Physiotherapy rehabilitation for osteoporotic vertebral fracture-a randomised controlled trial and economic evaluation (PROVE trial).

The trial compared three physiotherapy approaches: manual or exercise therapy compared with a single session of physiotherapy education (SSPT) for people with osteoporotic vertebral fracture(s). At 1 year, there were no statistically significant differences between the groups meaning there is inadequate evidence to support manual or exercise therapy. INTRODUCTION: To evaluate the clinical and cost-effectiveness of different physiotherapy approaches for people with osteoporotic vertebral fracture(s) (OVF). METHODS: >Prospective, multicentre, adaptive, three-arm randomised controlled trial. Six hundred fifteen adults with back pain, osteoporosis, and at least 1 OVF participated. INTERVENTIONS: 7 individual physiotherapy sessions over 12 weeks focused on either manual therapy or home exercise compared with a single session of physiotherapy education (SSPT). The co-primary outcomes were quality of life and back muscle endurance measured by the QUALEFFO-41 and timed loaded standing (TLS) test at 12 months. RESULTS: At 12 months, there were no statistically significant differences between groups. Mean QUALEFFO-41: - 1.3 (exercise), - 0.15 (manual), and - 1.2 (SSPT), a mean difference of - 0.2 (95% CI, - 3.2 to 1.6) for exercise and 1.3 (95% CI, - 1.8 to 2.9) for manual therapy. Mean TLS: 9.8 s (exercise), 13.6 s (manual), and 4.2 s (SSPT), a mean increase of 5.8 s (95% CI, - 4.8 to 20.5) for exercise and 9.7 s (95% CI, 0.1 to 24.9) for manual therapy. Exercise provided more quality-adjusted life years than SSPT but was more expensive. At 4 months, significant changes above SSPT occurred in endurance and balance in manual therapy, and in endurance for those ≤ 70 years, in balance, mobility, and walking in exercise. CONCLUSIONS: Adherence was problematic. Benefits at 4 months did not persist and at 12 months, we found no significant differences between treatments. There is inadequate evidence a short physiotherapy intervention of either manual therapy or home exercise provides long-term benefits, but arguably short-term benefits are valuable. TRIAL REGISTRATION: ISRCTN 49117867.

dfpk: An R-package for Bayesian dose-finding designs using pharmacokinetics (PK) for phase I clinical trials.

BACKGROUND AND OBJECTIVE: Dose-finding, aiming at finding the maximum tolerated dose, and pharmacokinetics studies are the first in human studies in the development process of a new pharmacological treatment. In the literature, to date only few attempts have been made to combine pharmacokinetics and dose-finding and to our knowledge no software implementation is generally available. In previous papers, we proposed several Bayesian adaptive pharmacokinetics-based dose-finding designs in small populations. The objective of this work is to implement these dose-finding methods in an R package, called dfpk. METHODS: All methods were developed in a sequential Bayesian setting and Bayesian parameter estimation is carried out using the rstan package. All available pharmacokinetics and toxicity data are used to suggest the dose of the next cohort with a constraint regarding the probability of toxicity. Stopping rules are also considered for each method. The ggplot2 package is used to create summary plots of toxicities or concentration curves. RESULTS: For all implemented methods, dfpk provides a function (nextDose) to estimate the probability of efficacy and to suggest the dose to give to the next cohort, and a function to run trial simulations to design a trial (nsim). The sim.data function generates at each dose the toxicity value related to a pharmacokinetic measure of exposure, the AUC, with an underlying pharmacokinetic one compartmental model with linear absorption. It is included as an example since similar data-frames can be generated directly by the user and passed to nsim. CONCLUSION: The developed user-friendly R package dfpk, available on the CRAN repository, supports the design of innovative dose-finding studies using PK information.

Performance characteristics of five triage tools for major incidents involving traumatic injuries to children.

