Publications
217 results found
Sin J, Henderson C, Elkes J, et al., 2022, Effect of digital psychoeducation and peer support on the mental health of family carers supporting individuals with psychosis in England (COPe-support): a randomised clinical trial, The Lancet Digital Health, Vol: 4, Pages: e320-e329, ISSN: 2589-7500
BACKGROUND: Psychoeducation delivered face-to-face is effective in alleviating mental health morbidities in family carers of individuals with psychosis. However, research in such interventions delivered online is scarce. We evaluated the effectiveness of a digital multicomponent intervention-COPe-support-in improving carers' mental wellbeing and caregiving-related outcomes. METHODS: In this two-arm, individually randomised, superiority trial, people aged 18 years or older who provided at least weekly support in any format for a relative or close friend affected by psychosis across England were randomly assigned (1:1) to either COPe-support or a passive online information resource using an independent online system. Participants were recruited through 30 mental health UK National Health Service trusts. The study team were masked to allocation and assessment of outcomes as all data collection took place online. Participants had access to either condition for 40 weeks and were advised to spend at least half an hour per week over the initial 20 weeks to go through materials at their own pace and to allow time to integrate knowledge and skills learned into practice. It was not feasible to mask participants or the online facilitator to intervention allocation. COPe-support provided psychoeducation on psychosis-related caregiving strategies and forums with professionals and other carers, and the control intervention comprised a passive online information resource. The primary outcome at 20 weeks was mental wellbeing measured by the Warwick-Edinburgh Mental Wellbeing Scale (WEMWBS; minimally clinically important difference [MCID] 3). This trial is registered with ISRCTN, 89563420. FINDINGS: Between March 1, 2018, and Feb 14, 2020, 407 participants were randomly assigned, with 204 allocated to COPe-support and 203 allocated to control. The participants (mean age 53·1 years, SD 13·2) were mostly female (330 [81%] of 407 participants) and White (359 [88%] of 407
Cornelius V, 2022, Improving the analysis of adverse event in randomised controlled trials, Journal of Clinical Epidemiology, Vol: 144, Pages: 185-192, ISSN: 0895-4356
Analyzing treatment harm is vital but problematic with the relatively small sample sizes afforded in randomized controlled trials (RCTs). Good analysis practice for efficacy outcomes are well established but there has been minimal progress for the analysis of adverse events (AEs). In this commentary we examine four key issues for AE analysis. Namely, why harm data in RCTs is undervalued, why AE analysis is difficult, what aspects of current analysis practice are unsatisfactory, and the challenges for selection and interpretation of AEs results in publications. We discuss how the value of harm data from RCTs could be better realized by reframing the research question to one for detecting signals of adverse reactions. We align established good statistical practice to current unsatisfactory practice. We encourage use of Bayesian analyses to enable cumulative assessment of harm across trial research phases and discourage selecting AEs to report based on arbitrary rules. We propose comprehendible summaries to be based on core outcome sets, serious and pre-specified events, and events leading to discontinuation. Analysis of AEs in contemporary clinical trials needs attention to progress. In the following we have outlined immediate, mid and longer-term strategies for trialists to adopt to support a change in practice
Cro S, Cornelius V, Capon F, et al., 2022, The interleukin 1 receptor antagonist anakinra to reduce disease severity of palmoplantar pustulosis in adults: APRICOT RCT and PLUM mechanistic study, Efficacy and Mechanism Evaluation, Vol: 9, Pages: 1-106, ISSN: 2050-4365
BackgroundPalmoplantar pustulosis is a rare, debilitating, chronic skin disease involving the hands and feet, and there are limited treatment options. Mechanistic findings suggest that interleukin 1 may be a pathogenic driver.ObjectiveTo determine whether or not anakinra [Sobi (Swedish Orphan Biovitrum AB), Stockholm, Sweden], an interleukin 1 receptor antagonist, delivers therapeutic benefit in palmoplantar pustulosis.DesignA Phase IV, randomised, double-blind, placebo-controlled study with two stages and an adaptive element (24 participants in stage 1, 64 participants in total) with an open-label extension.SettingSixteen hospitals across England, Scotland and Wales.ParticipantsAdults (aged ≥ 18 years) with a diagnosis of palmoplantar pustulosis and a disease duration of > 6 months and of sufficient impact and severity to require systemic therapy.InterventionsParticipants were randomised (1 : 1) to daily self-administered subcutaneous injection of either anakinra or a placebo for 8 weeks.Main outcome measuresThe primary outcome was the Palmoplantar Pustulosis Area and Severity Index score measured at 0, 1, 4, 8 and 12 weeks, with the primary end point at 8 weeks adjusted for baseline. Secondary outcomes included other investigator-assessed efficacy measures of disease severity, safety measures and participant-reported measures of efficacy and impact.ResultsA total of 64 participants (mean baseline Palmoplantar Pustulosis Area and Severity Index score of 17.8, standard deviation 10.5) received anakinra (n = 31) or the placebo (n = 33). In the primary intention-to-treat analysis, which estimated the effect of the treatment policy, the mean treatment group difference at 8 weeks after adjustment for baseline Palmoplantar Pustulosis Area and Severity Index score was –1.65 (95% confidence interval –4.77 to 1.47; p = 0.300), in favour of anakinra relative to placebo, but was not statis
Stewart L, McConnell BB, Darboe B, et al., 2022, Social singing, culture and health: interdisciplinary insights from the CHIME project for perinatal mental health in The Gambia, Health Promotion International, Vol: 37, Pages: i18-i25, ISSN: 0957-4824
Arts in Health initiatives and interventions to support health have emerged from and been applied to mainly WEIRD (Western, Educated, Industrialized, Rich and Democratic) contexts. This overlooks the rich cultural traditions that exist across the globe, where community groups often make prolific use of participatory song and dance as a part of ceremonies, ritual and gatherings in everyday life. Here, we argue that these practices can provide a valuable starting point for the co-development of health interventions, illustrated by the CHIME project for perinatal mental health in The Gambia, which worked with local Kanyeleng groups (female fertility societies) to design and evaluate a brief intervention to support maternal mental health through social singing. Here, we use the project as a lens through which to highlight the value of co-creation, cultural embeddedness and partnership building in global health research.
