The value of source data verification in a cancer clinical trial

Background Source data verification (SDV) is a resource intensive method of quality assurance frequently used in clinical trials. There is no empirical evidence to suggest that SDV would impact on comparative treatment effect results from a clinical trial. Methods Data discrepancies and comparative treatment effects obtained following 100% SDV were compared to those based on data without SDV. Overall survival (OS) and Progression-free survival (PFS) were compared using Kaplan-Meier curves, log-rank tests and Cox models. Tumour response classifications and comparative treatment Odds Ratios (ORs) for the outcome objective response rate, and number of Serious Adverse Events (SAEs) were compared. OS estimates based on SDV data were compared against estimates obtained from centrally monitored data. Findings Data discrepancies were identified between different monitoring procedures for the majority of variables examined, with some variation in discrepancy rates. There were no systematic patterns to discrepancies and their impact was negligible on OS, the primary outcome of the trial (HR (95% CI): 1.18(0.99 to 1.41), p = 0.064 with 100% SDV; 1.18(0.99 to 1.42), p = 0.068 without SDV; 1.18(0.99 to 1.40), p = 0.073 with central monitoring). Results were similar for PFS. More extreme discrepancies were found for the subjective outcome overall objective response (OR (95% CI): 1.67(1.04 to 2.68), p = 0.03 with 100% SDV; 2.45(1.49 to 4.04), p = 0.0003 without any SDV) which was mostly due to differing CT scans. Interpretation Quality assurance methods used in clinical trials should be informed by empirical evidence. In this empirical comparison, SDV was expensive and identified random errors that made little impact on results and clinical conclusions of the trial. Central monitoring using an external data source was a more efficient approach for the primary outcome of OS. For the subjective outcome objective response, an independent blinded review committee and tracking system to monitor missing scan data could be more efficient than SDV

Drooling Reduction Intervention randomised trial (DRI): comparing the efficacy and acceptability of hyoscine patches and glycopyrronium liquid on drooling in children with neurodisability

Objective: Investigate whether hyoscine patch or glycopyrronium liquid is more effective and acceptable to treat drooling in children with neurodisability. Design: Multicentre, single-blind, randomised controlled trial. Setting: Recruitment through neurodisability teams; treatment by parents. Participants: Ninety children with neurodisability who had never received medication for drooling (55 boys, 35 girls; median age 4 years). Exclusion criteria: medication contraindicated; in a trial that could affect drooling or management. Intervention: Children were randomised to receive a hyoscine skin patch or glycopyrronium liquid. Dose was increased over 4 weeks to achieve optimum symptom control with minimal side-effects; steady dose then continued to 12 weeks. Primary and secondary outcomes: Primary outcome: Drooling Impact Scale (DIS) score at week-4. Secondary outcomes: change in DIS scores over 12 weeks, Drooling Severity and Frequency Scale and Treatment Satisfaction Questionnaire for Medication; adverse events; children’s perception about treatment. Results: Both medications yielded clinically and statistically significant reductions in mean DIS at week-4 (25.0 (SD 22.2) for hyoscine and 26.6 (SD 16) for glycopyrronium). There was no significant difference in change in DIS scores between treatment groups. By week-12, 26/47 (55%) children starting treatment were receiving hyoscine compared with 31/38 (82%) on glycopyrronium. There was a 42% increased chance of being on treatment at week-12 for children randomised to glycopyrronium relative to hyoscine (1.42, 95% CI 1.04 to 1.95). Conclusions: Hyoscine and glycopyrronium are clinically effective in treating drooling in children with neurodisability. Hyoscine produced more problematic side effects leading to a greater chance of treatment cessation

Floating with seeds: understanding hydrochorous mangrove propagule dispersal: a field and modeling approach

Présentation avec posterinfo:eu-repo/semantics/publishedYoung Marine Scientists’ Day Vlaams Instituut voor de Zee (VLIZ), 24 février, Brugge, Belgiqu

The NAtional randomised controlled Trial of Tonsillectomy IN Adults (NATTINA) : a clinical and cost-effectiveness study: study protocol for a randomised control trial

