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PubMedDate not supplied

Support from health care providers and parental uncertainty during the diagnosis phase of perinatally acquired HIV infection.

Support from health care providers (HCPs) can reduce parental uncertainty during the diagnosis of serious childhood conditions, but the effect may change when the parent is chronically ill. The purpose of this study was to learn whether a mother's uncertainty about her HIV diminished the effect of support from HCPs on parental uncertainty during the diagnosis of perinatally acquired HIV infection. Participants were 25 women who accompanied their biological children to pediatric HIV screening clinics at two urban sites. Questionnaires were read to participants in a private area of clinic. To test for mediation, three models for parental uncertainty were examined using regression procedures. The results suggest that when a mother has HIV infection, HCPs can maximize the effect of their support on parental uncertainty by also addressing mother's uncertainty about her HIV during the baby's screening visits.

AIDS Serodiagnosis↗

PubMedDate not supplied

Impact of generic drug entry on cost-effectiveness analysis.

The market share of generic drugs has grown substantially since the passage of the Waxman-Hatch Act, increasing from 19% in 1984 to 50% in 2001. At entry, the generic drugs typically are priced lower than brand-name drugs; thus, incorporating the impact of the generic drug entry introduces an additional source of uncertainty in economic models as both the timing of entry and the level of generic drug pricing are subject to variation. In this article, the authors explored the impact of generic drug entry on cost-effectiveness analyses of new or brand-name drugs. Using a mathematical model, they argue that failure to incorporate the impact of generic drug entry will underestimate the incremental cost-effectiveness ratio (ICER) and, thus, overstate the economic benefit of the new product. The authors provide 2 examples to illustrate such impact on short-term and long-term cost-effectiveness analyses. To better assess the uncertainty associated with the impact of generic drug entry, in addition to a deterministic analysis, they also employed a Bayesian probabilistic approach to analyze these examples and presented the results using cost-effectiveness acceptability curves. They conclude that incorporating generic drug entry into pharmacoeconomic models will yield more accurate projections of the ICER and lead to better decision making.

Bayes Theorem↗

PubMed1997

Estimating test-retest reliability in functional MR imaging. I: Statistical methodology.

A common problem in the analysis of functional magnetic resonance imaging (fMRI) data is quantifying the statistical reliability of an estimated activation map. While visual comparison of the classified active regions across replications of an experiment can sometimes by informative, it is typically difficult to draw firm conclusions by inspection; noise and complex patterns in the estimated map make it easy to be misled. Here, several statistical models, of increasing complexity, are developed, under which "test-retest" reliability can be meaningfully defined and quantified. The method yields global measures of reliability that apply uniformly to a specified set of brain voxels. The estimates of these reliability measures and their associated uncertainties under these models can be used to compare statistical methods, to set thresholds for detecting activation, and to optimize the number of images that need to be acquired during an experiment.

Brain↗

PubMed2006

Dose uncertainties in photon pencil kernel calculations at off-axis positions.

The purpose of this study was to investigate the specific problems associated with photon dose calculations in points located at a distance from the central beam axis. These problems are related to laterally inhomogeneous energy fluence distributions and spectral variations causing a lateral shift in the beam quality, commonly referred to as off-axis softening (OAS). We have examined how the dose calculation accuracy is affected when enabling and disabling explicit modeling of these two effects. The calculations were performed using a pencil kernel dose calculation algorithm that facilitates modeling of OAS through laterally varying kernel properties. Together with a multi-source model that provides the lateral energy fluence distribution this generates the total dose output, i.e., the dose per monitor unit, at an arbitrary point of interest. The dose calculation accuracy was evaluated through comparisons with 264 measured output factors acquired at 5, 10, and 20 cm depth in four different megavoltage photon beams. The measurements were performed up to 18 cm from the central beam axis, inside square fields of varying size and position. The results show that calculations including explicit modeling of OAS were considerably more accurate, up to 4%, than those ignoring the lateral beam quality shift. The deviations caused by simplified head scatter modeling were smaller, but near the field edges additional errors close to 1% occurred. When enabling full physics modeling in the dose calculations the deviations display a mean value of -0.1%, a standard deviation of 0.7%, and a maximum deviation of -2.2%. Finally, the results were analyzed in order to quantify and model the inherent uncertainties that are present when leaving the central beam axis. The off-axis uncertainty component showed to increase with both off-axis distance and depth, reaching 1% (1 standard deviation) at 20 cm depth.

Algorithms↗

PubMed2001

The use of physiologically based models to integrate diverse data sets and reduce uncertainty in the prediction of perchlorate and iodide kinetics across life stages and species.