Batchelor R, Gulshan S, Shritharan H, et al., 2022, Perceived acceptability and experiences of a digital psychoeducation and peer support intervention (COPe-support): interview study with carers supporting individuals with psychosis, Journal of Medical Internet Research, Vol: 24, ISSN: 1438-8871
Background:Web-based mental health interventions offer a novel, accessible, and self-paced approach to care delivery to family carers (ie, relatives and close friends who support a loved one with psychosis). We coproduced COPe-support (Carers fOr People with Psychosis e-support), a psychoeducational intervention delivered via an enriched web-based learning environment with network support from professionals and peers. In addition to the rigorous investigation of the effectiveness of COPe-support on the well-being of carers and mental health outcomes, it is imperative to understand the experiences of using the web-based intervention by carers and its associated web-based implementation and facilitation strategies.Objective:This study aims to explore the experiences of carers and perceived acceptability of COPe-support and its different components, how carers found engagement with COPe-support affected their own well-being and caregiving, and the ideas of carers for improving COPe-support and its delivery to inform any future wider implementation.Methods:We conducted a qualitative study, individually interviewing 35 carers, following their use of COPe-support for 8 months through a web-based, randomized controlled trial across England. A semistructured guide with open-ended questions was used to explore the experiences of carers and perceived acceptability of the intervention and their ideas to improve the provision. All interviews were conducted remotely through mobile phones or internet communication media, audio recorded and transcribed verbatim. We used a thematic analysis framework to analyze the data.Results:Three key themes were identified: remote, flexible, and personalized support; impacts on well-being and outlook on caregiving; and future implementation and integration with existing services. Overall, carers found COPe-support a flexible source of knowledge and support from professionals and peers that they could personalize to suit their own needs and conv
Mace S, Dzahini O, Cornelius V, et al., 2022, Incident infection during the first year of treatment - a comparison of clozapine and paliperidone palmitate long-acting injection, Journal of Psychopharmacology, Vol: 36, Pages: 232-237, ISSN: 0269-8811
Background:To examine the risk of infection in patients prescribed clozapine compared with patients prescribed paliperidone palmitate long-acting injection (PPLAI).Method:A retrospective, 1-year, cohort study conducted on events occurring in eligible patients beginning treatment for the first time with clozapine or PPLAI between June 2017 and June 2019 in a UK mental health trust providing in-patient and out-patient services.Results:The study included 64 patients starting clozapine and 120 patients starting PPLAI. Incidence of infection was greater in clozapine starters than in PPLAI starters (28% vs 6%; p = 0.001; adjusted odds ratio 5.82 (95% confidence interval (CI) = 2.15–15.76, p = 0.001). Infectious episodes in clozapine patients were not related to changes in neutrophil counts. Incident infection in the clozapine group was highest in the first 3 months of treatment. The most commonly reported infection in the clozapine group was chest infection; however, the majority of infections were non-chest-related.Conclusion:Patients starting clozapine showed a substantially increased likelihood of infection compared with patients starting PPLAI.
Cro S, Cornelius VR, Pink AE, et al., 2022, Anakinra for palmoplantar pustulosis: results from a randomized, double-blind, multicentre, two staged, adaptive placebo controlled trial (APRICOT)., British Journal of Dermatology, Vol: 186, Pages: 245-256, ISSN: 0007-0963
BACKGROUND: Palmoplantar pustulosis (PPP) is a rare, debilitating, chronic inflammatory skin disease affecting the hands and feet. Clinical, immunological and genetic findings suggest a pathogenic role for interleukin (IL)-1. OBJECTIVE: To determine whether anakinra (an IL-1 receptor antagonist) delivers therapeutic benefit for PPP. METHODS: A randomised (1:1), double-blind, two-staged, adaptive, UK multi-centre, placebo-controlled trial. Participants had a diagnosis of PPP (>6 months) requiring systemic therapy. Treatment was eight weeks of anakinra or placebo via daily self-administered subcutaneous injections. The primary outcome was the Palmoplantar Pustulosis Psoriasis Area and Severity Index (PPPASI) at 8 weeks. RESULTS: A total of 374 patients were screened and 64 were enrolled (31 anakinra, 33 placebo) with mean baseline PPPASI 17.8 (SD=10.5); PPP investigator's global assessment severe (50%) or moderate (50%). The baseline adjusted mean difference in PPPASI favoured anakinra but did not demonstrate superiority in intention-to-treat analysis, -1.65, 95% CI [-4.77 to 1.47], p=0.300. Secondary objective measures including fresh pustule count (2.94, 95% CI [-26.44 to 32.33] favouring anakinra), total pustule count (-30.08, 95% CI [-83.20 to 23.05] favouring placebo), and patient-reported outcomes, similarly did not show superiority of anakinra. When modelling the impact of adherence, the PPPASI complier average causal effect (CACE) for an individual who receives ≥90% total treatment (48% anakinra group), was -3.80, 95% CI [-10.76 to 3.16], p=0.285. No serious adverse events occurred. CONCLUSIONS: No evidence for superiority of anakinra was found. IL-1 blockade is not a useful intervention for the treatment of PPP.
