Jason Madan

Granulocyte colony-stimulating factors for febrile neutropenia prophylaxis following chemotherapy: systematic review and meta-analysis

BackgroundFebrile neutropenia (FN) occurs following myelosuppressive chemotherapy and is associated with morbidity, mortality, costs, and chemotherapy reductions and delays. Granulocyte colony-stimulating factors (G-CSFs) stimulate neutrophil production and may reduce FN incidence when given prophylactically following chemotherapy.MethodsA systematic review and meta-analysis assessed the effectiveness of G-CSFs (pegfilgrastim, filgrastim or lenograstim) in reducing FN incidence in adults undergoing chemotherapy for solid tumours or lymphoma. G-CSFs were compared with no primary G-CSF prophylaxis and with one another. Nine databases were searched in December 2009. Meta-analysis used a random effects model due to heterogeneity.ResultsTwenty studies compared primary G-CSF prophylaxis with no primary G-CSF prophylaxis: five studies of pegfilgrastim; ten of filgrastim; and five of lenograstim. All three G-CSFs significantly reduced FN incidence, with relative risks of 0.30 (95% CI: 0.14 to 0.65) for pegfilgrastim, 0.57 (95% CI: 0.48 to 0.69) for filgrastim, and 0.62 (95% CI: 0.44 to 0.88) for lenograstim. Overall, the relative risk of FN for any primary G-CSF prophylaxis versus no primary G-CSF prophylaxis was 0.51 (95% CI: 0.41 to 0.62). In terms of comparisons between different G-CSFs, five studies compared pegfilgrastim with filgrastim. FN incidence was significantly lower for pegfilgrastim than filgrastim, with a relative risk of 0.66 (95% CI: 0.44 to 0.98).ConclusionsPrimary prophylaxis with G-CSFs significantly reduces FN incidence in adults undergoing chemotherapy for solid tumours or lymphoma. Pegfilgrastim reduces FN incidence to a significantly greater extent than filgrastim.

Effectiveness and cost-effectiveness of computer and other electronic aids for smoking cessation: a systematic review and network meta-analysis

