Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “sensitivity analysis”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 847 records · Page 47Linked to original sources
PubMed2006

Cost-benefit analysis of a plant sterol containing low-fat margarine for cholesterol reduction.

For decreasing the risk of coronary heart disease (CHD) it has been proposed to enrich food such as margarine with plant sterol esters which have been shown to reduce total and LDL cholesterol concentrations, two of the major risk factors. A Markov model was developed to assess the costs and benefits of consuming a low-fat plant sterol containing margarine (PS margarine). A health insurer's perspective was taken with a time frame of 10 years. Transition probabilities for CHD and CHD-related death were calculated on the basis of the Framingham risk equations. These were applied to a representative sample of the German population. The alteration in cholesterol levels after intake of PS margarine was estimated based on a meta-analysis of ten randomized controlled trials with parallel or crossover design that found a reduction of 5.7% in total cholesterol. Average annual costs of CHD were assumed to be at 3,000 euro. Costs for "no CHD" and "CHD-related death" were set to 0 euro since the intervention would solely be paid by the consumers. Sensitivity analyses were performed with regard to annual costs, risk estimation, PS margarine reduction in total cholesterol, discount factor, and risk of CHD-related death. The 10-year CHD risks are 6.1% (PS margarine) vs. 6.5% (control). Thus expected 10-year CHD costs are 696 euro (PS margarine) vs. 748 euro (control). The cost savings of 52 euro varied between 32 euro and 74 euro in the sensitivity analysis. A projection at the level of the population for which evidence (randomized controlled trials) exists that plant sterols lower cholesterol (25.35 million) leads to a reduction of 117,000 CHD cases over 10 years and a cost reduction of 1.3 billion euro for this time period (sensitivity analysis 0.8-1.9 billion euro).

Adolescent↗
PubMed2004

A decision chart for assessing and improving the transferability of economic evaluation results between countries.

OBJECTIVE: To develop a user-friendly tool for managing the transfer of economic evaluation results. METHODS: Factors that may influence the transfer of health economic study results were systematically identified and the way they impact on transferability was investigated. A transferability decision chart was developed that includes: knock-out criteria; a checklist based on the transferability factors; and methods for improving transferability and for assessing the uncertainty of transferred results. This approach was tested on various international cost-effectiveness studies in the areas of interventional cardiology, vaccination and screening. RESULTS: The transfer of study results is possible pending the outcomes of the transferability check and necessary adjustments. Transferability factors can be grouped into areas of methodological, healthcare system and population characteristics. Different levels of effort are required for analysis of factors, ranging from very low (e.g. discount rate) to very high (e.g. practice variation). The impact of differences of most transferability factors can be estimated via the key health economic determinants: capacity utilisation, effectiveness, productivity loss and returns to scale. Depending on the outcomes of the transferability check a correction of the study results for inflation and for differences related to currencies or purchasing power might be sufficient. Otherwise, modelling-based adjustments might be necessary, requiring the (re-)building and sometimes structural modification of the study model. For determination of the most essential adjustments, a univariate sensitivity analysis seems appropriate. If not all relevant study parameters can be substituted with country-specific ones, multivariate or probabilistic sensitivity analysis seems to be a promising way to quantify the uncertainty associated with a transfer. If study results cannot be transferred, the transfer of study models or designs should be investigated as this can significantly save time when conducting a new study. CONCLUSIONS: Our transferability decision chart is a transparent and user-friendly tool for assessing and improving the transferability of economic evaluation results. A state of the art description of the methodology in a study, providing detailed components for calculation, is not only essential for determining its transferability but also for improving it via modelling adjustments.

Cost-Benefit Analysis↗
PubMed2006

A multimedia environmental model of chemical distribution: fate, transport, and uncertainty analysis.

