase 3: Do doctors' and patients' have a shared understanding of blood tests and how could communication be improved? Phase 4: To synthesise results and develop a proposed intervention. Plan of investigation: Phase 1: Prospective cohort study using electronic primary care records in the Clinical Practice Research Datalink (CPRD) I will look at 30,000 patients with a raised inflammatory marker, 10,000 with normal inflammatory markers and 10,000 without. I will measure the subsequent incidence of cancer, infection and autoimmune diseases, to calculate the positive and negative predictive values of a raised inflammatory marker in primary care. Phase 2: Prospective cohort study of patients who have had inflammatory markers performed as a non-specific test of exclusion in Bristol GP practices. I will recruit 420 patients who have had inflammatory marker tests performed as a non-specific test of exclusion. Participants will be invited to fill out a questionnaire after receiving their test results measuring symptoms, self-assessed health and anxiety state. Medical records will be reviewed at one year to determine what follow on tests and new diagnoses were made. I will measure the benefits of testing in terms of yield of new diagnoses versus harms in terms of patient anxiety. Phase 3: Qualitative study exploring communication and shared decision making between doctors and patients.I will undertake in-depth semi-structured interviews with patients who have had recent inflammatory markers and GPs who requested the tests. I will ask doctors and patients why the tests were done, what the results show, and whether the results increased anxiety and/or reassurance. I will explore areas of congruence and dissonance between doctors' and patients' perspectives to explore how much the decision-making is shared, and how communication could be improved. Phase 4: Synthesis and recommendations I will develop an evidence based intervention to improve the appropriateness of inflammatory marker testing in primary care, which could be tested in post-doctoral work.Summary of potential benefits to patients and the NHS Results will help ensure patients get inflammatory marker tests performed when they need them, and help doctors interpret these results and explain them in a way patients can understand.

Lay abstract: BackgroundMany diseases cause inflammation in the body including infections, auto-immune conditions and cancer. Some blood tests, known as inflammatory markers', can detect this inflammation. The inflammation is probably due to illness of some sort, but the tests do not identify the exact cause: it might be as simple as a viral infection, or as serious as cancer. The advantage of these tests is they can help doctors feel more confident that they are not missing anything. The disadvantage is that they can sometimes sound a false alarm, or leave everyone uncertain. If they are abnormal a doctor might need to repeat the test or do further tests to find out what is wrong. This might be worrying for patients. Sometimes doctors never find a cause for the inflammation and the blood tests go back to normal on their own.Millions of inflammatory marker tests are ordered by GPs in England each year and rates of testing are rising. I have done research interviewing doctors and nurses about these tests. They have told me they are not always sure when to use these tests and what to do with the results. I have reviewed previous research but most was done in hospitals and does not provide clear guidance for GPs. AimsMy overall aim is to improve the use of inflammatory markers in primary care. I would like to find out: When should GPs use inflammatory marker tests? How should GPs interpret inflammatory marker test results? How should this information be shared with patients? MethodsI am planning four stages to my research: 1)The first part will help find out how GPs should interpret inflammatory marker test results. I will use an anonymised electronic primary care record database (called the CPRD' www.cprd.com) and look at 30,000 patients with raised inflammatory markers, 10,000 with normal inflammatory markers, and 10,000 with no inflammatory markers. I will measure the number of new cases of cancer, infections and autoimmune diseases in the year following testing. This will help doctors predict the chance of serious disease in patients who have had inflammatory marker blood tests. 2)The second part will help find out when to use these tests, in particular whether they are useful to rule out serious illness in patients with vague symptoms. Patients who have had inflammatory markers done for this reason will be invited to complete a questionnaire measuring symptoms and anxiety levels. Their medical records will then be reviewed after a year to determine what diagnoses were made. I will measure benefits from testing in terms of new diagnoses, and any harms of testing in terms of anxiety. 3)The third part will help GPs discuss inflammatory marker testing with patients. I will do paired interviews with patients who have had recent inflammatory markers, and with GPs who requested the tests. I will ask both doctors and patients why they think the tests were done, what the results show, and whether results caused anxiety or reassurance. I will compare doctors' and patients' perspectives to see whether they match, and explore how much the decision-making is shared. I will ask patients what they want to know about their blood tests and how communication and decision making could be improved. 4)Finally I aim to bring this all together to develop draft guidance, for testing in future work. This will help GPs decide when to test and how to interpret results. For patients this means getting tests done when they need them, and getting results explained in a way they can understand. Patient and public involvement I have used patient-public involvement from several sources when developing this proposal, and have recruited three lay members to sit on the project advisory group. I will contact them at key points throughout the study for advice on lay summaries, patient information leaflets, questionnaires and forms. I will also get their advice to make sure the findings are clearly understandable and available to the public as well as doctors. Dissemination As well as publishing results in academic journals and conferences I will use blogs and social media to reach a wider audience. My research team has strong links to the Department of Health, the National Condition Action Team and several condition charities, who will be offered results in the format most useful to them. I also have close links to the local laboratory, Clinical Commissioning Group, and NIHR CLARHC West allowing me to share my findings with practicing doctors for the benefit of patients and public.

Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: INFLAMMATORY AND IMMUNE SYSTEM