Van Vogt E, Cro S, Cornelius VR, et al., 2021, Individual participant data meta-analysis versus aggregate data meta-analysis: a case study in eczema and food allergy prevention., Clinical and Experimental Allergy, Vol: 52, ISSN: 0954-7894
INTRODUCTION: Meta-analysis traditionally uses aggregate data from published reports. Individual Participant Data (IPD) meta-analysis, which obtains and synthesises participant-level data, is potentially more informative, but resource-intensive. The impact on the findings of meta-analyses using IPD in comparison to aggregate data has rarely been formally evaluated. METHODS: We conducted a secondary analysis of a Cochrane systematic review of skin care interventions for preventing eczema and food allergy in infants to identify the impact of the analytical choice on the review's findings. We used aggregate data meta-analysis only and contrasted the results against those of the originally published IPD meta-analysis. All meta-analysis used random effects inverse variance models. Certainty of evidence was evaluated using GRADE. RESULTS: The pooled treatment effects for the Cochrane systematic review's co-primary outcomes of eczema and food allergy were similar in IPD meta-analysis (eczema RR 1.03, 95% CI 0.81, 1.31; I2 41%, 7 studies 3075 participants), and aggregate meta-analysis (eczema RR 1.01 95% CI 0.77, 1.33; I2 53%, 7 studies, 3089 participants). In aggregate meta-analysis the statistical heterogeneity could not be explained but using IPD it was explained by one trial which used a different, bathing intervention. For IPD meta-analysis, risk of bias was assessed as lower and more adverse event data were available compared with aggregate meta-analysis. This resulted in higher certainty of evidence, especially for adverse events. IPD meta-analysis enabled analysis of treatment interactions by age and hereditary eczema risk; and analysis of the effect of treatment adherence using pooled complier-adjusted-causal-effect analysis, none of which was possible in aggregate meta-analysis. CONCLUSIONS: For this systematic review, IPD did not significantly change primary outcome risk ratios compared with aggregate data meta-analysis. However, certainty of evidence, safety out
Partington G, Cro S, Mason A, et al., 2021, Design and analysis features used in small population and rare disease trials: A targeted review., Journal of Clinical Epidemiology, Vol: 144, Pages: 93-101, ISSN: 0895-4356
OBJECTIVE: Frequentist trials in Rare disease/small population trials often require unfeasibly large sample size to detect minimum clinically important differences. A targeted review was performed investigating what design and analysis methods these trials use when facing restricted recruitment. STUDY DESIGN AND SETTING: Targeted Review searching EMBASE and MEDLINE for Phase II-IV RCTs reporting 'rare' disease or 'small population' within title or abstract, since 2009. RESULTS: A total of 6,128 articles were screened with 64 trials eligible (4 Bayesian, 60 frequentist trials). Frequentists trials had planned power ranging 72-90% (median: 80%) but reported recruiting a mean of 6.6% below the planned sample size (n=38) [median 0%, IQR (-5%, 5%)], most used standard type 1 error (52 used 5% and 1 used 1%), and the average standardised effect was high (0.7) with 50% missing their assumed level. Of the 4 Bayesian trials, 3 used informed priors, 2 and 1 trials performed sensitivity analysis for the impact of priors on design and analysis respectively. Historical data, expert consensus, or both were used to construct informative priors. Bayesian trials required 30%-2400% less participants than using frequentist frameworks. CONCLUSION: Bayesian trials required lower sample size through use of informative priors. Most frequentists didn't achieve their target sample size. Bayesian methods offer promising solutions for such trials but are underutilised.
Munro APS, Janani L, Cornelius V, et al., 2021, Safety and immunogenicity of seven COVID-19 vaccines as a third dose (booster) following two doses of ChAdOx1 nCov-19 or BNT162b2 in the UK (COV-BOOST): a blinded, multicentre, randomised, controlled, phase 2 trial, The Lancet, Vol: 398, ISSN: 0140-6736
BACKGROUND: Few data exist on the comparative safety and immunogenicity of different COVID-19 vaccines given as a third (booster) dose. To generate data to optimise selection of booster vaccines, we investigated the reactogenicity and immunogenicity of seven different COVID-19 vaccines as a third dose after two doses of ChAdOx1 nCov-19 (Oxford-AstraZeneca; hereafter referred to as ChAd) or BNT162b2 (Pfizer-BioNtech, hearafter referred to as BNT). METHODS: COV-BOOST is a multicentre, randomised, controlled, phase 2 trial of third dose booster vaccination against COVID-19. Participants were aged older than 30 years, and were at least 70 days post two doses of ChAd or at least 84 days post two doses of BNT primary COVID-19 immunisation course, with no history of laboratory-confirmed SARS-CoV-2 infection. 18 sites were split into three groups (A, B, and C). Within each site group (A, B, or C), participants were randomly assigned to an experimental vaccine or control. Group A received NVX-CoV2373 (Novavax; hereafter referred to as NVX), a half dose of NVX, ChAd, or quadrivalent meningococcal conjugate vaccine (MenACWY) control (1:1:1:1). Group B received BNT, VLA2001 (Valneva; hereafter referred to as VLA), a half dose of VLA, Ad26.COV2.S (Janssen; hereafter referred to as Ad26) or MenACWY (1:1:1:1:1). Group C received mRNA1273 (Moderna; hereafter referred to as m1273), CVnCov (CureVac; hereafter referred to as CVn), a half dose of BNT, or MenACWY (1:1:1:1). Participants and all investigatory staff were blinded to treatment allocation. Coprimary outcomes were safety and reactogenicity and immunogenicity of anti-spike IgG measured by ELISA. The primary analysis for immunogenicity was on a modified intention-to-treat basis; safety and reactogenicity were assessed in the intention-to-treat population. Secondary outcomes included assessment of viral neutralisation and cellular responses. This trial is registered with ISRCTN, number 73765130. FINDINGS: Between June 1 and June
Ue KL, Hunter H, Cornelius V, et al., 2021, Preliminary results of a phase II trial of peanut oral immunotherapy in adults, Publisher: WILEY, Pages: 1655-1656, ISSN: 0954-7894
Batchelor R, Gulshan S, Shritharan H, et al., 2021, Perceived acceptability and experiences of a digital psychoeducation and peer support intervention (COPe-support): interview study with carers supporting individuals with psychosis (Preprint), Publisher: JMIR Publications Inc.
