Publications by authors named "Karla Hemming"

133 Publications

Looking at knock-on effects Univariable and multivariable linear regression.

BJOG 2021 Mar 17. Epub 2021 Mar 17.

Institute of Applied Health Research, University of Birmingham, B15 2TT.

Linear regression is used to describe the relationship between a continuous dependant variable of interest (outcome) and other patient characteristics or predictors (independent continuous, categorical or dichotomous variables). Fitting a linear regression model estimates a constant, predictor coefficients and their corresponding 95% confidence intervals (95%CI). In a univariable analysis only one independent variable is included in the model and the model shows the association between that variable and the outcome, without any consideration of other characteristics. In a multivariable analysis more than one predictor is included in the model.
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http://dx.doi.org/10.1111/1471-0528.16701DOI Listing
March 2021

What are the odds?

BJOG 2021 Mar 17. Epub 2021 Mar 17.

Institute of Applied Health Research, University of Birmingham, B15 2TT.

A case-control study used logistic regression to examine factors associated with maternal death due to direct pregnancy complication using 14 previously identified risk factors (Nair M et al. BJOG 2015;122:653-662). In a univariable analysis only one predictor is included in the model and the model shows the association between the single predictor and outcome, without any consideration of other characteristics. In a multivariable analysis more than one predictor is included in the model. Multivariable models depict the relationship between multiple characteristics and the outcome, allowing for the impact of other characteristics. This is sometimes referred to as an adjusted association. In Table 1 the adjusted odds ratios (ORs) and corresponding 95% confidence intervals for each variable are provided for all 14 variables.
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http://dx.doi.org/10.1111/1471-0528.16704DOI Listing
March 2021

Understanding Multiple Comparisons.

BJOG 2021 Mar 17. Epub 2021 Mar 17.

Institute of Applied Health Research - University of, Birmingham, Birmingham, UK, B15 2TT.

Type 1 errors arise when a hypothesis is rejected (i.e. a treatment is concluded to work) but the corresponding association is not true. Studies are usually designed so that the type 1 error is 5%, that is, we accept that we might make this mistake in about 5% of studies. When we increase the number of statistical tests, the risk of making a type I error increases. The issue of type I error comes to the forefront with multiple comparison groups. Consider an example.
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http://dx.doi.org/10.1111/1471-0528.16705DOI Listing
March 2021

Understanding Hypothesis Testing.

BJOG 2021 Mar 17. Epub 2021 Mar 17.

Institute of Applied Health Research - University of, Birmingham, Birmingham, UK, B15 2TT.

Simple statistical procedures, like testing for differences in the means or proportions of groups, become complicated when many groups are involved. This setting arises naturally and frequently in science: a study may include multiple treatment arms, important sub-groups, interim analyses, or multiple outcomes. We must correct for the number of statistical tests-called multiple comparisons-or face increased risk of invalid results. To truly grasp the problem, we must delve into the specifics of hypothesis testing.
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http://dx.doi.org/10.1111/1471-0528.16706DOI Listing
March 2021

Cognitive-behavioural therapy for a variety of conditions: an overview of systematic reviews and panoramic meta-analysis.

Health Technol Assess 2021 Feb;25(9):1-378

Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK.

Background: Cognitive-behavioural therapy aims to increase quality of life by changing cognitive and behavioural factors that maintain problematic symptoms. A previous overview of cognitive-behavioural therapy systematic reviews suggested that cognitive-behavioural therapy was effective for many conditions. However, few of the included reviews synthesised randomised controlled trials.

Objectives: This project was undertaken to map the quality and gaps in the cognitive-behavioural therapy systematic review of randomised controlled trial evidence base. Panoramic meta-analyses were also conducted to identify any across-condition general effects of cognitive-behavioural therapy.

Data Sources: The overview was designed with cognitive-behavioural therapy patients, clinicians and researchers. The Cochrane Library, MEDLINE, EMBASE, PsycINFO, Cumulative Index to Nursing and Allied Health Literature, Child Development & Adolescent Studies, Database of Abstracts of Reviews of Effects and OpenGrey databases were searched from 1992 to January 2019.

Review Methods: Study inclusion criteria were as follows: (1) fulfil the Centre for Reviews and Dissemination criteria; (2) intervention reported as cognitive-behavioural therapy or including one cognitive and one behavioural element; (3) include a synthesis of cognitive-behavioural therapy trials; (4) include either health-related quality of life, depression, anxiety or pain outcome; and (5) available in English. Review quality was assessed with A MeaSurement Tool to Assess systematic Reviews (AMSTAR)-2. Reviews were quality assessed and data were extracted in duplicate by two independent researchers, and then mapped according to condition, population, context and quality. The effects from high-quality reviews were pooled within condition groups, using a random-effect panoramic meta-analysis. If the across-condition heterogeneity was  < 75%, we pooled across conditions. Subgroup analyses were conducted for age, delivery format, comparator type and length of follow-up, and a sensitivity analysis was performed for quality.

Results: A total of 494 reviews were mapped, representing 68% (27/40) of the categories of the Eleventh Revision, Mortality and Morbidity Statistics. Most reviews (71%, 351/494) were of lower quality. Research on older adults, using cognitive-behavioural therapy preventatively, ethnic minorities and people living outside Europe, North America or Australasia was limited. Out of 494 reviews, 71 were included in the primary panoramic meta-analyses. A modest effect was found in favour of cognitive-behavioural therapy for health-related quality of life (standardised mean difference 0.23, 95% confidence interval 0.05 to 0.41, prediction interval -0.05 to 0.50,  = 32%), anxiety (standardised mean difference 0.30, 95% confidence interval 0.18 to 0.43, prediction interval -0.28 to 0.88,  = 62%) and pain (standardised mean difference 0.23, 95% confidence interval 0.05 to 0.41, prediction interval -0.28 to 0.74,  = 64%) outcomes. All condition, subgroup and sensitivity effect estimates remained consistent with the general effect. A statistically significant interaction effect was evident between the active and non-active comparator groups for the health-related quality-of-life outcome. A general effect for depression outcomes was not produced as a result of considerable heterogeneity across reviews and conditions.

