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The production and effects of uncertainty with special reference to diabetes mellitus.

Ninety-one patients of one consultant physician were followed up for 1 year. All were newly diagnosed as suffering from diabetes mellitus. Patients were found to be distressed by continuing uncertainties about the nature of the disease from which they suffered and about important aspects of self-management required of them. The 'doctor-centered' style of communication adopted by health professionals was not conducive to the resolution of these uncertainties.

Adaptation, Psychological↗

Overconfidence among physicians and nurses: the 'micro-certainty, macro-uncertainty' phenomenon.

Overconfidence in clinicians was examined in two independently designed studies, each using a different research approach. The first study examined treatment choices of physicians in treating breast cancer, and the second rapid decision making among nurses working in Intensive Care Units. In both studies, individual respondents were highly confident they had made the right choice ('micro-certainty'), although there was no consensus across respondents as to what the optimal treatment would be ('macro-uncertainty'). The difference between micro-certainty of individuals and macro-uncertainty within the clinical community may cast some light on the persistence of practice variation. The implications of overconfidence in clinical treatment for patients, practitioners, and professional regulation are discussed.

Decision Making↗

A method of incorporating organ motion uncertainties into three-dimensional conformal treatment plans.

PURPOSE: We describe a method of incorporating organ motion into three-dimensional (3D) conformal treatment plans, which predicts the effect of organ motion on the calculated dose to both the clinical target volume (CTV) and nontarget organs. METHODS AND MATERIALS: The method is based on measurements of organ motion by means of multiple computed tomography (CT) scans from a group of "reference" patients, in which the data consist of previously drawn contours of the target and nontarget organs. A computer program records the differences in contour position and shape that occur between scans in the reference data, and according to those differences adjusts the contours and dose calculation points of a "study" patient currently being planned, thus simulating organ motion. Dose-volume histograms (DVHs) are accumulated, and the process is repeated over the set of reference patient scans, resulting in a set of treatment plans that are ranked according to a dose-based endpoint. Two plans are selected corresponding to specified lower and upper confidence limits in the endpoint, and the DVHs from these plans are displayed for comparison with the DVHs from the nominal plan in the absence of motion. RESULTS: As an example of the method's use, it is applied to a 6-field conformal treatment plan for prostate cancer. Confidence limit DVHs of the CTV and rectal wall (in which the plans were ranked by probabilities for tumor control and normal tissue complication, respectively) are presented and compared to those from the nominal plan. CONCLUSION: The method provides a means of estimating the uncertainty in dose delivered by a treatment plan when organ motion is present. It is generally applicable to any treatment site for which data in the form of multiple CT scans are available, and can be extended to include other treatment uncertainties such as variation in patient positioning.

Humans↗

Low power? Use two-dimensional confidence regions as a graphical method for depicting uncertainty.

Prospective studies of rare outcomes, such as HIV seroconversion or obsessive-compulsive disorder, can often result in small sample sizes with limited power for detecting associations. For this reason, it is useful to develop graphical procedures that enable researchers to depict uncertainty around parameter estimates and examine the direction of association when statistical power is low. Classical procedures include the reporting of confidence intervals, which typically are derived from asymptotic normality of parameters estimated using large samples. In this paper, we present a likelihood-based procedure for the estimation of the confidence region of two parameters from a conditional logistic regression of a nested case-control study with a relatively small number of cases. Graphical depiction of the confidence regions provides an easily comprehensible procedure to quantify the uncertainty of the estimation based on small samples.

Adult↗

Limiting the uncertainty in risk assessment by the development of physiologically based pharmacokinetic and pharmacodynamic models.

Analysis of the default cancer risk assessment methodology suggests that the confidence interval usually associated with the prediction of an upper bound on risk underestimates the uncertainty in the risk estimate. This underestimate of uncertainty is based on the use of a large number of policy decisions or professional judgements that are incorporated into the methodology as exact values with no estimate of error. An alternative approach is to develop a comprehensive biologically based risk assessment that provides scientific data to substitute for many of the policy decisions of the default methodology.

Acrylates↗

Uncertainty in estimates of HIV prevalence derived by backcalculation.

