Cost-Effectiveness of Total Hip and Knee Replacements for the Australian Population with Osteoarthritis: Discrete-Event Simulation Model

Background: Osteoarthritis constitutes a major musculoskeletal burden for the aged Australians. Hip and knee replacement surgeries are effective interventions once all conservative therapies to manage the symptoms have been exhausted. This study aims to evaluate the cost-effectiveness of hip and knee replacements in Australia. To our best knowledge, the study is the first attempt to account for the dual nature of hip and knee osteoarthritis in modelling the severities of right and left joints separately

Cost-Effectiveness of Pharmacotherapy to Reduce Obesity

Aims: Obesity causes a high disease burden in Australia and across the world. We aimed to analyse the cost-effectiveness of weight reduction with pharmacotherapy in Australia, and to assess its potential to reduce the disease burden due to excess body weight

Five genetic variants associated with prostate cancer

The increasing availability of whole-genome sequence data is expected to increase the accuracy of genomic prediction. However, results from simulation studies and analysis of real data do not always show an increase in accuracy from sequence data compared to high-density (HD) single nucleotide polymorphism (SNP) chip genotypes. In addition, the sheer number of variants makes analysis of all variants and accurate estimation of all effects computationally challenging. Our objective was to find a strategy to approximate the analysis of whole-sequence data with a Bayesian variable selection model. Using a simulated dataset, we applied a Bayes R hybrid model to analyse whole-sequence data, test the effect of dropping a proportion of variants during the analysis, and test how the analysis can be split into separate analyses per chromosome to reduce the elapsed computing time. We also investigated the effect of imputation errors on prediction accuracy. Subsequently, we applied the approach to a dataset that contained imputed sequences and records for production and fertility traits for 38,492 Holstein, Jersey, Australian Red and crossbred bulls and cows

A generic model for the assessment of disease epidemiology: the computational basis of DisMod II

Epidemiology as an empirical science has developed sophisticated methods to measure the causes and patterns of disease in populations. Nevertheless, for many diseases in many countries only partial data are available. When the partial data are insufficient, but data collection is not an option, it is possible to supplement the data by exploiting the causal relations between the various variables that describe a disease process. We present a simple generic disease model with incidence, one prevalent state, and case fatality and remission. We derive a set of equations that describes this disease process and allows calculation of the complete epidemiology of a disease given a minimum of three input variables. We give the example of asthma with age-specific prevalence, remission, and mortality as inputs. Outputs are incidence and case fatality, among others. The set of equations is embedded in a software package called 'DisMod II', which is made available to the public domain by the World Health Organization

Projecting the future smoking prevalence in Norway

Background: Norway has achieved a noteworthy reduction in smoking prevalence over the past forty years. In 2015, 13% of Norwegians aged 13-74 smoked daily and a further 9% smoked occasionally. One of the objectives of the Norwegian 2013-16 national strategy for tobacco control is to achieve a reduction in the daily smoking prevalence t

Estimating the prevalence of breast cancer using a disease model: data problems and trends

BACKGROUND: Health policy and planning depend on quantitative data of disease epidemiology. However, empirical data are often incomplete or are of questionable validity. Disease models describing the relationship between incidence, prevalence and mortality are used to detect data problems or supplement missing data. Because time trends in the data affect their outcome, we compared the extent to which trends and known data problems affected model outcome for breast cancer. METHODS: We calculated breast cancer prevalence from Dutch incidence and mortality data (the Netherlands Cancer Registry and Statistics Netherlands) and compared this to regionally available prevalence data (Eindhoven Cancer Registry, IKZ). Subsequently, we recalculated the model adjusting for 1) limitations of the prevalence data, 2) a trend in incidence, 3) secondary primaries, and 4) excess mortality due to non-breast cancer deaths. RESULTS: There was a large discrepancy between calculated and IKZ prevalence, which could be explained for 60% by the limitations of the prevalence data plus the trend in incidence. Secondary primaries and excess mortality had relatively small effects only (explaining 17% and 6%, respectively), leaving a smaller part of the difference unexplained. CONCLUSION: IPM models can be useful both for checking data inconsistencies and for supplementing incomplete data, but their results should be interpreted with caution. Unknown data problems and trends may affect the outcome and in the absence of additional data, expert opinion is the only available judge