Limitations: Data extraction and analysis were conducted at the review level, rather than returning to the individual trial data. This meant that the risk of bias of the individual trials could not be accounted for, but only the quality of the systematic reviews that synthesised them.

Conclusion: Owing to the consistency and homogeneity of the highest-quality evidence, it is proposed that cognitive-behavioural therapy can produce a modest general, across-condition benefit in health-related quality-of-life, anxiety and pain outcomes.

Future Work: Future research should focus on how the modest effect sizes seen with cognitive-behavioural therapy can be increased, for example identifying alternative delivery formats to increase adherence and reduce dropout, and pursuing novel methods to assess intervention fidelity and quality.

Study Registration: This study is registered as PROSPERO CRD42017078690.

Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in ; Vol. 25, No. 9. See the NIHR Journals Library website for further project information.
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http://dx.doi.org/10.3310/hta25090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7957459PMC
February 2021

Reducing Medical Admissions and Presentations Into Hospital through Optimising Medicines (REMAIN HOME): a stepped wedge, cluster randomised controlled trial.

Med J Aust 2021 03 12;214(5):212-217. Epub 2021 Feb 12.

University of Queensland, Brisbane, QLD.

Objective: To investigate whether integrating pharmacists into general practices reduces the number of unplanned re-admissions of patients recently discharged from hospital.

Design, Setting: Stepped wedge, cluster randomised trial in 14 general practices in southeast Queensland.

Participants: Adults discharged from one of seven study hospitals during the seven days preceding recruitment (22 May 2017 - 14 March 2018) and prescribed five or more long term medicines, or having a primary discharge diagnosis of congestive heart failure or exacerbation of chronic obstructive pulmonary disease.

Intervention: Comprehensive face-to-face medicine management consultation with an integrated practice pharmacist within seven days of discharge, followed by a consultation with their general practitioner and further pharmacist consultations as needed.

Major Outcomes: Rates of unplanned, all-cause hospital re-admissions and emergency department (ED) presentations 12 months after hospital discharge; incremental net difference in overall costs.

Results: By 12 months, there had been 282 re-admissions among 177 control patients (incidence rate [IR], 1.65 per person-year) and 136 among 129 intervention patients (IR, 1.09 per person-year; fully adjusted IR ratio [IRR], 0.79; 95% CI, 0.52-1.18). ED presentation incidence (fully adjusted IRR, 0.46; 95% CI, 0.22-0.94) and combined re-admission and ED presentation incidence (fully adjusted IRR, 0.69; 95% CI, 0.48-0.99) were significantly lower for intervention patients. The estimated incremental net cost benefit of the intervention was $5072 per patient, with a benefit-cost ratio of 31:1.

Conclusion: A collaborative pharmacist-GP model of post-hospital discharge medicines management can reduce the incidence of hospital re-admissions and ED presentations, achieving substantial cost savings to the health system.

Trial Registration: Australian New Zealand Clinical Trials Registry, ACTRN12616001627448 (prospective).
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http://dx.doi.org/10.5694/mja2.50942DOI Listing
March 2021

An opportunistic evaluation of a routine service improvement project to reduce falls in hospital.

BMC Health Serv Res 2021 Jan 22;21(1):79. Epub 2021 Jan 22.

Institute of Applied Health Research, University of Birmingham, Edgbaston, B15 2TT, UK.

Background: Preventing falls in hospital is a perennial patient safety issue. The University Hospital Coventry and Warwickshire initiated a programme to train ward staff in accordance with guidelines. The National Institute for Health Research Collaboration for Leadership in Applied Health Research and Care West Midlands was asked to expedite an independent evaluation of the initiative. We set out to describe the intervention to implement the guidelines and to evaluate it by means of a step-wedge cluster study using routinely collected data.

Methods: The evaluation was set up as a partially randomised, step-wedge cluster study, but roll-out across wards was more rapid than planned. The study was therefore analysed as a time-series. Primary outcome was rate of falls per 1000 Occupied Bed Days (OBDs) collected monthly using routine data. Data was analysed using a mixed-effects Poisson regression model, with a fixed effect for intervention, time and post-intervention time. We allowed for random variations across clusters in initial fall rate, pre-intervention slope and post-intervention slope.

Results: There was an average of 6.62 falls per 1000 OBDs in the control phase, decreasing to an average of 5.89 falls per 1000 OBDs in the period after implementation to the study end. Regression models showed no significant step change in fall rates (IRR: 1.02, 95% CI: 0.92-1.14). However, there was a gradual decrease, of approximately 3%, after the intervention was introduced (IRR: 0.97 per month, 95% CI: 0.95-0.99).

Conclusion: The intervention was associated with a small but statistically significantly improvement in falls rates. Expedited roll-out of an intervention may vitiate a step-wedge cluster design, but the intervention can still be studied using a time-series analysis. Assuming that there is some value in time series analyses, this is better than no evaluation at all. However, care is needed in making causal inferences given the non-experimental nature of the design.
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http://dx.doi.org/10.1186/s12913-021-06073-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7821491PMC
January 2021

Reopening schools safely in the face of COVID-19: Can cluster randomized trials help?

Clin Trials 2021 Jan 21:1740774520984860. Epub 2021 Jan 21.

Department of Medical Ethics and Health Policy, Perelman School of Medicine, and Leonard Davis Institute of Health Economics, University of Pennsylvania, Philadelphia, PA, USA.