This paper presented a framework for analysis of chemical concentration in the environment and evaluation of variance propagation within the model. This framework was illustrated through a case study of selected organic compounds of benzo[alpha]pyrene (BAP) and hexachlorobenzene (HCB) in the Great Lakes region. A multimedia environmental fate model was applied to perform stochastic simulations of chemical concentrations in various media. Both uncertainty in chemical properties and variability in hydrometeorological parameters were included in the Monte Carlo simulation, resulting in a distribution of concentrations in each medium. Parameters of compartmental dimensions, densities, emissions, and background concentrations were assumed to be constant in this study. The predicted concentrations in air, surface water and sediment were compared to reported data for validation purpose. Based on rank correlations, a sensitivity analysis was conducted to determine the influence of individual input parameters on the output variance for concentration in each environmental medium and for the basin-wide total mass inventory. Results of model validation indicated that the model predictions were in reasonable agreement with spatial distribution patterns, among the five lake basins, of reported data in the literature. For the chemical and environmental parameters given in this study, parameters associated to air-ground partitioning (such as moisture in surface soil, vapor pressure, and deposition velocity) and chemical distribution in soil solid (such as organic carbon partition coefficient and organic carbon content in root-zone soil) were targeted to reduce the uncertainty in basin-wide mass inventory. This results of sensitivity analysis in this study also indicated that the model sensitivity to an input parameter might be affected by the magnitudes of input parameters defined by the parameter settings in the simulation scenario. Therefore, uncertainty and sensitivity analyses for environmental fate models was suggested to be conducted after the model output was validated based on an appropriate input parameter settings.

Benzopyrenes↗
PubMed2004

Mutational biases associated with potential iron-binding DNA motifs in rodent lacI and human p53 mutational databases.

The role of Fenton oxidants in DNA damage, aging, and cancer is appreciated, but not well understood. Six potential iron-binding (PIB) DNA motifs were previously identified as sites of preferential strand cleavage. Since DNA-metal binding domains are a known determinant of oxidative DNA damage, and the location of strand breaks explains where oxidant attack occurs, we sought to determine whether the likelihood of base change mutations is a function of neighboring PIB motifs. We developed a sliding window function that computes the density of PIB motifs on both strands, within 4-12bp, for each location along a target gene. This range of window sizes reflects known diffusion distances of Fenton reaction products. Using mutational databases, odds of mutation at each base were calculated relative to PIB motif density, for all PIB motif types in aggregate, or for individual PIB motifs. Using mutational data from lacI transgenic animals, we observed a non-random distribution of PIB motifs, associated with increased odds of mutation, showing a strand bias. Sensitivity analysis confirmed that the optimum association between PIB motif density and mutations occurs when a 7bp radius is used for the window size. Randomly simulated mutations showed no association with PIB motif density. When the method was applied to human TP53 mutation data, we saw similar results, but no strand bias. As PIB motif density rises, linear trends are observed for increasing odds of mutation. Sensitivity analysis revealed associations between PIB motifs and GC --> AT transitions and GC --> TA transversions-the most commonly observed types of mutations arising from oxidative DNA damage. DNA-metal binding motifs are found in a wide variety of biological contexts, including many where conformational sensitivity to redox state is important. These techniques can help elucidate how DNA-iron-binding may affect lesions and subsequent mutations from multiple agents.

Amino Acid Motifs↗
PubMed2005

Uncertainty analysis in pharmacokinetics and pharmacodynamics: application to naratriptan.

PURPOSE: The aim of the study was to predict pain relief of migraine in patients following naratriptan oral (tablet) administration by using uncertainty analysis. The analysis was based on phase I pharmacokinetic naratriptan data, sumatriptan pharmacodynamic data, and naratriptan preclinical (animal) potency information, together with general knowledge as to how migraine affects oral absorption. METHODS: A previously developed pharmacokinetic (PK)/pharmacodynamic (PD) model for naratriptan disposition and effect was used. The uncertain parameters in the model, which were associated with absorption and scaling between first-in-class compound sumatriptan and naratriptan, were modeled using fuzzy sets theory. Global sensitivity analysis was then used to investigate the impact of each PK/PD parameter on the responses. RESULTS: Acknowledging parametric uncertainty did not improve prediction of the probability of pain relief. Global sensitivity analysis demonstrated that predictions were heavily influenced by interindividual variability in pharmacodynamics, as the dose response relationship was relatively insensitive to the pharmacokinetics. CONCLUSIONS: To predict the probability of pain relief following oral (tablet) administration of naratriptan, a simple dose response, instead of the PK/PD model, would have yielded very similar predictions. The naratriptan PK/PD model may be improved by either refining the PD model or better still by specifying the interindividual error by additional data collecting with an improved design.

