Investigating harms of testing for ovarian cancer - psychological outcomes and cancer conversion rates in women with symptoms of ovarian cancer: A cohort study embedded in the multicentre ROCkeTS prospective diagnostic study.

OBJECTIVE: To investigate psychological correlates in women referred with suspected ovarian cancer via the fast-track pathway, explore how anxiety and distress levels change at 12 months post-testing, and report cancer conversion rates by age and referral pathway. DESIGN: Single-arm prospective cohort study. SETTING: Multicentre. Secondary care including outpatient clinics and emergency admissions. POPULATION: A cohort of 2596 newly presenting symptomatic women with a raised CA125 level, abnormal imaging or both. METHODS: Women completed anxiety and distress questionnaires at recruitment and at 12 months for those who had not undergone surgery or a biopsy within 3 months of recruitment. MAIN OUTCOME MEASURES: Anxiety and distress levels measured using a six-item short form of the State-Trait Anxiety Inventory (STAI-6) and the Impact of Event Scale - Revised (IES-r) questionnaire. Ovarian cancer (OC) conversion rates by age, menopausal status and referral pathway. RESULTS: Overall, 1355/2596 (52.1%) and 1781/2596 (68.6%) experienced moderate-to-severe distress and anxiety, respectively, at recruitment. Younger age and emergency presentations had higher distress levels. The clinical category for anxiety and distress remained unchanged/worsened in 76% of respondents at 12 months, despite a non-cancer diagnosis. The OC rates by age were 1.6% (95% CI 0.5%-5.9%) for age <40 years and 10.9% (95% CI 8.7%-13.6%) for age ≥40 years. In women referred through fast-track pathways, 3.3% (95% CI 1.9%-5.7%) of pre- and 18.5% (95% CI 16.1%-21.0%) of postmenopausal women were diagnosed with OC. CONCLUSIONS: Women undergoing diagnostic testing display severe anxiety and distress. Younger women are especially vulnerable and should be targeted for support. Women under the age of 40 years have low conversion rates and we advocate reducing testing in this group to reduce the harms of testing.

Periodontal health and patient-reported outcomes: A longitudinal analysis of data from non-specialist practice settings.

AIM: To explore the associations between periodontal health and patient-reported outcomes (PROs), accounting for changes over time, in a large, non-specialist dental practice patient cohort. MATERIALS AND METHODS: This longitudinal study used data from 13,162 dentate patients, collected by 162 dentists at routine appointments between May 2013 and April 2020, in 238 non-specialist dental practices across the United Kingdom. Dentists collected data, as part of routine clinical care, on periodontal probing pocket depths, alveolar bone loss, bleeding on probing, as well as a range of covariates. Patients inputted data on outcomes (oral pain/discomfort, dietary restrictions, and dental appearance). Mixed-effects logistic regression analysis was used to investigate the associations between periodontal health and PROs. Models accounted for clustering at the patient and dentist level and were adjusted for time and variables which were thought to confound these associations. RESULTS: The odds of all PROs tended to increase with worsening periodontal parameters. For example, the odds of reporting pain in the worst periodontal health category were 1.99 (95% confidence interval: 1.57-2.53) times higher than in the best periodontal health category. CONCLUSIONS: This study confirms, using a large longitudinal dataset from a unique non-specialist setting, the associations between poorer periodontal health and poorer PROs.

A novel method for the remote measurement of trismus in clinical trials using mobile phone cameras.

OBJECTIVE: To evaluate the reliability and validity of a novel method for remotely measuring trismus. MATERIALS AND METHODS: We recruited 60 volunteers who took three types of photographs at a fixed restricted jaw position mimicking limited mouth opening, including one selfie and one portrait with or without a reference frame. Additionally, the interincisal distance and the width of the upper central incisors were measured with a ruler, as per common practice. Measurements of trismus were made using image analysis software comparing different types of photos and calibration methods. Intraclass correlation coefficient (ICC) and 95% limits of agreement (LoA) with 95% confidence interval were calculated to evaluate reliability and validity. RESULTS: The proposed method demonstrated high reliability (ICC 0.998; 95% CI 0.997, 0.999). Calibration of photographs using at least a baseline photograph with an external reference frame yielded unbiased measurements and minimised variability. The use of selfies compared to portrait photos also increased variability. CONCLUSION: The measurement of trismus can be performed using images taken remotely by patients using their mobile phone cameras. The proposed method is highly accurate, with best results obtained by using a reference frame for calibration of portrait photographs. CLINICAL RELEVANCE: We propose an easy, cheap, and accurate method that allows for remote and frequent monitoring of trismus in clinical studies using patients' mobile phones.