The COVID-19 pandemic has highlighted the challenges of evidence-based health policymaking, as critical precautionary decisions, such as school closures, had to be made urgently on the basis of little evidence. As primary and secondary schools once again close in the face of surging infections, there is an opportunity to rigorously study their reopening. School-aged children appear to be less affected by COVID-19 than adults, yet schools may drive community transmission of the virus. Given the impact of school closures on both education and the economy, schools cannot remain closed indefinitely. But when and how can they be reopened safely? We argue that a cluster randomized trial is a rigorous and ethical way to resolve these uncertainties. We discuss key scientific, ethical, and resource considerations both to inform trial design of school reopenings and to prompt discussion of the merits and feasibility of conducting such a trial.
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http://dx.doi.org/10.1177/1740774520984860DOI Listing
January 2021

The evidence for cognitive behavioural therapy in any condition, population or context: a meta-review of systematic reviews and panoramic meta-analysis.

Psychol Med 2021 01 18;51(1):21-29. Epub 2021 Jan 18.

College of Medicine and Health, University of Exeter, Exeter, UK.

The majority of psychological treatment research is dedicated to investigating the effectiveness of cognitive behavioural therapy (CBT) across different conditions, population and contexts. We aimed to summarise the current systematic review evidence and evaluate the consistency of CBT's effect across different conditions. We included reviews of CBT randomised controlled trials in any: population, condition, format, context, with any type of comparator and published in English. We searched DARE, Cochrane, MEDLINE, EMBASE, PsycINFO, CINAHL, CDAS, and OpenGrey between 1992 and January 2019. Reviews were quality assessed, their data extracted and summarised. The effects upon health-related quality of life (HRQoL) were pooled, within-condition groups. If the across-condition heterogeneity was I2 < 75%, we pooled effects using a random-effect panoramic meta-analysis. We summarised 494 reviews (221 128 participants), representing 14/20 physical and 13/20 mental conditions (World Health Organisation's International Classification of Diseases). Most reviews were lower-quality (351/494), investigated face-to-face CBT (397/494), and in adults (378/494). Few reviews included trials conducted in Asia, South America or Africa (45/494). CBT produced a modest benefit across-conditions on HRQoL (standardised mean difference 0.23; 95% confidence intervals 0.14-0.33, I2 = 32%). The effect's associated prediction interval -0.05 to 0.50 suggested CBT will remain effective in conditions for which we do not currently have available evidence. While there remain some gaps in the completeness of the evidence base, we need to recognise the consistent evidence for the general benefit which CBT offers.
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http://dx.doi.org/10.1017/S0033291720005292DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7856415PMC
January 2021

Why proper understanding of confidence intervals and statistical significance is important.

Med J Aust 2021 02 13;214(3):116-118.e1. Epub 2021 Jan 13.

Ottawa Hospital Research Institute, Ottawa, Canada.

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http://dx.doi.org/10.5694/mja2.50926DOI Listing
February 2021

Effects on childhood infections of promoting safe and hygienic complementary-food handling practices through a community-based programme: A cluster randomised controlled trial in a rural area of The Gambia.

PLoS Med 2021 Jan 11;18(1):e1003260. Epub 2021 Jan 11.

London School of Hygiene & Tropical Medicine, London, United Kingdom.

Background: The Gambia has high rates of under-5 mortality from diarrhoea and pneumonia, peaking during complementary-feeding age. Community-based interventions may reduce complementary-food contamination and disease rates.

Methods And Findings: A public health intervention using critical control points and motivational drivers, delivered February-April 2015 in The Gambia, was evaluated in a cluster randomised controlled trial at 6- and 32-month follow-up in September-October 2015 and October-December 2017, respectively. After consent for trial participation and baseline data were collected, 30 villages (clusters) were randomly assigned to intervention or control, stratified by population size and geography. The intervention included a community-wide campaign on days 1, 2, 17, and 25, a reminder visit at 5 months, plus informal community-volunteer home visits. It promoted 5 key complementary-food and 1 key drinking-water safety and hygiene behaviours through performing arts, public meetings, and certifications delivered by a team from local health and village structures to all villagers who attended the activities, to which mothers of 6- to 24-month-old children were specifically invited. Control villages received a 1-day campaign on domestic-garden water use. The background characteristics of mother and clusters (villages) were balanced between the trial arms. Outcomes were measured at 6 and 32 months in a random sample of 21-26 mothers per cluster. There were no intervention or research team visits to villages between 6 and 32 months. The primary outcome was a composite outcome of the number of times key complementary-food behaviours were observed as a proportion of the number of opportunities to perform the behaviours during the observation period at 6 months. Secondary outcomes included the rate of each recommended behaviour; microbiological growth from complementary food and drinking water (6 months only); and reported acute respiratory infections, diarrhoea, and diarrhoea hospitalisation. Analysis was by intention-to-treat analysis adjusted by clustering. (Registration: PACTR201410000859336). We found that 394/571 (69%) of mothers with complementary-feeding children in the intervention villages were actively involved in the campaign. No villages withdrew, and there were no changes in the implementation of the intervention. The intervention improved behaviour adoption significantly. For the primary outcome, the rate was 662/4,351(incidence rate [IR] = 0.15) in control villages versus 2,861/4,378 (IR = 0.65) in intervention villages (adjusted incidence rate ratio [aIRR] = 4.44, 95% CI 3.62-5.44, p < 0.001), and at 32 months the aIRR was 1.17 (95% CI 1.07-1.29, p = 0.001). Secondary health outcomes also improved with the intervention: (1) mother-reported diarrhoea at 6 months, with adjusted relative risk (aRR) = 0.39 (95% CI 0.32-0.48, p < 0.001), and at 32 months, with aRR = 0.68 (95% CI 0.48-0.96, p = 0.027); (2) mother-reported diarrhoea hospitalisation at 6 months, with aRR = 0.35 (95% CI 0.19-0.66, p = 0.001), and at 32 months, with aRR = 0.38 (95% CI 0.18-0.80, p = 0.011); and (3) mother-reported acute respiratory tract infections at 6 months, with aRR = 0.67 (95% CI 0.53-0.86, p = 0.001), though at 32 months improvement was not significant (p = 0.200). No adverse events were reported. The main limitations were that only medium to small rural villages were involved. Obtaining laboratory cultures from food at 32 months was not possible, and no stool microorganisms were investigated.

