The cross-over of statistical thinking and practices: A pandemic catalyst.

Written during the SARS-CoV-2 pandemic, and in recognition of Andy Grieve, the polymath, this article looks at an eclectic mix of topics where statistical thinking and practices should transcend typical dividing lines-with a particular focus on the areas of drug development, public health and social science. The case is made for embedding an experimental (or quasi-experimental) framework within clinical practice for vaccines and treatments following their marketing authorisation. A similar case is made for public health interventions-facilitated by pre-specification of effect size and by the greater use of data standards. A number of recommendations are made whilst noting that progress is being made in some areas.

Effects of 'SPRAT' programme for dietary and lifestyle education to improve psychosomatic symptoms and dietary habits among adolescents: a cluster randomised controlled trial.

BACKGROUND: Dietary and lifestyle modifications to reduce subjective psychosomatic symptoms (SPS) have become an important topic worldwide. We developed a school-based dietary and lifestyle education programme that involved parents/guardians in reducing SPS in adolescents (SPRAT). The programme encouraged parents/guardians to participate in adolescents' healthy dietary and lifestyle modifications to reduce SPS, increase enjoyment of school life, and foster appropriate dietary intake. This study evaluated the effectiveness of SPRAT in reducing SPS and in altering dietary behaviour among adolescents. METHODS: A 6-month cluster randomised controlled trial using SPRAT and the usual school programme (control) was performed. Participants were middle school students in Japan who provided informed consent. Outcomes were SPS scores assessed at baseline and 2, 4, and 6 months after baseline and the proportions of dietary and lifestyle factors achieved such as enjoyment of school life and dietary intakes assessed by FFQW82. Change from baseline (CFB) at 6 months was the primary endpoint. A linear mixed-effects model was applied. As for dietary intake, the treatment effect was estimated as an interaction term between baseline and treatment "baseline*treatment". RESULTS: The intention-to treat analysis included 951 (94.7%) and 1035 (89.8%) individuals in the SPRAT and control groups, respectively. The CFB in the 6-month SPS score adjusted for baseline was lower in the SPRAT group (-0.29) than in the control group (0.62), but the difference was not statistically significant -0.91 (p = 0.093). CONCLUSIONS: Although the primary endpoint tended to denote improvement in the SPRAT group compared to the control group, the improvement was not significant. Favourable effects were observed in some secondary outcomes and statistically significant treatment*baseline interactions were observed for several dietary intakes. These results imply that CFBs of dietary intake were increased or decreased in a favourable direction depending on the baseline intake, especially in the SPRAT group. TRIAL REGISTRATION: UMIN000026715. (27/03/2017).

GERiatric Screening in the treatment of elderly patients with Ovarian Carcinoma (GERSOC): study protocol for a pragmatic, cluster randomised controlled trial.

BACKGROUND: Approximately 40% of the newly diagnosed patients with advanced ovarian cancer are aged 70 years or older. Standard treatment for advanced disease consists of cytoreductive surgery and combination chemotherapy. In older patients, standard treatment is often withheld or prematurely stopped due to suspected frailty. It remains challenging to distinguish fit elderly patients who can endure standard therapy from frail patients who may benefit from an adapted treatment strategy. As a comprehensive geriatric assessment (CGA) can contribute to the identification of frail patients and improve tailored therapy in this population, screening tests were developed to select those who may benefit from a CGA. However, the use of these geriatric screening tests has rarely been compared with usual clinical care. The GERSOC-trial will evaluate whether geriatric screening in elderly patients with advanced-stage ovarian cancer improves treatment completion and quality of life. METHODS: This pragmatic, cluster randomised controlled trial will be conducted at a minimum of 20 hospitals in the Netherlands. Hospitals are randomly assigned to geriatric screening care (in which a geriatric screening comprised of the G8 questionnaire and the Timed Up and Go test is performed), or care as usual (in which current usual care is continued). A total of 320 patients aged ≥ 70 years with primary, advanced-stage ovarian carcinoma will be included. Patients considered fit on geriatric screening will receive standard treatment; patients who are considered unfit will be referred to a geriatrician for analysis and treatment advice. The primary outcome is the percentage difference in completed standard and adapted therapies between the two study arms. Secondary outcomes include quality of life, cost-effectiveness and survival. DISCUSSION: This trial aims to gather evidence for the use of geriatric screening in treatment decision-making in elderly patients with advanced ovarian cancer. If proven feasible, beneficial and cost-effective, geriatric screening may be implemented in routine clinical practice. TRIAL REGISTRATION: Netherlands Trial Registry, ID: NL6745. Registered on 2 August 2017.

