Methodological bias in cluster randomised trials

Background: Cluster randomised trials can be susceptible to a range of methodological problems. These problems are not commonly recognised by many researchers. In this paper we discuss the issues that can lead to bias in cluster trials. Methods: We used a sample of cluster randomised trials from a recent review and from a systematic review of hip protectors. We compared the mean age of participants between intervention groups in a sample of 'good' cluster trials with a sample of potentially biased trials. We also compared the effect sizes, in a funnel plot, between hip protector trials that used individual randomisation compared with those that used cluster randomisation. Results: There is a tendency for cluster trials, with evidence methodological biases, to also show an age imbalance between treatment groups. In a funnel plot we show that all cluster trials show a large positive effect of hip protectors whilst individually randomised trials show a range of positive and negative effects, suggesting that cluster trials may be producing a biased estimate of effect. Conclusion: Methodological biases in the design and execution of cluster randomised trials is frequent. Some of these biases associated with the use of cluster designs can be avoided through careful attention to the design of cluster trials. Firstly, if possible, individual allocation should be used. Secondly, if cluster allocation is required, then ideally participants should be identified before random allocation of the clusters. Third, if prior identification is not possible, then an independent recruiter should be used to recruit participants

Using e-mail recruitment and an online questionnaire to establish effect size: A worked example

Background\ud Sample size calculations require effect size estimations. Sometimes, effect size estimations and standard deviation may not be readily available, particularly if efficacy is unknown because the intervention is new or developing, or the trial targets a new population. In such cases, one way to estimate the effect size is to gather expert opinion. This paper reports the use of a simple strategy to gather expert opinion to estimate a suitable effect size to use in a sample size calculation.\ud \ud Methods\ud Researchers involved in the design and analysis of clinical trials were identified at the University of Birmingham and via the MRC Hubs for Trials Methodology Research. An email invited them to participate.\ud \ud An online questionnaire was developed using the free online tool 'Survey Monkey©'. The questionnaire described an intervention, an electronic participant information sheet (e-PIS), which may increase recruitment rates to a trial. Respondents were asked how much they would need to see recruitment rates increased by, based on 90%. 70%, 50% and 30% baseline rates, (in a hypothetical study) before they would consider using an e-PIS in their research.\ud \ud Analyses comprised simple descriptive statistics.\ud \ud Results\ud The invitation to participate was sent to 122 people; 7 responded to say they were not involved in trial design and could not complete the questionnaire, 64 attempted it, 26 failed to complete it. Thirty-eight people completed the questionnaire and were included in the analysis (response rate 33%; 38/115). Of those who completed the questionnaire 44.7% (17/38) were at the academic grade of research fellow 26.3% (10/38) senior research fellow, and 28.9% (11/38) professor. Dependent upon the baseline recruitment rates presented in the questionnaire, participants wanted recruitment rate to increase from 6.9% to 28.9% before they would consider using the intervention.\ud \ud Conclusions\ud This paper has shown that in situations where effect size estimations cannot be collected from previous research, opinions from researchers and trialists can be quickly and easily collected by conducting a simple study using email recruitment and an online questionnaire. The results collected from the survey were successfully used in sample size calculations for a PhD research study protocol.\ud \u

Enclosing a pen to improve response rate to postal questionnaire: an embedded randomised controlled trial

Background: Poor response to questionnaires collecting outcome data in randomised controlled trials (RCTs) can affect the validity of trial results. The aim of this study within a trial (SWAT) was to evaluate the effectiveness of including a pen with a follow-up postal questionnaire on response rate. Methods: A two-armed RCT was embedded within SSHeW (Stopping Slips among Healthcare Workers), a trial of slip-resistant footwear to reduce slips in NHS staff. Participants were randomised 1:1 to receive a pen or no pen with their follow-up questionnaire. The primary outcome was the proportion of participants who returned the questionnaire. Secondary outcomes were: time to response, completeness of response, and whether a postal reminder notice was required. Data were analysed using logistic regression, linear regression and Cox proportional hazards regression. Results: Overall, 1466 SSHEW trial participants were randomised into the SWAT. In total, 13 withdrew from the host trial before they were due to be sent their follow-up questionnaire, 728 participants received a pen with their questionnaire, and 725 did not receive a pen. A questionnaire was returned from 67.7% of the pen group and 64.7% of the group who did not receive a pen. There was no significant difference in return rates between the two groups (OR 1.15, 95% CI 0.92 to 1.43, p=0.22), nor level of completeness of the questionnaires (AMD -0.01, 95% CI 0.06 to 0.05, p=0.77). There was weak evidence of a reduction in the proportion of participants requiring a reminder and in time to response in the pen group. Conclusion: Inclusion of a pen with the follow-up postal questionnaire sent to participants in the SSHeW trial did not statistically significantly increase the response rate. These results add to the body of evidence around improving response rates in trials. Trial registration: ISRCTN 33051393 (for SSHEW). Registered on 14/03/2017