Algorithms↗
PubMed2006

Primary resection with anastomosis vs. Hartmann's procedure in nonelective surgery for acute colonic diverticulitis: a systematic review.

PURPOSE: This study compares primary resection with anastomosis and Hartmann's procedure in an adult population with acute colonic diverticulitis. METHODS: Comparative studies published between 1984 and 2004 of primary resection with anastomosis vs. Hartmann's procedure were included. The primary end point was postoperative mortality. Secondary end points included surgical and medical morbidity, operative time, and length of postoperative hospitalization. Random effects model was used and sensitivity analysis was performed. RESULTS: Fifteen studies, including 963 patients (57 percent primary resection with anastomoses, 43 percent Hartmann's procedures), were analyzed. Overall mortality was significantly reduced with primary resection and anastomosis (4.9 vs. 15.1 percent; odds ratio = 0.41). Subgroup analysis of trials matched for emergency operations showed significantly decreased mortality with primary resection and anastomosis (7.4 vs. 15.6 percent; odds ratio = 0.44). No significant difference in mortality was observed in trials matched for severity of peritonitis Hinchey > 2 (14.1 vs. 14.4 percent; odds ratio = 0.85). Sensitivity analysis did not reveal significant heterogeneity between the studies for the primary outcome. CONCLUSIONS: Patients selected for primary resection and anastomosis have a lower mortality than those treated by Hartmann's procedure in the emergency setting and comparable mortality under conditions of generalized peritonitis (Hinchey > 2). The retrospective nature of the included studies allows for a considerable degree of selection bias that limits robust and clinically sound conclusions. This analysis highlights the need for high-quality randomized trials comparing the two techniques.

Acute Disease↗
PubMed2002

Flumazenil vs. placebo in hepatic encephalopathy in patients with cirrhosis: a meta-analysis.

BACKGROUND: Randomized controlled trials testing flumazenil in hepatic encephalopathy have shown conflicting results. AIM: To compare flumazenil and placebo in hepatic encephalopathy in patients with cirrhosis. METHODS: An overview of randomized controlled trials comparing flumazenil and placebo in hepatic encephalopathy in patients with cirrhosis was performed. For each end-point, heterogeneity and treatment efficacy were assessed by Peto and Der Simonian methods. As most trials were crossover in nature, a sensitivity analysis was performed including the two treatment periods. RESULTS: Six double-blind randomized controlled trials, including 641 patients (326 treated with flumazenil and 315 with placebo), were identified. The treatment duration ranged from 5 min to 3 days. Heterogeneity tests between control groups were not significant. The mean percentages of patients with clinical improvement (five trials) were 27% in treated groups and 3% in placebo groups. This difference was significant by both methods (Peto: odds ratio=6.15; 95% confidence interval, 4.0-9.5; P < 0.001; Der Simonian: mean rate difference, 29%; 95% confidence interval, 17-41; P < 0.001). The mean percentages of patients with electroencephalographic improvement were 19% in treated groups and 2% in placebo groups. This difference was significant only with the Peto method (odds ratio=5.8; 95% confidence interval, 3.4-9.7; P < 0.001). The sensitivity analysis showed similar results. CONCLUSIONS: This meta-analysis shows that flumazenil induces clinical and electroencephalographic improvement of hepatic encephalopathy in patients with cirrhosis.

Coma↗
PubMed2005

[Can PCI with drug-eluting stents replace coronary artery bypass surgery? A comparative economic analysis regarding both therapeutic options based on clinical 12-month data reflecting the German social health care insurance system].