High-dose oral vitamin D supplementation and mortality in people aged 65-84 years: the VIDAL cluster feasibility RCT of open versus double-blind individual randomisation.

BACKGROUND: Randomised controlled trials demonstrating improved longevity are needed to justify high-dose vitamin D supplementation for older populations. OBJECTIVES: To demonstrate the feasibility of a large trial (n ≈ 20,000) of high-dose vitamin D in people aged 65-84 years through general practitioner (GP) practices, and to cluster randomise participating practices between open-label and double-blind randomisation to compare effects on recruitment, compliance and contamination. DESIGN: Twenty GP practices were randomised in matched pairs between open-label and double-blind allocation. Within each practice, patients were individually randomised to vitamin D or control (i.e. no treatment or placebo). Participants were invited to attend their GP practice to provide a blood sample and complete a lifestyle questionnaire at recruitment and again at 2 years. Randomisation by telephone followed receipt of a serum corrected calcium assay confirming eligibility (< 2.65 nmol/l). Treatment compliance was reported by quarterly follow-up forms sent and returned by e-mail or post (participant choice). GP visits and infections were abstracted from GP records. Hospital attendances, cancer diagnoses and deaths were ascertained by linkage to Hospital Episode Statistics and national registration through NHS Digital. SETTING: GP practices in England. PARTICIPANTS: Recruitment opened in October 2013 and closed in January 2015. A total of 1615 registered patients aged 65-84 years were randomised: 407 to vitamin D and 421 to no treatment in open practices; 395 to vitamin D and 392 to placebo in blind practices. INTERVENTIONS: There was a 24-month treatment period: 12 monthly doses (100,000 IU of vitamin D3 or placebo as 5 ml oily solution) were posted after randomisation and at 1 year (100,000 IU per month corresponds to 3300 IU per day). Reminders were sent monthly by e-mail, text message or post. MAIN OUTCOME MEASURES: Recruitment, compliance, contamination and change in circulating 25-hydroxyvitamin D [25(OH)D] from baseline to 2 years. RESULTS: Participation rates (randomised/invited) were 15.0% in open practices and 13.4% in double-blind practices (p = 0.7). The proportion still taking study medication at 2 years was 91.2% in open practices and 89.2% in double-blind practices (p = 0.4). The proportion of control participants taking > 400 IU vitamin D per day at 2 years was 5.0% in open practices and 4.8% in double-blind practices. Mean serum 25(OH)D concentration was 51.5 nmol/l [95% confidence interval (CI) 50.2 to 52.8 nmol/l] with 82.6% of participants < 75 nmol/l at baseline. At 2 years, this increased to 109.6 nmol/l (95% CI 107.1 to 112.1 nmol/l) with 12.0% < 75 nmol/l in those allocated to vitamin D and was unaltered at 51.8 nmol/l (95% CI 49.8 to 53.8 nmol/l) in those allocated to no vitamin D (no treatment or placebo). CONCLUSIONS: A trial could recruit 20,000 participants aged 65-84 years through 200 GP practices over 2 years. Approximately 80% would be expected to adhere to allocated treatment (vitamin D or placebo) for 5 years. The trial could be conducted entirely by e-mail in participants aged < 80 years, but some participants aged 80-84 years would require postal follow-up. Recruitment and treatment compliance would be similar and contamination (self-administration of vitamin D) would be minimal, whether control participants are randomised openly to no treatment with no contact during the trial or randomised double-blind to placebo with monthly reminders. TRIAL REGISTRATION: Current Controlled Trials ISRCTN46328341 and EudraCT database 2011-003699-34. FUNDING: This project was funded by the National Institute for Health Research Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 10. See the NIHR Journals Library website for further project information.