Mind the gap: covariate constrained randomisation can protect against substantial power loss in parallel cluster randomised trials.

BACKGROUND: Cluster randomised trials often randomise a small number of units, putting them at risk of poor balance of covariates across treatment arms. Covariate constrained randomisation aims to reduce this risk by removing the worst balanced allocations from consideration. This is known to provide only a small gain in power over that averaged under simple randomisation and is likely influenced by the number and prognostic effect of the covariates. We investigated the performance of covariate constrained randomisation in comparison to the worst balanced allocations, and considered the impact on the power of the prognostic effect and number of covariates adjusted for in the analysis. METHODS: Using simulation, we examined the Monte Carlo type I error rate and power of cross-sectional, two-arm parallel cluster-randomised trials with a continuous outcome and four binary cluster-level covariates, using either simple or covariate constrained randomisation. Data were analysed using a small sample corrected linear mixed-effects model, adjusted for some or all of the binary covariates. We varied the number of clusters, intra-cluster correlation, number and prognostic effect of covariates balanced in the randomisation and adjusted in the analysis, and the size of the candidate set from which the allocation was selected. For each scenario, 20,000 simulations were conducted. RESULTS: When compared to the worst balanced allocations, covariate constrained randomisation with an adjusted analysis provided gains in power of up to 20 percentage points. Even with analysis-based adjustment for those covariates balanced in the randomisation, the type I error rate was not maintained when the intracluster correlation is very small (0.001). Generally, greater power was achieved when more prognostic covariates are restricted in the randomisation and as the size of the candidate set decreases. However, adjustment for weakly prognostic covariates lead to a loss in power of up to 20 percentage points. CONCLUSIONS: When compared to the worst balanced allocations, covariate constrained randomisation provides moderate to substantial improvements in power. However, the prognostic effect of the covariates should be carefully considered when selecting them for inclusion in the randomisation.

The current use of feasibility studies in the assessment of feasibility for stepped-wedge cluster randomised trials: a systematic review.

BACKGROUND: Stepped-wedge cluster randomised trials (SW-CRTs) are a pragmatic trial design, providing an unprecedented opportunity to increase the robustness of evidence underpinning implementation and quality improvement interventions. Given the complexity of the SW-CRT, the likelihood of trials not delivering on their objectives will be mitigated if a feasibility study precedes the definitive trial. It is not currently known if feasibility studies are being conducted for SW-CRTs nor what the objectives of these studies are. METHODS: Searches were conducted of several databases to identify published feasibility studies which were designed to inform a future SW-CRT. For each eligible study, data were extracted on the characteristics of and rationale for the feasibility study; the process for determining progression to the main trial; how the feasibility study informed the main trial; and whether the main trial went ahead. A narrative synthesis and descriptive analysis are presented. RESULTS: Eleven feasibility studies were identified, which included eight completed study reports and three protocols. Three studies used a stepped-wedge design and these were the only studies to be randomised. Studies were predominantly of a mixed-methods design. Only one study assessed specific features related to the feasibility of using a SW-CRT and one investigated the time taken to complete the study procedures. The other studies were mostly assessing the feasibility and acceptability of the intervention. CONCLUSION: Published feasibility studies for SW-CRTs are scarce and those that are being reported do not investigate issues specific to the complexities of the trial design. When conducting feasibility studies in advance of a definitive SW-CRT, researchers should consider assessing the feasibility of study procedures, particularly those specific to the SW-CRT design, and ensure that the findings are published for the benefit of other researchers.

The impact of an intervention to increase uptake to structured self-management education for people with type 2 diabetes mellitus in primary care (the embedding package), compared to usual care, on glycaemic control: study protocol for a mixed methods study incorporating a wait-list cluster randomised controlled trial.

