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Abstract Background In response to the global COVID-19 pandemic, many in vitro diagnostic (IVD) tests for SARS-CoV-2 have been developed. Given the urgent clinical demand, researchers must balance the desire for precise estimates of sensitivity and specificity against the need for rapid implementation. To complement estimates of precision used for sample size calculations, we aimed to estimate the probability that an IVD will fail to perform to expected standards after implementation, following clinical studies with varying sample sizes. Methods We assumed that clinical validation study estimates met the ‘desirable’ performance (sensitivity 97%, specificity 99%) in the target product profile (TPP) published by the Medicines and Healthcare products Regulatory Agency (MHRA). To estimate the real-world impact of imprecision imposed by sample size we used Bayesian posterior calculations along with Monte Carlo simulations with 10,000 independent iterations of 5,000 participants. We varied the prevalence between 1 and 15% and the sample size between 30 and 2,000. For each sample size, we estimated the probability that diagnostic accuracy would fail to meet the TPP criteria after implementation. Results For a validation study that demonstrates ‘desirable’ sensitivity within a sample of 30 participants who test positive for COVID-19 using the reference standard, the probability that real-world performance will fail to meet the ‘desirable’ criteria is 10.7–13.5%, depending on prevalence. Theoretically, demonstrating the 'desirable' performance in 90 positive participants would reduce that probability to below 5%. A marked reduction in the probability of failure to hit ‘desirable’ specificity occurred between samples of 100 (19.1–21.5%) and 160 (4.3–4.8%) negative participants. There was little further improvement above sample sizes of 160 negative participants. Conclusion Based on imprecision alone, small evaluation studies can lead to the acceptance of diagnostic tests which are likely to fail to meet performance targets when deployed. There is diminished return on uncertainty surrounding an accuracy estimate above a total sample size of 250 (90 positive and 160 negative).

Abstract Background Ventilator-associated pneumonia (VAP) is an important diagnosis in critical care. VAP research is complicated by the lack of agreed diagnostic criteria and reference standard test criteria. Our aim was to review which reference standard tests are used to evaluate novel index tests for suspected VAP. Methods We conducted a comprehensive search using electronic databases and hand reference checks. The Cochrane Library, MEDLINE, CINHAL, EMBASE, and web of science were searched from 2008 until November 2018. All terms related to VAP diagnostics in the intensive treatment unit were used to conduct the search. We adopted a checklist from the critical appraisal skills programme checklist for diagnostic studies to assess the quality of the included studies. Results We identified 2441 records, of which 178 were selected for full-text review. Following methodological examination and quality assessment, 44 studies were included in narrative data synthesis. Thirty-two (72.7%) studies utilised a sole microbiological reference standard; the remaining 12 studies utilised a composite reference standard, nine of which included a mandatory microbiological criterion. Histopathological criteria were optional in four studies but mandatory in none. Conclusions Nearly all reference standards for VAP used in diagnostic test research required some microbiological confirmation of infection, with BAL culture being the most common reference standard used.

Abstract Background Invasive urodynamics is used to investigate the causes of lower urinary tract symptoms; a procedure usually conducted in secondary care by specialist practitioners. No study has yet investigated the feasibility of carrying out this procedure in a non-specialist setting. Therefore, the aim of this study was to explore, using qualitative methodology, the feasibility and acceptability of conducting invasive urodynamic testing in primary care. Methods Semi-structured interviews were conducted during the pilot phase of the PriMUS study, in which men experiencing bothersome lower urinary tract symptoms underwent invasive urodynamic testing along with a series of simple index tests in a primary care setting. Interviewees were 25 patients invited to take part in the PriMUS study and 18 healthcare professionals involved in study delivery. Interviews were audio-recorded, transcribed verbatim and analysed using a framework approach. Results Patients generally found the urodynamic procedure acceptable and valued the primary care setting due to its increased accessibility and familiarity. Despite some logistical issues, facilitating invasive urodynamic testing in primary care was also a positive experience for urodynamic nurses. Initial issues with general practitioners receiving and utilising the results of urodynamic testing may have limited the potential benefit to some patients. Effective approaches to study recruitment included emphasising the benefits of the urodynamic test and maintaining contact with potential participants by telephone. Patients’ relationship with their general practitioner was an important influence on study participation. Conclusions Conducting invasive urodynamics in primary care is feasible and acceptable and has the potential to benefit patients. Facilitating study procedures in a familiar primary care setting can impact positively on research recruitment. However, it is vital that there is a support network for urodynamic nurses and expertise available to help interpret urodynamic results.