Background:Digital mental health interventions offer a novel, accessible and self-paced approach to care delivery to family carers, i.e., relatives and close friends who support a loved one with psychosis. We co-produced COPe-support, a psychoeducational intervention delivered via an enriched online environment with network support from professionals and peers. In addition to rigorous investigation of the effectiveness of COPe-support on carers’ wellbeing and mental health outcomes, it is imperative to understand carers’ experiences in using the digital intervention and its associated online implementation and facilitation strategies.Objective:This study aimed to explore (1) carers’ experience and perceived acceptability of COPe-support and its different components, and (2) how they found engagement with COPe-support affected their own wellbeing and caregiving.Methods:We conducted a qualitative study, individually interviewing 35 carers after their use of COPe-support for 8 months through an online randomised controlled trial across England. A semi-structured guide with open-ended questions was used to explore carers’ experience and perceived acceptability of the intervention, and their ideas to improve the provision. All interviews were conducted remotely through mobile phone or internet communication media, audio-recorded, and transcribed verbatim. We used the thematic analysis framework approach to analyse the data.Results:Three key themes were identified: (i) remote, flexible and personalised, (ii) impacts on well-being and outlook on caregiving, and (iii) future implementation and integration with existing services. Overall, carers identified COPe-support as a helpful resource for themselves and for their caregiving role. Participants’ experiences, usage and activity on COPe-support varied a great deal and differed amongst carers of various ages and level of computer literacy.Conclusions:Carers found COPe-support a flexible source
Charania AS, Vergis N, Phillips R, et al., 2021, Multi-Arm Trial of Inflammatory Signal Inhibitors (MATIS) for hospitalised patients with mild or moderate Covid-19 pneumonia: a structured summary of a study protocol for a randomised controlled trial, 63rd ASH Annual Meeting and Exposition, Publisher: American Society of Hematology, Pages: 4200-4200, ISSN: 0006-4971
Clark I, Wallman P, Cornelius V, et al., 2021, Factors predicting relapse and treatment discontinuation with paliperidone 3-monthly long-acting injection: a 2-year naturalistic follow-up study, European Psychiatry, Vol: 64, ISSN: 0924-9338
BackgroundPaliperidone 3-monthly (PP3M) long-acting injection has proven efficacy and effectiveness in schizophrenia. Little is known of its effectiveness in other diagnoses.MethodsAll patients starting PP3M were followed up for 2 years. Main outcome measures were relapse and discontinuation from PP3M. Post hoc we examined outcomes in those switched back to one monthly paliperidone (PP1M) long-acting injection.ResultsOverall, 186 patients were followed-up. At the 2-year end point, 110 patients (59%) were still receiving PP3M, and 129 (70%) were receiving some form of paliperidone long-acting injection. Discontinuation from paliperidone long-acting injections (PPLAIs) was more likely with a nonschizophrenia diagnosis (hazard ratio [HR] for continuation 0.429 [95% confidence intervals (CI) – 0.21, 0.87 p = 0.018)), and prior clozapine use [in PP3M patients; HR for discontinuation 1.87 [95% CI – 1.05, 3.30 p = 0.032]). Relapse occurred in 20 (11%) of those receiving PP3M. Relapse on PP3M and PPLAIs was more likely in nonschizophrenia diagnosis (HR 0.17 for remaining relapse-free [95% CI – 0.06, 0.50; p = 0.001]; HR 0.21 [95% CI – 0.08, 0.58 p = 0.002], respectively), polypharmacy in PP3M patients (HR for relapse 7.91 [95% CI – 3.73, 22.9; p < 0.001]) and PPLAI patients (HR for relapse 6.45 [95% CI – 2.49, 16.5; p < 0.001]), and prior clozapine use in PP3M patients (HR for relapse 6.11 [95% CI – 1.82, 20.5; p = 0.003]) and PPLAI patients (HR for relapse 4.52 (95% CI – 1.51, 13.5; p = 0.007).ConclusionsOutcomes with PP3M are excellent in practice, even when used outside its formal license. PP3M was relatively more effective in those with an F20 schizophrenia diagnosis and in those never before considered for or prescribed clozapine.
Gimeno H, Polatajko HJ, Cornelius V, et al., 2021, Rehabilitation in childhood-onset hyperkinetic movement disorders including dystonia: Treatment change in outcomes across the ICF and feasibility of outcomes for full trial evaluation, EUROPEAN JOURNAL OF PAEDIATRIC NEUROLOGY, Vol: 33, Pages: 159-167, ISSN: 1090-3798
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Chis Ster A, Phillips R, Sauzet O, et al., 2021, Improving analysis practice of continuous adverse event outcomes in randomised controlled trials – a distributional approach, Trials, Vol: 22, ISSN: 1745-6215
BackgroundRandomised controlled trials (RCTs) provide valuable information for developing harm profiles but current analysis practices to detect between-group differences are suboptimal. Drug trials routinely screen continuous clinical and biological data to monitor participant harm. These outcomes are regularly dichotomised into abnormal/normal values for analysis. Despite the simplicity gained for clinical interpretation, it is well established that dichotomising outcomes results in a considerable reduction in information and thus statistical power. We propose an automated procedure for the routine implementation of the distributional method for the dichotomisation of continuous outcomes proposed by Peacock and Sauzet, which retains the precision of the comparison of means.MethodsWe explored the use of a distributional approach to compare differences in proportions based on the comparison of means which retains the power of the latter. We applied this approach to the screening of clinical and biological data as a means to detect ‘signals’ for potential adverse drug reactions (ADRs). Signals can then be followed-up in further confirmatory studies. Three distributional methods suitable for different types of distributions are described. We propose the use of an automated approach using the observed data to select the most appropriate distribution as an analysis strategy in a RCT setting for multiple continuous outcomes. We illustrate this approach using data from three RCTs assessing the efficacy of mepolizumab in asthma or COPD. Published reference ranges were used to define the proportions of participants with abnormal values for a subset of 10 blood tests. The between-group distributional and empirical differences in proportions were estimated for each blood test and compared.ResultsWithin trials, the distributions varied across the 10 outcomes demonstrating value in a practical approach to selecting the distributional method in the context of multipl
Lammons W, Moss R, Battersby C, et al., 2021, Incorporating parent, former patient, and clinician perspectives in the design of a national UK double-cluster, randomised controlled trial addressing uncertainties in preterm nutrition, BMJ Paediatrics Open, Vol: 5, ISSN: 2399-9772
Background: Comparative effectiveness randomised controlled trials are powerful tools to resolve uncertainties in existing treatments and care processes. We sought parent and patient perspectives on the design of a planned national, double-cluster randomised controlled trial (COLLABORATE) to resolve two longstanding uncertainties in preterm nutrition.Methods: We used qualitative focus groups and interviews with parents, former patients and clinicians. We followed the Consolidated Criteria for Reporting Qualitative Research checklist and conducted framework analysis, a specific methodology within thematic analysis.Results: We identified support for the trial’s methodology and vision, and elicited themes illustrating parents’ emotional needs in relation to clinical research. These were: relieving the pressure on mothers to breastfeed; opt-out consent as reducing parent stress; the desire for research to be a partnership between clinicians, parents and researchers; the value of presenting trial information in a collaborative tone; and in a format that allows assimilation by parents at their own pace. We identified anxiety and cognitive dissonance among some clinicians in which they recognised the uncertainties that justify the trial but felt unable to participate because of their strongly held views.Conclusions: The early involvement of parents and former patients identified the centrality of parents’ emotional needs in the design of comparative effectiveness research. These insights have been incorporated into trial enrolment processes and information provided to participants. Specific outputs were a two-sided leaflet providing very brief as well as more detailed information, and use of language that parents perceive as inclusive and participatory. Further work is warranted to support clinicians to address personal biases that inhibit trial participation.
