Views of the public about Snacktivity™: a small changes approach to promoting physical activity and reducing sedentary behaviour.

BACKGROUND: Many people do not meet the recommended health guidance of participation in a minimum of 150-300 min of moderate intensity physical activity per week, often promoted as at least 30 min of physical activity on 5 days of the week. This is concerning and highlights the importance of finding innovative ways to help people to be physically active each day. Snacktivity™ is a novel approach that aims to encourage people to do small, 2-5 min bouts of physical activity 'snacks' throughout the whole day, such that they achieve at least 150 min of moderate intensity activity per week. However, before it can be recommended, there is a need to explore whether the concept is acceptable to the public. METHODS: A survey to assess the views of the public about Snacktivity™ was distributed to adult patients registered at six general practices in the West Midlands, UK and to health care employees in the same region. RESULTS: A total of 5989 surveys were sent to patients, of which 558 were returned (9.3%). A further 166 surveys were completed by health care employees. A total of 85% of respondents liked the Snacktivity™ concept. The flexibility of the approach was highly rated. A high proportion of participants (61%) reported that the ability to self-monitor their behaviour would help them to do Snacktivity™ throughout their day. Physically inactive participants perceived that Snacktivity™ would help to increase their physical activity, more than those who were physically active (OR = 0.41, 95% CI: 0.25-0.67). Approximately 90% of respondents perceived that Snacktivity™ was easy to do on a non-working day compared to 60% on a working day. Aerobic activity 'snacks' were preferred to those which were strength based. CONCLUSIONS: The Snacktivity™ approach to promoting physical activity was viewed positively by the public and interventions to test the merits of such an approach now need to be developed and tested in a variety of everyday contexts.

Feasibility and acceptability of a brief routine weight management intervention for postnatal women embedded within the national child immunisation programme in primary care: randomised controlled cluster feasibility trial.

BACKGROUND: The prevalence of obesity in women continues to rise and pregnancy is a high-risk time for excessive weight gain. The period after childbirth represents an opportunity to offer women support to manage their weight. The primary aim here was to investigate the acceptability and feasibility of delivering a self-management intervention to postnatal women to support weight loss, embedded within the national child immunisation programme. METHODS: The research involved a randomised controlled cluster feasibility trial. Data were collected at baseline and 3 months later. Twenty-eight postnatal women living with overweight or obesity were recruited via Birmingham Women Hospital or general practices. Babies are routinely immunised at 2, 3 and 4 months of age; the intervention was embedded within these appointments. The intervention involved brief motivation/support by practice nurses to encourage participants to make healthier lifestyle choices through self-monitoring of weight and signposting to an online weight management programme, when they attended their practice to have their child immunised. The role of the nurse was to provide external accountability for weight loss. Participants were asked to weigh themselves weekly and record this on a record card or using the online programme. The weight goal was for participants to lose 0.5 to 1 kg per week. Usual care received a healthy lifestyle leaflet. The primary outcome was the feasibility of a phase III trial to test the subsequent effectiveness of the intervention, as assessed against three stop-go traffic light criteria (recruitment, adherence to regular self-weighing and registration with an online weight management programme). RESULTS: The traffic light stop-go criteria results were red for recruitment (28/80, 35% of target), amber for registration with the online weight loss programme (9/16, 56%) and green for adherence to weekly self-weighing (10/16, 63%). Nurses delivered the intervention with high fidelity. DISCUSSION: Whilst participants and nurses followed the trial protocol well and adherence to self-weighing was acceptable, recruitment was challenging and there is scope to improve engagement with the online weight management programme component of the intervention. TRIAL REGISTRATION: ISRCTN 12209332 . Registration date is 04/12/18.

The economic case for prevention of population vitamin D deficiency: a modelling study using data from England and Wales.

BACKGROUND: Vitamin D deficiency (VDD) affects the health and wellbeing of millions worldwide. In high latitude countries such as the United Kingdom (UK), severe complications disproportionally affect ethnic minority groups. OBJECTIVE: To develop a decision-analytic model to estimate the cost effectiveness of population strategies to prevent VDD. METHODS: An individual-level simulation model was used to compare: (I) wheat flour fortification; (II) supplementation of at-risk groups; and (III) combined flour fortification and supplementation; with (IV) a 'no additional intervention' scenario, reflecting the current Vitamin D policy in the UK. We simulated the whole population over 90 years. Data from national nutrition surveys were used to estimate the risk of deficiency under the alternative scenarios. Costs incurred by the health care sector, the government, local authorities, and the general public were considered. Results were expressed as total cost and effect of each strategy, and as the cost per 'prevented case of VDD' and the 'cost per Quality Adjusted Life Year (QALY)'. RESULTS: Wheat flour fortification was cost saving as its costs were more than offset by the cost savings from preventing VDD. The combination of supplementation and fortification was cost effective (£9.5 per QALY gained). The model estimated that wheat flour fortification alone would result in 25% fewer cases of VDD, while the combined strategy would reduce the number of cases by a further 8%. CONCLUSION: There is a strong economic case for fortifying wheat flour with Vitamin D, alone or in combination with targeted vitamin D3 supplementation.

Providing an extended use of an otological-specific outcome instrument to derive cost-effectiveness estimates of treatment.

