Christian Asseburg

The Functional Response of a Generalist Predator

Background Predators can have profound impacts on the dynamics of their prey that depend on how predator consumption is affected by prey density (the predators functional response). Consumption by a generalist predator is expected to depend on the densities of all its major prey species (its multispecies functional response, or MSFR), but most studies of generalists have focussed on their functional response to only one prey species. Methodology and principal findings Using Bayesian methods, we fit an MSFR to field data from an avian predator (the hen harrier Circus cyaneus) feeding on three different prey species. We use a simple graphical approach to show that ignoring the effects of alternative prey can give a misleading impression of the predators effect on the prey of interest. For example, in our system, a “predator pit” for one prey species only occurs when the availability of other prey species is low. Conclusions and significance The Bayesian approach is effective in fitting the MSFR model to field data. It allows flexibility in modelling over-dispersion, incorporates additional biological information into the parameter priors, and generates estimates of uncertainty in the models predictions. These features of robustness and data efficiency make our approach ideal for the study of long-lived predators, for which data may be sparse and management/conservation priorities pressing.

Preventive strategies for group B streptococcal and other bacterial infections in early infancy: cost effectiveness and value of information analyses

Objective To determine the cost effectiveness of strategies for preventing neonatal infection with group B streptococci and other bacteria in the UK and the value of further information from research. Design Use of a decision model to compare the cost effectiveness of prenatal testing for group B streptococcal infection (by polymerase chain reaction or culture), prepartum antibiotic treatment (intravenous penicillin or oral erythromycin), and vaccination during pregnancy (not yet available) for serious bacterial infection in early infancy across 12 maternal risk groups. Model parameters were estimated using multi-parameter evidence synthesis to incorporate all relevant data inputs. Data sources 32 systematic reviews were conducted: 14 integrated results from published studies, 24 involved analyses of primary datasets, and five included expert opinion. Main outcomes measures Healthcare costs per quality adjusted life year (QALY) gained. Results Current best practice (to treat only high risk women without prior testing for infection) and universal testing by culture or polymerase chain reaction were not cost effective options. Immediate extension of current best practice to treat all women with preterm and high risk term deliveries without testing (11% treated) would result in substantial net benefits. Currently, addition of culture testing for low risk term women, while treating all preterm and high risk term women, would be the most cost effective option (21% treated). If available in the future, vaccination combined with treating all preterm and high risk term women and no testing for low risk women would probably be marginally more cost effective and would limit antibiotic exposure to 11% of women. The value of information is highest (�67m) if vaccination is included as an option. Conclusions Extension of current best practice to treat all women with preterm and high risk term deliveries is readily achievable and would be beneficial. The choice between adding culture testing for low risk women or vaccination for all should be informed by further research. Trials to evaluate vaccine efficacy should be prioritised.

Is primary angioplasty cost effective in the UK? Results of a comprehensive decision analysis

Objective: To assess the cost effectiveness of primary angioplasty, compared with medical management with thrombolytic drugs, to achieve reperfusion after acute myocardial infarction (AMI) from the perspective of the UK NHS. Design: Bayesian evidence synthesis and decision analytic model. Methods: A systematic review was conducted and Bayesian statistical methods used to synthesise evidence from 22 randomised control trials. Resource utilisation was based on UK registry data, published literature and national databases, with unit costs taken from routine NHS sources and published literature. Main outcome measure: Costs from a health service perspective and outcomes measured as quality-adjusted life years (QALYs). Results: For the base case, the incremental cost-effectiveness ratio of primary angioplasty was £9241 for each additional QALY, with a probability of being cost effective of 0.90 for a cost-effectiveness threshold of £20 000. Results were sensitive to variations in the additional time required to initiate treatment with primary angioplasty. Conclusions: Primary angioplasty is cost effective for the treatment of AMI on the basis of threshold cost-effectiveness values used in the NHS and subject to a delay of up to about 80 minutes. These findings are mainly explained by the superior mortality benefit and the prevention of non-fatal outcomes associated with primary angioplasty for delays of up to this length.