Tan P-T, Cro S, Van Vogt E, et al., 2021, A review of the use of controlled multiple imputation in randomised controlled trials with missing outcome data, BMC Medical Research Methodology, Vol: 21, ISSN: 1471-2288
Background:Missing data are common in randomised controlled trials (RCTs) and can bias results if not handled appropriately. A statistically valid analysis under the primary missing-data assumptions should be conducted, followed by sensitivity analysis under alternative justified assumptions to assess the robustness of results. Controlled Multiple Imputation (MI) procedures, including delta-based and reference-based approaches, have been developed for analysis under missing-not-at-random assumptions. However, it is unclear how often these methods are used, how they are reported, and what their impact is on trial results. This review evaluates the current use and reporting of MI and controlled MI in RCTs.Methods:A targeted review of phase II-IV RCTs (non-cluster randomised) published in two leading general medical journals (The Lancet and New England Journal of Medicine) between January 2014 and December 2019 using MI. Data was extracted on imputation methods, analysis status, and reporting of results. Results of primary and sensitivity analyses for trials using controlled MI analyses were compared.Results:A total of 118 RCTs (9% of published RCTs) used some form of MI. MI under missing-at-random was used in 110 trials; this was for primary analysis in 43/118 (36%), and in sensitivity analysis for 70/118 (59%) (3 used in both). Sixteen studies performed controlled MI (1.3% of published RCTs), either with a delta-based (n = 9) or reference-based approach (n = 7). Controlled MI was mostly used in sensitivity analysis (n = 14/16). Two trials used controlled MI for primary analysis, including one reporting no sensitivity analysis whilst the other reported similar results without imputation. Of the 14 trials using controlled MI in sensitivity analysis, 12 yielded comparable results to the primary analysis whereas 2 demonstrated contradicting results. Only 5/110 (5%) trials using missing-at-random MI and 5/16 (31%) trials using con
Vergis N, Phillips R, Cornelius V, et al., 2021, Multi-arm Trial of Inflammatory Signal Inhibitors (MATIS) for hospitalised patients with mild or moderate COVID-19 pneumonia: a structured summary of a study protocol for a randomised controlled trial, Trials, Vol: 22, ISSN: 1745-6215
OBJECTIVES: The primary objective of MATIS is to determine the efficacy of ruxolitinib (RUX) or fostamatinib (FOS) compared to standard of care (SOC) with respect to reducing the proportion of hospitalised patients progressing from mild or moderate to severe COVID-19 pneumonia. Secondary objectives, at 14 and 28 days, are to: Determine the efficacy of RUX or FOS to reduce mortality Determine the efficacy of RUX or FOS to reduce the need for invasive ventilation or ECMO Determine the efficacy of RUX or FOS to reduce the need for non-invasive ventilation Determine the efficacy of RUX or FOS to reduce the proportion of participants suffering significant oxygen desaturation Determine the efficacy of RUX or FOS to reduce the need for renal replacement therapy Determine the efficacy of RUX and FOS to reduce the incidence of venous thromboembolism Determine the efficacy of RUX and FOS to reduce the severity of COVID-19 pneumonia [graded by a 9-point modified WHO Ordinal Scale* Determine the efficacy of RUX or FOS to reduce systemic inflammation Determine the efficacy of RUX or FOS to the incidence of renal impairment Determine the efficacy of RUX or FOS to reduce duration of hospital stay Evaluate the safety of RUX and FOS for treatment of COVID-19 pneumonia. TRIAL DESIGN: A multi-arm, multi-stage (3-arm parallel-group, 2-stage) randomised controlled trial that allocates participants 1:1:1 and tests for superiority in experimental arms versus standard of care. PARTICIPANTS: Patients will be recruited while inpatients during hospitalisation for COVID-19 in multiple centres throughout the UK including Imperial College Healthcare NHS Trust. INCLUSION: Patients age ≥ 18 years at screening Patients with mild or moderate COVID-19 pneumonia, defined as Grade 3 or 4 severity by the WHO COVID-19 Ordinal Scale Patients meeting criteria: Hospitalization AND SARS-CoV2 infection (clinically suspected or laboratory confirmed) AND Radiological change consistent with COVID-19 disease C
Li C, Chen K, Cornelius V, et al., 2021, Applicability and cost-effectiveness of the Systolic Blood Pressure Intervention Trial (SPRINT) in the Chinese population: A cost-effectiveness modeling study, PLoS Medicine, Vol: 18, Pages: 1-14, ISSN: 1549-1277
BackgroundThe Systolic Blood Pressure Intervention Trial (SPRINT) showed significant reductions in death and cardiovascular disease (CVD) risk with a systolic blood pressure (SBP) goal of <120 mm Hg compared with a SBP goal of <140 mm Hg. Our study aimed to assess the applicability of SPRINT to Chinese adults. Additionally, we sought to predict the medical and economic implications of this intensive SBP treatment among those meeting SPRINT eligibility.Methods and findingsWe used nationally representative baseline data from the China Health and Retirement Longitudinal Study (CHARLS) (2011–2012) to estimate the prevalence and number of Chinese adults aged 45 years and older who meet SPRINT criteria. A validated microsimulation model was employed to project costs, clinical outcomes, and quality-adjusted life-years (QALYs) among SPRINT-eligible adults, under 2 alternative treatment strategies (SBP goal of <120 mm Hg [intensive treatment] and SBP goal of <140 mm Hg [standard treatment]). Overall, 22.2% met the SPRINT criteria, representing 116.2 (95% CI 107.5 to 124.8) million people in China. Of these, 66.4%, representing 77.2 (95% CI 69.3 to 85.0) million, were not being treated for hypertension, and 22.9%, representing 26.6 (95% CI 22.4 to 30.7) million, had a SBP between 130 and 139 mm Hg, yet were not taking antihypertensive medication. We estimated that over 5 years, compared to standard treatment, intensive treatment would reduce heart failure incidence by 0.84 (95% CI 0.42 to 1.25) million cases, reduce CVD deaths by 2.03 (95% CI 1.44 to 2.63) million cases, and save 3.84 (95% CI 1.53 to 6.34) million life-years. Estimated reductions of 0.069 (95% CI −0.28, 0.42) million myocardial infarction cases and 0.36 (95% CI −0.10, 0.82) million stroke cases were not statistically significant. Furthermore, over a lifetime, moving from standard to intensive treatment increased the mean QALYs from 9.51 to 9.87 (an increment of 0.38 [95% CI 0.13