OBJECTIVES: Although quality-adjusted life years (QALYs) are increasingly being used by decision-makers to make comparisons of cost-effectiveness, there are no otological-specific outcome measures that fit within this QALY framework. This study had two main objectives. The first was to provide a means to derive QALYs from a condition-specific otological instrument (Cambridge Otology Quality of Life, COQOL), and the second was to assess the convergent validity, or degree of correlation, between the COQOL and SF-6D, an established QALY instrument. DESIGN: Longitudinal cohort study designed to assess the convergent validity between SF-6D and COQOL and to generate a mapping function to enable SF-6D values to be predicted from the COQOL responses. SETTING: Cambridge University Hospital, UK. PARTICIPANTS: A total of 207 patients attending a routine outpatient general otology clinic. MAIN OUTCOME MEASURES: SF-6D and the COQOL instrument completed at baseline and again 3 months later. RESULTS: Convergent validity was demonstrated with mean SF-6D values decreasing linearly with increasing severity on the COQOL instrument. Overall, the correlation between the COQOL scores and the SF-6D values was moderate and statistically significant (r = 0.490, P = <0.001). A simple mapping model based on an ordinary least squares (OLS) regression function predicted SF-6D values from the COQOL data with a reasonable degree of accuracy. Further validation using the follow-up 3-month data confirmed the prediction power of this mapping model. CONCLUSIONS: This study provides a method for estimating QALYs from condition-specific COQOL data and provides the opportunity for the cost-effectiveness of otological treatment to be measured and placed within the national QALY framework.

Conservative management, surgery and radiosurgery for treatment of vestibular schwannomas: a model-based approach to cost-effectiveness.

OBJECTIVE: To undertake a cost-effectiveness analysis comparing conservative management, surgery and radiosurgery for treating small-to-medium (1-20 mm)-sized vestibular schwannomas. DESIGN: Model-based economic evaluation using individual-level data from a Birmingham-based longitudinal patient database and from published sources. Both a decision tree and state-transition (Markov) model were developed, from an National Health Service (NHS) perspective. Sensitivity analyses were also carried out. SETTING: Secondary care treatment for patients with small-to-medium-sized vestibular schwannomas. PARTICIPANTS: Three hypothetical cohorts of adult patients receiving conservative management, radiosurgery or surgery treatment, aged 58 years as starting age within model. MAIN OUTCOME MEASURES: Cost-effectiveness based on cost per quality-adjusted life year (QALY). RESULTS: Conservative management is the preferred strategy for the treatment of small-to-medium-sized vestibular schwannomas. Conservative management is both cheaper (-£ 722 and -£ 2764) and more effective (0.136 and 0.554 quality-adjusted life years) than both radiosurgery and surgery, respectively. A conservative strategy can therefore be considered as highly cost-effective. This result is sensitive to the assumed quality-of-life parameters in the model. Sensitivity analysis suggests that the probability of a conservative strategy being the most cost-effective approach compared with surgery and radiosurgery at a willingness to pay of £ 20 000/quality-adjusted life year gained is 80% and 55%, respectively. CONCLUSIONS: A conservative approach is the preferred strategy for treatment of small-to-medium vestibular schwannomas. This result is sensitive to quality-of-life values used in the analysis. More research is required to assess the impact of treatment upon patients' health-related quality of life over time.

rFV11a and paediatric open-heart surgery: thrombosis in the cardiopulmonary bypass circuit in spite of adequate markers of anticoagulation.

Recombinant activated factor V11 (rFV11a) is a relatively new procoagulant agent and its place in surgical practice continues to be investigated. We report the use of rFV11a to help manage bleeding in the operating theatre in a neonate, following weaning from cardiopulmonary bypass for arterial switch procedure, when bleeding continued in spite of maximal medical therapy and apparent exclusion of a surgical cause of bleeding. In this patient administration of rFV11a failed to facilitate haemostasis and cardiopulmonary bypass was re-instituted allowing location and repair of a small awkward surgical source. Separation from this additional 20 min of bypass was successful but a large thrombus was noted in the membrane oxygenator of the extracorporeal circuit in spite of the presence of adequate 'laboratory' markers of anticoagulation in the pump blood. No adverse sequelae to the patient occurred.

Short-term health system costs of paediatric in-hospital acute life-threatening events including cardiac arrest.

OBJECTIVES: Acute life-threatening events in children are medical emergencies requiring immediate intervention. They can be due to cardiac arrest, respiratory arrest or another cause of sudden compromise for example, choking. Internationally, hospital systems are being introduced to reduce preventable acute life-threatening events and, despite having significant resource implications, have not yet been subject to economic analysis. This study presents the additional short-term health service costs of in-hospital acute life-threatening events to inform a cost-effectiveness analysis of prevention strategies. METHODOLOGY: Patient level costs (GB pounds, price year 2005), in excess of baseline costs, were collected from a short-term NHS perspective. The cost per survivor to hospital discharge included the cost of the cardiopulmonary resuscitation attempt, resuscitation preparedness, and the cost of in-hospital post-resuscitation care. Acute life-threatening events calls were classified into two groups: cardiac arrest, and respiratory arrest and other acute life threatening events. Outcomes from these groups were compared to a similar group of unplanned Paediatric Intensive Care (PIC) admissions. All survival and length of stay outcomes were calculated for the first episode. RESULTS: The survival to hospital discharge was 64.4% (65/101), (95% Confidence Intervals 55.02, 73.70) for all acute life-threatening event calls, and 41.3% (12/29), (95% Confidence Intervals 23.45, 59.31) for cardiac arrest. The mean cost of the resuscitation attempt was pound3664 for all acute life-threatening event calls, and pound3884 for cardiac arrest. The annual cost of cardiopulmonary resuscitation preparedness was pound181,565. The mean cost of the post-event length of stay in hospital was pound22,562 for cardiac arrest, pound26,335 for other acute life-threatening events, and pound26,138 for urgent PIC admissions. The cost per survivor to hospital discharge was pound53,289. CONCLUSION: The short-term costs of paediatric in-hospital acute life-threatening events, including cardiac arrest, from an NHS perspective, are more expensive than those reported for adults, but similar to other life saving treatments. This new information will serve to improve efficiency in the current resuscitation programme and contribute to cost-effectiveness analysis of prevention strategies.

