The design and analysis of mixture experiments with applications to glazes.

This thesis is concerned with mixture experiments. A mixture experiment is one in which certain properties of a product depend on the relative proportions of its ingredients. This thesis looks at existing and new methods for generating optimal mixture designs, as well as the form of the optimal design. A mixture experiment of industrial relevance is designed and analysed. The example used is the production of suspensions of ceramic glaze. Johnson Matthey Ceramics plc (JM) are interested in producing a model for predicting the viscosity of these suspensions. This viscosity will depend on the proportions of each ingredient and certain processing variables. In seeking optimal designs attention is restricted to designs over candidate sets consisting of points which are known to occur frequently in optimal designs. A variety of computer based methods for generating optimal designs were investigated by comparing the designs they produce for the regular simplex with known optima. It is shown that exchange algorithms using these candidate sets produced near efficient designs. Little is known about the form of the optimal design for constrained mixture problems. An algorithm is developed to generate continuous D optimal designs over a given candidate set. The form of these D optimal designs is investigated for the quadratic and cubic models for three components (q=3), and the quadratic model for q=4. The designs for the quadratic models included all vertices plus selections from the mid points of long edges and the centroid. Designs for the cubic model also included selections from thirds of edges, Mikaeili points and axial check points. The weights of points were found to be particularly dependent on those of their near neighbours. The form of the V optimal design for a quadratic model and q=3 was also investigated. The conclusions were similar to those for D optimality, although the centroid was often weighted considerably more highly. Practical situations often require repeated trials. Various algorithms were developed for generating optimal designs with r trials included twice. For q > 3, the best results were obtained using an exchange algorithm which only considered designs with r trials repeated. Following an extensive programme of experimental work, and detailed discussion with JM to identify important responses, models were produced to describe the relationship between viscosity and the explanatory variables. It was found that increasing the amount of clay and frit in the mixture increased the viscosity, while increasing water decreased it. As particle size was reduced and flocculant was added the effects which the mixture variables had on the top plateau and yield point was found to increase in magnitude

A proportionate, universal parenting programme to enhance social-emotional well-being in infants and toddlers in England : the E-SEE Steps RCT

Background Mental disorders have become a public health crisis. Early prevention is key. Parenting programmes are effective for children aged ≥ 3 years; however, there is a lack of evidence of their effectiveness for children aged ≤ 2 years. Objectives To establish if the model named Enhancing Social–Emotional Health and Well-being in the Early Years (E-SEE) Steps can (1) enhance child social emotional well-being and establish whether or not it is cost-effective at 20 months of age when compared with services as usual; and (2) be delivered as a proportionate universal model with fidelity. Design A pragmatic two-arm randomised controlled trial and economic appraisal, with an embedded process evaluation to examine the outcomes, implementation and cost-effectiveness of the intervention, and intervention uptake, compared with services as usual. The study had an external pilot phase (which was originally planned as an internal pilot). Setting The intervention was delivered in community settings by early years children’s services and/or public health staff in four sites. Participants A total of 341 parents of infants aged ≤ 8 weeks were randomised in a ratio of 5 : 1 (intervention, n = 285; control, n = 56). The target sample was 606 parents. Intervention Two Incredible Years® parenting programmes (i.e. infant and toddler) delivered in a proportionate universal model with three levels [one universal (book) and two targeted group-based parenting programmes]. Main outcome measures Child social and emotional well-being (primary outcome) was assessed using the Ages and Stages Questionnaire: Social and Emotional, 2nd edition, at 2, 9 and 18 months after randomisation. Parent depression (secondary key outcome) was assessed using the Patient Health Questionnaire-9 items. Both questionnaires were eligibility screeners for targeted groups. Results The primary outcome analysis provided no evidence that the E-SEE Steps model was effective in enhancing child social and emotional well-being. The adjusted mean difference was 3.02 on the original Ages and Stages Questionnaire: Social and Emotional, 2nd edition, in favour of the control [95% confidence interval –0.03 to 6.08; p = 0.052; N = 321 (intervention, n = 268; control, n = 53)]. Analysis of the key secondary outcome (i.e. parent depression levels as assessed by the Patient Health Questionnaire-9 items) provided weak evidence on the Patient Health Questionnaire-9 items in favour of the intervention (adjusted mean difference –0.61, 95% confidence interval –1.34 to 0.12; p = 0.1). Other secondary outcomes did not differ between arms. The economic analysis showed that the E-SEE Steps model was associated with higher costs and was marginally more effective (0.031 quality-adjusted life-years gained from E-SEE Steps compared with SAU, 95% confidence interval –0.008 to 0.071) than services as usual, resulting in an incremental cost-effectiveness ratio of approximately £20,062 per quality-adjusted life-year compared with services as usual. Overall take-up of the targeted parenting programmes was low. Sites, although enthusiastic, identified barriers to delivering the intervention. Limitations The target sample size was not met and the study was not powered to explore the effectiveness of each level of intervention. Most parents in the sample were well educated and, therefore, the results are unlikely to be generalisable, particularly to those at greatest risk of poor social and emotional well-being. Conclusions The E-SEE Steps proportionate universal model did not enhance child social and emotional well-being, but generated non-significant improvements in parent health outcomes, resulting in considerable uncertainty around the cost-effectiveness of the intervention. The primary and key secondary outcome gave inconsistent signals. Although, with system changes, increased resources and adaptations to the intervention, the model could be implemented, evidence for positive outcomes from the E-SEE Steps model is poor. Future work The universal-level E-SEE Step data (i.e. the Incredible Years book) from the external pilot will be pooled with the main trial data for further exploration up to follow-up 1, which is the time point at which most change was seen. Trial registration This trial is registered as ISRCTN11079129. Funding This project was funded by the National Institute for Health and Care Research (NIHR) Public Health Research programme and will be published in full in Public Health Research; Vol. 10, No. 8. See the NIHR Journals Library website for further project information