High-dose vitamin D may reduce the risk of many diseases, but without large randomised controlled trials the evidence will remain inconclusive. We therefore proposed the Vitamin D and Longevity (VIDAL) trial, with 20,000 older people randomised to either no vitamin D medication or vitamin D medication for 5 years. The VIDAL feasibility study was conducted to establish the procedures required for the main trial, including assessment of recruitment, compliance (taking study treatment as directed) and contamination (how many control participants started taking vitamin D). This was done in two sets of general practitioner (GP) practices: (1) 'open' practices, in which participants knew their treatment allocation (2 years of 100,000 IU vitamin D monthly or no treatment), and (2) 'double-blind' practices, in which participants and their GPs did not know whether they were taking vitamin D or placebo oil. We invited 11,376 men and women aged 65­84 years from 20 GP practices in England and 1615 (14%) took part. Ninety per cent of participants allocated to monthly oil took it for 2 years and few participants used vitamin supplements outside the trial, with no marked differences between open-label and double-blind arms. The best way to conduct the main trial will therefore depend on other considerations. A double-blind trial provides reliable evidence on effects where reporting could be influenced by you or your doctor knowing your treatment, which is important for many illnesses and any side effects of treatment. However, any long-term effects are likely to be considerably greater if treatment continues instead of stopping after 5 years when the main trial ends. An open trial is easier to conduct and, when it ends, those taking vitamin D can be offered a continuing supply so that the effect of lifelong treatment can be studied for major diseases and life expectancy, which are unlikely to be affected by individuals knowing whether or not they are taking vitamin D.

Strategies for recruitment in general practice settings: the iSOLVE fall prevention pragmatic cluster randomised controlled trial.

BACKGROUND: Falls are common among older people, and General Practitioners (GPs) could play an important role in implementing strategies to manage fall risk. Despite this, fall prevention is not a routine activity in general practice settings. The iSOLVE cluster randomised controlled trial aimed to evaluate implementation of a fall prevention decision tool in general practice. This paper sought to describe the strategies used and reflect on the enablers and barriers relevant to successful recruitment of general practices, GPs and their patients. METHODS: Recruitment was conducted within the geographical area of a Primary Health Network in Northern Sydney, Australia. General practices and GPs were engaged via online surveys, mailed invitations to participate, educational workshops, practitioner networks and promotional practice visits. Patients 65 years or older were recruited via mailed invitations, incorporating the practice letterhead and the name(s) of participating GP(s). Observations of recruitment strategies, results and enabling factors were recorded in field notes as descriptive and narrative data, and analysed using mixed-methods. RESULTS: It took 19 months to complete recruitment of 27 general practices, 75 GPs and 560 patients. The multiple strategies used to engage general practices and GPs were collectively useful in reaching the targeted sample size. Practice visits were valuable in engaging GPs and staff, establishing interest in fall prevention and commitment to the trial. A mix of small, medium and large practices were recruited. While some were recruited as a whole-practice, other practices had few or half of the number of GPs recruited. The importance of preventing falls in older patients, simplicity of research design, provision of resources and logistic facilitation of patient recruitment appealed to GPs. Recruitment of older patients was successfully achieved by mailed invitations which was a strategy that was familiar to practice staff and patients. Patient response rates were above the expected 10% for most practices. Many practices (n = 17) achieved the targeted number of 20 or more patients. CONCLUSIONS: Recruitment in general practice settings can be successfully achieved through multiple recruitment strategies, effective communication and rapport building, ensuring research topic and design suit general practice needs, and using familiar communication strategies to engage patients. TRIAL REGISTRATION: The trial was prospectively registered on 29 April 2015 with the Australian New Zealand Clinical Trial Registry www.anzctr.org.au (trial ID: ACTRN12615000401550).