UNLABELLED: Context Triage tools are an essential component of the emergency response to a major incident. Although fortunately rare, mass casualty incidents involving children are possible which mandate reliable triage tools to determine the priority of treatment. OBJECTIVE: To determine the performance characteristics of five major incident triage tools amongst paediatric casualties who have sustained traumatic injuries. DESIGN, SETTING, PARTICIPANTS: Retrospective observational cohort study using data from 31,292 patients aged less than 16 years who sustained a traumatic injury. Data were obtained from the UK Trauma Audit and Research Network (TARN) database. Interventions Statistical evaluation of five triage tools (JumpSTART, START, CareFlight, Paediatric Triage Tape/Sieve and Triage Sort) to predict death or severe traumatic injury (injury severity score >15). Main outcome measures Performance characteristics of triage tools (sensitivity, specificity and level of agreement between triage tools) to identify patients at high risk of death or severe injury. RESULTS: Of the 31,292 cases, 1029 died (3.3%), 6842 (21.9%) had major trauma (defined by an injury severity score >15) and 14,711 (47%) were aged 8 years or younger. There was variation in the performance accuracy of the tools to predict major trauma or death (sensitivities ranging between 36.4 and 96.2%; specificities 66.0-89.8%). Performance characteristics varied with the age of the child. CareFlight had the best overall performance at predicting death, with the following sensitivity and specificity (95% CI) respectively: 95.3% (93.8-96.8) and 80.4% (80.0-80.9). JumpSTART was superior for the triaging of children under 8 years; sensitivity and specificity (95% CI) respectively: 86.3% (83.1-89.5) and 84.8% (84.2-85.5). The triage tools were generally better at identifying patients who would die than those with non-fatal severe injury. CONCLUSION: This statistical evaluation has demonstrated variability in the accuracy of triage tools at predicting outcomes for children who sustain traumatic injuries. No single tool performed consistently well across all evaluated scenarios.

Flexible sequential designs for multi-arm clinical trials.

Adaptive designs that are based on group-sequential approaches have the benefit of being efficient as stopping boundaries can be found that lead to good operating characteristics with test decisions based solely on sufficient statistics. The drawback of these so called 'pre-planned adaptive' designs is that unexpected design changes are not possible without impacting the error rates. 'Flexible adaptive designs' on the other hand can cope with a large number of contingencies at the cost of reduced efficiency. In this work, we focus on two different approaches for multi-arm multi-stage trials, which are based on group-sequential ideas, and discuss how these 'pre-planned adaptive designs' can be modified to allow for flexibility. We then show how the added flexibility can be used for treatment selection and sample size reassessment and evaluate the impact on the error rates in a simulation study. The results show that an impressive overall procedure can be found by combining a well chosen pre-planned design with an application of the conditional error principle to allow flexible treatment selection.

Adaptive designs for clinical trials assessing biomarker-guided treatment strategies.

BACKGROUND: The Biomarker Strategy Design has been proposed for trials assessing the value of a biomarker in guiding treatment in oncology. In such trials, patients are randomised to either receive the standard chemotherapy treatment or a biomarker-directed treatment arm, in which biomarker status is used to guide treatment. METHODS: Motivated by a current trial, we consider an adaptive design in which two biomarkers are assessed. The trial is conducted in two stages. In the first stage, patients in the biomarker-guided arm are assessed using a standard and an alternative cheaper biomarker, with the standard biomarker guiding treatment. An analysis comparing biomarker results is then used to choose the biomarker to use for the remainder of the trial. The new biomarker is used if the results for the two biomarkers are sufficiently similar. RESULTS: We show that in practical situations the first-stage results can be used to adapt the trial without type I error rate inflation. We also show that there can be considerable cost gains with only a small loss in power in the case where the alternative biomarker is highly concordant with the standard one. CONCLUSIONS: Adaptive designs have an important role in reducing the cost and increasing the clinical utility of trials evaluating biomarker-guided treatment strategies.

Effectiveness and cost-effectiveness of a universal parenting skills programme in deprived communities: multicentre randomised controlled trial.

OBJECTIVE: To evaluate the effectiveness and cost utility of a universally provided early years parenting programme. DESIGN: Multicentre randomised controlled trial with cost-effectiveness analysis. SETTING: Early years centres in four deprived areas of South Wales. PARTICIPANTS: Families with children aged between 2 and 4 years. 286 families were recruited and randomly allocated to the intervention or waiting list control. INTERVENTION: The Family Links Nurturing Programme (FLNP), a 10-week course with weekly 2 h facilitated group sessions. MAIN OUTCOME MEASURES: Negative and supportive parenting, child and parental well-being and costs assessed before the intervention, following the course (3 months) and at 9 months using standardised measures. RESULTS: There were no significant differences in primary or secondary outcomes between trial arms at 3 or 9 months. With '+' indicating improvement, difference in change in negative parenting score at 9 months was +0.90 (95%CI -1.90 to 3.69); in supportive parenting, +0.17 (95%CI -0.61 to 0.94); and 12 of the 17 secondary outcomes showed a non-significant positive effect in the FLNP arm. Based on changes in parental well-being (SF-12), the cost per quality-adjusted life year (QALY) gained was estimated to be £34 913 (range 21 485-46 578) over 5 years and £18 954 (range 11 664-25 287) over 10 years. Probability of cost per QALY gained below £30 000 was 47% at 5 years and 57% at 10 years. Attendance was low: 34% of intervention families attended no sessions (n=48); only 47% completed the course (n=68). Also, 19% of control families attended a parenting programme before 9-month follow-up. CONCLUSIONS: Our trial has not found evidence of clinical or cost utility for the FLNP in a universal setting. However, low levels of exposure and contamination mean that uncertainty remains. TRIAL REGISTRATION: The trial is registered with Current Controlled Trials ISRCTN13919732.