Effectiveness and Cost-Effectiveness of Antidepressants in Primary Care: A Multiple Treatment Comparison Meta-Analysis and Cost-Effectiveness Model

Objective To determine effectiveness and cost-effectiveness over a one-year time horizon of pharmacological first line treatment in primary care for patients with moderate to severe depression. Design A multiple treatment comparison meta-analysis was employed to determine the relative efficacy in terms of remission of 10 antidepressants (citalopram, duloxetine escitalopram, fluoxetine, fluvoxamine mirtazapine, paroxetine, reboxetine, sertraline and venlafaxine). The estimated remission rates were then applied in a decision-analytic model in order to estimate costs and quality of life with different treatments at one year. Data Sources Meta-analyses of remission rates from randomised controlled trials, and cost and quality-of-life data from published sources. Results The most favourable pharmacological treatment in terms of remission was escitalopram with an 8- to 12-week probability of remission of 0.47. Despite a high acquisition cost, this clinical effectiveness translated into escitalopram being both more effective and having a lower total cost than all other comparators from a societal perspective. From a healthcare perspective, the cost per QALY of escitalopram was €3732 compared with venlafaxine. Conclusion Of the investigated antidepressants, escitalopram has the highest probability of remission and is the most effective and cost-effective pharmacological treatment in a primary care setting, when evaluated over a one year time-horizon. Small differences in remission rates may be important when assessing costs and cost-effectiveness of antidepressants.

Assessing the effectiveness of primary angioplasty compared with thrombolysis and its relationship to time delay: a Bayesian evidence synthesis

Background: Meta-analyses of trials have shown greater benefits from angioplasty than thrombolysis after an acute myocardial infarction, but the time delay in initiating angioplasty needs to be considered. Objective: To extend earlier meta-analyses by considering 1- and 6-month outcome data for both forms of reperfusion. To use Bayesian statistical methods to quantify the uncertainty associated with the estimated relationships. Methods: A systematic review and meta-analysis published in 2003 was updated. Data on key clinical outcomes and the difference between time-to-balloon and time-to-needle were independently extracted by two researchers. Bayesian statistical methods were used to synthesise evidence despite differences between reported follow-up times and outcomes. Outcomes are presented as absolute probabilities of specific events and odds ratios (ORs; with 95% credible intervals (CrI)) as a function of the additional time delay associated with angioplasty. Results: 22 studies were included in the meta-analysis, with 3760 and 3758 patients randomised to primary angioplasty and thrombolysis, respectively. The mean (SE) angioplasty-related time delay (over and above time to thrombolysis) was 54.3 (2.2) minutes. For this delay, mean event probabilities were lower for primary angioplasty for all outcomes. Mortality within 1 month was 4.5% after angioplasty and 6.4% after thrombolysis (OR = 0.68 (95% CrI 0.46 to 1.01)). For non-fatal reinfarction, OR = 0.32 (95% CrI 0.20 to 0.51); for non-fatal stroke OR = 0.24 (95% CrI 0.11 to 0.50). For all outcomes, the benefit of angioplasty decreased with longer delay from initiation. Conclusions: The benefit of primary angioplasty, over thrombolysis, depends on the former’s additional time delay. For delays of 30–90 minutes, angioplasty is superior for 1-month fatal and non-fatal outcomes. For delays of around 90 minutes thrombolysis may be the preferred option as assessed by 6-month mortality; there is considerable uncertainty for longer time delays.

Cost-Effectiveness of Targeted Therapy With Cetuximab in Patients With K-ras Wild-Type Colorectal Cancer Presenting With Initially Unresectable Metastases Limited to the Liver in a German Setting

