Trial Forge Guidance 3: randomised trials and how to recruit and retain individuals from ethnic minority groups-practical guidance to support better practice.

Randomised trials, especially those intended to directly inform clinical practice and policy, should be designed to reflect all those who could benefit from the intervention under test should it prove effective. This does not always happen. The UK National Institute for Health and Care Research (NIHR) INCLUDE project identified many groups in the UK that are under-served by trials, including ethnic minorities.This guidance document presents four key recommendations for designing and running trials that include the ethnic groups needed by the trial. These are (1) ensure eligibility criteria and recruitment pathway do not limit participation in ways you do not intend, (2) ensure your trial materials are developed with inclusion in mind, (3) ensure staff are culturally competent and (4) build trusting partnerships with community organisations that work with ethnic minority groups. Each recommendation comes with best practice advice, public contributor testimonials, examples of the inclusion problem tackled by the recommendation, or strategies to mitigate the problem, as well as a collection of resources to support implementation of the recommendations.We encourage trial teams to follow the recommendations and, where possible, evaluate the strategies they use to implement them. Finally, while our primary audience is those designing, running and reporting trials, we hope funders, grant reviewers and approvals agencies may also find our guidance useful.

Core outcome set for symptomatic uncomplicated gallstone disease.

BACKGROUND: Heterogeneity of outcomes is a problem for assessing intervention effectiveness when considering treatments for uncomplicated symptomatic gallstone disease. The value to all stakeholders of outcomes that have been measured and reported to date is also unclear. The aim of this study was to develop a core outcome set for symptomatic uncomplicated gallstone disease. METHODS: An in person-meeting was held with patients to prioritize potentially important outcomes from a previously developed longlist of outcomes. This was followed by an online three-round Delphi survey that was conducted with healthcare professionals. The results of each consensus process were compared and combined to produce the final core outcome set. RESULTS: A total of 82 participants enrolled in round 1 of the Delphi survey, with a final sample of 40 participants contributing to round 3. Five patients contributed to the in-person group meeting. Following the consensus processes, 11 outcomes were considered to be core by patients and healthcare professionals, and included in the core outcome set. These were: quality of life; overall health state; overall satisfaction; overall pain; common bile duct injury; biliary leak; haemorrhage; need for endoscopic retrograde cholangiopancreatography; intra-abdominal collections; admission/readmission for problems; and reoperation. CONCLUSION: A core outcome set for symptomatic uncomplicated gallstone disease has been developed with patients and healthcare professionals. Eleven outcomes across four key domains have been identified. These represent the minimum set of outcomes that should be reported in trials evaluating interventions for gallstone disease.

Pulpotomy for the Management of Irreversible Pulpitis in Mature Teeth (PIP): a feasibility study.

BACKGROUND: Progression of dental caries can result in irreversible pulpal damage. Partial irreversible pulpitis is the initial stage of this damage, confined to the coronal pulp whilst the radicular pulp shows little or no sign of infection. Preserving the pulp with sustained vitality and developing minimally invasive biologically based therapies are key themes within contemporary clinical practice. However, root canal treatment involving complete removal of the pulp is often the only option (other than extraction) given to patients with irreversible pulpitis, with substantial NHS and patient incurred costs. The European Society of Endodontology's (ESE 2019) recent consensus statement recommends full pulpotomy, where the inflamed coronal pulp is removed with the goal of keeping the radicular pulp vital, as a more minimally invasive technique, potentially avoiding complex root canal treatment. Although this technique may be provided in secondary care, it has not been routinely implemented or evaluated in UK General Dental Practice. METHOD: This feasibility study aims to identify and assess in a primary care setting the training needs of general dental practitioners and clinical fidelity of the full pulpotomy intervention, estimate likely eligible patient pool and develop recruitment materials ahead of the main randomised controlled trial comparing the clinical and cost-effectiveness of full pulpotomy compared to root canal treatment in pre/molar teeth of adults 16 years and older showing signs indicative of irreversible pulpitis. The feasibility study will recruit and train 10 primary care dentists in the full pulpotomy technique. Dentists will recruit and provide full pulpotomy to 40 participants (four per practice) with indications of partial irreversible pulpitis. DISCUSSION: The Pulpotomy for the Management of Irreversible Pulpitis in Mature Teeth (PIP) study will address the lack of high-quality evidence in the treatment of irreversible pulpitis, to aid dental practitioners, patients and policymakers in their decision-making. The PIP feasibility study will inform the main study on the practicality of providing both training and provision of the full pulpotomy technique in general dental practice. TRIAL REGISTRATION: ISRCTN Registry, ISRCTN17973604 . Registered on 28 January 2021. Protocol version Protocol version: 1; date: 03.02.2021.

