Title: Developing evidence review methods to determine whether to change the test, interval or eligibility criteria of UK screening programmes
Funder: Department of Health and Social Care

Abstract: BackgroundScreening programmes and changes to screening programmes should be initiated on systematic reviews of Randomised Controlled Trials (RCTs). Evidence on benefits and harms is presented alongside economic models of cost-effectiveness. Decision-makers weigh mortality and morbidity benefits against harms such as false positive recalls, and overdiagnosis (disease correctly detected but would never cause symptoms). We regularly make changes to screening programmes, but it is often not possible to produce RCT evidence to support change (e.g. to the test, eligibility criteria, or screening interval). Instead we use lower standards of evidence, which may be biased, fail to measure all benefits and harms, or we may not combine it in a way that makes clear the gaps in knowledge. Such changes in programmes alter the balance of benefits and harms of screening, and may increase the harm of overdiagnosis by encouraging the detection of increasingly mild disease. Where RCT evidence is not available, the US and Canada have developed formal methods of evaluating and linking the chains of evidence, whereas in Europe iterations of the Wilson and Jungner list of criteria are still used, in the UK without guidance on methods to evaluate internal and external validity and synthesise the evidence. Aims1.To develop best practice evidence reviewing methods for evaluating changes to screening programmes, including estimation of all benefits (e.g. mortality and morbidity) and harms (e.g. overdiagnosis and false positive results). 2.To measure the impact on patient outcomes of changes in breast cancer screening (to test threshold and number of film-readers) and to determine how to maximise benefit from early detection whilst minimising harm from false positive results and overdiagnosis. Plan of investigationI will systematically review international evidence reviews on changes to screening programmes. I will conduct two further systematic reviews of evidence reviews related to starting new programmes, and of the overdiagnosis research literature in order to identify best practice methods from other fields. These reviews will be used to create a framework of methods to accurately assess benefits and harms, demonstrate where the evidence and links are strong or weak, and provide data to inform cost effectiveness models. I will survey experts to identify missing papers and methods, and to evaluate strengths and weaknesses of each method, and its applicability to different proposed changes and to different screening programmes. In collaboration with the UK National Screening Committee these findings will be developed into best practice guidelines. The balance of benefits and harms of two previous changes to breast screening will be evaluated using 13-year follow-up data for a cohort of 3.1 million women at the upper age limit who have attended their final breast screen. The effect of whether one or two film-readers examined their mammogram, and the film-reader recall threshold will be analysed using adjusted and unadjusted multi-level logistic regression to determine the numbers of women benefitting from early detection and harmed by overdiagnosis. Film-reader recall threshold will be determined from the previous two years of routine data. The primary outcome will be 13 year total cancer incidence (screen and symptomatically detected) as a measure of overdiagnosis. I will compare other methods of estimating patient outcomes, including short term test results, survival analysis and methods identified in the systematic review. Findings will inform breast screening quality assurance guidelines. Potential benefits to patients and the NHS The framework developed will support and improve decision making to maximise benefits from UK screening programmes, whilst minimising harm and costs to the NHS. This will result in NHS screening programmes which extend more lives, and give fewer people unneccessary treeatment and false positive test results (and associated anxiety).

Lay abstract: The aim of this research is to develop new evidence review guidelines for deciding whether to make changes to screening programmes and to measure how two changes to breast cancer screening affected women's health. Background Screening for disease can be lifesaving. Millions of people worldwide are helped by screening programmes. In the UK the National Health Service (NHS) screens for 30 diseases. Screening can bring many benefits but it can also cause harm. People and their families can suffer unnecessary treatment or worry as a result of screening. When deciding whether to start new screening programmes we summarise Randomised Controlled Trial (RCT) evidence in a flow-chart showing all benefits and harm, and create models to estimate cost effectiveness (costs and benefits). An RCT is the best evidence available, because it is not biased. When we make decisions about whether or not to change existing screening programmes, (for example changing the test, who is invited, or time between screening invitations) we often cannot use RCT evidence, because it is too expensive or we have to wait too long for outcomes. Instead we use lower standards of evidence, which may be biased and which may not measure all of the benefits and harms. Overdiagnosis is a harm we often fail to measure. It means that although we have correctly detected a disease by screening, it is a mild form which would never have caused health problems. So the person receives unnecessary treatment (for example surgery, radiotherapy, or a long-term restricted diet) for a disease which would never have troubled them. As a result we may mistakenly make changes to screening programmes which do more harm than good, and which may be very expensive for the NHS. In this fellowship I will develop new evidence review guidelines for deciding whether to make changes to screening programmes. I will create a framework to link together the evidence, clearly showing where it is strong or weak in a flow-chart of benefits and harms, and providing data to inform cost effectiveness models. This will help decision-makers to ensure that UK screening programmes give as much benefit as possible while keeping harm to a minimum. Work Package 1 To understand current practice I will systematically review the methods used to assess changes to screening programmes across 15 countries. A systematic review is a scientific way of searching for and combining published research. Then I will systematically review methods to measure overdiagnosis, as this is the most difficult part of the framework to measure. I will use an international expert group to identify the strengths and weaknesses of each of the methods I find and how they may link together, and I will identify which of these would be best to measure the benefits and harms of changes to screening programmes. Work Package 2 I will analyse the records of women who have been screened for breast cancer in the last 20 years. The Marmot review (2012) concluded that breast screening saves 1,400 lives every year, but causes 4,000 women to be overdiagnosed and treated for cancers which would not have given them symptoms. Since the evidence used in the Marmot review was collected, there have been changes to the screening programme and we do not know what effect these have had on benefits and harms for the women being screened. I will analyse the effects of two changes to breast screening. First, the change from one to two film-readers looking at each woman's mammograms (breast x-rays) for signs of cancer. Second, the decrease in recall threshold' which means that more women are called back for further tests. I will report the results to the NHS Breast Screening Programme, so that if needed, changes can be made to the quality assurance standards for breast screening. Patient representatives will lead focus groups to find other research questions which could be answered using the same data to increase value for money from this research. Developing best-practice guidelines I will work with experts at the UK National Screening Committee to develop best practice guidance for the UK when evaluating changes to screening programmes. This will include designing a framework to measure benefits and harms of the proposed changes, using published research (informed by work package 1) and information collected from the screening programmes (informed by work package 2). This will help people running screening programmes in the UK to provide more benefit and less harm to the UK population, and save NHS resources.

Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;4.4 POPULATION SCREENING
Health categories: CANCER AND NEOPLASMS