Pragmatic cluster randomised double-blind pilot and feasibility trial of an active behavioural physiotherapy intervention for acute non-specific neck pain: a mixed-methods protocol.

INTRODUCTION: Non-specific neck pain causes pain and disability and contributes substantial socioeconomic burden internationally. Up to 50% of adults experience neck pain annually, leading to reduced the quality of life. An active behavioural physiotherapy intervention (ABPI) may be feasible to manage patients with acute non-specific neck pain to prevent transition to chronicity. A recent pilot and feasibility trial investigating an acute whiplash-associated disorder population found potential value of the ABPI with 95% of participants fully recovered (Neck Disability Index: NDI ≤4, compared with 17% in the standard physiotherapy arm); supporting a definitive trial. Qualitative findings from the physiotherapists supported the potential of the ABPI in a non-specific neck pain population. METHODS AND ANALYSIS: Two phases: (1) Pragmatic cluster randomised double-blind, parallel 2-arm (ABPI vs standard physiotherapy intervention) pilot and feasibility trial to evaluate the procedures and feasibility of the ABPI for the management of acute non-specific neck pain. Six physiotherapy departments from six public hospitals in Thailand will be recruited and cluster randomised by a computer-generated randomisation sequence with block sampling. Sixty participants (30 each arm, 10 per hospital) will be assessed at baseline and 3 months following baseline for NDI, Numerical Rating Scale for pain intensity, cervical range of motion, fear-avoidance beliefs questionnaire and EuroQol-5 dimensions 5 levels outcomes, and (2) Embedded qualitative study using semistructured interviews to explore acceptability of the ABPI to participants (n=12) and physiotherapists (n=3). Descriptive analysis of the quantitative data and interpretative phenomenological analysis to code and analyse qualitative data (deductive and inductive) will inform feasibility for a future definitive trial. ETHICS AND DISSEMINATION: This trial is approved by the Naresuan University Institutional Review Board (NUIRB_0380/61). TRIAL REGISTRATION NUMBER AND STATUS: TCTR20180607001; Recruiting commenced 1 February 2019.

The impact of patient-held health records on continuity of care among asylum seekers in reception centres: a cluster-randomised stepped wedge trial in Germany.

INTRODUCTION: The aim of this study was to assess the effectiveness of a patient-held health record (PHR) for asylum seekers on the availability of health-related information. METHODS: An explorative, cluster-randomised stepped-wedge trial with reception centres as unit of randomisation was conducted. All reception centres (n=6) in two large administrative areas in South Germany with on-site health services were included. All physicians working at these centres were invited to participate in the study. The intervention was the implementation of a PHR. The primary outcome was the prevalence of written health-related information. Secondary outcomes were the physicians' dissatisfaction with the available written information and the prevalence of missing health-related information. All outcomes were measured at the level of patient-physician contacts by means of a standardised questionnaire, and analysed in logistic multi-level regression models. RESULTS: We obtained data on 2308 patient-physician contacts. The presence of the PHR increased the availability of health-related information (adjusted OR (aOR), 20.3, 95% CI: 12.74 to 32.33), and tended to reduce missing essential information (aOR 0.71, 95% CI: 0.39 to 1.26) and physicians' dissatisfaction with available information (aOR 0.5, 95% CI: 0.24 to 1.04). The availability of health-related information in the post-intervention period was higher (aOR 4.22, 95% CI: 2.64 to 6.73), missing information (aOR 0.89, 95% CI: 0.42 to 1.88) and dissatisfaction (aOR 0.43, 95% CI: 0.16 to 1.14) tended to be lower compared with the pre-intervention period. CONCLUSIONS: Healthcare planners should consider introducing PHRs in reception centres or comparable facilities. Future research should focus on the impact of PHRs on clinical outcomes and on intersectoral care. TRIAL REGISTRATION: ISRCTN13212716. Registered 24 November 2016. Retrospectively registered. http://www.isrctn.com/ISRCTN13212716.