BACKGROUND AND PURPOSE: It is generally known and accepted that percutaneous coronary intervention (PCI) has undergone a patient-relevant innovation with the introduction of drug-eluting stents (DES): prospective, randomized, controlled studies with a primary clinical endpoint have shown that DES, especially those releasing sirolimus from a polymer (SES) or those releasing paclitaxel from a polymer (PES), significantly and relevantly reduce the restenosis rate and hence the number of needed reinterventions in the target vessel (target vessel revascularization [TVR]) as compared to bare metal stents (BMS). For this improvement of quality of life, cost-effectiveness analyses comparing DES and BMS in the US and German health care systems have been reported. For the comparison of DES and coronary artery bypass graft surgery (CABG), no economic data regarding the German health care system have been published. The goal of the present study is to provide such an economic analysis investigating the question whether DES can reduce costs as compared to CABG within the German health care system. METHODS: Based on the clinical data for PCI with a PES for long and complex lesions (TAXUS VI) and for CABG (ARTS I), the comparison was calculated for the time interval of 1 year. The analysis of the PCI group was derived from a TVR of 11% including a CABG rate of 1%; the CABG group analysis was based on a TVR of 3.8% including a PCI rate of 3.1% and a re-CABG rate of 0.7%. At a stent factor of 2.75, the costs per stent were calculated to be 250 Euro for the BMS and 1,500 Euro for the PES. The total costs for 12 months included the follow-up costs for reinterventions. The results were tested for stability according to a sensitivity analysis. RESULTS: Patients' demographics were well comparable between the PCI and the CABG groups. The primary costs, including the reinterventions, were 7,841 Euro for PCI and 12,415 Euro for CABG. The sensitivity analysis revealed that only at more than eight stents per patient and a need for reintervention of ca. 10% did the cost of PCI with PES reach the level of the cost for CABG. CONCLUSION: Within the German health care system, in patients with a social insurance, PCI of long and complex lesions with PES significantly reduces costs as compared to CABG to the amount of 4,574 Euro per patient. The cost-effectiveness analyses of currently ongoing prospective, randomized trials (SYNTAX und FREEDOM) will provide more insight into the economic comparison of PCI with DES and CABG.

Angioplasty, Balloon, Coronary↗
PubMed2003

New choices for central venous catheters: potential financial implications.

OBJECTIVE: To determine the cost-effectiveness of the newer antiseptic and antibiotic-impregnated central venous catheters (CVCs) relative to uncoated CVCs and to each other. DESIGN: Decision model analysis of the cost and efficacy of CVCs coated with either chlorhexidine silver sulfadiazine (CSS) or rifampin-minocycline (RM) at preventing catheter-related bloodstream infections (CRBSIs). The primary outcome is the incremental cost (or savings) to prevent one additional CRBSI. Model estimates are derived from prospective trials of the CSS and RM CVCs and from other studies describing the costs of CRBSIs. SETTING AND PATIENTS: Hypothetical cohort of 1,000 patients requiring placement of a CVC. INTERVENTIONS: In the model, patients were managed with either an uncoated CVC, CSS CVC, or RM CVC. MEASUREMENTS AND MAIN RESULTS: The incremental cost-effectiveness of the treated CVCs was calculated as the savings resulting from CRBSIs averted less the additional costs of the newer devices. Sensitivity analysis of the effect of the major clinical inputs was performed. For the base case analysis, we assumed the incidence of CRBSIs was 3.3% with traditional catheters and that the CSS and RM CVC conferred a relative risk reduction for the development of CRBSIs of 60% and 85%, respectively. Despite their significantly higher cost than older catheters, both novel CVCs yield significant savings. Employing either of the treated CVCs saves approximately $10,000 per CRBSI prevented (relative to standard catheters). Comparing the RM CVC to the CSS CVC revealed the RM product to be economically superior, saving nearly $9,600 per CRBSI averted and $81 per patient in the cohort. For sensitivity analysis, we adjusted all model variables by 50% individually and then simultaneously. This demonstrated the model to be most sensitive to the cost of a CRBSI; however, with all inputs skewed by 50% against both the CSS CVC and the RM CVC, these devices remained economically attractive. Under this scenario, use of either treated device was less costly. CONCLUSIONS: Utilization of antiseptic and antibiotic-impregnated CVCs represent an attractive alternative for the prevention of CRBSIs and may lead to significant savings. Of the two newer, coated devices, the RM CVC performs better financially. These observations hold over a range of estimates for our model inputs.