Conclusions: We found that low-cost and culturally embedded behaviour change interventions were acceptable to communities and led to short- and long-term improvements in complementary-food safety and hygiene practices, and reported diarrhoea and acute respiratory tract infections.

Trial Registration: The trial was registered on the 17th October 2014 with the Pan African Clinical Trial Registry in South Africa with number (PACTR201410000859336) and 32-month follow-up as an amendment to the trial.
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http://dx.doi.org/10.1371/journal.pmed.1003260DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7799804PMC
January 2021

Design and analysis of three-arm parallel cluster randomized trials with small numbers of clusters.

Stat Med 2021 Feb 30;40(5):1133-1146. Epub 2020 Nov 30.

Institute of Applied Health Research, University of Birmingham, Birmingham, UK.

In this article, we review and evaluate a number of methods used in the design and analysis of small three-arm parallel cluster randomized trials. We conduct a simulation-based study to evaluate restricted randomization methods including covariate-constrained randomization and a novel method for matched-group cluster randomization. We also evaluate the appropriate modelling of the data and small sample inferential methods for a variety of treatment effects relevant to three-arm trials. Our results indicate that small-sample corrections are required for high (0.05) but not low (0.001) values of the intraclass correlation coefficient and their performance can depend on trial design, number of clusters, and the nature of the hypothesis being tested. The Satterthwaite correction generally performed best at an ICC of 0.05 with a nominal type I error rate for single-period trials, and in trials with repeated measures type I error rates were between 0.04 and 0.06. Restricted randomization methods produce little benefit in trials with repeated measures but in trials with single post-intervention design can provide relatively large gains in power when compared to the most unbalanced possible allocations. Matched-group randomization improves power but is not as effective as covariate-constrained randomization. For model-based analysis, adjusting for fewer covariates than were used in a restricted randomization process under any design can produce non-nominal type I error rates and reductions in power. Where comparisons to two-arm cluster trials are possible, the performance of the methods is qualitatively very similar.
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http://dx.doi.org/10.1002/sim.8828DOI Listing
February 2021

Use of multiple period, cluster randomised, crossover trial designs for comparative effectiveness research.

BMJ 2020 11 4;371:m3800. Epub 2020 Nov 4.

School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia.

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http://dx.doi.org/10.1136/bmj.m3800DOI Listing
November 2020

Prospective reporting of statistical analysis plans for randomised controlled trials.

Trials 2020 10 28;21(1):898. Epub 2020 Oct 28.

MRC Clinical Trials Unit at UCL, Institute of Clinical Trials & Methodology, London, UK.

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http://dx.doi.org/10.1186/s13063-020-04828-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7594284PMC
October 2020

Randomized parallel-group pilot trial (Best foods for your heart) comparing the effects of a Mediterranean Portfolio diet with a low saturated fat diet on HIV dyslipidemia.

Clin Nutr 2021 Mar 6;40(3):860-869. Epub 2020 Sep 6.

Clinical Research Core and Department of Medicine, Weill Cornell Medicine in Qatar and New York, Doha, Qatar.

Background & Aims: Mediterranean diets reduce the risk of cardiovascular disease (CVD). However, the effect is unknown in people living with HIV, who have an increased risk potentially due to the additional burdens of infection, inflammation and antiretroviral treatment (ART). We examined the feasibility of a 6-month dietary intervention in adults with HIV dyslipidemia using a sample size adequate to detect differences in LDL-cholesterol.

Methods: Sixty adults with stable HIV infection on ART and LDL-cholesterol >3 mmol/l were recruited. Participants were randomized (1:1) to receive dietary advice to reduce saturated fat intake to <10% of energy intake (Diet1), or supported to adopt the Mediterranean Portfolio Diet (Diet2) with additional cholesterol-lowering foods (nuts, stanols, soya, oats, beans) for 6 months. Recruitment, retention and intervention fidelity were monitored. Measurements were conducted at baseline, 6 and 12 months. A secondary analysis examined between group differences in CVD risk factors at month 6 adjusted for baseline values and potential confounders.

Results: Rates of recruitment, participation and attrition were 35%, 91%, and 12% respectively. Reported dietary adherence was 68% to Mediterranean foods and 59% to Portfolio components. At 6 months Diet2 participants (n = 29) had a significantly lower LDL-cholesterol (mean difference adjusted for baseline -0.4 mmol/l, 95%CI -0.7 to -0.1, P = 0.01), and systolic blood pressure (-7 mmHg, 95%CI -2 to -12, P = 0.008) compared to those in Diet1 (n = 31). These effects were not sustained at 1 year (LDL-cholesterol -0.05 mmol/l, 95%CI -0.33 to 0.23, P = 0.7; systolic blood pressure -3.5 mmHg, 95%CI -9.4 to 2.5, P = 0.2).

Conclusion: We showed the feasibility of adopting a Mediterranean Portfolio diet in people living with HIV. Our findings suggest this intervention might equate to short term improvements in diet quality, blood pressure, and LDL-cholesterol. Further definitive evaluations are required to determine if this is a viable strategy to facilitate cardiovascular risk reduction.

Clinical Trial Registry: ISRCTN32090191 Best Foods For your heart trial.
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http://dx.doi.org/10.1016/j.clnu.2020.08.038DOI Listing
March 2021

Extending the I-squared statistic to describe treatment effect heterogeneity in cluster, multi-centre randomized trials and individual patient data meta-analysis.

Stat Methods Med Res 2021 Feb 21;30(2):376-395. Epub 2020 Sep 21.

School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia.