The incidence of consistently defined acquired immunodeficiency syndrome (AIDS) among adults in the United States was used to "backcalculate" the prevalence of human immunodeficiency virus (HIV) as of January 1, 1985, and July 1, 1987. The sensitivity of estimates to random and systematic sources of uncertainty was assessed. Using a "standard" incubation distribution with a 10-year median time-to-AIDS, we estimated that 544,000 persons were infected as of January 1, 1985, and that 992,000 persons were infected as of July 1, 1987. Variation from model selection and fitting was only 2% and 5%, respectively. Perturbations of the AIDS incidence counts to reflect plausible reporting biases reduced prevalence estimates by as much as 9.6% and 16.0%, respectively. Uncertainty about the incubation distribution had an even greater impact. A "plausible range" of prevalence estimates was calculated using alternative "Fast" and "Slow" incubation distributions. The plausible range varied from 415,000 to 760,000 persons in 1985 and from 737,000 to 1.4 million persons in July 1987. Inclusion of AIDS incidence counts beyond mid-1987 can lead to serious underestimates of prevalence, because use of zidovudine and other therapies beginning in mid-1987 has lengthened the incubation distribution in many severely immunodepressed persons without AIDS.

Acquired Immunodeficiency Syndrome↗

Inference and uncertainty in radiology.

This paper seeks to enhance understanding of the philosophical underpinnings of our discipline and the resulting practical implications. Radiology reports exist in order to convey new knowledge about a patient's condition based on empiric observations from anatomic or functional images of the body. The route to explanation and prediction from empiric evidence is mostly through inference based on inductive (and sometimes abductive) arguments. The conclusions of inductive arguments are, by definition, contingent and provisional. Therefore, it is necessary to deal in some way with the uncertainty of inferential conclusions (i.e. interpretations) made in radiology reports. Two paradigms for managing uncertainty in natural sciences exist in dialectic tension with each other. These are the frequentist and Bayesian theories of probability. Tension between them is mirrored during routine interactions among radiologists and clinicians. I will describe these core issues and argue that they are quite relevant to routine image interpretation and reporting.

Bayes Theorem↗

The evaluation of uncertainty in low-level LSC measurements of water samples.

The uncertainty in measurements of gross alpha and beta activities in water samples by liquid scintillation counting with alpha/beta discrimination has been evaluated considering the problems typical of low-level measurements of environmental samples. The use of a pulse shape analysis device to discriminate alpha and beta events introduces a correlation between some of the input quantities, and it has to be considered. Main contributors to total uncertainty have been assessed by specifically designed experimental tests. Results have been fully examined and discussed.

Alpha Particles↗

Half-life measurement of 95mTc--refinement in the uncertainty value.

Measurements at Isotope Products Laboratories (IPL) carried out with a hyper-pure germanium (HPGe) spectrometer have sought to improve upon the accepted half-life value for 95mTc. The uncertainty associated with the currently accepted value of (61+/-2) days allows for potentially significant improvement. Through a series of 65 measurements over the course of nearly 2 years, using multiple source-to-detector counting distances and multiple reference photopeaks, the authors have determined a half-life that agrees with the current value while reducing the uncertainty of the value by 25-fold.

Computer Simulation↗

The influence of uncertainties of measurements in laboratory performance evaluation using an intercomparison program of radionuclide assays in environmental samples.

To show the influence of measurement uncertainties in performance evaluation of laboratories, data from 42 comparison runs were evaluated using two statistical criteria. The normalized standard deviation, D, used by US EPA, that mainly takes into account the accuracy, and the normalized deviation, E, that includes the individual laboratory uncertainty used for performance evaluation in the key-comparisons by BIPM. The results show that data evaluated by the different criteria give a significant deviation of laboratory performance in each radionuclide assay when we analyse a large quantity of data.

Brazil↗

Marine reserves with ecological uncertainty.

To help manage the fluctuations inherent in fish populations scientists have argued for both an ecosystem approach to management and the greater use of marine reserves. Support for reserves includes empirical evidence that they can raise the spawning biomass and mean size of exploited populations, increase the abundance of species and, relative to reference sites, raise population density, biomass, fish size and diversity. By contrast, fishers often oppose the establishment and expansion of marine reserves and claim that reserves provide few, if any, economic payoffs. Using a stochastic optimal control model with two forms of ecological uncertainty we demonstrate that reserves create a resilience effect that allows for the population to recover faster, and can also raise the harvest immediately following a negative shock. The tradeoff of a larger reserve is a reduced harvest in the absence of a negative shock such that a reserve will never encompass the entire population if the goal is to maximize the economic returns from harvesting, and fishing is profitable. Under a wide range of parameter values with ecological uncertainty, and in the 'worst case' scenario for a reserve, we show that a marine reserve can increase the economic payoff to fishers even when the harvested population is not initially overexploited, harvesting is economically optimal and the population is persistent. Moreover, we show that the benefits of a reserve cannot be achieved by existing effort or output controls. Our results demonstrate that, in many cases, there is no tradeoff between the economic payoff of fishers and ecological benefits when a reserve is established at equal to, or less than, its optimum size.