The effects of perchlorate on the incorporation of iodide into thyroid hormones have been studied for more than 40 years in many species and under varying exposure conditions. Nevertheless, the database for this drinking water contaminant is still incomplete, particularly with regard to human developmental risk. A method for integrating the available data and forming meaningful conclusions for risk assessment is needed. To this end, an initial suite of physiologically based pharmacokinetic (PBPK) models has been developed, which incorporates physiological data for the relevant species and life stages and kinetic data for perchlorate and iodide, as well as the interaction between the two anions. The validated models successfully describe perchlorate-induced inhibition of thyroid iodide uptake and perchlorate and iodide kinetics in the male, pregnant, lactating, fetal, and neonatal rats and the adult humans. The relationships of model-predicted internal dose metrics and kinetic parameters allow a direct comparison of internal dose metrics across life stages in rats and humans. By incorporating all the available data, these models provide a framework for species and life stage extrapolation where the lack of specific data sets would otherwise limit predictive capability. This paper demonstrates two approaches for calculating life stage-specific equivalent doses in a risk assessment for perchlorate: the direct combination of validated model predictions, and the development of preliminary PBPK models for the human-sensitive populations based on the relationship of the parameters in the validated rat and human models. Either approach can be used to perform the needed dosimetry. However, the second approach provides the advantage of a preliminary human life stage-specific PBPK model that can be used for identification of key data gaps and estimation of uncertainty.

Age Factors↗

PubMed2003

An assessment of the cord blood:maternal blood methylmercury ratio: implications for risk assessment.

In the current U.S. Environmental Protection Agency reference dose (RfD) for methylmercury, the one-compartment pharmacokinetic model is used to convert fetal cord blood mercury (Hg) concentration to a maternal intake dose. This requires a ratio relating cord blood Hg concentration to maternal blood Hg concentration. No formal analysis of either the central tendency or variability of this ratio has been done. This variability contributes to the overall variability in the dose estimate. A ratio of 1.0 is implicitly used in the model, but an uncertainty factor adjustment is applied to the central tendency estimate of dose to address variability in that estimate. Thus, incorporation of the cord:maternal ratio and its variability into the estimate of intake dose could result in a significant change in the value of the RfD. We analyzed studies providing data on the cord:maternal blood Hg ratio and conducted a Monte Carlo-based meta-analysis of 10 studies meeting all inclusion criteria to generate a comprehensive estimate of the central tendency and variability of the ratio. This analysis results in a recommended central tendency estimate of 1.7, a coefficient of variation of 0.56, and a 95th percentile of 3.4. By analogy to the impact of the similar hair:blood Hg ratio on the overall variability in the dose estimate, incorporation of the cord:maternal ratio may support a 3-fold uncertainty factor adjustment to the central tendency estimate of dose to account for pharmacokinetic variability. Whether the information generated in this analysis is sufficient to warrant a revision to the RfD will depend on the outcome of a comprehensive reanalysis of the entire one-compartment model. We are currently engaged in such an analysis.

Adult↗

PubMed2006

Continued decline of an Atlantic cod population: how important is gray seal predation?

The continental shelf ecosystem on the Eastern Scotian Shelf (ESS) has experienced drastic changes. Once common top predators are a small fraction of their historical abundance, and much of the current community structure is now dominated by pelagic fishes and invertebrates. Embedded within this food web, Atlantic cod and gray seal populations have recently exhibited nearly opposite trends. Since 1984, cod populations have decreased exponentially at a rate averaging 17% per year, whereas gray seals have continued to increase exponentially at a rate of 12%. We reexamined the impact of gray seals on Atlantic cod dynamics using more than 30 years of data on the population trends of cod and gray seals while incorporating new information on seal diet and seasonal distribution. The closure of the cod fishery over 10 years ago allowed for a better estimation of natural mortality rates. We quantified the impact of seals on ESS cod by (1) estimating trends in seal and cod abundance, (2) estimating the total energy needed for seal growth and maintenance from an energetics model, (3) using estimates of the percentage of cod in the total diet derived from quantitative fatty acid signature analysis (QFASA) and of the size-specific selectivity of cod consumed (derived from otoliths collected from fecal samples), and (4) assuming a gray seal functional response. Uncertainties of the model estimates were calculated using the Hessian approximation of the variance-covariance matrix. Between 1993 and 2000, cod comprised, on average, < 5% of a gray seal's diet. Our model shows that, since the closure of the fishery, gray seals have imposed a significant level of instantaneous mortality (0.21), and along with other unknown sources of natural mortality (0.62), are contributing to the failure of this cod stock to recover.