BACKGROUND Smoking is harmful to health. On average, lifelong smokers lose 10 years of life, and about half of all lifelong smokers have their lives shortened by smoking. Stopping smoking reverses or prevents many of these harms. However, cessation services in the NHS achieve variable success rates with smokers who want to quit. Approaches to behaviour change can be supplemented with electronic aids, and this may significantly increase quit rates and prevent a proportion of cases that relapse. OBJECTIVE The primary research question we sought to answer was: What is the effectiveness and cost-effectiveness of internet, pc and other electronic aids to help people stop smoking? We addressed the following three questions: (1) What is the effectiveness of internet sites, computer programs, mobile telephone text messages and other electronic aids for smoking cessation and/or reducing relapse? (2) What is the cost-effectiveness of incorporating internet sites, computer programs, mobile telephone text messages and other electronic aids into current nhs smoking cessation programmes? and (3) What are the current gaps in research into the effectiveness of internet sites, computer programs, mobile telephone text messages and other electronic aids to help people stop smoking? DATA SOURCES For the effectiveness review, relevant primary studies were sought from The Cochrane Library [Cochrane Central Register of Controlled Trials (CENTRAL)] 2009, Issue 4, and MEDLINE (Ovid), EMBASE (Ovid), PsycINFO (Ovid), Health Management Information Consortium (HMIC) (Ovid) and Cumulative Index to Nursing and Allied Health Literature (CINAHL) (EBSCOhost) from 1980 to December 2009. In addition, NHS Economic Evaluation Database (NHS EED) and Database of Abstracts of Reviews of Effects (DARE) were searched for information on cost-effectiveness and modelling for the same period. Reference lists of included studies and of relevant systematic reviews were examined to identify further potentially relevant studies. Research registries of ongoing studies including National Institute for Health Research (NIHR) Clinical Research Network Portfolio Database, Current Controlled Trials and ClinicalTrials.gov were also searched, and further information was sought from contacts with experts. REVIEW METHODS Randomised controlled trials (RCTs) and quasi-RCTs evaluating smoking cessation programmes that utilise computer, internet, mobile telephone or other electronic aids in adult smokers were included in the effectiveness review. Relevant studies of other design were included in the cost-effectiveness review and supplementary review. Pair-wise meta-analyses using both random- and fixed-effects models were carried out. Bayesian mixed-treatment comparisons (MTCs) were also performed. A de novo decision-analytical model was constructed for estimating the cost-effectiveness of interventions. Expected value of perfect information (EVPI) was calculated. Narrative synthesis of key themes and issues that may influence the acceptability and usability of electronic aids was provided in the supplementary review. RESULTS This effectiveness review included 60 RCTs/quasi-RCTs reported in 77 publications. Pooled estimate for prolonged abstinence [relative risk (RR) = 1.32, 95% confidence interval (CI) 1.21 to 1.45] and point prevalence abstinence (RR = 1.14, 95% CI 1.07 to 1.22) suggested that computer and other electronic aids increase the likelihood of cessation compared with no intervention or generic self-help materials. There was no significant difference in effect sizes between aid to cessation studies (which provide support to smokers who are ready to quit) and cessation induction studies (which attempt to encourage a cessation attempt in smokers who are not yet ready to quit). Results from MTC also showed small but significant intervention effect (time to relapse, mean hazard ratio 0.87, 95% credible interval 0.83 to 0.92). Cost-threshold analyses indicated some form of electronic intervention is likely to be cost-effective when added to non-electronic behavioural support, but there is substantial uncertainty with regard to what the most effective (thus most cost-effective) type of electronic intervention is, which warrants further research. EVPI calculations suggested the upper limit for the benefit of this research is around £ 2000-3000 per person. LIMITATIONS The review focuses on smoking cessation programmes in the adult population, but does not cover smoking cessation in adolescents. Most available evidence relates to interventions with a single tailored component, while evidence for different modes of delivery (e.g. e-mail, text messaging) is limited. Therefore, the findings of lack of sufficient evidence for proving or refuting effectiveness should not be regarded as evidence of ineffectiveness. We have examined only a small number of factors that could potentially influence the effectiveness of the interventions. A comprehensive evaluation of potential effect modifiers at study level in a systematic review of complex interventions remains challenging. Information presented in published papers is often insufficient to allow accurate coding of each intervention or comparator. A limitation of the cost-effectiveness analysis, shared with several previous cost-effectiveness analyses of smoking cessation interventions, is that intervention benefit is restricted to the first quit attempt. Exploring the impact of interventions on subsequent attempts requires more detailed information on patient event histories than is available from current evidence. CONCLUSIONS Our effectiveness review concluded that computer and other electronic aids increase the likelihood of cessation compared with no intervention or generic self-help materials, but the effect is small. The effectiveness does not appear to vary with respect to mode of delivery and concurrent non-electronic co-interventions. Our cost-effectiveness review suggests that making some form of electronic support available to smokers actively seeking to quit is highly likely to be cost-effective. This is true whether the electronic intervention is delivered alongside brief advice or more intensive counselling. The key source of uncertainty is that around the comparative effectiveness of different types of electronic interventions. Our review suggests that further research is needed on the relative benefits of different forms of delivery for electronic aids, the content of delivery, and the acceptability of these technologies for smoking cessation with subpopulations of smokers, particularly disadvantaged groups. More evidence is also required on the relationship between involving users in the design of interventions and the impact this has on effectiveness, and finally on how electronic aids developed and tested in research settings are applied in routine practice and in the community.

Calibrating Models in Economic Evaluation: A Seven-Step Approach

In economic evaluation, mathematical models have a central role as a way of integrating all the relevant information about a disease and health interventions, in order to estimate costs and consequences over an extended time horizon. Models are based on scientific knowledge of disease (which is likely to change over time), simplifying assumptions and input parameters with different levels of uncertainty; therefore, it is sensible to explore the consistency of model predictions with observational data. Calibration is a useful tool for estimating uncertain parameters, as well as more accurately defining model uncertainty (particularly with respect to the representation of correlations between parameters). Calibration involves the comparison of model outputs (e.g. disease prevalence rates) with empirical data, leading to the identification of model parameter values that achieve a good fit.This article provides guidance on the theoretical underpinnings of different calibration methods. The calibration process is divided into seven steps and different potential methods at each step are discussed, focusing on the particular features of disease models in economic evaluation. The seven steps are (i) Which parameters should be varied in the calibration process? (ii) Which calibration targets should be used? (iii) What measure of goodness of fit should be used? (iv) What parameter search strategy should be used? (v) What determines acceptable goodness-of-fit parameter sets (convergence criteria)? (vi) What determines the termination of the calibration process (stopping rule)? (vii) How should the model calibration results and economic parameters be integrated?The lack of standards in calibrating disease models in economic evaluation can undermine the credibility of calibration methods. In order to avoid the scepticism regarding calibration, we ought to unify the way we approach the problems and report the methods used, and continue to investigate different methods.