Non-invasive testing for early detection of neovascular macular degeneration in unaffected second eyes of older adults: EDNA diagnostic accuracy study.

BACKGROUND: Neovascular age-related macular degeneration is a leading cause of sight loss, and early detection and treatment is important. For patients with neovascular age-related macular degeneration in one eye, it is usual practice to monitor the unaffected eye. The test used to diagnose neovascular age-related macular degeneration, fundus fluorescein angiography, is an invasive test. Non-invasive tests are available, but their diagnostic accuracy is unclear. OBJECTIVES: The primary objective was to determine the diagnostic monitoring performance of tests for neovascular age-related macular degeneration in the second eye of patients with unilateral neovascular age-related macular degeneration. The secondary objectives were the cost-effectiveness of tests and to identify predictive factors of developing neovascular age-related macular degeneration. DESIGN: This was a multicentre, prospective, cohort, comparative diagnostic accuracy study in a monitoring setting for up to 3 years. A Cox regression risk prediction model and a Markov microsimulation model comparing cost-effectiveness of the index tests over 25 years were used. SETTING: This took place in hospital eye services. PARTICIPANTS: Participants were adults (aged 50-95 years) with newly diagnosed (within the previous 6 weeks) neovascular age-related macular degeneration in one eye and an unaffected second (study) eye who were attending for treatment injections in the first eye and who had a study eye baseline visual acuity of ≥ 68 Early Treatment Diabetic Retinopathy Study letters. INTERVENTIONS: The index tests were Amsler chart (completed by participants), fundus clinical examination, optical coherence tomography, self-reported vision assessment (completed by participants) and visual acuity. The reference standard was fundus fluorescein angiography. MAIN OUTCOME MEASURES: The main outcome measures were sensitivity and specificity; the performance of the risk predictor model; and costs and quality-adjusted life-years. RESULTS: In total, 552 out of 578 patients who consented from 24 NHS hospitals (n = 16 ineligible; n = 10 withdrew consent) took part. The mean age of the patients was 77.4 years (standard deviation 7.7 years) and 57.2% were female. For the primary analysis, 464 patients underwent follow-up fundus fluorescein angiography and 120 developed neovascular age-related macular degeneration on fundus fluorescein angiography. The diagnostic accuracy [sensitivity (%) (95% confidence interval); specificity (%) (95% confidence interval)] was as follows: optical coherence tomography 91.7 (85.2 to 95.6); 87.8 (83.8 to 90.9)], fundus clinical examination [53.8 (44.8 to 62.5); 97.6 (95.3 to 98.9)], Amsler [33.7 (25.1 to 43.5); 81.4 (76.4 to 85.5)], visual acuity [30.0 (22.5 to 38.7); 66.3 (61.0 to 71.1)] and self-reported vision [4.2 (1.6 to 9.8); 97.0 (94.6 to 98.5)]. Optical coherence tomography had the highest sensitivity across all secondary analyses. The final prediction model for neovascular age-related macular degeneration in the non-affected eye included smoking status, family history of neovascular age-related macular degeneration, the presence of nodular drusen with or without reticular pseudodrusen, and the presence of pigmentary abnormalities [c-statistic 0.66 (95% confidence interval 0.62 to 0.71)]. Optical coherence tomography monitoring generated the greatest quality-adjusted life-years gained per patient (optical coherence tomography, 5.830; fundus clinical examination, 5.787; Amsler chart, 5.736, self-reported vision, 5.630; and visual acuity, 5.600) for the lowest health-care and social care costs (optical coherence tomography, £19,406; fundus clinical examination, £19,649; Amsler chart, £19,751; self-reported vision, £20,198; and visual acuity, £20,444) over the lifetime of the simulated cohort. Optical coherence tomography dominated the other tests or had an incremental cost-effectiveness ratio below the accepted cost-effectiveness thresholds (£20,000) across the scenarios explored. LIMITATIONS: The diagnostic performance may be different in an unselected population without any history of neovascular age-related macular degeneration; the prediction model did not include genetic profile data, which might have improved the discriminatory performance. CONCLUSIONS: Optical coherence tomography was the most accurate in diagnosing conversion to neovascular age-related macular degeneration in the fellow eye of patients with unilateral neovascular age-related macular degeneration. Economic modelling suggests that optical coherence tomography monitoring is cost-effective and leads to earlier diagnosis of and treatment for neovascular age-related macular degeneration in the second eye of patients being treated for neovascular age-related macular degeneration in their first eye. FUTURE WORK: Future works should investigate the role of home monitoring, improved risk prediction models and impact on long-term visual outcomes. STUDY REGISTRATION: This study was registered as ISRCTN48855678. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 8. See the NIHR Journals Library website for further project information.