Advances in the meta-analysis of heterogeneous clinical trials I: the inverse variance heterogeneity model

This article examines an improved alternative to the random effects (RE) model for meta-analysis of heterogeneous studies. It is shown that the known issues of underestimation of the statistical error and spuriously overconfident estimates with the RE model can be resolved by the use of an estimator under the fixed effect model assumption with a quasi-likelihood based variance structure — the IVhet model. Extensive simulations confirm that this estimator retains a correct coverage probability and a lower observed variance than the RE model estimator, regardless of heterogeneity. When the proposed IVhet method is applied to the controversial meta-analysis of intravenous magnesium for the prevention of mortality after myocardial infarction, the pooled OR is 1.01 (95% CI 0.71–1.46) which not only favors the larger studies but also indicates more uncertainty around the point estimate. In comparison, under the RE model the pooled OR is 0.71 (95% CI 0.57–0.89) which, given the simulation results, reflects underestimation of the statistical error. Given the compelling evidence generated, we recommend that the IVhet model replace both the FE and RE models. To facilitate this, it has been implemented into free meta-analysis software called MetaXL which can be downloaded from www.epigear.com

THE USE OF SANDWICH-CULTURED RAT HEPATOCYTES TO DETERMINE THE INTRINSIC CLEARANCE OF COMPOUNDS WITH DIFFERENT EXTRACTION RATIOS: 7-ETHOXYCOUMARIN AND WARFARIN

ABSTRACT: The application of sandwich-cultured rat hepatocytes for the identification of the hepatic intrinsic clearance of compounds with widely varying extraction ratios was investigated. We previously showed the applicability of this in vitro system, in combination with a model describing molecular diffusion, hepatocyte/medium partition, and nonsaturated metabolism, which resulted in a successful identification of this parameter for tolbutamide. This approach is further validated using the compounds 7-ethoxycoumarin and warfarin, covering a 100-fold range of extraction ratios. Clearance of these two substrates could be reliably determined, but only if the depletion of the parent compound in medium as well as in the hepatocyte sandwich was measured. Sensitivity analyses showed that the time course of depletion of the parent compound in medium, especially for warfarin, is insensitive to the partition and diffusion parameter values, whereas depletion in the hepatocyte sandwich was far more sensitive. When varying the volumes of collagen in the sandwich culture, it appears that the most reliable kinetic parameters could be obtained by fitting the data with the smaller collagen volume and that these parameters obtained from fitting to data of the larger volumes generally cannot be verified satisfactorily with the data of the smaller volumes. The values of hepatic clearance that were obtained after extrapolation of the intrinsic clearance to the hepatic clearance from blood were comparable within a factor of 2 to hepatic clearance data in the literature. This indicates that this sandwich culture and modeling system can be applied for the identification of the hepatic intrinsic clearance rate of the total range from low to high clearance compounds. Predicting the kinetic parameters of compounds in vivo using data from in vitro experiments is a fast developing area of research Recently, we have successfully developed the alternative approach of using sandwich-cultured rat hepatocytes in determining the in vitro intrinsic clearance of the slowly metabolized compound tolbutamide In this alternative approach, the use of data on substrate depletion was chosen rather than the use of data on metabolite formation. Using data on metabolite formation may cause practical problems when analytical methods or standards to study the kinetics of metabolite Article, publication date, and citation information can be found at http://dmd.aspetjournals.org. doi:10.1124/dmd.105.004390. ABBREVIATIONS: CL bile , biliary clearance (ml/min/kg body weight); CL hep , hepatic clearance (ml/min/kg body weight); CL int , intrinsic clearance (ml/min); C m , concentration medium (M); C s , concentration sandwich (M); D m , diffusion coefficient in medium (cm 2 /min); D s , diffusion coefficient in sandwich (cm 2 /min); f a , fraction of cell activity; f m , free fraction medium; f h , free fraction hepatocytes; f n , fraction of cells; f s , free fraction sandwich; f u , free fraction in blood; f v , fraction of viable cells; K h , specific clearance (Ϫ/min); K l , specific intrinsic clearance of the liver (Ϫ/min; Ϫ/h); K m , Michaelis-Menten constant (M); K ow , partition coefficient octanol-water; K s , first-order metabolism (Ϫ/min); L m , medium layer thickness (cm); L s , sandwich layer thickness (cm); PBPK, physiologically based pharmacokinetics; P cm , collagen-medium partition coefficient; P hm , hepatoyctemedium partition coefficient; P sm , sandwich-medium partition coefficient; P, parameter value; Q h , hepatic blood flow (l/h); s, sensitivity; SRW, standard rat body weight (250 g); V c , volume of collagen (ml); V h , volume of hepatocytes (ml); V m , volume of medium (ml); V max , maximum rate of metabolism (M/min); V s , volume sandwich (ml); DMEM, Dulbecco's modified Eagle's medium; FCS, fetal calf serum; HPLC, high-performance liquid chromatography