A systematic literature review of the risk factors associated with children entering public care.

Children who enter public care are among the most vulnerable in society. In addition to services for their medical needs, a focus on identifying and intervening with families in need where children are at high risk of entering public care is a public health priority. This paper aims to identify the characteristics of children, their parents or their social circumstances which are associated with children entering public care. The databases searched were CSA Illumina, British Education Index, ChildData, CINAHL, Excerpta Medica, MEDLINE, the Campbell and Cochrane Collaborations, NHS Centre for Reviews and Dissemination, NHS Evidence, Social Care Online and TRIP; from start dates to 7 February 2011. A total of 6417 titles were reviewed. After review, 10 papers with cohort or case-control methodologies met the inclusion criteria and the included papers were appraised using questions from the Critical Appraisal Skills Programme to guide the critique of case-control and cohort studies. A narrative synthesis is used to describe the research identified. Socio-economic status, maternal age at birth, health risk factors and other factors including learning difficulties, membership of an ethnic minority group and single parenthood are described as risk factors associated with children entering public care. Health risk factors have been explored using databases developed for other purposes such as health insurance or hospital discharge. A number of risk factors for children entering public care are identified from the literature, some were culturally specific and may not generalize. The interaction between different risk factors needs testing in longitudinal data sets.

Selecting breast cancer patients for chemotherapy: the opening of the UK OPTIMA trial.

The mortality from breast cancer has improved steadily over the past two decades, in part because of the increased use of more effective adjuvant therapies. Thousands of women are routinely treated with intensive chemotherapy, which can be unpleasant, is expensive and is occasionally hazardous. Oncologists have long known that some of these women may not need treatment, either because they have a low risk of relapse or because they have tumour biology that makes them less sensitive to chemotherapy and more suitable for early adjuvant endocrine therapy. There is an urgent need to improve patient selection so that chemotherapy is restricted to those patients who will benefit from it. Here we review the emerging technologies that are available for improving patient selection for chemotherapy. We describe the OPTIMA trial, which has just opened to recruitment in the UK, is the latest addition to trials in this area, and is the first to focus on the relative cost-effectiveness of alternate predictive assays.

A conditional error function approach for subgroup selection in adaptive clinical trials.

Growing interest in personalised medicine and targeted therapies is leading to an increase in the importance of subgroup analyses. If it is planned to view treatment comparisons in both a predefined subgroup and the full population as co-primary analyses, it is important that the statistical analysis controls the familywise type I error rate. Spiessens and Debois (Cont. Clin. Trials, 2010, 31, 647-656) recently proposed an approach specific for this setting, which incorporates an assumption about the correlation based on the known sizes of the different groups, and showed that this is more powerful than generic multiple comparisons procedures such as the Bonferroni correction. If recruitment is slow relative to the length of time taken to observe the outcome, it may be efficient to conduct an interim analysis. In this paper, we propose a new method for an adaptive clinical trial with co-primary analyses in a predefined subgroup and the full population based on the conditional error function principle. The methodology is generic in that we assume test statistics can be taken to be normally distributed rather than making any specific distributional assumptions about individual patient data. In a simulation study, we demonstrate that the new method is more powerful than previously suggested analysis strategies. Furthermore, we show how the method can be extended to situations when the selection is not based on the final but on an early outcome. We use a case study in a targeted therapy in oncology to illustrate the use of the proposed methodology with non-normal outcomes.

Designing a seamless phase II/III clinical trial using early outcomes for treatment selection: an application in multiple sclerosis.