Structural neuroimaging in psychosis: a systematic review and economic evaluation.

OBJECTIVES: To establish the clinical effectiveness and cost-effectiveness of structural neuroimaging [structural magnetic resonance imaging (MRI) or computed tomography (CT) scanning] for all patients with psychosis, particularly a first episode of psychosis, relative to the current UK practice of selective screening only where it is clinically indicated. DATA SOURCES: Major electronic databases were searched from inception to November 2006. REVIEW METHODS: A systematic review of studies reporting the additional diagnostic benefit of structural MRI, CT or combinations of these in patients with psychosis was conducted. The economic assessment consisted of a systematic review of economic evaluations and the development of a threshold analysis to predict the gain in quality-adjusted life-years (QALYs) required to make neuroimaging cost-effective at commonly accepted threshold levels (20,000 pounds and 30,000 pounds per QALY). Sensitivity analyses of several parameters including prevalence of psychosis were performed. RESULTS: The systematic review included 24 studies of a diagnostic before-after type of design evaluating the clinical benefit of CT, structural MRI or combinations in treatment-naive, first-episode or unspecified psychotic patients, including one in schizophrenia patients resistant to treatment. Also included was a review of published case reports of misidentification syndromes. Almost all evidence was in patients aged less than 65 years. In most studies, structural neuroimaging identified very little that would influence patient management that was not suspected based on a medical history and/or physical examination and there were more incidental findings. In the four MRI studies, approximately 5% of patients had findings that would influence clinical management, whereas in the CT studies, approximately 0.5% of patients had these findings. The review of misidentification syndromes found that 25% of CT scans affected clinical management, but this may have been a selected and therefore unrepresentative sample. A threshold analysis with a 1-year time horizon was undertaken. This combined the incremental cost of routine scanning with a threshold cost per QALY value of 20,000 pounds and 30,000 pounds to predict the QoL gain required to meet these threshold values. Routine scanning versus selective scanning appears to produce different results for MRI and CT. With MRI scanning the incremental cost is positive, ranging from 37 pounds to 150 pounds; however, when scanning routinely using CT, the result is cost saving, ranging from 7 pounds to 108 pounds with the assumption of a 1% prevalence rate of tumours/cysts or other organic causes amenable to treatment. This means that for the intervention to be viewed as cost-effective, the QALY gain necessary for MRI scanning is 0.002-0.007 and with CT scanning the QALY loss that can be tolerated is between 0.0003 and 0.0054 using a 20,000 pounds threshold value. These estimates were subjected to sensitivity analysis. With a 3-month time delay, MRI remains cost-incurring with a small gain in QoL required for the intervention to be cost-effective; routine scanning with CT remains cost-saving. When the sensitivity of CT is varied to 50%, routine scanning is both cost-incurring or cost-saving depending on the scenario. Finally, the results have been shown to be sensitive to the assumed prevalence rate of brain tumours in a psychotic population. CONCLUSIONS: The evidence to date suggests that if screening with structural neuroimaging was implemented in all patients presenting with psychotic symptoms, little would be found to affect clinical management in addition to that suspected by a full clinical history and neurological examination. From an economic perspective, the outcome is not clear. The strategy of neuroimaging for all is either cost-incurring or cost-saving (dependent upon whether MRI or CT is used) if the prevalence of organic causes is around 1%. However, these values are nested within a number of assumptions, and so have to be interpreted with caution. The main research priorities are to monitor the current use of structural neuroimaging in psychosis in the NHS to identify clinical triggers to its current use and subsequent outcomes; to undertake well-conducted diagnostic before-and-after studies on representative populations to determine the clinical utility of structural neuroimaging in this patient group, and to determine whether the most appropriate structural imaging modality in psychosis should be CT or MRI.

Oral naltrexone as a treatment for relapse prevention in formerly opioid-dependent drug users: a systematic review and economic evaluation.