Accuracy of non-invasive prenatal testing using cell-free DNA for detection of Down, Edwards and Patau syndromes : a systematic review and meta-analysis

Objective To measure test accuracy of non-invasive prenatal testing (NIPT) for Down, Edwards and Patau syndromes using cell-free fetal DNA and identify factors affecting accuracy. Design Systematic review and meta-analysis of published studies. Data sources PubMed, Ovid Medline, Ovid Embase and the Cochrane Library published from 1997 to 9 February 2015, followed by weekly autoalerts until 1 April 2015. Eligibility criteria for selecting studies English language journal articles describing case–control studies with ≥15 trisomy cases or cohort studies with ≥50 pregnant women who had been given NIPT and a reference standard. Results 41, 37 and 30 studies of 2012 publications retrieved were included in the review for Down, Edwards and Patau syndromes. Quality appraisal identified high risk of bias in included studies, funnel plots showed evidence of publication bias. Pooled sensitivity was 99.3% (95% CI 98.9% to 99.6%) for Down, 97.4% (95.8% to 98.4%) for Edwards, and 97.4% (86.1% to 99.6%) for Patau syndrome. The pooled specificity was 99.9% (99.9% to 100%) for all three trisomies. In 100 000 pregnancies in the general obstetric population we would expect 417, 89 and 40 cases of Downs, Edwards and Patau syndromes to be detected by NIPT, with 94, 154 and 42 false positive results. Sensitivity was lower in twin than singleton pregnancies, reduced by 9% for Down, 28% for Edwards and 22% for Patau syndrome. Pooled sensitivity was also lower in the first trimester of pregnancy, in studies in the general obstetric population, and in cohort studies with consecutive enrolment. Conclusions NIPT using cell-free fetal DNA has very high sensitivity and specificity for Down syndrome, with slightly lower sensitivity for Edwards and Patau syndrome. However, it is not 100% accurate and should not be used as a final diagnosis for positive cases. Trial registration number CRD42014014947.

An Evaluation of the Feasibility, Cost and Value of Information of a Multicentre Randomised Controlled Trial of Intravenous Immunoglobulin for Sepsis (Severe Sepsis and Septic Shock): Incorporating a Systematic Review, Meta-Analysis and Value of Information Analysis