Animals↗

PubMed2006

Quantifying uncertainty in the potential distribution of an invasive species: climate and the Argentine ant.

Maps of a species' potential range make an important contribution to conservation and invasive species risk analysis. Spatial predictions, however, should be accompanied by an assessment of their uncertainty. Here, we use multimodel inference to generate confidence intervals that incorporate both the uncertainty involved in model selection as well as the error associated with model fitting. In the case of the invasive Argentine ant, we found that it was most likely to occur where the mean daily temperature in mid-winter was 7-14 degrees C and maximum daily temperatures during the hottest month averaged 19-30 degrees C. Uninvaded regions vulnerable to future establishment include: southern China, Taiwan, Zimbabwe, central Madagascar, Morocco, high-elevation Ethiopia, Yemen and a number of oceanic islands. Greatest uncertainty exists over predictions for China, north-east India, Angola, Bolivia, Lord Howe Island and New Caledonia. Quantifying the costs of different errors (false negatives vs. false positives) was considered central for connecting modelling to decision-making and management processes.

Animals↗

PubMed2006

Consumer-phase Salmonella enterica serovar enteritidis risk assessment for egg-containing food products.

We describe a one-dimensional probabilistic model of the role of domestic food handling behaviors on salmonellosis risk associated with the consumption of eggs and egg-containing foods. Six categories of egg-containing foods were defined based on the amount of egg contained in the food, whether eggs are pooled, and the degree of cooking practiced by consumers. We used bootstrap simulation to quantify uncertainty in risk estimates due to sampling error, and sensitivity analysis to identify key sources of variability and uncertainty in the model. Because of typical model characteristics such as nonlinearity, interaction between inputs, thresholds, and saturation points, Sobol's method, a novel sensitivity analysis approach, was used to identify key sources of variability. Based on the mean probability of illness, examples of foods from the food categories ranked from most to least risk of illness were: (1) home-made salad dressings/ice cream; (2) fried eggs/boiled eggs; (3) omelettes; and (4) baked foods/breads. For food categories that may include uncooked eggs (e.g., home-made salad dressings/ice cream), consumer handling conditions such as storage time and temperature after food preparation were the key sources of variability. In contrast, for food categories associated with undercooked eggs (e.g., fried/soft-boiled eggs), the initial level of Salmonella contamination and the log10 reduction due to cooking were the key sources of variability. Important sources of uncertainty varied with both the risk percentile and the food category under consideration. This work adds to previous risk assessments focused on egg production and storage practices, and provides a science-based approach to inform consumer risk communications regarding safe egg handling practices.

Bacteriophage Typing↗

PubMed1995

Uncertainty, variability, and sensitivity analysis in physiological pharmacokinetic models.

Physiologically based pharmacokinetic (PBPK) models are now commonly used to predict the dose of toxic metabolites of chemical substances reaching target tissues. A typical PBPK model can involve 20 or more physiological, physiochemical, and biochemical parameters, each of which is estimated with some degree of error. In this article, methods for assessing the impact of uncertainty in the parameter values on prediction of tissue dose are proposed, along with methods for identifying those parameters to which predictions of tissue doses are most sensitive. Many of the model parameters are related to body weight, which is assumed to vary in accordance with a doubly truncated normal distribution. The application of the proposed methods is illustrated using a PBPK model for benzene.

Animals↗

PubMed2005

106Ru/106Rh plaque and proton radiotherapy for ocular melanoma: a comparative dosimetric study.

The objective of this study was to perform comparative dosimetric studies of both 106Ru/106Rh plaque brachytherapy and external beam proton therapy proposed for ocular treatments at the University of Texas M. D. Anderson Cancer Center, Houston, TX, USA. These modalities were also compared with traditional 125I plaque brachytherapy. Using a standardised eye model with a representative ocular melanoma tumour, the relative dose distributions within the tumour and surrounding tissue were calculated using the Monte Carlo code MCNPX. Published absorbed dose distributions benchmarked the Monte Carlo models. Results indicate that the proton beam provided superior dose uniformity within the tumour volume, whereas the dose distribution from 106Ru/106Rh was more heterogeneous. Relative to 125I COMS plaque, both 106Ru/106Rh and protons have shown more confined dose distributions to the tumour volume in this situation, thus sparing other critical ocular structures. For protons, it has been shown that only doses lower than the maximum dose are delivered outside the tumour volume. Depending on the clinical situation, this may aid in the sparing of critical structures located in the sclera and optic disc boundary. The Monte Carlo model's statistical uncertainties of the mean dose estimates for the 106Ru/106Rh plaque and proton beam were 3 and 2.5%, respectively.