Sequential boundaries approach in clinical trials with unequal allocation ratios

BACKGROUND: In clinical trials, both unequal randomization design and sequential analyses have ethical and economic advantages. In the single-stage-design (SSD), however, if the sample size is not adjusted based on unequal randomization, the power of the trial will decrease, whereas with sequential analysis the power will always remain constant. Our aim was to compare sequential boundaries approach with the SSD when the allocation ratio (R) was not equal. METHODS: We evaluated the influence of R, the ratio of the patients in experimental group to the standard group, on the statistical properties of two-sided tests, including the two-sided single triangular test (TT), double triangular test (DTT) and SSD by multiple simulations. The average sample size numbers (ASNs) and power (1-β) were evaluated for all tests. RESULTS: Our simulation study showed that choosing R = 2 instead of R = 1 increases the sample size of SSD by 12% and the ASN of the TT and DTT by the same proportion. Moreover, when R = 2, compared to the adjusted SSD, using the TT or DTT allows to retrieve the well known reductions of ASN observed when R = 1, compared to SSD. In addition, when R = 2, compared to SSD, using the TT and DTT allows to obtain smaller reductions of ASN than when R = 1, but maintains the power of the test to its planned value. CONCLUSION: This study indicates that when the allocation ratio is not equal among the treatment groups, sequential analysis could indeed serve as a compromise between ethicists, economists and statisticians

Patient acceptability of larval therapy for leg ulcer treatment: a randomised survey to inform the sample size calculation of a randomised trial

BACKGROUND: A trial was commissioned to evaluate the effectiveness of larval therapy to debride and heal sloughy and necrotic venous leg ulcers. Larval therapy in the trial was to be delivered in either loose or bagged form. Researchers were concerned that resistance to larval therapy may threaten the feasibility of the trial. Additionally there was concern that the use of larval therapy may require a larger effect size in time to healing than originally proposed by the investigators. METHODS: To formally evaluate patient preferences a survey using two randomly allocated, nurse administered questionnaires was undertaken. Patients were randomised to receive one of the two following questionnaires (i) preferences between loose larvae and standard treatment (hydrogel) or (ii) patient preferences between bagged larvae and standard therapy (hydrogel). The study was undertaken in a Vascular Clinic, in an Outpatients Department of a large teaching hospital in the North of England. The sample consisted of 35 people aged 18 years and above with at least one leg ulcer of venous or mixed (venous and arterial) aetiology. RESULTS: Approximately 25% of participants would not consider the use of larval therapy as an acceptable treatment option for leg ulcers, regardless of the method of containment. For the patients that would consider the use of larval therapy, different preferences in healing times required to use the therapy were observed depending upon the method of containment. The median response of those participants questioned about bagged larvae found that they would be willing to use this therapy even if they were equally able to achieve healing with the use of hydrogel by 20 weeks. For those participants questioned about the use of loose larvae complete healing would have to have taken place over 17 weeks for them to choose larvae as their preferred option rather than hydrogel. This difference was not significant (p = 0.075). CONCLUSION: We found no evidence of widespread resistance to the utilisation of larval therapy from patients regardless of the method of larval therapy containment. These methods have the potential to inform sample size calculations where there are concerns of patient acceptability

Increasing recruitment to randomised trials: a review of randomised controlled trials

BACKGROUND: Poor recruitment to randomised controlled trials (RCTs) is a widespread and important problem. With poor recruitment being such an important issue with respect to the conduct of randomised trials, a systematic review of controlled trials on recruitment methods was undertaken in order to identify strategies that are effective. METHODS: We searched the register of trials in Cochrane library from 1996 to end of 2004. We also searched Web of Science for 2004. Additional trials were identified from personal knowledge. Included studies had to use random allocation and participants had to be allocated to different methods of recruitment to a 'real' randomised trial. Trials that randomised participants to 'mock' trials and trials of recruitment to non-randomised studies (e.g., case control studies) were excluded. Information on the study design, intervention and control, and number of patients recruited was extracted by the 2 authors. RESULTS: We identified 14 papers describing 20 different interventions. Effective interventions included: telephone reminders; questionnaire inclusion; monetary incentives; using an 'open' rather than placebo design; and making trial materials culturally sensitive. CONCLUSION: Few trials have been undertaken to test interventions to improve trial recruitment. There is an urgent need for more RCTs of recruitment strategies

A liftless intervention to prevent preterm birth and low birthweight among pregnant Ghanaian women : protocol of a stepped-wedge cluster randomized controlled trial