In recent years adaptive seamless phase II/III designs (ASDs) allowing treatment or dose selection at an interim analysis have gained much attention because of their potential to save development costs and to shorten time-to-market of a new compound compared to conventional drug development programmes with separate trials for individual phases. In this paper, we describe an ASD with treatment selection based on early outcome data, specifically considering the situation where no final outcomes are observed at the time of the interim analysis. Bringing together combination tests for adaptive designs and the closure principle for multiple testing, control of the familywise type I error rate in the strong sense is achieved. Furthermore, a simulation model is proposed based on standardized test statistics that allows the generation of virtual trials for a variety of outcomes. We use this simulation model to investigate the actual type I error rate of the proposed testing procedure and find that the familywise type I error rate is controlled as expected. The method is often conservative, with the degree of conservatism depending on the correlation between early and late outcome, the true mean values of the early outcome in the different treatment groups and the selection rule. The investigations are motivated and illustrated by an application of the proposed design and simulation model to progressive multiple sclerosis.

In 'big bang' major incidents do triage tools accurately predict clinical priority?: a systematic review of the literature.

INTRODUCTION: The term "big bang" major incidents is used to describe sudden, usually traumatic,catastrophic events, involving relatively large numbers of injured individuals, where demands on clinical services rapidly outstrip the available resources. Triage tools support the pre-hospital provider to prioritise which patients to treat and/or transport first based upon clinical need. The aim of this review is to identify existing triage tools and to determine the extent to which their reliability and validity have been assessed. METHODS: A systematic review of the literature was conducted to identify and evaluate published data validating the efficacy of the triage tools. Studies using data from trauma patients that report on the derivation, validation and/or reliability of the specific pre-hospital triage tools were eligible for inclusion.Purely descriptive studies, reviews, exercises or reports (without supporting data) were excluded. RESULTS: The search yielded 1982 papers. After initial scrutiny of title and abstract, 181 papers were deemed potentially applicable and from these 11 were identified as relevant to this review (in first figure). There were two level of evidence one studies, three level of evidence two studies and six level of evidence three studies. The two level of evidence one studies were prospective validations of Clinical Decision Rules (CDR's) in children in South Africa, all the other studies were retrospective CDR derivation, validation or cohort studies. The quality of the papers was rated as good (n=3), fair (n=7), poor (n=1). CONCLUSION: There is limited evidence for the validity of existing triage tools in big bang major incidents.Where evidence does exist it focuses on sensitivity and specificity in relation to prediction of trauma death or severity of injury based on data from single or small number patient incidents. The Sacco system is unique in combining survivability modelling with the degree by which the system is overwhelmed in the triage decision system. The practicalities, training implications, performance characteristics and reliance on computer technology during a mass casualty incident require further evaluation.

Emergency nurse practitioners and doctors consulting with patients in an emergency department: a comparison of communication skills and satisfaction.

BACKGROUND: Emergency nurse practitioners (ENPs) play an increasingly important role in UK emergency departments (EDs), but there is limited evidence about how this affects patient care and outcome. A study was undertaken to compare the content of, and satisfaction with, consultations made with patients presenting with problems of low acuity to an ED. METHODS: Patients presenting with "primary care" problems were allocated to senior house officers (SHOs, n = 10), specialist registrars/staff grades (n = 7), sessionally-employed general practitioners (GPs, n = 12) or ENPs (n = 6) randomly rostered to work in a consulting room that had a wall-mounted video camera. At the end of each consultation the doctor/ENP and the patient were asked to complete the Physician/Patient Satisfaction Questionnaire. A stratified sample of videotaped consultations (n = 296) was analysed in depth using the Roter Interaction Analysis System. The main outcome measures were length of consultation; numbers of utterances of doctor/ENP and patient talk related to building a relationship, data gathering, activating/partnering, and patient education/counselling; doctor/ENP and patient consultation satisfaction scores. RESULTS: ENPs and GPs focused more on patient education and counselling about the medical condition or therapeutic regimen than did ED doctors. There were no significant differences in consultation length. ENPs had higher levels of overall self-satisfaction with their consultations than ED doctors. Patient satisfaction with how actively they participated in the consultation was significantly associated with the amount of talk relating to building a relationship and activating and partnering, and patient satisfaction with information giving in the consultation was significantly associated with the amount of talk relating to building a relationship. CONCLUSION: These findings suggest differences between ENP and ED doctor consultations which are associated with some aspects of patient satisfaction. In contrast to previous reports, consultation length was not greater for ENPs than for doctors. There is a need for further research to test the generalisability of these findings and their impact on clinical outcome.

Local impact of the English arm of the UK Bowel Cancer Screening Pilot study.