OBJECTIVES: To investigate the clinical effectiveness and cost-effectiveness of naltrexone for relapse prevention in detoxified formerly opioid-dependent individuals compared with any strategy that does not use naltrexone, including treatment with placebo, other pharmacological treatments, psychosocial interventions or no treatment. DATA SOURCES: Major electronic databases were searched from inception to September 2005. REVIEW METHODS: Selected studies were screened and quality assessed. Meta-analyses were carried out as appropriate. A decision-analytic model using Monte Carlo simulation was developed that compared naltrexone as an adjunctive therapy to no naltrexone. It assumed compliance rates that were not enhanced by contingent management rewards (because this is current UK practice). Utility values could not be identified from the literature and so were obtained by research specially commissioned from the Value of Health Panel. RESULTS: The methodological quality of the 26 randomised controlled trials (RCTs) that met the inclusion criteria was poor to moderate. The results suggest that naltrexone as maintenance therapy may be better than placebo in terms of retention in treatment, but this was not statistically significant. A meta-analysis of seven included RCTs gave the relative risk (RR) of loss of retention in treatment in the naltrexone arm as 0.94. The pooled hazard ratio (HR) reported in five of the RCTs for retention in treatment data followed up to 35 weeks was calculated as 0.90 in favour of naltrexone and also did not reach statistical significance. The risk of drug abuse in naltrexone versus placebo, with or without psychological support given in both arms, gave a pooled RR of 0.72, which was a statistically significant difference in favour of naltrexone. The pooled HR from three RCTs for opioid relapse-free rates was significantly different from placebo in favour of naltrexone 0.53; however, this fell off over time and may be of limited clinical significance. The RR of reimprisonment while on naltrexone therapy showed results in favour of naltrexone in the combined two studies of parolees or people on probation, but the number of participants was small. One study of 52 participants found that the difference in improvement score for risky sexual behaviour in the naltrexone group compared with the placebo group was not statistically significant. The adverse events data reported showed no significant difference between the naltrexone and placebo arms. The quality of the nine RCTs of interventions designed to increase retention with naltrexone was poor to moderate; however, all three different modalities of enhanced care showed some evidence of effectiveness. All of the contingency management programmes used incentive vouchers; the mean duration of treatment retention was 7.4 weeks for the contingency management intervention compared with 2.3-5.6 weeks for the naltrexone treatment alone. The mean length of time for which patients stayed on naltrexone was 84-103 days with additional psychosocial therapy compared with 43-64 days for the control group. In trials with added pharmacological agents the RRs of stopping treatment were 1.63 at 6 months and 1.31 at 12 months (in favour of naltrexone plus fluoxetine). It became statistically significant at 6 months, but not at 12 months. A meta-analysis of the RR of stopping treatment at week 12 (the minimum follow-up period) was carried out using six of the nine studies. The pooled RR of stopping treatment was 0.81. The results indicated that overall the intervention groups had 19% fewer patients who stopped treatment compared with the control group, but there was only a small number of studies and their quality was relatively poor. No existing economic evaluations were identified. The point estimate for the cost-effectiveness of naltrexone was pound42,500 per quality-adjusted life-year (QALY). Sensitivity analysis was carried out and the incremental cost-effectiveness ratio varied between pound34,600 and pound42,500 per QALY gained. CONCLUSIONS: Following successful withdrawal from opioids, naltrexone may be administered on a chronic basis to block any future effects of opioids. Naltrexone appears to have some limited benefit in helping formerly opioid-dependent individuals to remain abstinent, although the quality of the evidence is relatively poor and heterogeneous. The limited quality and extent of the studies precluded an analysis of subgroups likely to benefit from naltrexone prescribing. Oral naltrexone is used infrequently in current UK practice, and this review suggests that this is appropriate as there is little evidence to support its wider implementation. There is an important deficit in information about the quality of life of people who use illicit opioids and this would perhaps be a worthwhile area of research in informing policy questions about the cost-effectiveness of different programmes and interventions.

Methadone and buprenorphine for the management of opioid dependence: a systematic review and economic evaluation.