BACKGROUND In patients with metastases limited to the liver (liver-limited disease [LLD]), effective therapies such as monoclonal antibodies combined with chemotherapy may facilitate metastasis resection and improve long-term survival. OBJECTIVE This study assessed the cost-effectiveness of bevacizumab and cetuximab in the treatment of patients with colorectal cancer presenting with initially unresectable liver metastases of the Kirsten rat sarcoma viral oncogene homolog (K-ras) wild type, from the perspective of German statutory health insurance. METHODS The health-economic modeling approach presented here made indirect comparisons between available data on bevacizumab and cetuximab treatment outcomes using evidence synthesis techniques, extrapolating from the follow-up duration of identified clinical trials to a longer time horizon of up to 10 years and inferring costs and health outcomes based on modeled patient pathways. Expert opinion and Delphi panel methods were used for some assumptions, when evidence was missing. Probabilistic sensitivity analyses and different scenario analyses were applied to test for uncertainty around input parameters and assumptions. RESULTS For the metastatic colorectal cancer LLD population with K-ras wild-type genotype, mean overall survival estimates were 37.7 months for first-line treatment with cetuximab plus FOLFIRI (irinotecan, leucovorin, fluorouracil) and 30.4 months for bevacizumab plus FOLFOX (oxaliplatin, leucovorin, fluorouracil). Corresponding discounted survival estimates were 2.88 life-years with cetuximab plus FOLFIRI versus 2.38 life-years with bevacizumab plus FOLFOX, an average gain of 0.50 discounted life-years. The incremental cost-effectiveness ratio of cetuximab plus FOLFIRI versus bevacizumab plus FOLFOX was €15,020 (year 2010 €) per life-year gained in the base case (with a 95% CI from the probabilistic sensitivity analysis of €3806-€24,660). Results were robust in different scenario analyses as well as in the probabilistic sensitivity analysis. CONCLUSIONS First-line treatment with cetuximab plus FOLFIRI offers a cost-effective treatment option versus bevacizumab plus FOLFOX for the metastatic colorectal cancer LLD population with K-ras wild-type genotype in Germany. K-ras testing should be performed on all presenting cases of metastatic colorectal cancer to ensure access to this treatment option.

Short-course adjuvant trastuzumab therapy in early stage breast cancer in Finland: Cost-effectiveness and value of information analysis based on the 5-year follow-up results of the FinHer Trial

Abstract Background. Trastuzumab is a standard treatment of HER2-positive early breast cancer in many countries, and it is usually given as a one year adjuvant treatment. However, its cost-effectiveness has not been assessed in Finland. The Finland Herceptin (FinHer) trial has compared a shorter 9-week treatment protocol against no trastuzumab with promising results. The aim of this study was to assess the potential cost-effectiveness of the 9-week treatment based on the recently published five-year follow-up results of the FinHer trial. Methods. An evaluation model of breast cancer treatment was constructed using fitted survival estimates and a long-term Markov model. The cost-effectiveness of 9-week adjuvant treatment was assessed in a Finnish setting, compared to treatment without trastuzumab. The analysis was performed from a societal perspective, and a 3% discount rate was applied for future costs and outcomes. Value of information analysis was performed to estimate the potential value of further research. Results. According to the probabilistic analysis, the incremental cost-effectiveness ratio was €12 000 per quality adjusted life year (QALY), and €9300 per life year gained (LYG), when comparing adjuvant trastuzumab therapy to standard treatment without trastuzumab. The modelled incremental outcomes for trastuzumab treatment were 0.66 QALY and 0.85 LYG for a lifetime perspective. Value of information analysis showed that additional research on treatment effects would be most valuable for reducing uncertainty in the adoption decision. Conclusions. Adjuvant 9-week trastuzumab is likely to be a cost-effective treatment in the Finnish setting. Results from an ongoing trial comparing adjuvant 9-week treatment with the 12-month treatment will play a key role in addressing the uncertainty related to the treatment effect and potential cost-effectiveness of these two treatment protocols.

Validation of economic and health outcomes simulation model of type 2 diabetes mellitus (ECHO-T2DM)