Body Burden↗

PubMed1997

Competition and sharing of processing resources in visual discrimination.

Discrimination thresholds for spatial frequency and contrast tested individually were compared with dual discrimination of contrast and spatial frequency, and dual discrimination of 2 contrast or spatial frequency components. The components were presented overlapping, forming a compound grating or as side-by-side simple gratings. When observers had to judge contrast and spatial frequency simultaneously, discrimination thresholds increased by an amount predicted by a model of stimulus uncertainty for orthogonal dimensions (1.7); when they had to judge 2 frequency or contrast components, discrimination thresholds increased by a factor of 3-6 compared with the single-judgment task. The relative spatial location of the components did not interact with task complexity. The results are consistent with a model assuming a set of parallel special-purpose attentional mechanisms.

Analysis of Variance↗

PubMed1990

Parental uncertainty in critical care hospitalization of children.

The purpose of this qualitative study was to explore the dimensions of uncertainty, including the source, family effect, and parental response, of parents whose child was hospitalized in a pediatric intensive care unit (PICU). A convenience sample of 13 parents of 8 critically ill children served as subjects for this study. Data were collected using a modified grounded theory method with 1 to 1-1/2 hour interviews of parents within 2-4 days after admission of their child to the PICU. A model of PICU uncertainty was derived which identified four areas in which ambiguity, conflicting information, or perceived inefficiency gave rise to uncertainty. These areas included: environmental uncertainty, illness uncertainty, caregiver uncertainty, and family systems uncertainty. Findings are related to Mishel's Theory of Uncertainty (1987) and implications for pediatric nursing research are discussed.

Adult↗

PubMed1998

Effects of the analytical treatment of exposure data on associations of cancer and occupational magnetic field exposure.

Epidemiological studies of cancer among workers exposed to magnetic fields have yielded inconsistent results. This variability may be partly explained by differences in study methods. To assess sensitivity to such methods, data from a previous study of brain cancer and leukemia among electric power company workers were reanalyzed using alternative models, which incorporated uncertainty about the intensity of historical exposures, alternative cut points for categorizing the exposure variable for analysis, and a range of lags for describing cancer latency. Mortality rate ratios for leukemia ranged from 0.8-1.5. For brain cancer, increasing cumulative magnetic field exposure was associated with increasing mortality in virtually all models, with rate ratios between 1.3-3.4 for the most exposed workers. These rate ratios are consistent with previous analyses suggesting a 1.5-3.0-fold increase in the risk of brain cancer but no association with leukemia, and confirm that the previous results are not dependent on arbitrary decisions in applying the exposure data.

Brain Neoplasms↗

PubMed2003

Cost comparison of three HIV counseling and testing technologies.

BACKGROUND: In the United States, more than 2 million human immunodeficiency virus (HIV) antibody tests are performed annually at publicly funded HIV counseling and testing (CT) clinics. Clients do not receive results from one third of these tests because of low return rates. New rapid-testing technologies may improve receipt of results, but no study has systematically analyzed the costs of these newer technologies compared with the standard protocol. OBJECTIVE: To estimate and compare the economic costs associated with three HIV CT protocols: the standard protocol and the one-step and two-step rapid protocols. METHODS: A cost analysis model was developed in 2002 to calculate the intervention costs for HIV CT services with the standard CT protocol and the one-step and two-step rapid-test protocols for a hypothetical client in a publicly funded HIV clinic. Sensitivity analyses were performed to ascertain the effects of uncertainty in the model parameters. RESULTS: The one-step rapid protocol was generally the least expensive of the three protocols. The standard protocol cost less than the two-step protocol per HIV-positive client notified of his or her HIV status, but cost more per HIV-negative client. The sensitivity analysis indicated overlap in the cost estimates for HIV-negative clients, reflecting the generally similar costs of the three testing protocols. Taking into account HIV seroprevalence, the two-step rapid protocol would be less expensive than the standard protocol for most publicly funded testing programs in the United States. CONCLUSIONS: Rapid test protocols offer economic advantages as well as convenience, compared to the standard testing protocol. The cost estimates presented here should prove helpful to HIV program managers and other public health decision makers who need information on these counseling and testing technologies.

AIDS Serodiagnosis↗

PubMed2005

Modelling the effect of function and disease activity on costs and quality of life in rheumatoid arthritis.

