Title: Multi-centred validation of digital whole slide imaging for routine diagnosis
Funder: Department of Health and Social Care

Abstract: Digital pathology (DP) refers to the use of high throughput slide scanners to digitise diagnostic histopathology slides that are then reported on computer workstations as opposed to a microscope. The development allows electronic distribution of work to pathologists helping to address the pathologist capacity problem in many NHS hospitals. Sharing difficult cases more easily may help reduce error, and improve high complexity specialties such as renal pathology, that also require out of hours reporting. Prior to adoption, it is important to demonstrate that DP is fit for purpose of providing tissue imaging of sufficient quality to ensure diagnostic accuracy equivalent to light microscopy (LM), the current standard of care. Few comparison studies published have been adequately powered and cancer screening samples have not been specifically studied. Since the image produced in DP systems is inferior to resolution provided by LM it is questionable if DP is suitable for specialties requiring fine resolution such as renal biopsy interpretation. In addition, none of the published trials has examined the use of DP in immunofluorescence, which is essential if the DP is going to be used for renal biopsies. This study uses teams of 4 pathologists all examining the same series of samples, on both LM and DP. Samples will be randomised (excepting renal samples) to which modality is used first, and there will be a 6 week washout period between viewings. Reports will be scrutinised for differences, which will then be classified by an independent pathologist into major (would alter clinical management) and minor (would not). The original report gives the reference diagnosis. The ground truth (GT) for each case is decided on conclusion of the readings, by consensus of the study pathologists, using multihead LM viewing and taking into account the reference diagnosis if needed. This allows comparison of each pathologist’s performance on LM and DP against the GT. The study will examine 2000 complete histopathology samples including 600 samples each of breast, gastrointestinal (both including 200 cancer screening samples) and skin, and 200 renal samples performed for native or transplant related renal disease. The renal biopsies will include immunofluorescence for detection of immunoglobulin deposits, necessitating the first read to be performed on LM. The population of cases recruited will be selected sequentially from study centres’ archives and (except for renal) be enriched with 10% moderately difficult and 10% difficult samples. A qualitative study will examine, by means of structured interview, perceptions and experiences of pathologists prior to and during the progress of the study; assessing acceptability, timing and attitudes to DP. Eye tracking software will be used to examine pathologists’ examination techniques and this will be analysed alongside reporting discrepancies to identify if poor technique contributes to error in reporting. A Health Economic study will use lean working based value mapping to study the costs associated with review of cases for multi-disciplinary meetings and measure the potential efficiencies achieved by digitisation. Time for reporting cases with both modalities will be recorded to provide measurements of pathologist time saved. Clinically significant discrepancies will be further analysed to assess the likely variance in treatment cost compared to best standard of care, and the estimated impact on the patient.

Lay abstract: Pathologists (doctors who diagnose disease by studying tissue samples) use a microscope to examine tissue samples collected from patients. This is called light microscopy. It enables them to make a diagnosis and to give information on treatment and prognosis to clinicians (doctors). Digital pathology is a process to scan microscope slides into computer image files (digitised slides) which the pathologist can then examine on a computer screen. Digitised slides can be transferred electronically to allow pathologists to view cases at any location. This makes cases easy to share with colleagues, confirm diagnoses for patients, reduce errors and create better practices for sharing workload between departments. This will save time and resources for the NHS. We can also use computer assisted tools to help make the diagnosis. None of these benefits can be realised until we know pathologists can use digital pathology safely and accurately for routine reporting. Our study will compare light microscopy to digital pathology by examining 2000 samples. These will include samples collected from patients as part of the national breast cancer and bowel cancer screening programmes, and samples from skin and kidneys. Skin and kidney were chosen in consultation with our patient representatives. Both areas are challenging for pathology departments – skin because they have a high number of samples to examine and kidney because they are difficult and need specialists to interpret the results. In each of the four areas (breast, bowel, skin and kidney), four pathologists will examine the same series of cases using both light microscopy and digital pathology, each time reporting on their diagnosis. The four pathologists will then get together and decide between them the correct (or ground truth) result for all cases. The differences discovered in results between the two methods (light microscopy and digital pathology), will be passed to an independent pathologist who will judge whether the difference is major (i.e. they would alter the treatment of the patient) or minor (they would not alter the treatment). We will investigate any major differences to see if the reason for the difference is due to digital pathology. Based on assumptions from published literature, statisticians have advised how many cases are needed from each of the four areas to measure accurately how well the results from light microscopy to digital pathology agree. This will show if digital pathology is safe and reliable to use. We will do a pilot study first to test if our assumptions are accurate and, if necessary, we will adjust the study numbers. This process and the main study will be managed through an oversight committee. Alongside the main study, we will also use eye tracking technology to follow pathologists’ eye movements as they examine cases using digital pathology. This will help us to understand how errors arise and explore how we can prevent these happening. We will also study how pathologists and laboratory staff perceive digital pathology before and after it is implemented in the laboratory. Studies of health economics and process management will measure the changes when examining samples with digital pathology which could help improve efficiency, speed up diagnosis and save money for the NHS.

Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;7.3 MANAGEMENT AND DECISION MAKING
Health categories: GENERIC HEALTH RELEVANCE