Abstract Objective: This study constructed the Economic and Health Outcomes Model for type 2 diabetes mellitus (ECHO-T2DM), a long-term stochastic microsimulation model, to predict the costs and health outcomes in patients with T2DM. Naturally, the usefulness of the model depends upon its predictive accuracy. The objective of this work is to present results of a formal validation exercise of ECHO-T2DM. Methods: The validity of ECHO-T2DM was assessed using criteria recommended by the International Society for Pharmacoeconomics and Outcomes Research/Society for Medical Decision Making (ISPOR/SMDM). Specifically, the results of a number of clinical trials were predicted and compared with observed study end-points using a scatterplot and regression approach. An F-test of the best-fitting regression was added to assess whether it differs statistically from the identity (45°) line defining perfect predictions. In addition to testing the full model using all of the validation study data, tests were also performed of microvascular, macrovascular, and survival outcomes separately. The validation tests were also performed separately by type of data (used vs not used to construct the model, economic simulations, and treatment effects). Results: The intercept and slope coefficients of the best-fitting regression line between the predicted outcomes and corresponding trial end-points in the main analysis were −0.0011 and 1.067, respectively, and the R2 was 0.95. A formal F-test of no difference between the fitted line and the identity line could not be rejected (p = 0.16). The high R2 confirms that the data points are closely (and linearly) associated with the fitted regression line. Additional analyses identified that disagreement was highest for macrovascular end-points, for which the intercept and slope coefficients were 0.0095 and 1.225, respectively. The R2 was 0.95 and the estimated intercept and slope coefficients were 0.017 and 1.048, respectively, for mortality, and the F-test was narrowly rejected (p = 0.04). The sub-set of microvascular end-points showed some tendency to over-predict (the slope coefficient was 1.095), although concordance between predictions and observed values could not be rejected (p = 0.16). Limitations: Important study limitations include: (1) data availability limited one to tests based on end-of-study outcomes rather than time-varying outcomes during the studies analyzed; (2) complex inclusion and exclusion criteria in two studies were difficult to replicate; (3) some of the studies were older and reflect outdated treatment patterns; and (4) the authors were unable to identify published data on resource use and costs of T2DM suitable for testing the validity of the economic calculations. Conclusions: Using conventional methods, ECHO-T2DM simulated the treatment, progression, and patient outcomes observed in important clinical trials with an accuracy consistent with other well-accepted models. Macrovascular outcomes were over-predicted, which is common in health-economic models of diabetes (and may be related to a general over-prediction of event rates in the United Kingdom Prospective Diabetes Study [UKPDS] Outcomes Model). Work is underway in ECHO-T2DM to incorporate new risk equations to improve model prediction.

Hospitalisation Utilisation and Costs in Schizophrenia Patients in Finland before and after Initiation of Risperidone Long-Acting Injection

Objectives. Quantify changes in hospital resource use in Finland following initiation of risperidone long-acting injection (RLAI). Materials and Methods. A retrospective multi-center chart review (naturalistic setting) was used to compare annual hospital bed-days and hospital episodes for 177 schizophrenia patients (mean age 47.1 years, 52% female, 72% hospitalized) before and after initiation of RLAI (between January 2004 and June 2005) using the within-patient “mirror-image” study design. The base case analytical approach allocated hospital episodes overlapping the start date entirely to the preinitiation period. In order to investigate the impact of inpatient care ongoing at baseline, the change in bed-days was also estimated using an alternative analytical approached related to economic modelling. Results. In the conventional analysis, the mean annual hospitalisation costs declined by €11,900 and the number of bed-days was reduced by 40%, corresponding to 0.19 fewer hospital episodes per year. The reductions in bed-days per patient-year were similar for patients switched to RLAI as inpatients and as outpatients. In the modelling-based analysis, an 8% reduction in bed-days per year was observed. Conclusion. Despite uncertainty in the choice of analytic approach for allocating inpatient episodes that overlapping this initiation, consistent reductions in resource use are associated with the initiation of RLAI in Finland.

SENSITIVITY TO ASSUMPTIONS IN MODELS OF GENERALIST PREDATION ON A CYCLIC PREY

Ecological theory predicts that generalist predators should damp or suppress long-term periodic fluctuations (cycles) in their prey populations and depress their average densities. However, the magnitude of these impacts is likely to vary depending on the availability of alternative prey species and the nature of ecological mechanisms driving the prey cycles. These multispecies effects can be modeled explicitly if parameterized functions relating prey consumption to prey abundance, and realistic population dynamical models for the prey, are available. These requirements are met by the interaction between the Hen Harrier (Circus cyaneus) and three of its prey species in the United Kingdom, the Meadow Pipit (Anthus pratensis), the field vole (Microtus agrestis), and the Red Grouse (Lagopus lagopus scoticus). We used this system to investigate how the availability of alternative prey and the way in which prey dynamics are modeled might affect the behavior of simple trophic networks. We generated cycles in one of the prey species (Red Grouse) in three different ways: through (1) the interaction between grouse density and macroparasites, (2) the interaction between grouse density and male grouse aggressiveness, and (3) a generic, delayed density-dependent mechanism. Our results confirm that generalist predation can damp or suppress grouse cycles, but only when the densities of alternative prey are low. They also demonstrate that diametrically opposite indirect effects between pairs of prey species can occur together in simple systems. In this case, pipits and grouse are apparent competitors, whereas voles and grouse are apparent facilitators. Finally, we found that the quantitative impacts of the predator on prey density differed among the three models of prey dynamics, and these differences were robust to uncertainty in parameter estimation and environmental stochasticity.