OBJECTIVES: To assess the clinical effectiveness and cost-effectiveness of buprenorphine maintenance therapy (BMT) and methadone maintenance therapy (MMT) for the management of opioid-dependent individuals. DATA SOURCES: Major electronic databases were searched from inception to August 2005. Industry submissions to the National Institute for Health and Clinical Excellence were accessed. REVIEW METHODS: The assessment of clinical effectiveness was based on a review of existing reviews plus an updated search for randomised controlled trials (RCTs). A decision tree with Monte Carlo simulation model was developed to assess the cost-effectiveness of BMT and MMT. Retention in treatment and opiate abuse parameters were sourced from the meta-analysis of RCTs directly comparing flexible MMT with flexible dose BMT. Utilities were derived from a panel representing a societal perspective. RESULTS: Most of the included systematic reviews and RCTs were of moderate to good quality, and focused on short-term (up to 1-year follow-up) outcomes of retention in treatment and the level of opiate use (self-report or urinalysis). Most studies employed a trial design that compared a fixed-dose strategy (i.e. all individuals received a standard dose) of MMT or BMT and were conducted in predominantly young men who fulfilled criteria as opiate-dependent or heroin-dependent users, without significant co-morbidities. RCT meta-analyses have shown that a fixed dose of MMT or BMT has superior levels of retention in treatment and opiate use than placebo or no treatment, with higher fixed doses being more effective than lower fixed doses. There was evidence, primarily from non-randomised observational studies, that fixed-dose MMT reduces mortality, HIV risk behaviour and levels of crime compared with no therapy and one small RCT has shown the level of mortality with fixed-dose BMT to be significantly less than with placebo. Flexible dosing (i.e. individualised doses) of MMT and BMT is more reflective of real-world practice. Retention in treatment was superior for flexible MMT than flexible BMT dosing but there was no significant difference in opiate use. Indirect comparison of data from population cross-sectional studies suggests that mortality with BMT may be lower than that with MMT. A pooled RCT analysis showed no significant difference in serious adverse events with MMT compared with BMT. Although treatment modifier evidence was limited, adjunct psychosocial and contingency interventions (e.g. financial incentives for opiate-free urine samples) appeared to enhance the effects of both MMT and BMT. Also, MMT and BMT appear to be similarly effective whether delivered in a primary care or outpatient clinic setting. Although most of the included economic evaluations were considered to be of high quality, none used all of the appropriate parameters, effectiveness data, perspective and comparators required to make their results generalisable to the NHS context. One company (Schering-Plough) submitted cost-effectiveness evidence based on an economic model that had a 1-year time horizon and sourced data from a single RCT of flexible-dose MMT compared with flexible-dose BMT and utility values obtained from the literature; the results showed that for MMT vs no drug therapy, the incremental cost-effectiveness ratio (ICER) was pound 12,584/quality-adjusted life-year (QALY), for BMT versus no drug therapy, the ICER was pound 30,048/QALY and in a direct comparison, MMT was found to be slightly more effective and less costly than BMT. The assessment group model found for MMT versus no drug therapy that the ICER was pound 13,697/QALY, for BMT versus no drug therapy that the ICER was pound 26,429/QALY and, as with the industry model, in direct comparison, MMT was slightly more effective and less costly than BMT. When considering social costs, both MMT and BMT gave more health gain and were less costly than no drug treatment. These findings were robust to deterministic and probabilistic sensitivity analyses. CONCLUSIONS: Both flexible-dose MMT and BMT are more clinically effective and more cost-effective than no drug therapy in dependent opiate users. In direct comparison, a flexible dosing strategy with MMT was found be somewhat more effective in maintaining individuals in treatment than flexible-dose BMT and therefore associated with a slightly higher health gain and lower costs. However, this needs to be balanced by the more recent experience of clinicians in the use of buprenorphine, the possible risk of higher mortality of MMT and individual opiate-dependent users' preferences. Future research should be directed towards the safety and effectiveness of MMT and BMT; potential safety concerns regarding methadone and buprenorphine, specifically mortality and key drug interactions; efficacy of substitution medications (in particular patient subgroups, such as within the criminal justice system, or within young people); and uncertainties in cost-effectiveness identified by current economic models.

The clinical effectiveness and cost-effectiveness of enzyme replacement therapy for Gaucher's disease: a systematic review.

OBJECTIVES: The aim of this review is to determine the clinical effectiveness and cost-effectiveness of enzyme replacement therapy (ERT) in the treatment of symptomatic Gaucher's disease. DATA SOURCES: Major electronic databases were searched from their inception to August 2003; and updated from January 2003 to July/August 2004. REVIEW METHODS: Databases were searched for studies that met the criteria and selected data were extracted and evaluated. Studies were assessed for their relevance to the UK context and the review objective. The bibliographic databases were also searched to identify existing cost studies, economic evaluations and models. A Markov decision model was constructed based on patients moving between states defined by the modified Severity Score Index (SSI). Most of the parameters were derived from the published literature. ERT was assumed to restore patients to full health in the base case. RESULTS: Sixty-three studies were included, all suggestive of benefit with ERT. However, the way in which the effects translate into patient well-being and survival or the need for services and resources has not been reliably estimated. Quality of life improvements with ERT have been reported. Nonetheless, studies based on the Short Form 36 (SF-36) indicate that patients treated with ERT continue to have reduced health-related quality of life (HRQoL) compared with the general population. No study attached utility values to quality of life measures for ERT-treated patients. Thirty-one studies relevant to the natural history of the disease were found. Sixteen looked at multiple clinical characteristics of a cohort of patients with type I Gaucher's disease. There was considerable within-study and between-study heterogeneity, but all showed that Gaucher's disease was a progressive condition. Some suggested that the disease may become more indolent in adulthood; however, studies were discrepant on this point. Most disease is diagnosed in adulthood, although about one-quarter presented in childhood, these patients having the most severe symptoms and greatest rate of progression. Modelling of natural history was undertaken using the five papers that reported the SSI for each patient, along with patient-level data on age, age at diagnosis, splenectomy status and genotype, to address the question of whether disease stabilises in adulthood and the degree of correlation between phenotype and genotype. Analysis of the available data suggested that disease progression is likely to slow markedly in adulthood and that genotype is a useful predictor of clinical expression of the disease. Five studies looked at quality of life. Data on this topic were also obtained from the registries. The evidence suggests that the vast majority of the clinical characteristics of type I Gaucher's disease have little impact on subjective HRQoL and that therefore for the majority of people with type I Gaucher's disease this may not be a severe condition. Bone and skeletal symptoms contribute most to the morbidity of the disease and can lead to severe pain and immobility. The mean cost per patient treated was approximately pounds sterling 86,000 per annum in England and Wales. The cost per patient varied considerably by dose. Four existing economic evaluations were found, all of which calculated a very high cost per quality-adjusted life-year (QALY). Using the Markov decision model, ERT was assumed to restore patients to full health in the base case. The estimated incremental cost per QALY [incremental cost-effectiveness ratio (ICER)] in the base case ranged from pounds sterling 380,000 to pounds sterling 476,000 per QALY, depending on genotype. Univariate sensitivity analyses examined ERT not restoring full health, more severe disease progression in the untreated cohort, and only treating the most severely affected patients. These produced ICERs of approximately pounds sterling 1.4 million, pounds sterling 296,000 and pounds sterling 275,000 per QALY, respectively. The base-case unit cost of the drug is pounds sterling 2.975. The unit cost would have had to be reduced ten-fold, to pounds sterling 0.30, to obtain an ICER of pounds sterling 30,000 per QALY. At a unit cost of pounds sterling 1 the ICER would be pounds sterling 120,000 per QALY. CONCLUSIONS: Although ERT for treating the 'average' Gaucher's disease patient exceeds the normal upper threshold for cost-effectiveness seen in NHS policy decisions by over ten-fold, some argue that since orphan drug legislation encouraged the manufacture of Cerezyme, and Gaucher's disease can be defined as an orphan disease, the NHS has little option but to provide it, despite its great expense. More information is required before the generalisability of the findings can be determined. Although data from the UK have been used wherever possible, these were very thin indeed. Nonetheless, even large errors in estimates of the distribution of genotype, genotype--phenotype associations, effectiveness and numbers of patients will not reduce the ICER to anywhere near the upper level of treatments usually considered cost-effective. Further research could help to clarify the many uncertainties that exist. However, although doing so will be of clinical interest, it is questionable whether, within the current pricing environment, such research would have any substantive impact on policy decisions. It is highly improbable that, whatever the findings of such research, the ICER could be brought down by the orders of magnitude required to make ERT an efficient use of health service resources. (The possible exception to this would be investigating the most efficient alternative treatment strategies for using ERT in a paediatric population only.) Moreover, if under equity considerations for orphan diseases the NHS feels it is important to provide this drug, regardless of its cost-effectiveness, then refining the precision of the ICER estimate also becomes superfluous.