Study protocol for a cluster randomised controlled factorial design trial to assess the effectiveness and feasibility of reactive focal mass drug administration and vector control to reduce malaria transmission in the low endemic setting of Namibia.

INTRODUCTION: To interrupt malaria transmission, strategies must target the parasite reservoir in both humans and mosquitos. Testing of community members linked to an index case, termed reactive case detection (RACD), is commonly implemented in low transmission areas, though its impact may be limited by the sensitivity of current diagnostics. Indoor residual spraying (IRS) before malaria season is a cornerstone of vector control efforts. Despite their implementation in Namibia, a country approaching elimination, these methods have been met with recent plateaus in transmission reduction. This study evaluates the effectiveness and feasibility of two new targeted strategies, reactive focal mass drug administration (rfMDA) and reactive focal vector control (RAVC) in Namibia. METHODS AND ANALYSIS: This is an open-label cluster randomised controlled trial with 2×2 factorial design. The interventions include: rfMDA (presumptive treatment with artemether-lumefantrine (AL)) versus RACD (rapid diagnostic testing and treatment using AL) and RAVC (IRS with Acellic 300CS) versus no RAVC. Factorial design also enables comparison of the combined rfMDA+RAVC intervention to RACD. Participants living in 56 enumeration areas will be randomised to one of four arms: rfMDA, rfMDA+RAVC, RACD or RACD+RAVC. These interventions, triggered by index cases detected at health facilities, will be targeted to individuals residing within 500 m of an index. The primary outcome is cumulative incidence of locally acquired malaria detected at health facilities over 1 year. Secondary outcomes include seroprevalence, infection prevalence, intervention coverage, safety, acceptability, adherence, cost and cost-effectiveness. ETHICS AND DISSEMINATION: Findings will be reported on clinicaltrials.gov, in peer-reviewed publications and through stakeholder meetings with MoHSS and community leaders in Namibia. TRIAL REGISTRATION NUMBER: NCT02610400; Pre-results.

Randomised and non-randomised studies to estimate the effect of community-level public health interventions: definitions and methodological considerations.

BACKGROUND: The preferred method to evaluate public health interventions delivered at the level of whole communities is the cluster randomised trial (CRT). The practical limitations of CRTs and the need for alternative methods continue to be debated. There is no consensus on how to classify study designs to evaluate interventions, and how different design features are related to the strength of evidence. ANALYSIS: This article proposes that most study designs for the evaluation of cluster-level interventions fall into four broad categories: the CRT, the non-randomised cluster trial (NCT), the controlled before-and-after study (CBA), and the before-and-after study without control (BA). A CRT needs to fulfil two basic criteria: (1) the intervention is allocated at random; (2) there are sufficient clusters to allow a statistical between-arm comparison. In a NCT, statistical comparison is made across trial arms as in a CRT, but treatment allocation is not random. The defining feature of a CBA is that intervention and control arms are not compared directly, usually because there are insufficient clusters in each arm to allow a statistical comparison. Rather, baseline and follow-up measures of the outcome of interest are compared in the intervention arm, and separately in the control arm. A BA is a CBA without a control group. CONCLUSION: Each design may provide useful or misleading evidence. A precise baseline measurement of the outcome of interest is critical for causal inference in all studies except CRTs. Apart from statistical considerations the exploration of pre/post trends in the outcome allows a more transparent discussion of study weaknesses than is possible in non-randomised studies without a baseline measure.

The evaluation of enhanced feedback interventions to reduce unnecessary blood transfusions (AFFINITIE): protocol for two linked cluster randomised factorial controlled trials.