Bacteremia↗
PubMed2002

Initial evaluation of rectal bleeding in young persons: a cost-effectiveness analysis.

BACKGROUND: Evaluation of rectal bleeding in young patients is a frequent diagnostic challenge. OBJECTIVE: To determine the relative cost-effectiveness of alternative diagnostic strategies for young patients with rectal bleeding. DESIGN: Cost-effectiveness analysis using a Markov model. DATA SOURCES: Probability estimates were based on published medical literature. Cost estimates were based on Medicare reimbursement rates and published medical literature. TARGET POPULATION: Persons 25 to 45 years of age with otherwise asymptomatic rectal bleeding. TIME HORIZON: The patient's lifetime. PERSPECTIVE: Modified societal perspective. INTERVENTIONS: Diagnostic strategies included no evaluation, colonoscopy, flexible sigmoidoscopy, barium enema, anoscopy, or any feasible combination of these procedures. OUTCOME MEASURES: Life expectancy and costs. RESULTS OF BASE-CASE ANALYSIS: For 35-year-old patients, the no-evaluation strategy yielded the least life expectancy. The incremental cost-effectiveness of flexible sigmoidoscopy compared with no evaluation or with any strategy incorporating anoscopy (followed by further evaluation if no anal disease was found on anoscopy) was less than $5300 per year of life gained. A strategy of flexible sigmoidoscopy plus barium enema yielded the greatest life expectancy, with an incremental cost of $23 918 per additional life-year gained compared with flexible sigmoidoscopy alone. RESULTS OF SENSITIVITY ANALYSIS: As patient age at presentation of rectal bleeding increased, evaluation of the entire colon became more cost-effective. The incremental cost-effectiveness of flexible sigmoidoscopy plus barium enema compared with colonoscopy was sensitive to estimates of the sensitivity of the tests. In a probabilistic sensitivity analysis comparing flexible sigmoidoscopy with anoscopy followed by flexible sigmoidoscopy if needed, the middle 95th percentile of the distribution of the incremental cost-effectiveness ratios ranged from flexible sigmoidoscopy yielding an increased life expectancy at reduced cost to $52 158 per year of life gained (mean, $11 461 per year of life saved). CONCLUSIONS: Evaluation of the colon of persons 25 to 45 years of age with otherwise asymptomatic rectal bleeding increases the life expectancy at a cost comparable to that of colon cancer screening.

Adult↗
PubMed2000

Application of neural computing methods for interpreting phospholipid fatty acid profiles of natural microbial communities.

The microbial community compositions of surface and subsurface marine sediments and sediments lining burrows of marine polychaetes and hemichordates from the North Inlet estuary (near Georgetown, S.C. ) were analyzed by comparing ester-linked phospholipid fatty acid (PLFA) profiles with a back-propagating neural network (NN). The NNs were trained to relate PLFA inputs to sediment type outputs (e.g., surface, subsurface, and burrow lining) and worm species (e.g., Notomastus lobatus, Balanoglossus aurantiacus, and Branchyoasychus americana). Sensitivity analysis was used to determine which of the 60 PLFAs significantly contributed to training the NN. The NN architecture was optimized by changing the number of hidden neurons and calculating the cross-validation error between predicted and actual outputs of training and test data. The optimal NN architecture was found to be four hidden neurons with 60-input neurons representing the 60 PLFAs, and four output neurons coding for both sediment types and worm species. Comparison of cross-validation results using NNs and linear discriminant analysis (LDA) revealed that NNs had significantly fewer incorrect classifications (2.7%) than LDA (8.4%). For the NN cross-validation, both sediment type and worm species had 3 incorrect classifications out of 112. For the LDA cross-validation, sediment type and worm species had 7 and 12 incorrect classifications out of 112, respectively. Sensitivity analysis of the trained NNs revealed that 17 fatty acids explained 50% of variability in the data set. These PLFAs were highly different among sediments and burrow types, indicating significant differences in the microbiota.