Abstract Objectives The second wave of the coronavirus pandemic is now established, occurring at a time of winter pressure on acute care in the NHS. This is likely to be more challenging then the first wave for the diagnosis of COVID-19 because of the similar symptomology with other respiratory conditions highly prevalent in winter. This study sought to understand the care pathways in place in UK NHS hospitals during the first wave (March–July 2020) for identification of patients with COVID-19 and to learn lessons to inform optimal testing strategies within the COVID-19 National Diagnostic Research and Evaluation Platform (CONDOR). Design, setting & participants Sixteen hospital-based clinicians from 12 UK NHS Trusts covering 10 different specialties were interviewed following a semi-structured topic guide. Data were coded soon after the interviews and analysed thematically. Results We developed a diagrammatic, high-level visualisation of the care pathway describing the main clinical decisions associated with the diagnosis and management of patients with suspected COVID-19. COVID-19 testing influenced infection control considerations more so than treatment decisions. Two main features of service provision influenced the patient management significantly: access to rapid laboratory testing and the number of single occupancy rooms. If time to return of result was greater than 24 h, patients with a presumptive diagnosis would often be cohorted based on clinical suspicion alone. Undetected COVID-19 during this time could therefore lead to an increased risk of viral transmission. Conclusions During the winter months, priority for provision of rapid testing at admission should be given to hospitals with limited access to laboratory services and single room availability. Access to rapid testing is essential for urgent decisions related to emergency surgery, maternity services and organ transplant. The pathway and prioritization of need will inform the economic modelling, clinical evaluations, and implementation of new clinical tests in UK.

Abstract Background Staquet et al. and Brenner both developed correction methods to estimate the sensitivity and specificity of a binary-response index test when the reference standard is imperfect and its sensitivity and specificity are known. However, to our knowledge, no study has compared the statistical properties of these methods, despite their long application in diagnostic accuracy studies. Aim To compare the correction methods developed by Staquet et al. and Brenner. Methods Simulations techniques were employed to compare the methods under assumptions that the new test and the reference standard are conditionally independent or dependent given the true disease status of an individual. Three clinical datasets were analysed to understand the impact of using each method to inform clinical decision-making. Results Under the assumption of conditional independence, the Staquet et al. correction method outperforms the Brenner correction method irrespective of the prevalence of disease and whether the performance of the reference standard is better or worse than the index test. However, when the prevalence of the disease is high (> 0.9) or low (

No routine laboratory biomarkers perform well enough in diagnosing COVID-19 in isolation for them to be used as a standalone diagnostic test or to help clinicians prioritize patients for treatment. Instead, other diagnostic tests are needed. The aim of this work was to statistically summarise routine laboratory biomarker measurements in COVID-19-positive and -negative patients to inform future work. A systematic literature review and meta-analysis were performed. The search included names of commonly used, routine laboratory tests in the UK NHS, and focused on research papers reporting laboratory results of patients diagnosed with COVID-19. A random effects meta-analysis of the standardized mean difference between COVID-19-positive and -negative groups was conducted for each biomarker. When comparing reported laboratory biomarker results, we identified decreased white blood cell, neutrophil, lymphocyte, eosinophil, and platelet counts; while lactate dehydrogenase, aspartate aminotransferase, and alanine aminotransferase were elevated in COVID-19-positive compared to COVID-19-negative patients. Differences were identified across a number of routine laboratory biomarkers between COVID-19-positive and -negative patients. Further research is required to identify whether routine laboratory biomarkers can be used in the development of a clinical scoring system to aid with triage of patients.