Comparative effectiveness of malaria prevention measures: a systematic review and network meta-analysis.

Malaria causes significant morbidity and mortality worldwide. There are several preventive measures that are currently employed, including insecticide-treated nets (ITNs, including long-lasting insecticidal nets and insecticidal-treated bed nets), indoor residual spraying (IRS), prophylactic drugs (PD), and untreated nets (UN). However, it is unclear which measure is the most effective for malaria prevention. We therefore undertook a network meta-analysis to compare the efficacy of different preventive measures on incidence of malaria infection. A systematic literature review was undertaken across four medical and life sciences databases (PubMed, Cochrane Central, Embase, and Web of Science) from their inception to July 2016 to compare the effectiveness of different preventive measures on malaria incidence. Data from the included studies were analysed for the effectiveness of several measures against no intervention (NI). This was carried out using an automated generalized pairwise modeling (GPM) framework for network meta-analysis to generate mixed treatment effects against a common comparator of no intervention (NI). There were 30 studies that met the inclusion criteria from 1998-2016. The GPM framework led to a final ranking of effectiveness of measures in the following order from best to worst: PD, ITN, IRS and UN, in comparison with NI. However, only ITN (RR: 0.49, 95% CI: 0.32-0.74) showed precision while other methods [PD (RR: 0.24, 95% CI: 0.004-15.43), IRS (RR: 0.55, 95% CI: 0.20-1.56) and UN (RR: 0.73, 95% CI: 0.28-1.90)] demonstrating considerable uncertainty associated with their point estimates. Current evidence is strong for the protective effect of ITN interventions in malaria prevention. Even though ITNs were found to be the only preventive measure with statistical support for their effectiveness, the role of other malaria control measures may be important adjuncts in the global drive to eliminate malaria

Contribution of trans-fatty acid intake to coronary heart disease burden in Australia: a modelling study

Trans-fatty acids (TFAs) intake has been consistently associated with a higher risk of coronary heart disease (CHD) mortality. We provided an updated assessment of TFA intake in Australian adults in 2010 and conducted modeling to estimate CHD mortality attributable to TFA intake. Data of the 2011–2012 National Nutrition and Physical Activity Survey was used to assess TFA intake. The CHD burden attributable to TFA was calculated by comparing the current level of TFA intake to a counterfactual setting where consumption was lowered to a theoretical minimum distribution of 0.5% energy. The average TFA intake among adults was 0.59% energy, and overall 10% of adults exceeded the World Health Organization (WHO) recommended limit of 1% energy. Education and income were moderately and inversely associated with TFA intake (p-value ≤ 0.001), with one in seven adults in the lowest income and education quintile having >1% energy from TFA. Australia had 487 CHD deaths (95% uncertainty interval, 367–615) due to TFA exposure, equivalent to 1.52% (95% uncertainty limits: 1.15%–1.92%) of all CHD mortality. The relative impact of TFA exposure on CHD mortality in Australia is limited, but, in absolute terms, still substantial. Policies aimed at reducing industrial TFA exposure can reduce socioeconomic inequalities in health and may therefore be desirable