BACKGROUND: The English arm of the UK Bowel Cancer Screening Pilot study recently concluded its third round. The primary aim was to assess the impact of faecal occult blood test (FOBT) screening on the detection of symptomatic (non-screen-detected) cancers within the target age group (50-69 years). The secondary aim was to assess differences between screened and non-screened cohorts in Dukes' classification at diagnosis. METHODS: This population-based study utilized retrospective analysis of existing validated colorectal cancer (CRC) data over 5 years (April 2000 to March 2005), encompassing rounds one and two of screening. RESULTS: There was a 23 per cent (P = 0.011) reduction in the diagnosis of over the 5 years. Presentations with symptomatic cancer reduced by 49 per cent (P = 0.049), with a proportionate (2.6-fold) rise in the detection of screened (asymptomatic) malignancy. Cancers were diagnosed at an earlier stage in the screened population, with significantly more Dukes' A tumours than in the non-screen-detected cohort (P < 0.001) and an estimated odds ratio of 0.27 (95 per cent confidence interval 0.08 to 0.91) (P = 0.035) for Dukes' 'D' cancers. CONCLUSION: FOBT screening resulted in a significant reduction in the number of symptomatic cancers detected within the target age group. Tumours detected by screening were diagnosed at an earlier pathological stage.

Morbidity from diarrhoea, cough and fever among young children in Nigeria.

Diarrhoea, cough and fever are the leading causes of childhood morbidity and mortality in sub-Saharan Africa. Despite it being a determinant of mortality in many developing countries, geographical location has seldom been considered as an explanatory factor for the large regional variations seen in the childhood morbidity attributed to these causes in this area. The relevant data collected in two Nigerian Demographic and Health Surveys, one in 1999 and the other in 2003, have now therefore been analysed and compared. The aim was to reveal and explore inequalities in the health of Nigerian children by mapping the spatial distribution of childhood morbidity associated with recent diarrhoea, cough and fever and accounting for important risk factors, using a Bayesian geo-additive model based on Markov-chain-Monte-Carlo techniques. Although the overall prevalences of recent diarrhoea, cough and fever recorded in 1999 (among children aged <3 years) were similar to those seen in 2003 (among children aged <5 years), the mapping of residual spatial effects indicated that, in each survey, the morbidity attributable to each of these causes varied, differently, at state level. Place of birth (hospital v. other), type of feeding (breastfed only v. other), parental education, maternal visits to antenatal clinics, household economic status, marital status of mother and place of residence were each significantly associated with the childhood morbidity investigated. In both surveys, children from urban areas were found to have a significantly lower risk of fever than their rural counterparts. Most other factors affecting diarrhoea, cough and fever differed in the two surveys. The risk of developing each of these three conditions increased in the first 6-8 months after birth but then gradually declined. The analysis explained a significant share of the pronounced residual spatial effects. Maps showing the prevalences of diarrhoea, cough and fever in young children across Nigeria were generated during this study. Such maps should facilitate the development of policies to fulfil the Millennium Development Goals in Nigeria and throughout sub-Saharan Africa.

Optimal adaptive designs for binary response trials.

We derive the optimal allocation between two treatments in a clinical trial based on the following optimality criterion: for fixed variance of the test statistic, what allocation minimizes the expected number of treatment failures? A sequential design is described that leads asymptotically to the optimal allocation and is compared with the randomized play-the-winner rule, sequential Neyman allocation, and equal allocation at similar power levels. We find that the sequential procedure generally results in fewer treatment failures than the other procedures, particularly when the success probabilities of treatments are smaller.

Learning from previous responses in phase I dose-escalation studies.

Dose escalation in phase I studies is generally performed on the basis of clinical experience and judgement. In this paper some of the statistical approaches that have been proposed for the formalization of the procedure are described. Apart from the use of the Continual Reassessment Method in oncology studies, such formal methods have received little implementation. The purpose of presenting them here is to promote their further exploration and appropriate implementation. Certain limitations are discussed, which will be best overcome by collaboration between clinical pharmacologists and statisticians.

Interim analyses and sequential designs in phase III studies.

Recruitment of patients to a clinical trial usually occurs over a period of time, resulting in the steady accumulation of data throughout the trial's duration. Yet, according to traditional statistical methods, the sample size of the trial should be determined in advance, and data collected on all subjects before analysis proceeds. For ethical and economic reasons, the technique of sequential testing has been developed to enable the examination of data at a series of interim analyses. The aim is to stop recruitment to the study as soon as there is sufficient evidence to reach a firm conclusion. In this paper we present the advantages and disadvantages of conducting interim analyses in phase III clinical trials, together with the key steps to enable the successful implementation of sequential methods in this setting. Examples are given of completed trials, which have been carried out sequentially, and references to relevant literature and software are provided.