Kelleher MM, Cro S, Van Vogt E, et al., 2021, Skincare interventions in infants for preventing eczema and food allergy: A cochrane systematic review and individual participant data meta-analysis, Clinical and Experimental Allergy, Vol: 51, Pages: 402-418, ISSN: 0954-7894
ObjectiveEczema and food allergy start in infancy and have shared genetic risk factors that affect skin barrier. We aimed to evaluate whether skincare interventions can prevent eczema or food allergy.DesignA prospectively planned individual participant data meta‐analysis was carried out within a Cochrane systematic review to determine whether skincare interventions in term infants prevent eczema or food allergy.Data sourcesCochrane Skin Specialised Register, CENTRAL, MEDLINE, Embase and trial registries to July 2020.Eligibility criteria for selected studiesIncluded studies were randomized controlled trials of infants <1 year with healthy skin comparing a skin intervention with a control, for prevention of eczema and food allergy outcomes between 1 and 3 years.ResultsOf the 33 identified trials, 17 trials (5823 participants) had relevant outcome data and 10 (5154 participants) contributed to IPD meta‐analysis. Three of seven trials contributing to primary eczema analysis were at low risk of bias, and the single trial contributing to primary food allergy analysis was at high risk of bias. Interventions were mainly emollients, applied for the first 3–12 months. Skincare interventions probably do not change risk of eczema by age 1–3 years (RR 1.03, 95% CI 0.81, 1.31; I2=41%; moderate certainty; 3075 participants, 7 trials). Sensitivity analysis found heterogeneity was explained by increased eczema in a trial of daily bathing as part of the intervention. It is unclear whether skincare interventions increase risk of food allergy by age 1–3 years (RR 2.53, 95% CI 0.99 to 6.47; very low certainty; 996 participants, 1 trial), but they probably increase risk of local skin infections (RR 1.34, 95% CI 1.02, 1.77; I2=0%; moderate certainty; 2728 participants, 6 trials).ConclusionRegular emollients during infancy probably do not prevent eczema and probably increase local skin infections.
Kelleher MM, Cro S, Cornelius V, et al., 2021, Skin care interventions in infants for preventing eczema and food allergy., Cochrane Database of Systematic Reviews, Vol: 2021, Pages: 1-165, ISSN: 1469-493X
BACKGROUND: Eczema and food allergy are common health conditions that usually begin in early childhood and often occur together in the same people. They can be associated with an impaired skin barrier in early infancy. It is unclear whether trying to prevent or reverse an impaired skin barrier soon after birth is effective in preventing eczema or food allergy. OBJECTIVES: Primary objective To assess effects of skin care interventions, such as emollients, for primary prevention of eczema and food allergy in infants Secondary objective To identify features of study populations such as age, hereditary risk, and adherence to interventions that are associated with the greatest treatment benefit or harm for both eczema and food allergy. SEARCH METHODS: We searched the following databases up to July 2020: Cochrane Skin Specialised Register, CENTRAL, MEDLINE, and Embase. We searched two trials registers and checked reference lists of included studies and relevant systematic reviews for further references to relevant randomised controlled trials (RCTs). We contacted field experts to identify planned trials and to seek information about unpublished or incomplete trials. SELECTION CRITERIA: RCTs of skin care interventions that could potentially enhance skin barrier function, reduce dryness, or reduce subclinical inflammation in healthy term (> 37 weeks) infants (0 to 12 months) without pre-existing diagnosis of eczema, food allergy, or other skin condition were included. Comparison was standard care in the locality or no treatment. Types of skin care interventions included moisturisers/emollients; bathing products; advice regarding reducing soap exposure and bathing frequency; and use of water softeners. No minimum follow-up was required. DATA COLLECTION AND ANALYSIS: This is a prospective individual participant data (IPD) meta-analysis. We used standard Cochrane methodological procedures, and primary ana
Gimeno H, Polatajko HJ, Lin J-P, et al., 2021, Cognitive strategy training in childhood-onset movement disorders: replication across therapists, Frontiers in Pediatrics, Vol: 8, Pages: 1-22, ISSN: 2296-2360
Objective: To explore preliminary effectiveness of the Cognitive Orientation to daily Occupational Performance (CO-OP) Approach in improving outcomes in childhood-onset hyperkinetic movement disorders (HMDs) including dyskinetic cerebral palsy following deep brain stimulation (DBS) across UK clinical occupational therapists.Methods: Randomized, multiple-baseline, Single Case Experimental Design N-of-1 trial with replications across participants. Five self-selected goals were identified: three goals were worked on during CO-OP and two goals were left untreated and used to assess skills transfer. Participants were between 6 and 21 years and had received DBS surgery with baseline Manual Ability Classification System (MACS) levels I–IV. Participants were randomized to typical or extended baseline (2 vs. 6 weeks), followed by 10 weekly individual CO-OP sessions. The primary outcome was functional performance measured by the Performance Quality Rating Scale-Individualized (PQRS-I), assessed before, during, and following treatment. Outcome assessors were blinded to baseline allocation, session number, and assessment time. A non-overlapping index, Tau-U, was used to measure effect size.Results: Of the 12 participants recruited, 10 commenced and completed treatment. In total, 63% of trained goals improved with effect sizes 0.66–1.00 (“moderate” to “large” effect), seen for all children in at least one goal. Skills transfer was found in 37% of the untrained goals in six participants.Conclusions: Cognitive strategy use improved participant-selected functional goals in childhood-onset HMD, more than just practice during baseline. Preliminary effectiveness is shown when the intervention is delivered in clinical practice by different therapists in routine clinical settings.