A systematic review of the clinical effectiveness and cost-effectiveness of enzyme replacement therapies for Fabry's disease and mucopolysaccharidosis type 1.

OBJECTIVES: To determine the clinical effectiveness and cost-effectiveness of the administration of intravenous enzyme replacement therapy (ERT) to symptomatic patients for the prevention of long-term damage and symptoms in Fabry's disease and in mucopolysaccharidosis type 1 (MPS1). DATA SOURCES: Electronic databases from inception up to mid-2004. Contact with clinical experts. REVIEW METHODS: Relevant studies were identified and assessed using recommended quality criteria. RESULTS: The results suggested beneficial effects of ERT for Fabry's disease on measures of pain, cardiovascular function and some end-points reflecting neurosensory function. Renal function appeared to be stabilised by ERT. At present there are no utility-related health-related quality of life data on which to assess the relative health gain of ERT in MPS1. In order to be able to demonstrate the full extent of health gain from treatment, it was necessary to review the natural history of untreated patients in each disease in order to try to estimate the health loss prevented. The published information for Fabry's disease tallied with descriptions of a multi-system, life-threatening disorder particularly involving kidney, heart and brain with individual patients exhibiting many manifestations. The fragmentary information reviewed in 16 studies relevant to the natural history of MPS1 did not generate a coherent picture of disease progression and could provide little added value to published narrative reviews. For Fabry's disease, the mean cost per patient (50 kg) treated is around pounds sterling 85,000 per annum in England and Wales. The cost per patient varies considerably by dose. No published evidence reporting an economic evaluation of ERT for Fabry's disease was identified by this review. A dynamic decision model was constructed based on a birth cohort of male patients who are followed up until death. Owing to lack of information reported in the literature, many assumptions had to be applied. The key assumptions were that ERT returns patients to full health and a normal life expectancy. As far as possible, all assumptions favoured rather than detracted from the value of ERT. ERT was assumed to restore patients to full health in the base case. The estimated incremental cost-effectiveness ratio (ICER) in the base case was pounds sterling 252,000 per QALY (agalsidase beta). Univariate sensitivity analysis around the key assumptions produced ICERs ranging from pounds sterling 602,000 to pounds sterling 241,000. The base case unit cost of ERT was taken as pounds sterling 65.1/mg based on the cost of agalsidase beta. The unit cost would have had to be reduced to pounds sterling 9 to obtain an ICER of pounds sterling 30,000 per QALY. For MPS1, the mean cost per child patient (20 kg) treated is approximately pounds sterling 95,000 and an adult (70 kg) around pounds sterling 335,000 per annum in England and Wales. The cost per patient varies considerably by dose. There is no published evidence reporting an economic evaluation of ERT for MPS1 and no study was identified that reported the quality of life of MPS1 patients within a utility format. Furthermore, no or minimal information of the severity and rate of change of clinical manifestations of disease or the impact of ERT on these factors was identified. Information on the effect of ERT on mortality is also lacking owing to the relatively short time that the treatment has been available. Given this lack of data, it was not possible to develop a cost-effectiveness model of ERT treatment for MPS1 as the model would consist almost completely of assumptions based on no published evidence, leading to an incremental cost per QALY result that would be meaningless. CONCLUSIONS: Although ERT for treating the 'average' patient with Fabry's disease exceeds the normal upper threshold for cost-effectiveness seen in NHS policy decisions by over sixfold, and the value for MPS1 is likely to be of a similar order of magnitude, clinicians and the manufacturers argue that, as the disease is classified as an orphan disease under European Union legislation, it has special status, and the NHS has no option but to provide ERT. More information is required before the generalisability of the findings can be determined. Although data from the UK have been used wherever possible, this was very thin indeed. Nonetheless, even large errors in assumptions made will not reduce the ICER to anywhere near the upper level of treatments usually considered cost-effective. In order to overcome limited evidence on the natural history of the disease and the clinical effectiveness of the intervention, the establishment of disease-specific data registries is suggested to facilitate the process of technology assessment and improving patient care. These registries should attempt to include all affected patients in the UK, and collect longitudinal patient level data on clinically relevant problems, interventions received and quality of life in a utility format.