BACKGROUND: Blood for transfusion is a frequently used clinical intervention, and is also a costly and limited resource with risks. Many transfusions are given to stable and non-bleeding patients despite no clear evidence of benefit from clinical studies. Audit and feedback (A&F) is widely used to improve the quality of healthcare, including appropriate use of blood. However, its effects are often inconsistent, indicating the need for coordinated research including more head-to-head trials comparing different ways of delivering feedback. A programmatic series of research projects, termed the 'Audit and Feedback INterventions to Increase evidence-based Transfusion practIcE' (AFFINITIE) programme, aims to test different ways of developing and delivering feedback within an existing national audit structure. METHODS: The evaluation will comprise two linked 2×2 factorial, cross-sectional cluster-randomised controlled trials. Each trial will estimate the effects of two feedback interventions, 'enhanced content' and 'enhanced follow-on support', designed in earlier stages of the AFFINITIE programme, compared to current practice. The interventions will be embedded within two rounds of the UK National Comparative Audit of Blood Transfusion (NCABT) focusing on patient blood management in surgery and use of blood transfusions in patients with haematological malignancies. The unit of randomisation will be National Health Service (NHS) trust or health board. Clusters providing care relevant to the audit topics will be randomised following each baseline audit (separately for each trial), with stratification for size (volume of blood transfusions) and region (Regional Transfusion Committee). The primary outcome for each topic will be the proportion of patients receiving a transfusion coded as unnecessary. For each audit topic a linked, mixed-method fidelity assessment and cost-effectiveness analysis will be conducted in parallel to the trial. DISCUSSION: AFFINITIE involves a series of studies to explore how A&F may be refined to change practice including two cluster randomised trials linked to national audits of transfusion practice. The methodology represents a step-wise increment in study design to more fully evaluate the effects of two enhanced feedback interventions on patient- and trust-level clinical, cost, safety and process outcomes. TRIAL REGISTRATION: http://www.isrctn.com/ISRCTN15490813.

Acute Whiplash Injury Study (AWIS): a protocol for a cluster randomised pilot and feasibility trial of an Active Behavioural Physiotherapy Intervention in an insurance private setting.

INTRODUCTION: Whiplash-associated disorder (WAD) causes substantial social and economic burden internationally. Up to 60% of patients with WAD progress to chronicity. Research therefore needs to focus on effective management in the acute stage to prevent the development of chronicity. Approximately 93% of patients are classified as WADII (neck complaint and musculoskeletal sign(s)), and in the UK, most are managed in the private sector. In our recent systematic review, a combination of active and behavioural physiotherapy was identified as potentially effective in the acute stage. An Active Behavioural Physiotherapy Intervention (ABPI) was developed through combining empirical (modified Delphi study) and theoretical (social cognitive theory focusing on self-efficacy) evidence. This pilot and feasibility trial has been designed to inform the design of an adequately powered definitive randomised controlled trial. METHODS AND ANALYSIS: Two parallel phases. (1) An external pilot and feasibility cluster randomised double-blind (assessor and participants), parallel two-arm (ABPI vs standard physiotherapy) clinical trial to evaluate procedures and feasibility. Six UK private physiotherapy clinics will be recruited and cluster randomised by a computer-generated randomisation sequence. Sixty participants (30 each arm) will be assessed at recruitment (baseline) and at 3 months postbaseline. The planned primary outcome measure is the neck disability index. (2) An embedded exploratory qualitative study using semistructured indepth interviews (n=3-4 physiotherapists) and a focus group (n=6-8 patients) and entailing the recruitment of purposive samples will explore perceptions of the ABPI. Quantitative data will be analysed descriptively. Qualitative data will be coded and analysed deductively (identify themes) and inductively (identify additional themes). ETHICS AND DISSEMINATION: This trial is approved by the University of Birmingham Ethics Committee (ERN_15-0542). TRIAL REGISTRATION NUMBER: ISRCTN84528320.