Sin J, Elkes J, Batchelor R, et al., 2021, Mental health and caregiving experiences of family carers supporting people with psychosis, Epidemiology and Psychiatric Sciences, Vol: 30, Pages: 1-9, ISSN: 2045-7979
Background: Family carers supporting an individual with psychosis often experience distress associated with caregiving responsibility. However, scarce research evidence exists investigating mental health morbidities in carers of people with psychosis. Methods: We conducted an online cross-sectional study with adult carers supporting a relative or close friend with psychosis in England. We collected participants’ demographic and health outcome data, including wellbeing (primary outcome) using Warwick-Edinburgh Mental Wellbeing Scale (WEMWBS). We explored the relationships between carers’ characteristics for each outcome in turn, using linear regression. We compared carers’ wellbeing with Health Survey England (HSE 2016) general population data using a meta-analysis.Findings: Between March 2018 and February 2020, 407 carers across England provided study data. Carers had a mean WEMWBS score of 42∙2 (SD 9∙21), and their overall weighted pooled WEMWBS score was 7∙3 (95% CI -8∙6 to -6∙0, p<0∙01) lower than the HSE sample, indicating carers have poorer mental wellbeing by more than double the minimum clinically important difference of 3 points on WEMWBS. Among all caring relationships, partners had poorer wellbeing compared to parents with lower WEMWBS score (-6∙8, -16∙9 to 3∙3, p=0∙03). Single or lone carers had significantly poorer wellbeing (-3∙6, -5∙6 to -1∙5, p<0∙01) than those who were cohabiting.Interpretation: Carers of people with psychosis have poorer mental health than non-carers; partners and lone carers most at risk of poor outcomes. Future large-scale prospective studies are needed to develop a predictive model for healthcare clinicians to use and to inform tailored intervention development.Funding Statement: NIHR Post-Doctoral Research Fellowship.Declaration of Interests: All authors have no conflicts of interests to declare.Ethics Approval Statement: The RCT has been reviewed and approved by South Central – Oxford C Research Et
Cornelius V, Cro S, Phillips R, 2020, Advantages of visualisations to evaluate and communicate adverse event information in randomised controlled trials, Trials, Vol: 21, ISSN: 1745-6215
BackgroundRandomised controlled trials (RCTs) provide valuable information and inform the development of harm profiles of new treatments. Harms are typically assessed through the collection of adverse events (AEs). Despite AEs being routine outcomes collected in trials, analysis and reporting of AEs in journal articles are continually shown to be suboptimal. One key challenge is the large volume of AEs, which can make evaluation and communication problematic. Prominent practice is to report frequency tables of AEs by arm. Visual displays offer an effective solution to assess and communicate complex information; however, they are rarely used and there is a lack of practical guidance on what and how to visually display complex AE data.MethodsIn this article, we demonstrate the use of two plots identified to be beneficial for wide use in RCTs, since both can display multiple AEs and are suitable to display point estimates for binary, count, or time-to-event AE data: the volcano and dot plots. We compare and contrast the use of data visualisations against traditional frequency table reporting, using published AE information in two placebo-controlled trials, of remdesivir for COVID-19 and GDNF for Parkinson disease. We introduce statistical programmes for implementation in Stata.Results/case studyVisualisations of AEs in the COVID-19 trial communicated a risk profile for remdesivir which differed from the main message in the published authors’ conclusion. In the Parkinson’s disease trial of GDNF, the visualisation provided immediate communication of harm signals, which had otherwise been contained within lengthy descriptive text and tables. Asymmetry in the volcano plot helped flag extreme events that were less obvious from review of the frequency table and dot plot. The dot plot allowed a more comprehensive representation by means of a more detailed summary.ConclusionsVisualisations can better support investigators to assimilate large volumes of data and ena
Harris J, Purssell E, Cornelius V, et al., 2020, Development and internal validation of a predictive risk model for anxiety after completion of treatment for early stage breast cancer, Journal of Patient-Reported Outcomes, Vol: 4, ISSN: 2509-8020
OBJECTIVE: To develop a predictive risk model (PRM) for patient-reported anxiety after treatment completion for early stage breast cancer suitable for use in practice and underpinned by advances in data science and risk prediction. METHODS: Secondary analysis of a prospective survey of > 800 women at the end of treatment and again 6 months later using patient reported outcome (PRO) the hospital anxiety and depression scale-anxiety (HADS-A) and > 20 candidate predictors. Multiple imputation using chained equations (for missing data) and least absolute shrinkage and selection operator (LASSO) were used to select predictors. Final multivariable linear model performance was assessed (R2) and bootstrapped for internal validation. RESULTS: Five predictors of anxiety selected by LASSO were HADS-A (Beta 0.73; 95% CI 0.681, 0.785); HAD-depression (Beta 0.095; 95% CI 0.020, 0.182) and having caring responsibilities (Beta 0.488; 95% CI 0.084, 0.866) increased risk, whereas being older (Beta - 0.010; 95% CI -0.028, 0.004) and owning a home (Beta 0.432; 95% CI -0.954, 0.078) reduced the risk. The final model explained 60% of variance and bias was low (- 0.006 to 0.002). CONCLUSIONS: Different modelling approaches are needed to predict rather than explain patient reported outcomes. We developed a parsimonious and pragmatic PRM. External validation is required prior to translation to digital tool and evaluation of clinical implementation. The routine use of PROs and data driven PRM in practice provides a new opportunity to target supportive care and specialist interventions for cancer patients.