This project is funded by the National Institute for Health Research (NIHR) Health Technology Assessment (HTA) Programme (project number 12/146/06).BACKGROUND: The role of tonsillectomy in the management of adult tonsillitis remains uncertain and UK regional variation in tonsillectomy rates persists. Patients, doctors and health policy makers wish to know the costs and benefits of tonsillectomy against conservative management and whether therapy can be better targeted to maximise benefits and minimise risks of surgery, hence maximising cost-effective use of resources. NATTINA incorporates the first attempt to map current NHS referral criteria against other metrics of tonsil disease severity. METHODS/DESIGN: A UK multi-centre, randomised, controlled trial for adults with recurrent tonsillitis to compare the clinical and cost-effectiveness of tonsillectomy versus conservative management. An initial feasibility study comprises qualitative interviews to investigate the practicality of the protocol, including willingness to randomise and be randomised. Approximately 20 otolaryngology staff, 10 GPs and 15 ENT patients will be recruited over 5 months in all 9 proposed main trial participating sites. A 6-month internal pilot will then recruit 72 patients across 6 of the 9 sites. Participants will be adults with recurrent acute tonsillitis referred by a GP to secondary care. Randomisation between tonsillectomy and conservative management will be according to a blocked allocation method in a 1:1 ratio stratified by centre and baseline disease severity. If the pilot is successful, the main trial will recruit a further 528 patients over 18 months in all 9 participating sites. All participants will be followed up for a total of 24 months, throughout which both primary and secondary outcome data will be collected. The primary outcome is the number of sore throat days experienced over the 24-month follow-up. The pilot and main trials include an embedded qualitative process evaluation. DISCUSSION: NATTINA is designed to evaluate the relative effectiveness and efficiency of tonsillectomy versus conservative management in patients with recurrent sore throat who are eligible for surgery. Most adult tonsil disease and surgery has an impact on economically active age groups, with individual and societal costs through loss of earnings and productivity. Avoidance of unnecessary operations and prioritisation of those individuals likely to gain most from tonsillectomy would reduce costs to the NHS and society. TRIAL REGISTRATION: ISRCTN55284102, Date of Registration: 4 August 2014.Publisher PDFPeer reviewe

Antiplatelet therapy in the primary prevention of cardiovascular disease in patients with chronic obstructive pulmonary disease: protocol of a randomised controlled proof-of-concept trial (APPLE COPD-ICON 2)

Introduction: The antiplatelet therapy in the primary prevention of cardiovascular disease in patients with chronic obstructive pulmonary disease (APPLE COPD-ICON2) trial is a prospective 2×2 factorial, double-blinded proof-of-concept randomised controlled trial targeting patients with chronic obstructive pulmonary disease (COPD) at high risk of cardiovascular disease. The primary goal of this trial is to investigate if treatment with antiplatelet therapy will produce the required response in platelet function measured using the Multiplate test in patients with COPD. Methods and analysis: Patients with COPD are screened for eligibility using inclusion and exclusion criteria. Eligible patients are randomised and allocated into one of four groups to receive aspirin plus placebo, ticagrelor plus placebo, aspirin plus ticagrelor or placebo only. Markers of systemic inflammation, platelet reactivity, arterial stiffness, carotid intima-media thickness (CIMT), lung function and quality of life questionnaires are assessed. The primary outcome consists of inhibition (binary response) of aspirin and ADP-induced platelet function at 6 months. Secondary outcomes include changes in inflammatory markers, CIMT, non-invasive measures of vascular stiffness, quality of life using questionnaires (EuroQol–five dimensions–five levels of perceived problems (EQ5D-5L), St. George’s COPD questionnaire) and to record occurrence of repeat hospitalisation, angina, myocardial infarction or death from baseline to 6 months. Safety outcomes will be rates of major and minor bleeding, forced expiratory volume in 1 s, forced vital capacity and Medical Research Council dyspnoea scale. Ethics and dissemination: The study was approved by the North East-Tyne and Wear South Research Ethics Committee (15/NE/0155). Findings of the study will be presented in scientific sessions and published in peer-reviewed journals. Trial registration number: ISRCTN43245574; Pre-results

Diagnostic and mechanistic implications of serum free light chains, albumin and alpha-fetoprotein in hepatocellular carcinoma

Background: Mass spectroscopy analysis suggested low serum albumin and high immunoglobulin free light chain (sFLC) levels may have diagnostic value in hepatocellular carcinoma (HCC). Our aims were to apply quantitative assays to confirm these observations, determine their diagnostic utility, and investigate the mechanisms involved. Methods: Albumin, sFLC, routine liver and renal function tests were measured in patients with chronic liver disease with (n=102) and without (n=113) HCC. The discriminant performance was compared with the current standard serological test alpha-fetoprotein (AFP) using receiver operating characteristic (ROC) and area under the curve (AUC) analyses. Results: sFLC and serum albumin were each confirmed to have discriminatory utility in HCC with AUC values of 0.7 and 0.8, respectively. sFLC were strongly correlated with gammaglobulin levels and both these were inversely related to serum albumin levels. The discriminatory utility of sFLC was retained after adjusting for renal and liver function. Conclusions: Serum levels of sFLC and albumin were strongly associated with HCC as predicted by mass spectroscopy. Discrimination of HCC by AFP was improved by the addition of either albumin or sFLC. Larger prospective studies are required to determine how AFP, sFLC and albumin might be combined in a useful diagnostic approach for HCC