The clinical effectiveness and cost-effectiveness of newer drugs for children with epilepsy. A systematic review.

OBJECTIVES: To examine the clinical effectiveness and cost-effectiveness of newer antiepileptic drugs (AEDs) for epilepsy in children: gabapentin, lamotrigine, levetiracetam, oxcarbazepine, tiagabine, topiramate and vigabatrin. DATA SOURCES: Electronic databases. Drug company submissions. REVIEW METHODS: For the systematic review of clinical and cost-effectiveness, studies were assessed for inclusion according to predefined criteria. Data extraction and quality assessment were also undertaken. A decision-analytic model was constructed to estimate the cost-effectiveness of the newer agents in children with partial seizures, the only condition where there were sufficient trial data to inform a model. RESULTS: The quality of the randomised controlled trial (RCT) data was generally poor. For each of the epilepsy subtypes considered in RCTs identified for this review (partial epilepsy with or without secondary generalisation, Lennox-Gastaut syndrome, infantile spasms, absence epilepsy and benign epilepsy with centrotemporal spikes), there is some evidence from placebo-controlled trials that the newer agents tested are of some value in the treatment of these conditions. Where active controls have been used, the limited evidence available does not indicate a difference in effectiveness between newer and older drugs. The data are not sufficient to inform a prescribing strategy for any of the newer agents in any of these conditions. In particular, there is no clinical evidence to suggest that the newer agents should be considered as a first-choice treatment in any form of epilepsy in children. Annual drug costs of the newer agents ranges from around 400 pound to 1200 pound, depending on age and concomitant medications. An AED that is ineffective or has intolerable side-effects will only be used for a short period of time, and many patients achieving seizure freedom will successfully withdraw from drug treatment without relapsing. The results of the decision-analytic model do not suggest that the use of the newer agents in any of the scenarios considered is clearly cost-effective but, similarly, do not indicate that they are clearly not cost-effective. CONCLUSIONS: The prognosis for children diagnosed with epilepsy is generally good, with a large proportion responding well to the first treatment given. A substantial proportion, however, will not respond well to treatment, and for these patients the clinical goal is to find an optimal balance between the benefits and side-effects of any treatment given. For the newly, or recently, diagnosed population, the key question for the newer drugs is how soon they should be tried. The cost-effectiveness of using these agents early, in place of one of the older agents, will depend on the effectiveness and tolerability of these agents compared with the older agents; the evidence from the available trial data so far suggests that the newer agents are no more effective but may be somewhat better tolerated than the older agents, and so the cost-effectiveness for early use will depend on the trade-off between effectiveness and tolerability, both in terms of overall (long-term) treatment retention and overall utility associated with effects on seizure rate and side-effects. There are insufficient data available to estimate accurately the nature of this trade off either in terms of long-term treatment retention or utility. Better information is required from RCTs before any rational evidence-based prescribing strategy could be developed. Ideally, RCTs should be conducted from a 'public health' perspective, making relevant comparisons and incorporating outcomes of interest to clinicians and patients, with sufficiently long-term follow-up to determine reliably the clinical utility of different treatments, particularly with respect to treatment retention and the balance between effectiveness and tolerability. RCTs should mirror clinical practice with respect to diagnosis, focusing on defined syndromes or, where no syndrome is identified, on groups defined by specific seizure type(s) and aetiology. Epilepsy in children is a complex disease, with a variety of distinct syndromes and many alternative treatment options and outcomes. Diagnosis-specific decision-analytic models are required; further research may be required to inform parameter values adequately with respect to epidemiology and clinical practice.

The effectiveness and cost-effectiveness of parent training/education programmes for the treatment of conduct disorder, including oppositional defiant disorder, in children.