Treatment effect heterogeneity is commonly investigated in meta-analyses to identify if treatment effects vary across studies. When conducting an aggregate level data meta-analysis it is common to describe the magnitude of any treatment effect heterogeneity using the I-squared statistic, which is an intuitive and easily understood concept. The effect of a treatment might also vary across clusters in a cluster randomized trial, or across centres in multi-centre randomized trial, and it can be of interest to explore this at the analysis stage. In cross-over trials and other randomized designs, in which clusters or centres are exposed to both treatment and control conditions, this treatment effect heterogeneity can be identified. Here we derive and evaluate a comparable I-squared measure to describe the magnitude of heterogeneity in treatment effects across clusters or centres in randomized trials. We further show how this methodology can be used to estimate treatment effect heterogeneity in an individual patient data meta-analysis.
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http://dx.doi.org/10.1177/0962280220948550DOI Listing
February 2021

Mixed-effects models for the design and analysis of stepped wedge cluster randomized trials: An overview.

Stat Methods Med Res 2021 Feb 6;30(2):612-639. Epub 2020 Jul 6.

Department of Biostatistics, School of Public Health, University of Washington, Seattle, WA, USA.

The stepped wedge cluster randomized design has received increasing attention in pragmatic clinical trials and implementation science research. The key feature of the design is the unidirectional crossover of clusters from the control to intervention conditions on a staggered schedule, which induces confounding of the intervention effect by time. The stepped wedge design first appeared in the Gambia hepatitis study in the 1980s. However, the statistical model used for the design and analysis was not formally introduced until 2007 in an article by Hussey and Hughes. Since then, a variety of mixed-effects model extensions have been proposed for the design and analysis of these trials. In this article, we explore these extensions under a unified perspective. We provide a general model representation and regard various model extensions as alternative ways to characterize the secular trend, intervention effect, as well as sources of heterogeneity. We review the key model ingredients and clarify their implications for the design and analysis. The article serves as an entry point to the evolving statistical literatures on stepped wedge designs.
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http://dx.doi.org/10.1177/0962280220932962DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785651PMC
February 2021

An integrated approach to improve maternal and perinatal outcomes in rural Guatemala: A stepped-wedge cluster randomized trial.

Int J Gynaecol Obstet 2020 Oct 27;151(1):109-116. Epub 2020 Jul 27.

University of California, San Francisco, CA, USA.

Objective: To evaluate the impact of an intervention package on maternal and newborn health indicators.

Methods: A randomized stepped-wedge non-blind trial was conducted across six subdistricts within two districts in Guatemala from January 2014 to January 2017. Data on outcomes were collected on all deliveries in all 33 health centers. The intervention package included distribution of promotional materials encouraging health center delivery; education for traditional birth attendants about the importance of health center delivery; and provider capacity building using simulation training. Main outcomes were number of health center deliveries, maternal morbidity, and perinatal morbidity and mortality.

Results: Overall, there were 24 412 deliveries. Health center deliveries per 1000 live births showed an overall increase, although after adjustment for secular trends and clustering, the relative risk for the treatment effect was not statistically significant (aRR, 1.04; 95% confidence interval [CI], 0.97-1.11, P=0.242). Although not statistically significant, maternal morbidity (aRR, 0.78; 95% CI, 0.60-1.02; P=0.068) and perinatal morbidity (aRR, 0.84; 95% CI, 0.68-1.05; P=0.133) showed a tendency toward a decrease.

Conclusion: The present study represents one of the few randomized evaluations of an integrated approach to improve birth outcomes in a low-income setting. ClinicalTrials.gov: NCT0315107.
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http://dx.doi.org/10.1002/ijgo.13262DOI Listing
October 2020

Response.

Clin Trials 2020 08 19;17(4):461-462. Epub 2020 May 19.

Rotman Institute of Philosophy, Western University, London, ON, Canada.

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http://dx.doi.org/10.1177/1740774520920578DOI Listing
August 2020

Reflection on modern methods: when is a stepped-wedge cluster randomized trial a good study design choice?

Int J Epidemiol 2020 06;49(3):1043-1052

Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada.

The stepped-wedge cluster randomized trial (SW-CRT) involves the sequential transition of clusters (such as hospitals, public health units or communities) from control to intervention conditions in a randomized order. The use of the SW-CRT is growing rapidly. Yet the SW-CRT is at greater risks of bias compared with the conventional parallel cluster randomized trial (parallel-CRT). For this reason, the CONSORT extension for SW-CRTs requires that investigators provide a clear justification for the choice of study design. In this paper, we argue that all other things being equal, the SW-CRT is at greater risk of bias due to misspecification of the secular trends at the analysis stage. This is particularly problematic for studies randomizing a small number of heterogeneous clusters. We outline the potential conditions under which an SW-CRT might be an appropriate choice. Potentially appropriate and often overlapping justifications for conducting an SW-CRT include: (i) the SW-CRT provides a means to conduct a randomized evaluation which otherwise would not be possible; (ii) the SW-CRT facilitates cluster recruitment as it enhances the acceptability of a randomized evaluation either to cluster gatekeepers or other stakeholders; (iii) the SW-CRT is the only feasible design due to pragmatic and logistical constraints (for example the roll-out of a scare resource); and (iv) the SW-CRT has increased statistical power over other study designs (which will include situations with a limited number of clusters). As the number of arguments in favour of an SW-CRT increases, the likelihood that the benefits of using the SW-CRT, as opposed to a parallel-CRT, outweigh its risks also increases. We argue that the mere popularity and novelty of the SW-CRT should not be a factor in its adoption. In situations when a conventional parallel-CRT is feasible, it is likely to be the preferred design.
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http://dx.doi.org/10.1093/ije/dyaa077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7394949PMC
June 2020

Ethical issues in cluster randomized trials conducted in low- and middle-income countries: an analysis of two case studies.

Trials 2020 Apr 16;21(Suppl 1):314. Epub 2020 Apr 16.