Animals↗
PubMed1999

The cost of obesity in Canada.

BACKGROUND: Almost one-third of adult Canadians are at increased risk of disability, disease and premature death because of being obese. In order to allocate limited health care resources rationally, it is necessary to elucidate the economic burden of obesity. OBJECTIVE: To estimate the direct costs related to the treatment of and research into obesity in Canada in 1997. METHODS: The prevalence of obesity (body mass index of 27 or greater) in Canada was determined using data from the National Population Health Survey, 1994-1995. Ten comorbidities of obesity were identified from the medical literature. A population attributable fraction (PAF) was calculated for each comorbidity with data from large cohort studies to determine the extent to which each comorbidity and its management costs were attributable to obesity. The direct cost of each comorbidity was determined using data from the Canadian Institute of Health Information (for direct expenditure categories) and from Health Canada (for the proportion of expenditure category attributable to the comorbidity). This prevalence-based approach identified the direct costs of hospital care, physician services, services of other health professionals, drugs, other health care and health research. For each comorbidity, the cost attributable to obesity was determined by multiplying the PAF by the total direct cost of the comorbidity. The overall impact of obesity was estimated as the sum of the PAF-weighted costs of treating the comorbidities. A sensitivity analysis was completed on both the estimated costs and the PAFs. RESULTS: The total direct cost of obesity in Canada in 1997 was estimated to be over $1.8 billion. This corresponded to 2.4% of the total health care expenditures for all diseases in Canada in 1997. The sensitivity analysis revealed that the total cost could be as high as $3.5 billion or as low as $829.4 million; this corresponded to 4.6% and 1.1% respectively of the total health care expenditures in 1997. When the contributions of the comorbidities to the total cost were considered, the 3 largest contributors were hypertension ($656.6 million), type 2 diabetes mellitus ($423.2 million) and coronary artery disease ($346.0 million). INTERPRETATION: A considerable proportion of health care dollars is devoted to the treatment and management of obesity-related comorbidities in Canada. Further research into the therapeutic benefits and cost-effectiveness of management strategies for obesity is required. It is anticipated that the prevention and treatment of obesity will have major positive effects on the overall cost of health care.

Adult↗
PubMed2006

Dependence of intramyocardial pressure and coronary flow on ventricular loading and contractility: a model study.

The phasic coronary arterial inflow during the normal cardiac cycle has been explained with simple (waterfall, intramyocardial pump) models, emphasizing the role of ventricular pressure. To explain changes in isovolumic and low afterload beats, these models were extended with the effect of three-dimensional wall stress, nonlinear characteristics of the coronary bed, and extravascular fluid exchange. With the associated increase in the number of model parameters, a detailed parameter sensitivity analysis has become difficult. Therefore we investigated the primary relations between ventricular pressure and volume, wall stress, intramyocardial pressure and coronary blood flow, with a mathematical model with a limited number of parameters. The model replicates several experimental observations: the phasic character of coronary inflow is virtually independent of maximum ventricular pressure, the amplitude of the coronary flow signal varies about proportionally with cardiac contractility, and intramyocardial pressure in the ventricular wall may exceed ventricular pressure. A parameter sensitivity analysis shows that the normalized amplitude of coronary inflow is mainly determined by contractility, reflected in ventricular pressure and, at low ventricular volumes, radial wall stress. Normalized flow amplitude is less sensitive to myocardial coronary compliance and resistance, and to the relation between active fiber stress, time, and sarcomere shortening velocity.

Animals↗
PubMed1994

An inversion algorithm for determining area-source emissions from downwind concentration measurements.