BACKGROUND Sepsis is a syndrome characterised by a systemic inflammatory response to infection that leads to rapid acute organ failure and potentially rapid decline to death. Intravenous immunoglobulin (IVIG), a blood product derived from human donor blood, has been proposed as an adjuvant therapy for sepsis. OBJECTIVES To describe current practice in the management of adult patients severely ill with sepsis (severe sepsis or septic shock) in the UK; to assess the clinical effectiveness of IVIG for severe sepsis and septic shock and to obtain the appropriate inputs for the relative efficacy parameters, and the key uncertainties associated with these parameters, required to populate the decision model; to develop a decision-analytic model structure and identify key parameter inputs consistent with the decision problem and relevant to an NHS setting; and to populate the decision model and determine the cost-effectiveness of IVIG and to estimate the value of additional primary research. DATA SOURCES Existing literature on IVIG and severe sepsis. Existing case-mix and outcome data on critical care admissions. Survey data on management of admissions with severe sepsis. Databases searched for clinical effectiveness were Cochrane Infectious Diseases Group Specialized Trials Register, the Cochrane Trials Register, MEDLINE and EMBASE. Dates searched were 1 January 2002 to 2 October 2009 to update previous Cochrane review. Databases searched for cost-effectiveness were NHS Economic Evaluation Database (NHS EED) to 2 October 2009, MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations and EMBASE to 20 October 2009. REVIEW METHODS Systematic literature searching with data extraction, descriptive analysis and clinical effectiveness and cost-effectiveness modelling of IVIG in severe sepsis. Additional primary data analysis. Expected value of information (EVI) analysis. RESULTS Our meta-analysis, the first to simultaneously allow for type of IVIG (IVIG or immunoglobulin M-enriched polyclonal IVIG), choice of control (no treatment or albumin), study quality/publication bias and other potential covariates, indicated that the treatment effect of IVIG on mortality for patients with severe sepsis is borderline significant with a large degree of heterogeneity in treatment effect between individual studies. Modelling indicated that there were issues with bias associated with trial methodology, publication and small-study effects with the current evidence. The large degree of heterogeneity in treatment effects between studies, however, could be explained (best-fitting model) by a measure of study quality (i.e. use of albumin as control - as an indicator of proper blinding to treatment as a proxy for study quality - associated with decreased effect) and duration of IVIG therapy (longer duration associated with increased effect). In-depth discussion within the Expert Group on duration of IVIG therapy, with daily dose and total dose also clearly inter-related, indicated no clear clinical rationale for this association and exposed a lack of evidence on the understanding of the mechanism of action of IVIG in severe sepsis. Although the EVI analyses suggested substantial expected net benefit from a large, multicentre randomised controlled trial (RCT) evaluating the clinical effectiveness of IVIG, the remaining uncertainties around the design of such a study mean that we are unable to recommend it at this time. LIMITATIONS As has been identified in previous meta-analyses, there are issues with the methodological quality of the available evidence. CONCLUSIONS Although the results highlight the value for money obtained in conducting further primary research in this area, the biggest limitation for such research regards the uncertainties over the mechanism of action of IVIG and the heterogeneous nature of severe sepsis. Resolving these would allow for better definition of the plausibility of the effectiveness scenarios presented and, consequently, a better understanding of the cost-effectiveness of this treatment. This information would also inform the design of future, primary evaluative research. Our recommendations for future research focus on filling the knowledge gaps to inform a future multicentre RCT prior to recommending its immediate design and conduct. FUNDING The National Institute for Health Research Health Technology Assessment programme.

Economic evaluation of the practical approach to lung health and informal provider interventions for improving the detection of tuberculosis and chronic airways disease at primary care level in Malawi: study protocol for cost-effectiveness analysis

BackgroundChronic airway diseases pose a big challenge to health systems in most developing countries, particularly in Sub-Saharan Africa. A diagnosis for people with chronic or persistent cough is usually delayed because of individual and health system barriers. However, delayed diagnosis and treatment facilitates further transmission, severity of disease with complications and mortality. The objective of this study is to assess the cost-effectiveness of the practical approach to lung health strategy, a patient-centred approach for diagnosis and treatment of common respiratory illnesses in primary healthcare settings, as a means of strengthening health systems to improve the quality of management of respiratory diseases.Methods/designEconomic evaluation nested in a cluster randomised controlled trial with three arms will be performed. Measures of effectiveness and costs for all arms of the study will be obtained from the cluster randomised controlled clinical trial. The main outcome measures are a combined rate of major respiratory diseases milestones and process indicators extracted from the practical approach to lung health strategy. For analysis, descriptive as well as regression techniques will be used. A cost-effectiveness analysis will be performed according to intention-to-treat principle and from a societal perspective. Cost-effectiveness ratios will be calculated using bootstrapping techniques.DiscussionWe hope to demonstrate the cost-effectiveness of the practical approach to lung health and informal healthcare providers, see an improvement in patients’ quality of life, achieve a reduction in the duration and occurrence of episodes and the chronicity of respiratory diseases, and are able to report a decrease in the social cost. If the practical approach to lung health and informal healthcare provider’s interventions are cost-effective, they could be scaled up to all primary healthcare centres.Trial registrationPACTR: PACTR201411000910192

Cost-effectiveness of disease-modifying therapies in the management of multiple sclerosis for the Medicare population.