Background: Preterm birth (PTB) is a leading cause of infant morbidity and mortality worldwide. Every year, 20 million babies are born with low birthweight (LBW), about 96% of which occur in low-income countries. Despite the associated dangers, in about 40%-50% of PTB and LBW cases, the causes remain unexplained. Existing evidence is inconclusive as to whether occupational physical activities such as heavy lifting are implicated. African women bear the transport burden of accessing basic needs for their families. Ghana’s PTB rate is 14.5%, whereas the global average is 9.6%. The proposed liftless intervention aims to decrease lifting exposure during pregnancy among Ghanaian women. We hypothesize that a reduction in heavy lifting among pregnant women in Ghana will increase gestational age and birthweight. Objective: To investigate the effects of the liftless intervention on the incidence of PTB and LBW among pregnant Ghanaian women. Methods: A cohort stepped-wedge cluster randomized controlled trial in 10 antenatal clinics will be carried out in Ghana. A total of 1000 pregnant participants will be recruited for a 60-week period. To be eligible, the participant should have a singleton pregnancy between 12 and 16 weeks gestation, be attending any of the 10 antenatal clinics, and be exposed to heavy lifting. All participants will receive standard antenatal care within the control phase; by random allocation, two clusters will transit into the intervention phase. The midwife-led 3-component liftless intervention consists of health education, a take-home reminder card mimicking the colors of a traffic light, and a shopping voucher. The primary outcome are gestational ages of <28, 28-32, and 33-37 weeks. The secondary outcomes are LBW (preterm LBW, term but LBW, and postterm), compliance, prevalence of low back and pelvic pain, and premature uterine contractions. Study midwives and participants will not be blinded to the treatment allocation. Results: Permission to conduct the study at all 10 antenatal clinics has been granted by the Ghana Health Service. Application for funding to begin the trial is ongoing. Findings from the main trial are expected to be published by the end of 2019. Conclusions: To the best of our knowledge, there has been no randomized trial of this nature in Ghana. Minimizing heavy lifting among pregnant African women can reduce the soaring rates of PTB and LBW. The findings will increase the knowledge of the prevention of PTB and LBW worldwide. Trial Registration: Pan African Clinical Trial Register (PACTR201602001301205); http://apps.who.int/trialsearch/ Trial2.aspx?TrialID=PACTR201602001301205 (Archived by WebCite at http://www.webcitation.org/71TCYkHzu) Registered Report Identifier: RR1-10.2196/1009

Visualising Evolution History in Multi- and Many-Objective Optimisation

Evolutionary algorithms are widely used to solve optimisation problems. However, challenges of transparency arise in both visualising the processes of an optimiser operating through a problem and understanding the problem features produced from many-objective problems, where comprehending four or more spatial dimensions is difficult. This work considers the visualisation of a population as an optimisation process executes. We have adapted an existing visualisation technique to multi- and many-objective problem data, enabling a user to visualise the EA processes and identify specific problem characteristics and thus providing a greater understanding of the problem landscape. This is particularly valuable if the problem landscape is unknown, contains unknown features or is a many-objective problem. We have shown how using this framework is effective on a suite of multi- and many-objective benchmark test problems, optimising them with NSGA-II and NSGA-III

Cost-effectiveness of hydroxychloroquine versus placebo for hand osteoarthritis: economic evaluation of the HERO trial

Background: An economic evaluation alongside the Hydroxychloroquine Effectiveness in Reducing symptoms of hand Osteoarthritis (HERO) trial was undertaken to assess the cost-effectiveness of hydroxychloroquine compared with placebo for symptomatic treatment of hand osteoarthritis for patients with at least moderate hand pain and inadequate response to current therapies. Methods: A trial-based cost–utility analysis was undertaken from the perspective of the UK National Health Service and Personal Social Services over a 12-month time horizon, using evidence from 248 participants included in the HERO trial, conducted in England. Patient-level data were collected prospectively over a 12-month period, using participant-completed questionnaires and investigator forms, to collect healthcare utilisation, costs and quality-adjusted life years (QALYs) using the EQ-5D-5L. The base-case analysis was conducted on an intention-to-treat basis and used multiple imputation methods to deal with missing data. Results were presented in terms of incremental cost-effectiveness ratios (incremental cost per QALY) and net health benefit, with uncertainty surrounding the findings explored using cost-effectiveness acceptability curves. Results: The base-case analysis estimated slightly lower costs on average (−£11.80; 95% confidence interval (CI) −£15.60 to −£8.00) and marginally fewer QALYs (−0.0052; 95% CI −0.0057 to −0.0047) for participants in the hydroxychloroquine group versus placebo group at 12 months. The resulting incremental cost-effectiveness ratio of £2,267 per QALY lost indicated that although costs were saved, health-related quality of life was lost. Even assuming symmetrical preferences regarding losses and gains for health benefits, the findings do not fall within the cost-effective region. Similar findings arose for analyses conducted from the societal perspective and using complete cases only. Conclusions: This economic evaluation indicates that hydroxychloroquine is unlikely to provide a cost-effective pain relief option for improving health-related quality of life in adult patients with moderate-to-severe hand osteoarthritis