Measuring emissions from nonuniform area sources, such as waste repository sites, has been a difficult problem. A simple but reliable method is not available. An objective method of inverting downwind concentration measurements, utilizing an assumed form of atmospheric dispersion to reconstruct total emission rate and distribution, is described in this study. The Gaussian dispersion model is compared to a more realistic model based on K-theory and similarity expressions. A sensitivity analysis is presented indicating the atmospheric conditions under which a successful application of the method could be anticipated. Field releases of sulfur hexafluoride (SF6) from a simulated area source in flat terrain were conducted to check the method, ability to reconstruct source distribution, and total emission rate. The sensitivity analysis and the field study confirm that a few ground-level concentration measurements and a simple determination of the atmospheric dispersion characteristics are sufficient, under neutral to stable conditions, to obtain the total emission rate accurately. Reconstruction of the spatial pattern of the source is possible by utilizing concentration information from samplers located on two separate ground-level receptor lines, if a shift in the wind direction occurs and if it can be assumed that the total emission rate is time invariant. A method of cross-checking the accuracy of the reconstruction, using a simultaneous tracer release, is presented.

Air Pollutants, Occupational↗
PubMed2003

A significant drug-metabolizing role for CYP3A5?

Recent research on CYP3A5 in vitro and in humans has provided discordant information on whether CYP3A5 plays a significant role in the metabolism of CYP3A substrates in vivo. For example, six separate studies have reported CYP3A5 to contribute between 2 and 60% of the total hepatic CYP3A. Suggested explanations for the reported differences in hepatic CYP3A5 levels are evaluated in this article. Furthermore, a sensitivity analysis of the contribution of CYP3A5 (in addition to CYP3A4) to the metabolism of a "midazolam"-type substrate based on recently published in vitro and clinical data is compared with the results of two in vivo studies that investigated the influence of CYP3A5 genotype on midazolam pharmacokinetics. The sensitivity analysis predicts an approximately 3-fold lower AUCoral for midazolam for those expressing the highest hepatic and intestinal levels of CYP3A5 (e.g., possessing CYP3A5*1 alleles) compared with those individuals who express insignificant amounts of CYP3A5, assuming CYP3A4 levels are the same in both groups and that CYP3A5 levels do not exceed those of CYP3A4 in CYP3A5*1 homozygotes. In contrast, the two in vivo studies show no statistically significant influence of CYP3A5 genotype on midazolam pharmacokinetics. The discordance between the prediction and the results from the two in vivo studies is discussed.

Animals↗
PubMed2004

Uncertainty and the value of diagnostic information, with application to axillary lymph node dissection in breast cancer.

In clinical decision making, it is common to ask whether, and how much, a diagnostic procedure is contributing to subsequent treatment decisions. Statistically, quantification of the value of the information provided by a diagnostic procedure can be carried out using decision trees with multiple decision points, representing both the diagnostic test and the subsequent treatments that may depend on the test's results. This article investigates probabilistic sensitivity analysis approaches for exploring and communicating parameter uncertainty in such decision trees. Complexities arise because uncertainty about a model's inputs determines uncertainty about optimal decisions at all decision nodes of a tree. We present the expected utility solution strategy for multistage decision problems in the presence of uncertainty on input parameters, propose a set of graphical displays and summarization tools for probabilistic sensitivity analysis in multistage decision trees, and provide an application to axillary lymph node dissection in breast cancer.

Axilla↗
PubMed2005

Acyclovir prophylaxis for pregnant women with a known history of herpes simplex virus: a cost-effectiveness analysis.

OBJECTIVE: Previous literature has shown acyclovir to be cost-effective as prophylaxis for women with genital symptomatic herpes simplex virus infection recurrence during pregnancy. We extend this analysis by adding quality-adjusted life year measurements and considering women with a diagnosed history of herpes simplex virus infection but without recurrence in pregnancy. STUDY DESIGN: A decision analytic model was designed that compared acyclovir prophylaxis versus no acyclovir for women with a history of diagnosed genital herpes simplex virus infection but without recurrence in pregnancy. Sensitivity analysis and Monte Carlo simulations were performed to test for robustness. RESULTS: We found that 22,286 women must be treated to prevent 1 neonatal death, 8985 women to prevent 1 affected child, and 177 women to prevent 1 cesarean delivery. As compared with no acyclovir, acyclovir prophylaxis at 36 weeks of gestation saves approximately dollar 20 per person and increases total quality-adjusted life years by 0.01. In univariate sensitivity analysis, this result was robust to all reasonable probability and quality-adjusted life year estimates. Monte Carlo simulation demonstrated acyclovir to be cost-effective 100% of the time and cost saving >99% of the time. CONCLUSION: Acyclovir prophylaxis versus no treatment for pregnant women with a diagnosed history of genital herpes simplex virus infection but without recurrence during pregnancy is cost-effective over a wide range of assumptions.