Hadfield D, Rose L, Reid F, et al., 2020, Factors affecting the use of neurally adjusted ventilatory assist in the adult critical care unit: a clinician survey, BMJ Open Respiratory Research, Vol: 7, ISSN: 2052-4439
BACKGROUND: Neurally adjusted ventilatory assist (NAVA) involves an intricate interaction between patient, clinician and technology. To improve our understanding of this complex intervention and to inform future trials, this survey aimed to examine clinician attitudes, beliefs and barriers to NAVA use in critically ill adults within an institution with significant NAVA experience. METHODS: A survey of nurses, doctors and physiotherapists in four Intensive Care Units (ICUs) of one UK university-affiliated hospital (75 NAVA equipped beds). The survey consisted of 39 mixed open and structured questions. The hospital had 8 years of NAVA experience prior to the survey. RESULTS: Of 466 distributed questionnaires, 301 (64.6%) were returned from 236 nurses (78.4%), 53 doctors (17.6%) and 12 physiotherapists (4.0%). Overall, 207/294 (70.4%) reported clinical experience. Most agreed that NAVA was safe (136/177, 76.8%) and clinically effective (99/176, 56.3%) and most perceived 'improved synchrony', 'improved comfort' and 'monitoring the diaphragm' to be key advantages of NAVA. 'Technical issues' (129/189, 68.3%) and 'NAVA signal problems' (94/180, 52.2%) were the most cited clinical disadvantage and cause of mode cross-over to Pressure Support Ventilation (PSV), respectively. Most perceived NAVA to be more difficult to use than PSV (105/174, 60.3%), although results were mixed when compared across different tasks. More participants preferred PSV to NAVA for initiating ventilator weaning (93/171 (54.4%) vs 29/171 (17.0%)). A key barrier to use and a consistent theme throughout was 'low confidence' in relation to NAVA use. CONCLUSIONS: In addition to broad clinician support for NAVA, this survey describes technical concerns, low confidence and a perception of difficulty above that associated with PSV. In this context, high-quality training and usage algorithms are critically important to the design and of future trials, to clinician acceptance and to the clinical impleme
Harris J, Purssell E, Ream E, et al., 2020, How to develop statistical predictive risk models in oncology nursing to enhance psychosocial and supportive care., Seminars in Oncology Nursing, Vol: 36, Pages: 1-9, ISSN: 0749-2081
OBJECTIVES: Predictive risk models are advocated in psychosocial oncology practice to provide timely and appropriate support to those likely to experience the emotional and psychological consequences of cancer and its treatments. New digital technologies mean that large scale and routine data collection are becoming part of everyday clinical practice. Using these data to try to identify those at greatest risk for late psychosocial effects of cancer is an attractive proposition in a climate of unmet need and limited resource. In this paper, we present a framework to support the development of high-quality predictive risk models in psychosocial and supportive oncology. The aim is to provide awareness and increase accessibility of best practice literature to support researchers in psychosocial and supportive care to undertake a structured evidence-based approach. DATA SOURCES: Statistical prediction risk model publications. CONCLUSION: In statistical modeling and data science different approaches are needed if the goal is to predict rather than explain. The deployment of a poorly developed and tested predictive risk model has the potential to do great harm. Recommendations for best practice to develop predictive risk models have been developed but there appears to be little application within psychosocial and supportive oncology care. IMPLICATIONS FOR NURSING PRACTICE: Use of best practice evidence will ensure the development and validation of predictive models that are robust as these are currently lacking. These models have the potential to enhance supportive oncology care through harnessing routine digital collection of patient-reported outcomes and the targeting of interventions according to risk characteristics.
Phillips R, Cornelius V, Sauzet O, 2020, Statistical methods for the analysis of adverse event data in randomised controlled trials: a scoping review and taxonomy, BMC Medical Research Methodology, Vol: 20, ISSN: 1471-2288
BackgroundStatistical methods for the analysis of harm outcomes in randomised controlled trials (RCTs) are rarely used, and there is a reliance on simple approaches to display information such as in frequency tables. We aimed to identify whether any statistical methods had been specifically developed to analyse prespecified secondary harm outcomes and non-specific emerging adverse events (AEs).MethodsA scoping review was undertaken to identify articles that proposed original methods or the original application of existing methods for the analysis of AEs that aimed to detect potential adverse drug reactions (ADRs) in phase II-IV parallel controlled group trials. Methods where harm outcomes were the (co)-primary outcome were excluded.Information was extracted on methodological characteristics such as: whether the method required the event to be prespecified or could be used to screen emerging events; and whether it was applied to individual events or the overall AE profile. Each statistical method was appraised and a taxonomy was developed for classification.ResultsForty-four eligible articles proposing 73 individual methods were included. A taxonomy was developed and articles were categorised as: visual summary methods (8 articles proposing 20 methods); hypothesis testing methods (11 articles proposing 16 methods); estimation methods (15 articles proposing 24 methods); or methods that provide decision-making probabilities (10 articles proposing 13 methods). Methods were further classified according to whether they required a prespecified event (9 articles proposing 12 methods), or could be applied to emerging events (35 articles proposing 61 methods); and if they were (group) sequential methods (10 articles proposing 12 methods) or methods to perform final/one analyses (34 articles proposing 61 methods).ConclusionsThis review highlighted that a broad range of methods exist for AE analysis. Immediate implementation of some of these could lead to improved inference for
Sanfilippo KRM, McConnell B, Cornelius V, et al., 2020, Community psychosocial music intervention (CHIME) to reduce antenatal common mental disorder symptoms in The Gambia: a feasibility trial., BMJ Open, Vol: 10, Pages: 1-13, ISSN: 2044-6055
OBJECTIVES: Examine the feasibility of a Community Health Intervention through Musical Engagement (CHIME) in The Gambia to reduce common mental disorder (CMD) symptoms in pregnant women. DESIGN: Feasibility trial testing a randomised stepped-wedge cluster design. SETTING: Four local antenatal clinics. PARTICIPANTS: Women who were 14-24 weeks pregnant and spoke Mandinka or Wolof were recruited into the intervention (n=50) or control group (n=74). INTERVENTION: Music-based psychosocial support sessions designed and delivered by all-female fertility societies. Sessions lasted 1 hour and were held weekly for 6 weeks. Delivered to groups of women with no preselection. Sessions were designed to lift mood, build social connection and provide health messaging through participatory music making. The control group received standard antenatal care. OUTCOMES: Demographic, feasibility, acceptability outcomes and the appropriateness of the study design were assessed. Translated measurement tools (Self-Reporting Questionnaire (SRQ-20); Edinburgh Postnatal Depression Scale (EPDS)) were used to assess CMD symptoms at baseline, post-intervention and 4-week follow-up. RESULTS: All clinics and 82% of women approached consented to take part. A 33% attrition rate across all time points was observed. 72% in the intervention group attended at least three sessions. Audio and video analysis confirmed fidelity of the intervention and a thematic analysis of participant interviews demonstrated acceptability and positive evaluation. Results showed a potential beneficial effect with a reduction of 2.13 points (95% CI (0.89 to 3.38), p<0.01, n=99) on the SRQ-20 and 1.98 points (95% CI (1.06 to 2.90), p<0.01, n=99) on the EPDS at the post-intervention time point for the intervention group compared with standard care. CONCLUSION: Results demonstrate that CHIME is acceptable and feasible in The Gambia. To our knowledge, CHIME is the first example of a music-based psy
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