Good Statistical Practice-development of tailored Good Clinical Practice training for statisticians

BACKGROUND: Statisticians are fundamental in ensuring clinical research, including clinical trials, are conducted with quality, transparency, reproducibility and integrity. Good Clinical Practice (GCP) is an international quality standard for the conduct of clinical trials research. Statisticians are required to undertake training on GCP but existing training is generic and, crucially, does not cover statistical activities. This results in statisticians undertaking training mostly unrelated to their role and variation in awareness and implementation of relevant regulatory requirements with regards to statistical conduct. The need for role-relevant training is recognised by the UK NHS Health Research Authority and the Medicines and Healthcare products Regulatory Agency (MHRA).METHODS: The Good Statistical Practice (GCP for Statisticians) project was instigated by the UK Clinical Research Collaboration (UKCRC) Registered Clinical Trials Unit (CTU) Statisticians Operational Group and funded by the National Institute for Health and Care Research (NIHR), to develop materials to enable role-specific GCP training tailored to statisticians. Review of current GCP training was undertaken by survey. Development of training materials were based on MHRA GCP. Critical review and piloting was conducted with UKCRC CTU and NIHR researchers with comment from MHRA. Final review was conducted through the UKCRC CTU Statistics group.RESULTS: The survey confirmed the need and desire for the development of dedicated GCP training for statisticians. An accessible, comprehensive, piloted training package was developed tailored to statisticians working in clinical research, particularly the clinical trials arena. The training materials cover legislation and guidance for best practice across all clinical trial processes with statistical involvement, including exercises and real-life scenarios to bridge the gap between theory and practice. Comprehensive feedback was incorporated. The training materials are freely available for national and international adoption.CONCLUSION: All research staff should have training in GCP yet the training undertaken by most academic statisticians does not cover activities related to their role. The Good Statistical Practice (GCP for Statisticians) project has developed and extensively piloted new, role-specific, comprehensive, accessible GCP training tailored to statisticians working in clinical research, particularly the clinical trials arena. This role-specific training will encourage best practice, leading to transparent and reproducible statistical activity, as required by regulatory authorities and funders.</p

Artificial intelligence in digital pathology: a diagnostic test accuracy systematic review and meta-analysis

Ensuring diagnostic performance of AI models before clinical use is key to the safe and successful adoption of these technologies. Studies reporting AI applied to digital pathology images for diagnostic purposes have rapidly increased in number in recent years. The aim of this work is to provide an overview of the diagnostic accuracy of AI in digital pathology images from all areas of pathology. This systematic review and meta-analysis included diagnostic accuracy studies using any type of artificial intelligence applied to whole slide images (WSIs) in any disease type. The reference standard was diagnosis through histopathological assessment and / or immunohistochemistry. Searches were conducted in PubMed, EMBASE and CENTRAL in June 2022. We identified 2976 studies, of which 100 were included in the review and 48 in the full meta-analysis. Risk of bias and concerns of applicability were assessed using the QUADAS-2 tool. Data extraction was conducted by two investigators and meta-analysis was performed using a bivariate random effects model. 100 studies were identified for inclusion, equating to over 152,000 whole slide images (WSIs) and representing many disease types. Of these, 48 studies were included in the meta-analysis. These studies reported a mean sensitivity of 96.3% (CI 94.1-97.7) and mean specificity of 93.3% (CI 90.5-95.4) for AI. There was substantial heterogeneity in study design and all 100 studies identified for inclusion had at least one area at high or unclear risk of bias. This review provides a broad overview of AI performance across applications in whole slide imaging. However, there is huge variability in study design and available performance data, with details around the conduct of the study and make up of the datasets frequently missing. Overall, AI offers good accuracy when applied to WSIs but requires more rigorous evaluation of its performance.Comment: 26 pages, 5 figures, 8 tables + Supplementary material

Laryngeal Dysplasia and narrow band imaging: secondary analysis of published data supports the role in patient follow up

Background: Clinicians have recognised the role of narrow band imaging (NBI) in the management of head and neck cancer in several studies. However, a recent systematic review was unable to pool the data on diagnostic efficacy in this setting owing to the heterogeneity in the published data. Methods: Secondary analysis of data, utilising Bayes’ theorem, from meta‐analyses and randomised trials Results: In patients with a histological diagnosis of mild dysplasia who show no abnormalities on NBI, the post‐test probability of malignancy is 2.3%, compared to 10.3% with conventional white light imaging (WLI). For severe dysplasia, similar post‐test probabilities after NBI and WLI are 8.0% and 29.7% respectively. Post‐test probabilities in this setting indicate the chance of missing malignancy following a negative NBI or WLI in patients who undergo no further intervention. This paper also provides a nomogram designed for use in this setting. Conclusions: This paper identifies the evidence base for use of NBI in the follow up for laryngeal dysplasia