Rotman Institute of Philosophy, Western University, London, Canada.

Background: Cluster randomized trials are common in health research in low- and middle-income countries raising issues that challenge interpretation of standard ethical guidelines. While the Ottawa Statement on the ethical design and conduct of cluster randomized trials provides guidance for researchers and research ethics committees, it does not explicitly focus on low- and middle-income settings.

Main Body: In this paper, we use the lens of the Ottawa Statement to analyze two cluster randomized trials conducted in low- and middle-income settings in order to identify gaps or ethical issues requiring further analysis and guidance. The PolyIran trial was a parallel-arm, cluster trial examining the effectiveness of a polypill for prevention of cardiovascular disease in Golestan province, Iran. The PASTAL trial was an adaptive, multistage, parallel-arm, cluster trial evaluating the effect of incentives for human immunodeficiency virus self-testing and follow-up on male partners of pregnant women in Malawi. Through an in-depth case analysis of these two studies we highlight several issues in need of further exploration. First, standards for verbal consent and waivers of consent require methods for operationalization if they are to be employed consistently. Second, the appropriate choice of a control arm remains contentious. Particularly in the case of implementation interventions, locally available care is required as the comparator to address questions of comparative effectiveness. However, locally available care might be lower than standards set out in national guidelines. Third, while the need for access to effective interventions post-trial is widely recognized, it is often not possible to guarantee this upfront. Clarity on what is required of researchers and sponsors is needed. Fourth, there is a pressing need for ethics education and capacity building regarding cluster randomized trials in these settings.

Conclusion: We identify four issues in cluster randomized trials conducted in low- and middle-income countries for which further ethical analysis and guidance is required.
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http://dx.doi.org/10.1186/s13063-020-04269-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7161096PMC
April 2020

A tutorial on sample size calculation for multiple-period cluster randomized parallel, cross-over and stepped-wedge trials using the Shiny CRT Calculator.

Int J Epidemiol 2020 06;49(3):979-995

Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada.

It has long been recognized that sample size calculations for cluster randomized trials require consideration of the correlation between multiple observations within the same cluster. When measurements are taken at anything other than a single point in time, these correlations depend not only on the cluster but also on the time separation between measurements and additionally, on whether different participants (cross-sectional designs) or the same participants (cohort designs) are repeatedly measured. This is particularly relevant in trials with multiple periods of measurement, such as the cluster cross-over and stepped-wedge designs, but also to some degree in parallel designs. Several papers describing sample size methodology for these designs have been published, but this methodology might not be accessible to all researchers. In this article we provide a tutorial on sample size calculation for cluster randomized designs with particular emphasis on designs with multiple periods of measurement and provide a web-based tool, the Shiny CRT Calculator, to allow researchers to easily conduct these sample size calculations. We consider both cross-sectional and cohort designs and allow for a variety of assumed within-cluster correlation structures. We consider cluster heterogeneity in treatment effects (for designs where treatment is crossed with cluster), as well as individually randomized group-treatment trials with differential clustering between arms, for example designs where clustering arises from interventions being delivered in groups. The calculator will compute power or precision, as a function of cluster size or number of clusters, for a wide variety of designs and correlation structures. We illustrate the methodology and the flexibility of the Shiny CRT Calculator using a range of examples.
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http://dx.doi.org/10.1093/ije/dyz237DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7394950PMC
June 2020

Polypill for prevention of cardiovascular diseases - Authors' reply.

Lancet 2020 02;395(10222):414-415

Digestive Disease Research Center, Digestive Disease Research Institute, Shariati Hospital, Tehran University of Medical Sciences, Tehran 1411713135, Iran. Electronic address:

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http://dx.doi.org/10.1016/S0140-6736(19)32966-6DOI Listing
February 2020

Effectiveness and cost-effectiveness of The Daily Mile on childhood weight outcomes and wellbeing: a cluster randomised controlled trial.

Int J Obes (Lond) 2020 04 28;44(4):812-822. Epub 2020 Jan 28.

Institute of Applied Health Research, University of Birmingham, Birmingham, B15 2TT, UK.

Background: The Daily Mile is designed to increase physical activity levels with children running or walking around school grounds for 15-min daily. It has been adopted by schools worldwide and endorsed as a solution to tackle obesity, despite no robust evidence of its benefits. We conducted a cluster randomised controlled trial to determine its clinical and cost-effectiveness.

Methods: Forty schools were randomly assigned (1:1) to either the Daily Mile intervention or control group in which only the usual school health and wellbeing activities were implemented. The primary outcome was BMI z-score (BMIz) at 12 months follow-up from baseline, with planned subgroup analysis to examine differential effects. Primary economic analysis outcome was incremental cost per Quality-Adjusted-Life-Year (QALY) gained.

Results: Using a constrained randomisation approach, balanced on school size, baseline BMIz and proportion of pupils eligible for free school meals, 20 schools were allocated to intervention (n = 1,153 participants) and 20 to control (n = 1,127); 3 schools withdrew (2 intervention, 1 control). At 12 months, BMIz data were available for 18 intervention schools (n = 850) and 19 control schools (n = 820 participants). Using intention-to-treat analysis the adjusted mean difference (MD) in BMIz (intervention - control) was -0.036 (95% CI: -0.085 to 0.013, p = 0.146). Pre-specified subgroup analysis showed a significant interaction with sex (p = 0.001) suggesting a moderate size benefit of The Daily Mile in girls (MD -0.097, 95% CI -0.156 to -0.037). This was consistent with the exploratory economic results that showed The Daily Mile to be highly cost-effective in girls (£2,492 per QALY), but not in boys, and overall to have a 76% chance of cost-effectiveness for the whole sample, at the commonly applied UK threshold of £20,000 per QALY.