OBJECTIVE To evaluate the cost-effectiveness of disease-modifying therapies (DMTs) for the management of multiple sclerosis (MS) compared to best supportive care in the United States. METHODS Cost-effectiveness analysis was undertaken using a state transition model of disease natural history and the impact of DMTs for the representative Medicare beneficiary with MS. Costs and outcomes were evaluated from the health-care payer perspective using a 50-year time horizon. Natural history data were drawn from a longitudinal cohort study. The effectiveness of the DMTs was evaluated through a systematic review. Utility data were taken from a study of patients with clinically definite MS in Nova Scotia. Resource use and cost data were derived from the Sonya Slifka database and associated literature. RESULTS When based on placebo-controlled evidence, the marginal cost-effectiveness of interferon beta (IFNβ) and glatiramer acetate compared to best supportive care is expected to be in excess of

Indirect effects of childhood pneumococcal conjugate vaccination on invasive pneumococcal disease: a systematic review and meta-analysis

100,000 per quality-adjusted life-year gained. When evidence from head-to-head trials is incorporated into the model, the cost-effectiveness of 6 MIU IFNβ-1a is expected to be considerably less favorable. Treatment discontinuation upon progression to Expanded Disability Status Scale 7.0 is expected to improve the cost-effectiveness of all DMTs. CONCLUSIONS Further research is required to examine the long-term clinical effectiveness and cost-effectiveness of these therapies. There is no definitive guidance in the United States concerning discontinuation of DMTs; this study suggests that the prudent use of a treatment discontinuation rule may considerably improve the cost-effectiveness of DMTs.

Analysis of the factors influencing the cardiac phenotype in Friedreich's ataxia.

BACKGROUND The full extent to which childhood pneumococcal conjugate vaccines (PCV) can indirectly reduce illness in unvaccinated populations is not known. We aimed to estimate the magnitude and timing of indirect effects of PCVs on invasive pneumococcal disease. METHODS In this systematic review and meta-analysis, we searched bibliographic databases for non-randomised quasi-experimental or observational studies reporting invasive pneumococcal disease changes following PCV introduction in unvaccinated populations (studies published Sept 1, 2010, to Jan 6, 2016), updating the previous systematic review of the same topic (studies published Jan 1, 1994, to Sept 30, 2010). Two reviewers extracted summary data by consensus. We used a Bayesian mixed-effects model to account for between-study heterogeneity to estimate temporal indirect effects by pooling of invasive pneumococcal disease changes by serotype and serogroup. FINDINGS Data were extracted from 70 studies included in the previous review and 172 additional studies, covering 27 high-income and seven middle-income countries. The predicted mean times to attaining a 90% reduction in invasive pneumococcal disease were 8·9 years (95% credible interval [CrI] 7·8-10·3) for grouped serotypes contained in the seven-valent PCV (PCV7), and 9·5 years (6·1-16·6) for the grouped six additional serotypes contained in the 13-valent PCV (PCV13) but not in PCV7. Disease due to grouped serotypes contained in the 23-valent pneumococcal polysaccharide vaccine (PPV23) decreased at similar rates per year in adults aged 19-64 years (relative risk [RR] 0·85, 95% CrI 0·75-0·95) and 65 years and older (0·87, 0·84-0·90). However, we noted no changes in either group in invasive pneumococcal disease caused by the additional 11 serotypes covered by PPV23 but not PCV13. INTERPRETATION Population childhood PCV programmes will lead, on average, to substantial protection across the whole population within a decade. This large indirect protection should be considered when assessing vaccination of older age groups. FUNDING Policy Research Programme of the Department of Health, England.

Indirect and mixed treatment comparisons in arthritis research

Friedreichs ataxia (FRDA) has been associated with both cardiac hypertrophy and to a lesser degree dilated cardiomyopathy. We have conducted a cross sectional magnetic resonance imaging (MRI) study of 25 patients with clinically and genetically confirmed FRDA and 24 healthy controls to analyse how disease parameters influence cardiac features in FRDA. MR cine imaging in the long and short axis planes was performed alongside clinical assessments. LV mass was most pronounced in FRDA patients with a larger genetic mutation (GAA1 repeats >600), earlier age of onset (<16years) and a shorter disease duration (<15 years). LV mass decreased with longer disease duration (>15 years), and independent of GAA1 repeat size and age of onset, suggesting cardiac thinning occurred with prolonged disease. Heart function was lower in patients with larger GAA1 repeat number and longer disease duration. Consequently, cardiac hypertrophy was more marked in FRDA patients with a larger GAA1 repeat number and younger age of onset, while prolonged disease duration was associated with lower LV mass and decreased heart function. It is important not only to understand the biochemical basis for these cardiac changes but also allow for these changes when assessing the effect of treatment of FRDA patients.