BACKGROUND: Approximately 425 million people globally have diabetes, with ~ 90% of these having Type 2 Diabetes Mellitus (T2DM). This is a condition that leads to a poor quality of life and increased risk of serious health complications. Structured self-management education (SSME) has been shown to be effective in improving glycaemic control and patient related outcome measures and to be cost-effective. However, despite the demonstrated benefits, attendance at SSME remains low. An intervention has been developed to embed SSME called the 'Embedding Package'. The intervention aims to address barriers and enhance enablers to uptake of SSME at patient, healthcare professional and organisational levels. It comprises a marketing strategy, user friendly and effective referral pathways, new roles to champion SSME and a toolkit of resources. METHODS: A mixed methods study incorporating a wait-list cluster randomised trial and ethnographic study, including 66 UK general practices, will be conducted with two intervention start times (at 0 and 9 months), each followed by an active delivery phase. At 18 months, the intervention will cease to be actively delivered and a 12 month observational follow-up phase will begin. The intervention, the Embedding Package, aims to increase SSME uptake and subsequent improvements in health outcomes, through a clear marketing strategy, user friendly and effective referral pathways, a local clinical champion and an 'Embedder' and a toolkit of resources for patients, healthcare professionals and other key stakeholders. The primary aim is, through increasing uptake to and attendance at SSME, to reduce HbA1c in people with T2DM compared with usual care. Secondary objectives include: assessing whether there is an increase in referral to and uptake of SSME and improvements in biomedical and psychosocial outcomes; an assessment of the sustainability of the Embedding Package; contextualising the process of implementation, sustainability of change and the 'fit' of the Embedding Package; and an assessment of the cost-effectiveness of the Embedding Package. DISCUSSION: This study will assess the effectiveness, cost-effectiveness and sustainability of the Embedding Package, an intervention which aims to improve biomedical and psychosocial outcomes of people with T2DM, through increased referral to and uptake of SSME. TRIAL REGISTRATION: International Standard Randomised Controlled Trials Number ISRCTN23474120. Assigned 05/04/2018. The study was prospectively registered. On submission of this manuscript practice recruitment is complete, participant recruitment is ongoing and expected to be completed by the end of 2019.

Increasing uptake of structured self-management education programmes for type 2 diabetes in a primary care setting: a feasibility study.

BACKGROUND: Structured self-management education (SSME) for people with type 2 diabetes mellitus (T2DM) improves biomedical and psychological outcomes, whilst being cost-effective. Yet uptake in the UK remains low. An 'Embedding Package' addressing barriers and enablers to uptake at patient, health care professional and organisational levels has been developed. The aim of this study was to test the feasibility of conducting a subsequent randomised controlled trial (RCT) to evaluate the Embedding Package in primary care, using a mixed methods approach. METHODS: A concurrent mixed methods approach was adopted. Six general practices in the UK were recruited and received the intervention (the Embedding Package). Pseudonymised demographic, biomedical and SSME data were extracted from primary care medical records for patients recorded as having a diagnosis of T2DM. Descriptive statistics assessed quantitative data completeness and accuracy. Quantitative data were supplemented and validated by a patient questionnaire, for which two recruitment methods were trialled. Where consent was given, the questionnaire and primary care data were linked and compared. The cost of the intervention was estimated. An integrated qualitative study comprising ethnography and stakeholder and patient interviews explored the process of implementation, sustainability of change and 'fit' of the intervention. Qualitative data were analysed using a thematic framework guided by the Normalisation Process Theory (NPT). RESULTS: Primary care data were extracted for 2877 patients. The primary outcome for the RCT, HbA1c, was over 90% complete. Questionnaires were received from 423 (14.7%) participants, with postal invitations yielding more participants than general practitioner (GP) prompts. Ninety-one percent of questionnaire participants consented to data linkage. The mean cost per patient for the Embedding Package was £8.94, over a median follow-up of 162.5 days. Removing the development cost, this reduces to £5.47 per patient. Adoption of ethnographic and interview methods in the collection of data was appropriate, and the use of NPT, whilst challenging, enhanced the understanding of the implementation process. The need to delay the collection of patient interview data to enable the intervention to inform patient care was highlighted. CONCLUSIONS: It is feasible to collect data with reasonable completeness and accuracy for the subsequent RCT, although refinement to improve the quality of the data collected will be undertaken. Based on resource use data collected, it was feasible to produce cost estimates for each individual component of the Embedding Package. The methods chosen to generate, collect and analyse qualitative data were satisfactory, keeping participant burden low and providing insight into potential refinements of the Embedding Package and customisation of the methods for the RCT. TRIAL REGISTRATION: ISRCTN, ISRCTN21321635, Registered 07/07/2017-retrospectively registered.

Unequal cluster sizes in stepped-wedge cluster randomised trials: a systematic review.