Wet age-related macular degeneration is the leading cause of sight loss in older people. It is diagnosed using fundus fluorescein angiography, which involves photographing the retina after the injection of a dye into a vein in the arm, which may result in allergic reactions. Many people with wet age-related macular degeneration in one eye will also develop it in their second eye. To avoid regular fundus fluorescein angiography, non-invasive tests are used to routinely monitor for wet age-related macular degeneration in the second eye of patients with wet age-related macular degeneration already in one eye. We studied five commonly used and easily performed non-invasive tests to see which best detected the onset of wet age-related macular degeneration. The five tests were: self-report of visionself-completion of an Amsler charta standard sight testexamination of the retina by a specialistoptical coherence tomography, which is a non-invasive scan of the central retina. If any tests suggested wet age-related macular degeneration, fundus fluorescein angiography was performed to compare results. In total, 552 hospital eye clinic patients who had wet age-related macular degeneration in only one eye took part. Over a 3-year period, wet age-related macular degeneration developed in the second eye in 145 people (26%), of whom 120 had undergone fundus fluorescein angiography. In 25 people with wet age-related macular degeneration, fundus fluorescein angiography was not carried out for safety reasons or because the patient did not want to undergo it. Of all the tests, only optical coherence tomography was good at detecting wet age-related macular degeneration correctly (92% sensitivity) and at detecting those who did not have wet age-related macular degeneration (88% specificity). All other tests either did not detect wet age-related macular degeneration consistently when it occurred or gave a false positive result when it had not occurred. This study confirmed that optical coherence tomography detected wet age-related macular degeneration correctly in the second eye of people with wet age-related macular degeneration in their first eye, and may offer cost saving for the NHS.

Early detection of neovascular age-related macular degeneration: an economic evaluation based on data from the EDNA study.

BACKGROUND/AIMS: To evaluate the cost-effectiveness of non-invasive monitoring tests to detect the onset of neovascular age-related macular degeneration (nAMD) in the unaffected second eye of patients receiving treatment for unilateral nAMD in a UK National Health Service (NHS) hospital outpatient setting. METHODS: A patient-level state transition model was constructed to simulate the onset, detection, and treatment of nAMD in the second eye. Five index tests were compared: self-reported change in visual function, Amsler test, clinic measured change in visual acuity from baseline, fundus assessment by clinical examination or colour photography, and spectral domain optical coherence tomography (SD-OCT). Diagnosis of nAMD was confirmed by fundus fluorescein angiography (FFA) before prompt initiation of antivascular endothelial growth factor treatment. Quality-adjusted life-years (QALYs) and costs of health and social care were modelled over a 25-year time horizon. RESULTS: SD-OCT generated more QALYs (SD-OCT, 5.830; fundus assessment, 5.787; Amsler grid, 5.736, patient's subjective assessment, 5.630; and visual acuity, 5.600) and lower health and social care costs (SD-OCT, £19 406; fundus assessment, £19 649; Amsler grid, £19 751; patient's subjective assessment, £20 198 and visual acuity, £20 444) per patient compared with other individual monitoring tests. Probabilistic sensitivity analysis indicated a high probability (97%-99%) of SD-OCT being the preferred test across a range of cost-effectiveness thresholds (£13 000-£30 000) applied in the UK NHS. CONCLUSIONS: Early treatment of the second eye following FFA confirmation of SD-OCT positive findings is expected to maintain better visual acuity and health-related quality of life and may reduce costs of health and social care over the lifetime of patients.