Conclusions: Overall the Daily Mile had a small but non-significant effect on BMIz, however, it had a greater effect in girls suggesting that it might be considered as a cost-effective component of a system-wide approach to childhood obesity prevention.
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http://dx.doi.org/10.1038/s41366-019-0511-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7101281PMC
April 2020

Ethical issues in the design and conduct of stepped-wedge cluster randomized trials in low-resource settings.

Trials 2019 Dec 19;20(Suppl 2):703. Epub 2019 Dec 19.

University Medical Center Utrecht, Utrecht University, Julius Center, Utrecht, The Netherlands.

Background: Stepped-wedge cluster randomized trials (SW-CRTs) are increasingly popular in health-related research in both high- and low-resource settings. There may be specific ethical issues that researchers face when designing and conducting SW-CRTs in low-resource settings. Knowledge of these issues can help to improve the ethical conduct of SW-CRTs in a global health context.

Methods: We performed an ethical analysis of two studies using SW-CRT designs in low-resource settings: the Que Vivan Las Madres study conducted from 2014 to 2017 in Guatemala and the Atmiyata study conducted from 2017 to 2018 in rural parts of India. For both case studies, we identified and evaluated the classification of the study as research or nonresearch and the ethical issues regarding the justification of the design, including the delayed rollout of an intervention that had a promising effect.

Results: In our case studies, some minor ethical issues surfaced about the registration and stakeholder pressure on the order of randomization, but both included good justification for the design and delayed rollout. Our analysis did, however, demonstrate that careful consideration of the role of randomization and registration of the trials is important.

Discussion: SW-CRTs can provide an opportunity for rigorous evaluation of interventions destined to be rolled out on the basis of limited evidence. Furthermore, in SW-CRTs, the underlying objective is often to provide a robust evaluation of the effectiveness for generalized dissemination, and this makes the SW-CRT no less a research study than any other form of cluster randomized trial.

Conclusion: The design and conduct of stepped-wedge cluster randomized trials raises at least two ethical issues that need special consideration in both high- and low-resource settings: the justification for using the design, specifically the delayed rollout of the intervention to the control group, and the classification of the study as research or nonresearch. In our case studies, these issues did not seem to raise special ethical scrutiny in low-resource settings. Further ethical evaluation will hopefully result in specific ethical guidelines for the use of SW-CRTs in both high- and low-resource settings to contribute to responsible functioning of these trials and adequate protection of participants.
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http://dx.doi.org/10.1186/s13063-019-3842-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6921381PMC
December 2019

Stepped-wedge trials should be classified as research for the purpose of ethical review.

Clin Trials 2019 12;16(6):580-588

Rotman Institute of Philosophy, Western University, London, ON, Canada.

Background: All studies classified as research involving human participants require research ethics review. Most regulation and guidance on ethical oversight of research involving human participants was written for pharmacotherapy interventions. Interpretation of such guidance for cluster-randomized trials and stepped-wedge trials, which commonly evaluate complex non-therapeutic interventions such as knowledge translation, public health, or health service delivery interventions, can pose challenges to researchers and regulators.

Current Guidance: The provides guidance on the ethical oversight and consent procedures for cluster-randomized trials, and while not explicit, this includes stepped-wedge trials. Yet, stepped-wedge trials have unique characteristics that differentiate them from standard cluster-randomized trials. In particular, they can be used to evaluate knowledge translation interventions within the context of a routine health system rollout; they may have a non-randomized design; and the decision to implement the intervention is not always made by the researcher. Many stepped-wedge trials do not undergo ethical review and do not report trial registration. This suggests that those undertaking these studies and research ethics committees perceive them as non-research activities.

Recommendations: Through an ethical analysis of two case studies, we argue that stepped-wedge trials, like parallel arm cluster trials, are systematic investigations designed to produce generalizable knowledge. We contend that stepped-wedge trials usually include human research participants, which may be patients, health care providers, or both. Stepped-wedge trials are therefore research involving human participants for the purpose of ethical review. Nevertheless, the use of a waiver or alteration of consent may be appropriate in many stepped-wedge trials due to the infeasibility of obtaining informed consent and the low-risk nature of the interventions. To ensure that traditional ethical principles such as respect for persons are upheld, these studies must undergo research ethics review.
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http://dx.doi.org/10.1177/1740774519873322DOI Listing
December 2019

Effects of emergency obstetric care training on maternal and perinatal outcomes: a stepped wedge cluster randomised trial in South Africa.

BMJ Glob Health 2019 10;4(6):e001670. Epub 2019 Nov 10.

MRC Maternal and Infant Health Care Strategies Unit, University of Pretoria, Pretoria, South Africa.

Introduction: Two-thirds of maternal deaths and 40% of intrapartum-related neonatal deaths are thought to be preventable through emergency obstetric and newborn care (EmOC&NC). The effectiveness of 'skills and drills' training of maternity staff in EmOC&NC was evaluated.

Methods: Implementation research using a stepped wedge cluster randomised trial including 127 of 129 healthcare facilities (HCFs) across the 11 districts in South Africa with the highest maternal mortality. The sequence in which all districts received EmOC&NC training was randomised but could not be blinded. The timing of training resulted in 10 districts providing data before and 10 providing data after EmOC&NC training. Primary outcome measures derived for HCFs are as follows: stillbirth rate (SBR), early neonatal death (ENND) rate, institutional maternal mortality ratio (iMMR) and direct obstetric case fatality rate (CFR), number of complications recognised and managed and CFR by complication.

Results: At baseline, median SBR (per 1000 births) and ENND rate (per 1000 live births) were 9 (IQR 0-28) and 0 (IQR 0-9). No significant changes following training in EmOC&NC were detected for any of the stated outcomes: SBR (adjusted incidence rate ratio (aIRR) 0.97, 95% CI 0.91 to 1.05), iMMR (aIRR 1.23, 95% CI 0.80 to 1.90), ENND rate (aIRR 1.04, 95% CI 0.92 to 1.17) and direct obstetric CFR (aIRR 1.15, 95% CI 0.66 to 2.02). The number of women who were recognised to need and received EmOC was significantly increased overall (aIRR 1.14, 95% CI 1.02 to 1.27), for haemorrhage (aIRR 1.31, 95% CI 1.13 to 1.52) and for postpartum sepsis (aIRR 1.86, 95% CI 1.17 to 2.95).