OBJECTIVES: To investigate the extent to which cluster sizes vary in stepped-wedge cluster randomised trials (SW-CRT) and whether any variability is accounted for during the sample size calculation and analysis of these trials. SETTING: Any, not limited to healthcare settings. PARTICIPANTS: Any taking part in an SW-CRT published up to March 2016. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome is the variability in cluster sizes, measured by the coefficient of variation (CV) in cluster size. Secondary outcomes include the difference between the cluster sizes assumed during the sample size calculation and those observed during the trial, any reported variability in cluster sizes and whether the methods of sample size calculation and methods of analysis accounted for any variability in cluster sizes. RESULTS: Of the 101 included SW-CRTs, 48% mentioned that the included clusters were known to vary in size, yet only 13% of these accounted for this during the calculation of the sample size. However, 69% of the trials did use a method of analysis appropriate for when clusters vary in size. Full trial reports were available for 53 trials. The CV was calculated for 23 of these: the median CV was 0.41 (IQR: 0.22-0.52). Actual cluster sizes could be compared with those assumed during the sample size calculation for 14 (26%) of the trial reports; the cluster sizes were between 29% and 480% of that which had been assumed. CONCLUSIONS: Cluster sizes often vary in SW-CRTs. Reporting of SW-CRTs also remains suboptimal. The effect of unequal cluster sizes on the statistical power of SW-CRTs needs further exploration and methods appropriate to studies with unequal cluster sizes need to be employed.

An imbalance in cluster sizes does not lead to notable loss of power in cross-sectional, stepped-wedge cluster randomised trials with a continuous outcome.

BACKGROUND: The current methodology for sample size calculations for stepped-wedge cluster randomised trials (SW-CRTs) is based on the assumption of equal cluster sizes. However, as is often the case in cluster randomised trials (CRTs), the clusters in SW-CRTs are likely to vary in size, which in other designs of CRT leads to a reduction in power. The effect of an imbalance in cluster size on the power of SW-CRTs has not previously been reported, nor what an appropriate adjustment to the sample size calculation should be to allow for any imbalance. We aimed to assess the impact of an imbalance in cluster size on the power of a cross-sectional SW-CRT and recommend a method for calculating the sample size of a SW-CRT when there is an imbalance in cluster size. METHODS: The effect of varying degrees of imbalance in cluster size on the power of SW-CRTs was investigated using simulations. The sample size was calculated using both the standard method and two proposed adjusted design effects (DEs), based on those suggested for CRTs with unequal cluster sizes. The data were analysed using generalised estimating equations with an exchangeable correlation matrix and robust standard errors. RESULTS: An imbalance in cluster size was not found to have a notable effect on the power of SW-CRTs. The two proposed adjusted DEs resulted in trials that were generally considerably over-powered. CONCLUSIONS: We recommend that the standard method of sample size calculation for SW-CRTs be used, provided that the assumptions of the method hold. However, it would be beneficial to investigate, through simulation, what effect the maximum likely amount of inequality in cluster sizes would be on the power of the trial and whether any inflation of the sample size would be required.

The use of feasibility studies for stepped-wedge cluster randomised trials: protocol for a review of impact and scope.

INTRODUCTION: The stepped-wedge cluster randomised trial (SW-CRT) is a complex design, for which many decisions about key design parameters must be made during the planning. These include the number of steps and the duration of time needed to embed the intervention. Feasibility studies are likely to be useful for informing these decisions and increasing the likelihood of the main trial's success. However, the number of feasibility studies being conducted for SW-CRTs is currently unknown. This review aims to establish the number of feasibility studies being conducted for SW-CRTs and determine which feasibility issues are commonly investigated. METHODS AND ANALYSIS: Fully published feasibility studies for SW-CRTs will be identified, according to predefined inclusion criteria, from searches conducted in Ovid MEDLINE, Scopus, Embase and PsycINFO. To also identify and gain information on unpublished feasibility studies the following will be contacted: authors of published SW-CRTs (identified from the most recent systematic reviews); contacts for registered SW-CRTs (identified from clinical trials registries); lead statisticians of UK registered clinical trials units and researchers known to work in the area of SW-CRTs.Data extraction will be conducted independently by two reviewers. For the fully published feasibility studies, data will be extracted on the study characteristics, the rationale for the study, the process for determining progression to a main trial, how the study informed the main trial and whether the main trial went ahead. The researchers involved in the unpublished feasibility studies will be contacted to elicit the same information.A narrative synthesis will be conducted and provided alongside a descriptive analysis of the study characteristics. ETHICS AND DISSEMINATION: This review does not require ethical approval, as no individual patient data will be used. The results of this review will be published in an open-access peer-reviewed journal.