Play brick therapy to aid the social skills of children and young people with autism spectrum disorder : the I-SOCIALISE cluster RCT

BACKGROUND: Social skills interventions are commonly recommended to help children and young people with autism spectrum disorder develop social skills, but some struggle to engage in these interventions. LEGO ® (LEGO System A/S, Billund, Denmark) based therapy, a group social skills intervention, aims to be more interesting and engaging. OBJECTIVE: To evaluate the clinical effectiveness of LEGO ® based therapy on the social and emotional skills of children and young people with autism spectrum disorder in school settings compared with usual support. Secondary objectives included evaluations of cost-effectiveness, acceptability and treatment fidelity. DESIGN: A cluster randomised controlled trial randomly allocating participating schools to either LEGO ® based therapy and usual support or usual support only. SETTING: Mainstream schools in the north of England. PARTICIPANTS: Children and young people (aged 7-15 years) with autism spectrum disorder, their parent/guardian, an associated teacher/teaching assistant and a facilitator teacher/teaching assistant (intervention schools only). INTERVENTION: Schools randomised to the intervention arm delivered 12 weekly sessions of LEGO ® based therapy, which promotes collaborative play and encourages social problem-solving in groups of three children and young people with a facilitator (trained teacher or teaching assistant). Participants received usual support from school and community services. Participants in the control arm received usual support only. Research assistants and statisticians were blind to treatment allocation. MAIN OUTCOME MEASURE: The social skills subscale of the Social Skills Improvement System (SSIS), completed by the children and young people's unblinded teacher pre randomisation and 20 weeks post randomisation. The SSIS social skills subscale measures social skills including social communication, co-operation, empathy, assertion, responsibility and self-control. Participants completed a number of other pre- and post-randomisation measures of emotional health, quality of life, loneliness, problem behaviours, academic competence, service resource utilisation and adverse events. RESULTS: A total of 250 children and young people from 98 schools were randomised: 127 to the intervention arm and 123 to the control arm. Intention-to-treat analysis of the main outcome measure showed a modest positive difference of 3.74 points (95% confidence interval -0.16 to 7.63 points, standardised effect size 0.18; p  = 0.06) in favour of the intervention arm. Statistical significance increased in per-protocol analysis, with a modest positive difference (standardised effect size 0.21; p  = 0.036). Cost-effectiveness of the intervention was found in reduced service use costs and a small increase in quality-adjusted life-years. Intervention fidelity and acceptability were positive. No intervention-related adverse events or effects were reported. CONCLUSIONS: The primary and pre-planned sensitivity analysis of the primary outcome consistently showed a positive clinical difference, with modest standardised effect sizes of between 0.15 and 0.21. There were positive health economics and qualitative findings, corroborated by the difference between arms for the majority of secondary outcomes, which were not statistically significant but favoured the intervention arm. Post hoc additional analysis was exploratory and was not used in drawing this conclusion. Given the small positive change, LEGO ® based therapy for children and young people with autism spectrum disorder in schools should be considered. LIMITATIONS: The primary outcome measure was completed by an unblinded teacher (rather than by the facilitator). FUTURE WORK: The study team recommends future research into LEGO ® based therapy, particularly in school environments. TRIAL REGISTRATION: This trial is registered as ISRCTN64852382. FUNDING: This award was funded by the National Institute for Health and Care Research (NIHR) Public Health Research programme (NIHR award ref: 15/49/32) and is published in full in Public Health Research; Vol. 11, No. 12. See the NIHR Funding and Awards website for further award information

Efficacy and safety of autologous haematopoietic stem cell transplantation versus alemtuzumab, ocrelizumab, ofatumumab or cladribine in relapsing remitting multiple sclerosis (StarMS): protocol for a randomised controlled trial

