Title: Developing a framework for including and utilising pre-analytical and analytical factors within economic evaluations of diagnostic tests.
Funder: Department of Health and Social Care

Abstract: Background: Best practice methods for conducting evaluations of diagnostic tests are still evolving. An issue which has not yet been tackled is how data on pre-analytical and analytical factors- which can have a significant impact on test accuracy- should be incorporated and utilised within economic evaluations to accurately assess cost-effectiveness. Currently these factors are not formally assessed within diagnostic Health Technology Assessments (HTAs) and are routinely ignored in economic evaluations. This could compromise patients' health if inappropriate test adoption decisions are made based on biased or inaccurate results. A test which has been shown to be affected by pre-analytical and analytical factors is faecal calprotectin (FC). FC is recommended by the National Institute of Health and Care Excellence (NICE) as an option to help clinicians diagnose Inflammatory Bowel Disease (IBD): a group of chronic and disabling gastrointestinal disorders that affect over 300,000 people in the UK. There is also currently growing interest in the use of FC to monitor IBD; recent studies indicate that FC monitoring may improve patient health by pre-empting disease relapses, allowing early modification of treatments and avoidance of invasive diagnostic procedures. Before a crucial decision can be made regarding whether or not FC should be funded in this context, a comprehensive economic evaluation, including an assessment of the impact of pre-analytical and analytical factors, is required.Aim: To develop a framework for the incorporation and utilisation of pre-analytical and analytical factors within economic evaluations, and to use that framework to: (a) conduct a re-assessment of FC for IBD diagnosis, to determine the impact of factors on the original results; (b) conduct a de novo economic evaluation of FC for IBD monitoring, to inform future clinical guidance; and (c) identify key test performance goals for FC, to inform optimal testing procedures. Plan of Investigation: This study consists of four phases of analysis. The first two phases will focus on evidence collection, which will inform the subsequent framework development and economic evaluation. In Phase 1 a methodology review will be conducted to identify potential methodology to incorporate pre-analytical and analytical factors within diagnostic economic evaluations. In Phase 2 a mapping exercise will be undertaken to identify the types of pre-analytical and analytical factors that may affect diagnostic tests; subsequently a systematic review will be conducted to assess factors specifically affecting the performance of FC tests. In Phase 3 a framework for how to include and utilise pre-analytical and analytical factors within economic decision models will be developed, within the context of conducting a re-analysis of a recent NICE assessment of FC for IBD diagnosis. In Phase 4 this framework will be used to conduct a de novo economic evaluation of FC tests (including quantitative laboratory-based tests, point-of-care tests, and home-based testing kits) for IBD monitoring, to inform a test-adoption decision and future clinical guidance in this area. Potential benefits to patients and the NHS: This study will have a significant impact on patients and the NHS. Most importantly the de novo economic evaluation of FC for monitoring IBD will directly inform an accurate test adoption decision for FC in this setting, and will contribute to clinical guidance in this area to improve patient healthcare. This analysis will also help to optimise the performance of FC tests (and thereby patient health), by identifying key analytical performance goals which will inform the optimal implementation of FC in practice. Finally, the developed methodology framework will inform future reliable NHS test adoption decisions across other disease areas, by providing a generalizable framework to conduct accurate diagnostic evaluations.

Lay abstract: Diagnostic tests are becoming increasingly important in modern health care. As well as informing initial diagnoses, diagnostic tests can help to determine disease severity, identify patient risks and monitor patients' ongoing condition. A specific Diagnostic Assessment Programme (DAP) was recently established by the UK's healthcare regulatory body- the National Institute of Health and Care Excellence (NICE); the aim of this programme is to promote the adoption of diagnostic technologies into the National Health Service (NHS) that are effective and cost-effective (i.e. represent value for money). Each DAP evaluation consists of a clinical assessment, to determine the impact of tests on patient health, and an economic evaluation (a comparative assessment of health outcomes and costs), to determine test cost-effectiveness. These assessments are vital to ensure that new tests are appropriately adopted into the NHS i.e. that tests are funded when there is sufficient evidence that they provide a meaningful benefit to patients, at a reasonable cost. However, the techniques used to conduct these assessments are still evolving. Much still needs to be done to continue to improve these methods, to ensure that diagnostic assessments provide reliable results. An issue which has not yet been tackled is how data on pre-analytical and analytical factors affecting how well tests perform should be incorporated within economic evaluations. Pre-analytical factors are factors affecting tests which occur up to the point that the test sample (e.g. blood or urine) is analysed: these include patient biological variation (age, sex, weight), environmental factors (temperature and time of day), and technical factors (method of sample collection and storage). Analytical factors are factors that occur during sample analysis, such as how the sample is prepared and measured, and the laboratory environment. All of these factors can have a significant impact on the accuracy of test results, by affecting the concentration of substances within a test sample. Currently, however, the impact of these factors is not formally assessed within diagnostic evaluations. This may compromise patients' health if incorrect test adoption decisions are made based on biased or inaccurate results. A test which has been shown to be affected by pre-analytical and analytical factors is faecal calprotectin (FC). FC measures the concentration of calprotectin (a marker of inflammation) in stool samples, and is recommended by NICE as an option to help doctors diagnose Inflammatory Bowel Disease (IBD). IBD refers to a group of lifelong conditions that involve inflammation of the gut and are characterised by episodes of remission (low inflammation) and relapse (high inflammation). The disease has a huge impact on patients' quality of life, with common symptoms including diarrhoea, severe abdominal pain and chronic fatigue. In recent years the incidence of IBD has been rising rapidly, and currently affects over 300,000 people in the UK. As well as diagnosing IBD, there is now growing interest in the use of FC to monitor patients with IBD. Recent studies indicate that FC monitoring may help to pre-empt episodes of disease relapse, allowing for early treatment modification, avoidance of painful diagnostic procedures, and subsequent improvements in patient long-term outcomes. At the same time there is increasing evidence to suggest that variation in pre-analytical and analytical factors may affect FC results; studies indicate that the accuracy of FC is affected by a range of factors including the timing of stool sampling, individual patients' disease activity, and the temperature and length of sample storage. Before a crucial decision can be made regarding whether or not FC should be funded as a monitoring test for IBD, a comprehensive economic evaluation, including an assessment of the impact of pre-analytical and analytical factors, is required.This study will develop a framework for the incorporation and utilisation of pre-analytical and analytical factors within economic evaluations. The framework will be developed within the context of conducting a re-analysis of the recent NICE assessment of FC for diagnosing IBD, which will be used to explore the impact of pre-analytical and analytical factors on the original results. This framework will then be used to conduct a new economic evaluation of FC for monitoring IBD, to inform future clinical guidance in this area. This analysis will both help to improve care for patients with IBD, and will inform future reliable test adoption decisions across other disease areas, by providing a generalizable framework to conduct accurate diagnostic evaluations.

Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: ORAL AND GASTROINTESTINAL