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.

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.

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.

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.

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.

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.

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.

Splenic rupture following cardiopulmonary resuscitation.

Cardiopulmonary resuscitation has improved outcome from cardiac arrest. However complications may occur secondary to the resuscitation efforts. We present a case of intraabdominal haemorrhage, due to traumatic rupture of the spleen and discuss the problems of diagnosing intraabdominal haemorrhage in the post cardiac arrest patient, whose hypotension may be ascribed to myocardial dysfunction.

The fixed-dose procedure and the acute-toxic-class method: a mathematical comparison.

The fixed-dose procedure (FDP), proposed by the British Toxicology Society, and the acute-toxic-class (ATC) method, proposed by the German Federal Health Authority, provide alternatives to the LD50 test for classifying substances by their acute oral toxicity. This paper presents a mathematical model that is used to compare the two procedures in terms of their classification properties and the required numbers of animals. It is found that the classification properties of the procedures depend on the dose levels used, the number of animals tested per dose and the criteria that are used to decide whether testing should continue at a higher or lower dose. For substances with steep dose-response curves, the most likely classification is determined chiefly by the choice of the dose levels whilst the number of animals and continuation criteria used are increasingly important for substances with dose-response curves with a smaller slope. The use of toxicity as a possible endpoint as in the FDP and the use of a two-stage testing procedure at each dose as in the ATC method are both found to reduce the expected numbers of animals required with little effect on the classification properties. On the strength of these findings it is indicated that a new procedure combining the dose levels and testing approach of the ATC method with the inclusion of toxicity as an endpoint as in the FDP would be more efficient than either the FDP or the ATC method.

Reducing animal numbers in the fixed-dose procedure.

The fixed-dose procedure (FDP) was proposed by the British Toxicology Society (1984) as an alternative to assessment of acute oral toxicity via estimation of the LD50. The procedure is incorporated in OECD guidelines on acute oral toxicity testing. Whitehead and Curnow (1992) used a mathematical model to describe the statistical properties of the FDP. This paper uses a simplified model to investigate further the procedure. In particular the effects of altering the number of animals included at each stage in the procedure are evaluated. It is shown that a reduction in the number of animals tested makes little difference to the toxic classification of a substance with a steep dose-response curve, but has increasing effect as the dose-response curve becomes shallower. The simplified model also shows that in the proposed procedure the most likely classification depends on the LD of the substance tested. Changing the number of animals tested results in the most likely classification depending on other LD values. The effect of additional variation is also considered. Such variation might arise from within-laboratory differences. Although this increases the range of substances for which misclassification is likely, the increase is not much affected by the number of animals tested.

Estimating the magnitude of carcinogenic effects in long-term animal studies.

Carcinogenicity studies seek to compare the incidence of tumours in animals exposed to the substance under investigation and animals used as controls. The conventional method of analysis is the Peto test, which assumes that tumours are either instantly fatal or have no effect on mortality and requires a judgement to be made regarding the lethality of each tumour. Such an assumption seems unrealistic and the judgement is often difficult to make and unreliable. The need for such a judgement and the assumption of extreme lethality can be removed by using parametric multi-state models. In this modelling approach the transition of animals between the states 'alive without a tumour', 'alive with a tumour' and 'dead' is modelled mathematically. This paper compares the Peto test with tests based on two parametric multi-state models in terms of the sensitivity of the tests to detect carcinogenicity. The sensitivity, or power, is shown to be low for commonly used numbers of animals, depending chiefly on the expected total number of animals with tumours. The Omar and Whitehead multi-state model is found to be slightly more powerful than the Dewanji et al. model and at least as powerful as the Peto test. Provided the parametric assumptions are appropriate, this method thus gives a test that is more sensitive than the Peto test and enables estimation of tumour onset and mortality rates without the requirement of tumour lethality judgements.

The effect of a new ejection seat headbox and high G garments on head mobility during air combat.

Full coverage anti-G trousers, a chest counter pressure garment for positive pressure breathing for G tolerance, and a smaller ejection seat headbox have been developed for future agile aircraft. The hypotheses that the new headbox might improve, and that the more restrictive high G garments might compromise, pilot head mobility were tested. The RAF institute of Aviation Medicine Hawk aircraft was equipped with a wide angle video camera facing the front seat pilot. Two experimental conditions were compared to the control air combat sortie: 1. standard garments and the smaller headbox; 2. high G garments and the smaller headbox. Data were recorded from five instructor pilots during three scheduled air combat training sorties. Their helmets were marked with 10-mm white dots in a standardized pattern. Software for recording helmet dot positions from single frame video images, and a trigonometric method for calculating head rotation and translation from changes in the helmet dot positions were devised. No differences were found between headboxes or garments at the three extremes of head movements analyzed. Observed neck rotations were similar to maximal seated norms. Optimal head and neck extension is impeded by the ejection seat headbox. Pilots' head movements are not restricted during air combat at moderate G levels.

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.

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.

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.