Introduction: Autologous haematopoietic stem cell transplantation (aHSCT) is increasingly used as treatment for patients with active multiple sclerosis (MS), typically after failure of disease-modifying therapies (DMTs). A recent phase III trial, ‘Multiple Sclerosis International Stem Cell Transplant, MIST’, showed that aHSCT resulted in prolonged time to disability progression compared with DMTs in patients with relapsing remitting MS (RRMS). However, the MIST trial did not include many of the current high-efficacy DMTs (alemtuzumab, ocrelizumab, ofatumumab or cladribine) in use in the UK within the control arm, which are now offered to patients with rapidly evolving severe MS (RES-MS) who are treatment naïve. There remain, therefore, unanswered questions about the relative efficacy and safety of aHSCT over these high-efficacy DMTs in these patient groups. The StarMS trial (Autologous Stem Cell Transplantation versus Alemtuzumab, Ocrelizumab, Ofatumumab or Cladribine in Relapsing Remitting Multiple Sclerosis) will assess the efficacy, safety and long-term impact of aHSCT compared with high-efficacy DMTs in patients with highly active RRMS despite the use of standard DMTs or in patients with treatment naïve RES-MS. Methods and analysis: StarMS is a multicentre parallel-group rater-blinded randomised controlled trial with two arms. A total of 198 participants will be recruited from 19 regional neurology secondary care centres in the UK. Participants will be randomly allocated to the aHSCT arm or DMT arm in a 1:1 ratio. Participants will remain in the study for 2 years with follow-up visits at 3, 6, 9, 12, 18 and 24 months postrandomisation. The primary outcome is the proportion of patients who achieve ‘no evidence of disease activity’ during the 2-year postrandomisation follow-up period in an intention to treat analysis. Secondary outcomes include efficacy, safety, cost-effectiveness and immune reconstitution of aHSCT and the four high-efficacy DMTs. Ethics and dissemination: The study was approved by the Yorkshire and Humber—Leeds West Research Ethics Committee (20/YH/0061). Participants will provide written informed consent prior to any study specific procedures. The study results will be submitted to a peer-reviewed journal and abstracts will be submitted to relevant national and international conferences. Trial registration number: ISRCTN88667898

Intra-cluster correlation for patient reported outcome measures in individually randomised cluster trials

Poster presented at the International Clinical Trials Methodology Conference (ICTMC) 2022.  Our aim was to calculate the intra-cluster correction (ICC) from a number of individually randomised trials that had a patient reported outcome measure (PROM) as an outcome and clustering in the trial design. This analysis aims to inform ICC assumptions in the design of individually randomised cluster trials in the absence of trial specific outcome data. Ethics approval for the secondary analysis of data was obtained through the University of Sheffield School of Health and Related Research (ScHARR) Ethics Committee (Reference: 034554). </p

Efficacy and safety of autologous haematopoietic stem cell transplantation versus alemtuzumab, ocrelizumab, ofatumumab or cladribine in relapsing remitting multiple sclerosis (StarMS): protocol for a randomised controlled trial.

Peer reviewed: TrueAcknowledgements: This is independent research funded by EME and carried out at the National Institute for Health and Care Research (NIHR) Sheffield Biomedical Research Centre (NIHR203321). The views expressed are those of the authors and not necessarily those of EME, the NIHR or the Department of Health and Social Care. The authors would like to acknowledge the crucial roles of the trial steering committee, data monitoring and ethics committee as well as all site PIs.INTRODUCTION: Autologous haematopoietic stem cell transplantation (aHSCT) is increasingly used as treatment for patients with active multiple sclerosis (MS), typically after failure of disease-modifying therapies (DMTs). A recent phase III trial, 'Multiple Sclerosis International Stem Cell Transplant, MIST', showed that aHSCT resulted in prolonged time to disability progression compared with DMTs in patients with relapsing remitting MS (RRMS). However, the MIST trial did not include many of the current high-efficacy DMTs (alemtuzumab, ocrelizumab, ofatumumab or cladribine) in use in the UK within the control arm, which are now offered to patients with rapidly evolving severe MS (RES-MS) who are treatment naïve. There remain, therefore, unanswered questions about the relative efficacy and safety of aHSCT over these high-efficacy DMTs in these patient groups. The StarMS trial (Autologous Stem Cell Transplantation versus Alemtuzumab, Ocrelizumab, Ofatumumab or Cladribine in Relapsing Remitting Multiple Sclerosis) will assess the efficacy, safety and long-term impact of aHSCT compared with high-efficacy DMTs in patients with highly active RRMS despite the use of standard DMTs or in patients with treatment naïve RES-MS. METHODS AND ANALYSIS: StarMS is a multicentre parallel-group rater-blinded randomised controlled trial with two arms. A total of 198 participants will be recruited from 19 regional neurology secondary care centres in the UK. Participants will be randomly allocated to the aHSCT arm or DMT arm in a 1:1 ratio. Participants will remain in the study for 2 years with follow-up visits at 3, 6, 9, 12, 18 and 24 months postrandomisation. The primary outcome is the proportion of patients who achieve 'no evidence of disease activity' during the 2-year postrandomisation follow-up period in an intention to treat analysis. Secondary outcomes include efficacy, safety, cost-effectiveness and immune reconstitution of aHSCT and the four high-efficacy DMTs. ETHICS AND DISSEMINATION: The study was approved by the Yorkshire and Humber-Leeds West Research Ethics Committee (20/YH/0061). Participants will provide written informed consent prior to any study specific procedures. The study results will be submitted to a peer-reviewed journal and abstracts will be submitted to relevant national and international conferences. TRIAL REGISTRATION NUMBER: ISRCTN88667898