Conclusion: Following EmOC&NC training, healthcare providers are more able to recognise and manage complications at time of birth. This trial did not provide evidence that the intervention was effective in reducing adverse clinical outcomes, but demonstrates randomised evaluations are feasible in implementation research.

Trial Registration Number: ISRCTN11224105.
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http://dx.doi.org/10.1136/bmjgh-2019-001670DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6861119PMC
November 2019

The CHIRPY DRAGON intervention in preventing obesity in Chinese primary-school--aged children: A cluster-randomised controlled trial.

PLoS Med 2019 11 26;16(11):e1002971. Epub 2019 Nov 26.

Institute of Applied Health Research, University of Birmingham, Edgbaston, Birmingham, United Kingdom.

Background: In countries undergoing rapid economic transition such as China, rates of increase in childhood obesity exceed that in the West. However, prevention trials in these countries are inadequate in both quantity and methodological quality. In high-income countries, recent reviews have demonstrated that school-based prevention interventions are moderately effective but have some methodological limitations. To address these issues, this study evaluated clinical- and cost- effectiveness of the Chinese Primary School Children Physical Activity and Dietary Behaviour Changes Intervention (CHIRPY DRAGON) developed using the United Kingdom Medical Research Council complex intervention framework to prevent obesity in Chinese primary-school-aged children.

Methods And Findings: In this cluster-randomised controlled trial, we recruited 40 state-funded primary schools from urban districts of Guangzhou, China. A total of 1,641 year-one children with parent/guardian consent took part in baseline assessments prior to stratified randomisation of schools (intervention arm, 20 schools, n = 832, mean age = 6.15 years, 55.6% boys; control arm n = 809, mean age = 6.14 years, 53.3% boys). The 12-month intervention programme included 4 school- and family-based components delivered by 5 dedicated project staff. We promoted physical activity and healthy eating behaviours through educational and practical workshops, family activities, and supporting the school to improve physical activity and food provision. The primary outcome, assessed blind to allocation, was between-arm difference in body mass index (BMI) z score at completion of the intervention. A range of prespecified, secondary anthropometric, behavioural, and psychosocial outcomes were also measured. We estimated cost effectiveness based on quality-adjusted life years (QALYs), taking a public sector perspective. Attrition was low with 55 children lost to follow up (3.4%) and no school dropout. Implementation adherence was high. Using intention to treat analysis, the mean difference (MD) in BMI z scores (intervention - control) was -0.13 (-0.26 to 0.00, p = 0.048), with the effect being greater in girls (MD = -0.18, -0.32 to -0.05, p = 0.007, p for interaction = 0.015) and in children with overweight or obesity at baseline (MD = -0.49, -0.73 to -0.25, p < 0.001, p for interaction < 0.001). Significant beneficial intervention effects were also observed on consumption of fruit and vegetables, sugar-sweetened beverages and unhealthy snacks, screen-based sedentary behaviour, and physical activity in the intervention group. Cost effectiveness was estimated at £1,760 per QALY, with the probability of the intervention being cost effective compared with usual care being at least 95% at a willingness to pay threshold of £20,000 to 30,000 per QALY. There was no evidence of adverse effects or harms. The main limitations of this study were the use of dietary assessment tools not yet validated for Chinese children and the use of the UK value set to estimate QALYS.

Conclusions: This school- and family-based obesity prevention programme was effective and highly cost effective in reducing BMI z scores in primary-school-aged children in China. Future research should identify strategies to enhance beneficial effects among boys and investigate the transferability of the intervention to other provinces in China and countries that share the same language and cultures.

Trial Registration: ISRCTN Identifier ISRCTN11867516.
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http://dx.doi.org/10.1371/journal.pmed.1002971DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6879117PMC
November 2019

Sedation AND Weaning In Children (SANDWICH): protocol for a cluster randomised stepped wedge trial.

BMJ Open 2019 11 10;9(11):e031630. Epub 2019 Nov 10.

MRC Centre for Inflammation Research, The Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, UK.

Introduction: Weaning from ventilation is a complex process involving several stages that include recognition of patient readiness to begin the weaning process, steps to reduce ventilation while optimising sedation in order not to induce distress and removing the endotracheal tube. Delay at any stage can prolong the duration of mechanical ventilation. We developed a multicomponent intervention targeted at helping clinicians to safely expedite this process and minimise the harms associated with unnecessary mechanical ventilation.

Methods And Analysis: This is a 20-month cluster randomised stepped wedge clinical and cost-effectiveness trial with an internal pilot and a process evaluation. It is being conducted in 18 paediatric intensive care units in the UK to evaluate a protocol-based intervention for reducing the duration of invasive mechanical ventilation. Following an initial 8-week baseline data collection period in all sites, one site will be randomly chosen to transition to the intervention every 4 weeks and will start an 8-week training period after which it will continue the intervention for the remaining duration of the study. We aim to recruit approximately 10 000 patients. The primary analysis will compare data from before the training (control) with that from after the training (intervention) in each site. Full details of the analyses will be in the statistical analysis plan.

Ethics And Dissemination: This protocol was reviewed and approved by NRES Committee East Midlands-Nottingham 1 Research Ethics Committee (reference: 17/EM/0301). All sites started patient recruitment on 5 February 2018 before randomisation in April 2018. Results will be disseminated in 2020. The results will be presented at national and international conferences and published in peer-reviewed medical journals.

Trial Registration Number: ISRCTN16998143.
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http://dx.doi.org/10.1136/bmjopen-2019-031630DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6858098PMC
November 2019