Selective Caries Removal in Permanent Teeth (SCRiPT) for the treatment of deep carious lesions: a randomised controlled clinical trial in primary care.

BACKGROUND: Dental caries is one of the most prevalent non-communicable disease globally and can have serious health sequelae impacting negatively on quality of life. In the UK most adults experience dental caries during their lifetime and the 2009 Adult Dental Health Survey reported that 85% of adults have at least one dental restoration. Conservative removal of tooth tissue for both primary and secondary caries reduces the risk of failure due to tooth-restoration, complex fracture as well as remaining tooth surfaces being less vulnerable to further caries. However, despite its prevalence there is no consensus on how much caries to remove prior to placing a restoration to achieve optimal outcomes. Evidence for selective compared to complete or near-complete caries removal suggests there may be benefits for selective removal in sustaining tooth vitality, therefore avoiding abscess formation and pain, so eliminating the need for more complex and costly treatment or eventual tooth loss. However, the evidence is of low scientific quality and mainly gleaned from studies in primary teeth. METHOD: This is a pragmatic, multi-centre, two-arm patient randomised controlled clinical trial including an internal pilot set in primary dental care in Scotland and England. Dental health professionals will recruit 623 participants over 12-years of age with deep carious lesions in their permanent posterior teeth. Participants will have a single tooth randomised to either the selective caries removal or complete caries removal treatment arm. Baseline measures and outcome data (during the 3-year follow-up period) will be assessed through clinical examination, patient questionnaires and NHS databases. A mixed-method process evaluation will complement the clinical and economic outcome evaluation and examine implementation, mechanisms of impact and context. The primary outcome at three years is sustained tooth vitality. The primary economic outcome is net benefit modelled over a lifetime horizon. Clinical secondary outcomes include pulp exposure, progession of caries, restoration failure; as well as patient-centred and economic outcomes. DISCUSSION: SCRiPT will provide evidence for the most clinically effective and cost-beneficial approach to managing deep carious lesions in permanent posterior teeth in primary care. This will support general dental practitioners, patients and policy makers in decision making. Trial Registration Trial registry: ISRCTN. TRIAL REGISTRATION NUMBER: ISRCTN76503940. Date of Registration: 30.10.2019. URL of trial registry record: https://www.isrctn.com/ISRCTN76503940?q=ISRCTN76503940%20&filters=&sort=&offset=1&totalResults=1&page=1&pageSize=10&searchType=basic-search .

Diagnostic Accuracy of Monitoring Tests of Fellow Eyes in Patients with Unilateral Neovascular Age-Related Macular Degeneration: Early Detection of Neovascular Age-Related Macular Degeneration Study.

PURPOSE: To evaluate the diagnostic accuracy of routinely used tests of visual function and retinal morphology compared with fundus fluorescein angiography (FFA) to detect onset of active macular neovascularization in unaffected fellow eyes of patients with unilateral neovascular age-related macular degeneration (nAMD). DESIGN: Prospective diagnostic accuracy cohort study conducted in 24 eye clinics in the United Kingdom over 3 years. PARTICIPANTS: Older adults (>50 years) with recently diagnosed unilateral nAMD with a fellow (study) eye free of nAMD. METHODS: Self-reported vision, Amsler, clinic-measured visual acuity (VA), fundus assessment, and spectral domain OCT. The reference standard is FFA. MAIN OUTCOME MEASURES: Sensitivity and specificity of the 5 index tests. RESULTS: Of 552 participants monitored for up to 3 years, 145 (26.3%) developed active nAMD in the study eye, of whom 120 had an FFA at detection and constituted the primary analysis cohort. Index test positives at nAMD detection in those confirmed by FFA were self-reported vision much worse (5), distortion on Amsler (33), 10-letter decrease in acuity from baseline (36), fundus examination (64), and OCT (110). Percentage index test sensitivities were: self-reported vision 4.2 (95% confidence interval [CI], 1.6-9.8); Amsler 33.7 (95% CI, 25.1-43.5); VA 30.0 (95% CI, 22.5-38.7); fundus examination 53.8 (95% CI, 44.8-62.5); and OCT 91.7 (95% CI, 85.2-95.6). All 5 index test specificities were high at 97.0 (95% CI, 94.6-98.5), 81.4 (95% CI, 76.4-85.5), 66.3 (95% CI, 61.0-71.1), 97.6 (95% CI, 95.3-98.9), and 87.8 (95% CI, 83.8-90.9), respectively. The combination of OCT with one other index test that was a secondary outcome measure increased sensitivity marginally and decreased specificity for all combinations except fundus examination. CONCLUSIONS: Tests of self-reported change in vision, unmasking of new distortion, measurements of acuity, and fundus checks to diagnose active nAMD performed poorly in contrast to OCT. Our findings support a change to guidelines in clinical practice to monitor for onset of nAMD.