OBJECTIVES: To assess the clinical and cost-effectiveness of parent training programmes for the treatment of children with conduct disorder (CD) up to the age of 18 years. DATA SOURCES: Electronic databases. REVIEW METHODS: For the effectiveness review, relevant studies were identified and evaluated. A quantitative synthesis of behavioural outcomes across trials was also undertaken using two approaches: vote counting and meta-analysis. The economic analysis consisted of reviewing previous economic/cost evaluations of parent training/education programmes and the economic information within sponsor's submissions; carrying out a detailed exploration of costs of parent training/education programmes; and a de novo modelling assessment of the cost-effectiveness of parent training/education programmes. The potential budget impact to the health service of implementing such programmes was also considered. RESULTS: Many of the 37 randomised controlled trials that met the review inclusion and exclusion criteria were assessed as being of poor methodological quality. Studies were clinically heterogeneous in terms of the population, type of parent training/education programme and content, setting, delivery, length and child behaviour outcomes used. Both vote counting and meta-analysis revealed a consistent trend across all studies towards short-term effectiveness (up to 4 months) of parent training/education programmes (compared with control) as measured by a change in child behaviour. Pooled estimates showed a statistically significant improvement on the Eyberg Child Behaviour Inventory frequency and intensity scales, the Dyadic Parent-Child Interaction Coding System and the Child Behaviour Checklist. No studies reported a statistically significant result favouring control over parent training/education programmes. There were few statistically significant differences between different parent training/education programmes, although there was a trend towards more intensive interventions (e.g. longer contact hours, additional child involvement) being more effective. The cost of treating CD is high, with costs incurred by many agencies. A recent study suggested that by age 28, costs for individuals with CD were around 10 times higher than for those with no problems, with a mean cost of 70,019 pounds sterling. Criminality incurs the greatest cost, followed by educational provision, foster and residential care and state benefits. Only a small proportion of these costs fall on health services. Using a 'bottom-up' costing approach, the costs per family of providing parent training/education programmes range from 629 pounds sterling to 3839 pounds sterling depending on the type and style of delivery. Using the conservative assumption that there are no cost savings from treatment, a total lifetime quality of life gain of 0.1 would give a cost per quality-adjusted life-year of between 38,393 pounds sterling and 6288 pounds sterling depending on the type of programme delivery and setting. CONCLUSIONS: Parent training/education programmes appear to be an effective and potentially cost-effective therapy for children with CD. However, the relative effectiveness and cost-effectiveness of different models (such as therapy intensity and setting) require further investigation. Further research is required on the impact of parent training/education programmes on the quality of life of children with CD and their parents/carers, as well as on longer term child outcomes.

Eliciting relative preferences for two methods of colorectal cancer screening.

Two methods of mass population screening for colorectal cancer - faecal occult blood testing and sigmoidoscopy - have been the subject of randomized controlled trials in the UK. A national screening programme is currently under consideration and the choice of screening method remains open. To be successful, a programme will require high levels of uptake, and uptake is likely to depend upon subjects' attitudes towards the screening method introduced. Although a preferred screening method has already been identified from a questionnaire survey, we undertook a further interview study (n = 106), with a view to comparing the results of two different approaches to eliciting public preferences. In comparison with the questionnaire study, a higher proportion of interview subjects stated a preference. Interview subjects were generally more favourably disposed towards sigmoidoscopy, excepting those with previous experience. Compared with the questionnaire survey, the interviews provided richer information on the reasons for preferences offered. Individual preferences were evidently subjective and dependant on attitudes towards a variety of method characteristics, such as discomfort, convenience and perceived sophistication. Characteristics such as age and low income, which had predicted preferences in the questionnaire study, predicted preferences in the interview study also. The difference between the results obtained by the different elicitation techniques can be explained in terms of the differential provision of information and sample selection. Conclusions made about public preferences are likely to depend on the technique employed in eliciting them.

Colorectal cancer, screening and survival: the influence of socio-economic deprivation.

OBJECTIVES: To determine the extent to which socio-economic deprivation explains colorectal cancer prevalence, subject participation in screening, and postoperative survival and life expectancy. METHODS: Regression analyses of clinical data from a large randomized controlled trial, augmented by geographical-based indices of deprivation. RESULTS: Deprivation appears to exert no significant impact on colorectal cancer prevalence but is a major factor explaining subject participation in screening. Cancer detection at later stages reduces life expectancy at time of treatment. Females from more-deprived areas have poorer post-treatment life expectancies and survival prospects, independently of their screening behaviour. CONCLUSIONS: Screening increases the chances of having a cancer treated at an earlier stage, and treatment at an earlier stage is associated with longer subsequent life expectancy. However, those from more-deprived areas are less likely to accept an invitation to be screened.

Willingness-to-pay for colorectal cancer screening.

Willingness-to-pay (WTP) techniques are increasingly being used in economic evaluation, as a means of assessing the value of new health care technologies. This paper presents the results of a WTP investigation of two types of screening for colorectal cancer. A questionnaire was issued to a general population via general practitioners (GPs), yielding a sample of approximately 2000 cases for analysis. Regression models demonstrated that WTP was significantly influenced by factors such as gender, income, age, risk perceptions, illness experiences and health beliefs. The median WTP for screening emerged as being pound30 or pound50, depending on the method used to elicit WTP, but independent of the screening protocol. Combining the results with those from related research, it emerged, first, that WTP subjects offered higher values for flexible sigmoidoscopy screening than the costs actually incurred by revealed preference studies and, second, they offered WTP values similar to the likely resource costs of the screening procedures.

An essential role for BAFF in the normal development of B cells through a BCMA-independent pathway.

The B cell activating factor BAFF (BlyS/TALL-1/zTNF4) is a tumor necrosis factor (TNF)-related ligand that promotes B cell survival and binds to three receptors (BCMA, TACI, and the recently described BAFF-R). Here we report an absolute requirement for BAFF in normal B cell development. Examination of secondary lymphoid organs from BAFF-deficient mice revealed an almost complete loss of follicular and marginal zone B lymphocytes. In contrast, mice lacking BCMA had normal-appearing B lymphocyte compartments. BAFF therefore plays a crucial role in B cell development and can function through receptors other than BCMA.