OBJECTIVE: When treatments with the potential to change the natural history of a disease are introduced, their longer-term effect on costs and quality of life (utility) has to be estimated using economic models. However, to remain useful tools, models must be updated when new information becomes available. Our earlier models in rheumatoid arthritis (RA) have been based on functional status, but it has recently been shown that disease activity might have an independent effect on utility. The objective of this study was to improve the model by incorporating the effect of a subjective measure of disease severity and activity (global VAS). METHODS: A Markov model was constructed with five states according to functional status (HAQ), and each state was subdivided according to the VAS (<40 and >40). Disease development (transition probabilities between the states) was taken from a longitudinal cohort study of patients with early RA in Sweden. A recent population-based survey of 616 patients with RA provided data on costs and utilities. The model incorporates the full distribution of costs and utilities from the survey, and long-term projections are made using Monte Carlo simulation. RESULTS: The global VAS had a highly significant effect on utilities independently of HAQ. For resource consumption, only HAQ was a significant predictor, with the exception of sick leave, which was correlated with the VAS but not with HAQ. Using the cohort distribution from the longitudinal study, expected mean costs per patient over 10 yr were 106 034 euros (s.d. 5091 euros) (1 euro = SEK 9.20) and the expected number of quality-adjusted life years (QALYs) was 5.08 (s.d. 0.09). Patients starting at HAQ <0.6 but with consistently high VAS scores would have expected costs of 102 830 euros and 4.96 QALYs, while patients with low VAS scores would have costs of 81 603 euros and 6.01 QALYs. CONCLUSION: Our new model incorporates for the first time the effect of a subjective measure of disease severity and activity on both costs and utility, making it a sensitive tool to estimate the cost-effectiveness of disease-modifying treatments. New data on resource consumption indicate a shift to higher direct costs, particularly in early disease, and lower indirect costs in more advanced disease. The large size of the data sets used in this model reduces the uncertainty and makes estimates very stable.

Adult↗

PubMed2006

Case finding for hepatitis C in primary care: a cost utility analysis.

BACKGROUND: Hepatitis C is an important public health problem. The need for more intensified action to identify those infected with the virus has been recognized. Primary care is an important setting for case finding. OBJECTIVES: To estimate the cost utility of case finding for hepatitis C in primary care, specifically amongst former injecting drug users (IDUs). METHODS: A Markov model was developed to investigate the impact of case finding and treatment on progression of hepatitis C (HCV) in a hypothetical cohort of 1000 former IDUs. Comparison was made with a similar cohort in which no systematic case finding was implemented but spontaneous presentation for testing was allowed. Two scenarios were explored. The testing protocol utilized ELISA and PCR tests. Those eligible for treatment received combination therapy with pegylated interferon and ribavirin. Parameter estimates were obtained from literature searches and experts in the field. RESULTS: Few estimates of the uptake of HCV testing in primary care are available. Cost utility was estimated at around 16,000 pounds sterling/QALY for both scenarios. At a willingness to pay of 30,000 pounds sterling/QALY, there is approximately a 75% probability that the initiatives would be cost-effective. Choices regarding the utility data, discounting and the rates of spontaneous/re-presentation outside of a case-finding programme appear to be important areas of uncertainty in this model. CONCLUSION: Case finding for HCV in primary care is likely to be considered cost-effective but substantial uncertainties remain. Further research is needed on different approaches to case finding in primary care.

Algorithms↗

PubMed2004

Focal treatment for refractory epilepsy: hope for the future?

Despite advances in anti-epileptic drug therapy and epilepsy surgery in recent years, intractable epilepsy remains a large clinical problem. Surgical resection, which can have an excellent outcome, is appropriate for only a minority of patients in whom an identifiable focus in non-eloquent brain can be identified. Systemic drug delivery is inevitably limited by the potential for unwanted side effects, due to actions both outside the CNS and in non-epileptic brain regions. Thus for a substantial number of patients novel treatment approaches are urgently needed. Both focal drug delivery and neuronal stem cell grafting have been evaluated in a variety of experimental epilepsy models in recent years, targeting either the seizure focus or key propagation pathways. The literature in this field is critically reviewed and considered in a clinical context. Studies in both areas are hampered by the limitations of available animal models, and by uncertainties in discerning which changes in the epileptic brain directly promote seizures, and which are compensatory. However, in many cases promising, though short-term, results have been obtained. Before such studies could be considered in humans further investigations that include long-term seizure and behavioural outcomes, in clinically relevant experimental models, are required. However, the current literature does provide proof in principle for a focal treatment approach, which may offer hope for many currently intractable patients for whom drug developments and surgical advances have proved disappointing.

Animals↗