Acyclovir↗
PubMed2005

Enamel matrix derivative (Emdogain) for periodontal tissue regeneration in intrabony defects.

BACKGROUND: Periodontitis is a chronic infective disease of the gums caused by bacteria present in dental plaque. This condition induces the breakdown of the tooth supporting apparatus until teeth are lost. Surgery may be indicated to arrest disease progression and regenerate lost tissues. Several surgical techniques have been developed to regenerate periodontal tissues including guided tissue regeneration (GTR), bone grafting (BG) and the use of enamel matrix derivative (EMD). EMD is an extract of enamel matrix and contains amelogenins of various molecular weights. Amelogenins are involved in the formation of enamel and periodontal attachment formation during tooth development. OBJECTIVES: To test whether EMD is effective, and to compare EMD versus GTR, and various BG procedures for the treatment of intrabony defects. SEARCH STRATEGY: We searched the Cochrane OHG Trials Register, Cochrane Central Register of Controlled Trials, MEDLINE and EMBASE. Several journals were handsearched. No language restrictions were applied. Authors of RCTs identified, personal contacts and the manufacturer were contacted to identify unpublished trials. Most recent search: May 2005. SELECTION CRITERIA: RCTs on patients affected by periodontitis having intrabony defects of at least 3 mm treated with EMD compared with open flap debridement, GTR and various BG procedures with at least 1 year follow up. The outcome measures considered were: tooth loss, changes in probing attachment levels (PAL), pocket depths (PPD), gingival recessions (REC), bone levels from the bottom of the defects on intraoral radiographs, aesthetics and adverse events. The following time-points were to be evaluated: 1, 5 and 10 years. DATA COLLECTION AND ANALYSIS: Screening of eligible studies, assessment of the methodological quality of the trials and data extraction were conducted in duplicate and independently by two authors. Results were expressed as random-effects models using mean differences for continuous outcomes and risk ratios (RR) for dichotomous outcomes with 95% confidence intervals (CI). It was decided not to investigate heterogeneity, but a sensitivity analysis for the risk of bias of the trials was performed. MAIN RESULTS: Ten trials were included out of 29 potentially eligible trials. No included trial presented data after 5 years of follow up, therefore all data refer to the 1-year time point. A meta-analysis including eight trials showed that EMD treated sites displayed statistically significant PAL improvements (mean difference 1.2 mm, 95% CI 0.7 to 1.7) and PPD reduction (0.8 mm, 95% CI 0.5 to 1.0) when compared to placebo or control treated sites, though a high degree of heterogeneity was found. Significantly more sites had < 2 mm PAL gain in the control group, with RR 0.48 (95% CI 0.29 to 0.80). Approximately six patients needed to be treated (NNT) to have one patient gaining 2 mm or more PAL over the control group, based on a prevalence in the control group of 35%. No differences in tooth loss or aesthetic appearance as judged by the patients were observed. When evaluating the only two trials at a low risk of bias in a sensitivity analysis, the effect size for PAL was 0.6 mm, which was less than 1.2 mm for the overall result. Comparing EMD with GTR (five trials), GTR showed a statistically significant increase of REC (0.4 mm) and significantly more postoperative complications. No trials were found comparing EMD with BG. AUTHORS' CONCLUSIONS: One year after its application, EMD significantly improved PAL levels (1.2 mm) and PPD reduction (0.8 mm) when compared to a placebo or control, however, the high degree of heterogeneity observed among trials suggests that results have to be interpreted with great caution. In addition a sensitivity analyses indicated that the overall treatment effect might be overestimated. The actual clinical advantages of using EMD are unknown. With the exception of significantly more postoperative complications in the GTR group, there was no evidence of clinically important differences between GTR and EMD.

Alveolar Bone Loss↗