Developing the INCLUDE Ethnicity Framework-a tool to help trialists design trials that better reflect the communities they serve.

BACKGROUND: Ensuring that a trial is designed so that its participants reflect those who might benefit from the results, or be spared harms, is key to the potential benefits of the trial reaching all they should. This paper describes the process, facilitated by Trial Forge, that was used between July 2019 and October 2020 to develop the INCLUDE Ethnicity Framework, part of the wider INCLUDE initiative from the National Institute for Health Research to improve inclusion of under-served groups in clinical research studies. METHODS: Development of the Framework was done in seven phases: (1) outline, (2) initial draft, (3) stakeholder meeting, (4) modify draft, (5) Stakeholder feedback, (6) applying the Framework and (7) packaging. Phases 2 and 3 were face-to-face meetings. Consultation with stakeholders was iterative, especially phases 4 to 6. Movement to the next phase was done once all or most stakeholders were comfortable with the results of the current phase. When there was a version of the Framework that could be considered final, the Framework was applied to six trials to create a set of examples (phase 6). Finally, the Framework, guidance and examples were packaged ready for dissemination (phase 7). RESULTS: A total of 40 people from stakeholder groups including patient and public partners, clinicians, funders, academics working with various ethnic groups, trial managers and methodologists contributed to the seven phases of development. The Framework comprises two parts. The first part is a list of four key questions: 1. Who should my trial apply to? 2. Are the groups identified likely to respond in different ways? 3. Will my study intervention make it harder for some groups to engage? 4. Will the way I have designed the study make it harder for some groups to engage? The second part is a set of worksheets to help trial teams address these questions. The Framework can be used for any stage of trial, for a healthcare intervention in any disease area. The Framework was launched on 1st October 2020 and is available open access at the Trial Forge website: https://www.trialforge.org/trial-forge-centre/include/ . CONCLUSION: Thinking about the number of people in our trials is not enough: we need to start thinking more carefully about who our participants are.

Using systematic data categorisation to quantify the types of data collected in clinical trials: the DataCat project.

BACKGROUND: Data collection consumes a large proportion of clinical trial resources. Each data item requires time and effort for collection, processing and quality control procedures. In general, more data equals a heavier burden for trial staff and participants. It is also likely to increase costs. Knowing the types of data being collected, and in what proportion, will be helpful to ensure that limited trial resources and participant goodwill are used wisely. AIM: The aim of this study is to categorise the types of data collected across a broad range of trials and assess what proportion of collected data each category represents. METHODS: We developed a standard operating procedure to categorise data into primary outcome, secondary outcome and 15 other categories. We categorised all variables collected on trial data collection forms from 18, mainly publicly funded, randomised superiority trials, including trials of an investigational medicinal product and complex interventions. Categorisation was done independently in pairs: one person having in-depth knowledge of the trial, the other independent of the trial. Disagreement was resolved through reference to the trial protocol and discussion, with the project team being consulted if necessary. KEY RESULTS: Primary outcome data accounted for 5.0% (median)/11.2% (mean) of all data items collected. Secondary outcomes accounted for 39.9% (median)/42.5% (mean) of all data items. Non-outcome data such as participant identifiers and demographic data represented 32.4% (median)/36.5% (mean) of all data items collected. CONCLUSION: A small proportion of the data collected in our sample of 18 trials was related to the primary outcome. Secondary outcomes accounted for eight times the volume of data as the primary outcome. A substantial amount of data collection is not related to trial outcomes. Trialists should work to make sure that the data they collect are only those essential to support the health and treatment decisions of those whom the trial is designed to inform.

Diagnostic accuracy of optical coherence tomography for diagnosing glaucoma: secondary analyses of the GATE study.

BACKGROUND/AIMS: To assess the diagnostic performance of retinal nerve fibre layer (RNFL) data of optical coherence tomography (OCT) for detecting glaucoma. METHODS: Secondary analyses of a prospective, multicentre diagnostic study (Glaucoma Automated Tests Evaluation (GATE)) referred to hospital eye services in the UK were conducted. We included data from 899 of 966 participants referred to hospital eye services with suspected glaucoma or ocular hypertension. We used both eyes' data and logistic regression-based receiver operator characteristics analysis to build a set of models to measure the sensitivity and specificity of the average and inferior quadrant RNFL thickness data of OCT. The reference standard was expert clinician examination including automated perimetry. The main outcome measures were sensitivity at 0.95 specificity and specificity at 0.95 sensitivity and the corresponding RNFL thickness thresholds. We explored the possibility of accuracy improvement by adding measures of within-eye and between-eye variation, scan quality, intraocular pressure (IOP) and age. RESULTS: Glaucoma was diagnosed in at least one eye in 17% of participants. Areas under the curve were between 0.83 and 0.88. When specificity was fixed at 0.95, the sensitivity was between 0.38 and 0.55, and the highest values were reached with models including the inferior quadrant rather than the average RNFL thickness. Fixing sensitivity at 0.95, the specificity was between 0.36 and 0.58. The addition of age, refractive error, IOP or within-subject variation did not improve the accuracy. CONCLUSION: RNFL thickness data of OCT can be used as a diagnostic test, but accuracy estimates remain moderate even in exploratory multivariable modelling of aiming to improve accuracy.

Can Automated Imaging for Optic Disc and Retinal Nerve Fiber Layer Analysis Aid Glaucoma Detection?

PURPOSE: To compare the diagnostic performance of automated imaging for glaucoma. DESIGN: Prospective, direct comparison study. PARTICIPANTS: Adults with suspected glaucoma or ocular hypertension referred to hospital eye services in the United Kingdom. METHODS: We evaluated 4 automated imaging test algorithms: the Heidelberg Retinal Tomography (HRT; Heidelberg Engineering, Heidelberg, Germany) glaucoma probability score (GPS), the HRT Moorfields regression analysis (MRA), scanning laser polarimetry (GDx enhanced corneal compensation; Glaucoma Diagnostics (GDx), Carl Zeiss Meditec, Dublin, CA) nerve fiber indicator (NFI), and Spectralis optical coherence tomography (OCT; Heidelberg Engineering) retinal nerve fiber layer (RNFL) classification. We defined abnormal tests as an automated classification of outside normal limits for HRT and OCT or NFI ≥ 56 (GDx). We conducted a sensitivity analysis, using borderline abnormal image classifications. The reference standard was clinical diagnosis by a masked glaucoma expert including standardized clinical assessment and automated perimetry. We analyzed 1 eye per patient (the one with more advanced disease). We also evaluated the performance according to severity and using a combination of 2 technologies. MAIN OUTCOME MEASURES: Sensitivity and specificity, likelihood ratios, diagnostic, odds ratio, and proportion of indeterminate tests. RESULTS: We recruited 955 participants, and 943 were included in the analysis. The average age was 60.5 years (standard deviation, 13.8 years); 51.1% were women. Glaucoma was diagnosed in at least 1 eye in 16.8%; 32% of participants had no glaucoma-related findings. The HRT MRA had the highest sensitivity (87.0%; 95% confidence interval [CI], 80.2%-92.1%), but lowest specificity (63.9%; 95% CI, 60.2%-67.4%); GDx had the lowest sensitivity (35.1%; 95% CI, 27.0%-43.8%), but the highest specificity (97.2%; 95% CI, 95.6%-98.3%). The HRT GPS sensitivity was 81.5% (95% CI, 73.9%-87.6%), and specificity was 67.7% (95% CI, 64.2%-71.2%); OCT sensitivity was 76.9% (95% CI, 69.2%-83.4%), and specificity was 78.5% (95% CI, 75.4%-81.4%). Including only eyes with severe glaucoma, sensitivity increased: HRT MRA, HRT GPS, and OCT would miss 5% of eyes, and GDx would miss 21% of eyes. A combination of 2 different tests did not improve the accuracy substantially. CONCLUSIONS: Automated imaging technologies can aid clinicians in diagnosing glaucoma, but may not replace current strategies because they can miss some cases of severe glaucoma.

Automated imaging technologies for the diagnosis of glaucoma: a comparative diagnostic study for the evaluation of the diagnostic accuracy, performance as triage tests and cost-effectiveness (GATE study).

BACKGROUND: Many glaucoma referrals from the community to hospital eye services are unnecessary. Imaging technologies can potentially be useful to triage this population. OBJECTIVES: To assess the diagnostic performance and cost-effectiveness of imaging technologies as triage tests for identifying people with glaucoma. DESIGN: Within-patient comparative diagnostic accuracy study. Markov economic model comparing the cost-effectiveness of a triage test with usual care. SETTING: Secondary care. PARTICIPANTS: Adults referred from the community to hospital eye services for possible glaucoma. INTERVENTIONS: Heidelberg Retinal Tomography (HRT), including two diagnostic algorithms, glaucoma probability score (HRT-GPS) and Moorfields regression analysis (HRT-MRA); scanning laser polarimetry [glaucoma diagnostics (GDx)]; and optical coherence tomography (OCT). The reference standard was clinical examination by a consultant ophthalmologist with glaucoma expertise including visual field testing and intraocular pressure (IOP) measurement. MAIN OUTCOME MEASURES: (1) Diagnostic performance of imaging, using data from the eye with most severe disease. (2) Composite triage test performance (imaging test, IOP measurement and visual acuity measurement), using data from both eyes, in correctly identifying clinical management decisions, that is 'discharge' or 'do not discharge'. Outcome measures were sensitivity, specificity and incremental cost per quality-adjusted life-year (QALY). RESULTS: Data from 943 of 955 participants were included in the analysis. The average age was 60.5 years (standard deviation 13.8 years) and 51.1% were females. Glaucoma was diagnosed by the clinician in at least one eye in 16.8% of participants; 37.9% of participants were discharged after the first visit. Regarding diagnosing glaucoma, HRT-MRA had the highest sensitivity [87.0%, 95% confidence interval (CI) 80.2% to 92.1%] but the lowest specificity (63.9%, 95% CI 60.2% to 67.4%) and GDx had the lowest sensitivity (35.1%, 95% CI 27.0% to 43.8%) but the highest specificity (97.2%, 95% CI 95.6% to 98.3%). HRT-GPS had sensitivity of 81.5% (95% CI 73.9% to 87.6%) and specificity of 67.7% (95% CI 64.2% to 71.2%) and OCT had sensitivity of 76.9% (95% CI 69.2% to 83.4%) and specificity of 78.5% (95% CI 75.4% to 81.4%). Regarding triage accuracy, triage using HRT-GPS had the highest sensitivity (86.0%, 95% CI 82.8% to 88.7%) but the lowest specificity (39.1%, 95% CI 34.0% to 44.5%), GDx had the lowest sensitivity (64.7%, 95% CI 60.7% to 68.7%) but the highest specificity (53.6%, 95% CI 48.2% to 58.9%). Introducing a composite triage station into the referral pathway to identify appropriate referrals was cost-effective. All triage strategies resulted in a cost reduction compared with standard care (consultant-led diagnosis) but with an associated reduction in effectiveness. GDx was the least costly and least effective strategy. OCT and HRT-GPS were not cost-effective. Compared with GDx, the cost per QALY gained for HRT-MRA is £22,904. The cost per QALY gained with current practice is £156,985 compared with HRT-MRA. Large savings could be made by implementing HRT-MRA but some benefit to patients will be forgone. The results were sensitive to the triage costs. CONCLUSIONS: Automated imaging can be effective to aid glaucoma diagnosis among individuals referred from the community to hospital eye services. A model of care using a triage composite test appears to be cost-effective. FUTURE WORK: There are uncertainties about glaucoma progression under routine care and the cost of providing health care. The acceptability of implementing a triage test needs to be explored. FUNDING: The National Institute for Health Research Health Technology Assessment programme.