Algorithms↗

Analysis of pesticides and metabolites in Spanish surface waters by isotope dilution gas chromatography/mass spectrometry with previous automated solid-phase extraction Estimation of the uncertainty of the analytical results.

A method based on isotope dilution gas chromatography/mass spectrometry (GC/MS) with automated solid-phase extraction (SPE) is described for the analysis of 32 pesticides and metabolites in surface waters. This approach consist in the use of nine isotopically labelled representative pesticides as internal standards, which allows high accuracy (trueness and precision) and sensitivity for most analysed compounds, as it is required for isotope dilution-based methods. Uncertainties associated with pesticide determination in real samples were estimated using quality assurance/quality control (QA/QC) data. For most pesticides expanded uncertainty was below 40%, according to the commonly established requirements for analytical results. Ninety three Spanish surface waters collected in June-July and September-November 2004 were analysed. Concentration and occurrence of pesticides were evaluated. These parameters were higher in the summer than in the autumn period. In summer four pesticides were found in more than 50% of the analysed samples and four compounds were detected above the concentration level of 1 microg/l (atrazine, terbutylazine, 3,4-dichloroaniline and fenitrothion), while in autumn percentage of detection was below 50% for all pesticides and only one compound (terbutylazine) exceeded 1 microg/l.

Fresh Water↗

Problems and uncertainties with multiple point A's during multiple high-dose-rate intracavitary brachytherapy in carcinoma of the cervix.

AIMS: This study evaluates the consequences of point A as a dose prescription point during multiple high-dose-rate (HDR) intracavitary brachytherapy (ICBT) in cancer cervix. MATERIALS AND METHODS: Fifty patients who had received teletherapy were randomised into two groups of 25 to receive three HDR ICBT fractions of 6 Gy each at point A with either a flexible Ralstron (Shimadzu Corporation, Japan) or rigid Rotterdam (Nucletron, Netherlands) applicator. The orthogonal radiographs of the 150 applications were evaluated for applicator geometry and point A co-ordinates. RESULTS: Irrespective of the nature and rigidity of the applicators, its various components exhibited a highly significant variation during multiple fractionated HDR ICBT. The Cartesian co-ordinates of point A (left and right) for the applicator geometry also showed significant variation during multiple HDR ICBT procedures. This resulted in an average shift of 9.5 mm (SD= +/-4.4) and 11.1 mm (SD= +/-6.4) in right point A, 10.2 mm (SD= +/-4.5) and 10.8 mm (SD= +/-6.6) in left point A for Ralstron and Rotterdam applicator, respectively, during the three HDR ICBT. Consequently, doses to both right and left point A's showed significant variation during multiple ICBT application and were independent of the applicator type. CONCLUSION: Applicator variation in the components and spatial position in the pelvis during multiple HDR ICBT results in multiple point A's irrespective of the nature of applicator, leading to uncertainty in the dose prescription. These uncertainties, which have a bearing on clinical end points, could be minimised by shifting from point-based dose prescription to image-based target localisation and treatment planning in ICBT.

Adult↗

The US EPA reference dose for methylmercury: sources of uncertainty.

The US Environmental Protection Agency (EPA) derived a reference dose for methylmercury in 2001, based on an extensive analysis by the National Research Council (NRC) of the National Academy of Sciences. The NRC performed benchmark dose analysis on a number of endpoints from three longitudinal prospective studies: the Seychelles Islands, the Faroe Islands, and the New Zealand studies. Adverse effects were reported in the latter two studies, but not in the Seychelles study. The NRC also performed an integrative analysis of all three studies. Dose conversion from cord blood or maternal hair mercury concentration was performed by EPA using a one-compartment pharmacokinetic model. A total uncertainty factor of 10 was applied for intrahuman pharmacokinetic and pharmacodynamic variability. There are numerous decisions made by the NRC/EPA that could greatly affect the value of the reference dose (RfD). Some of these include the choice of a linear model for the relationship between mercury body burden and neuropsychological performance, the choice of values of P0 and the benchmark response, the use of the "critical study/critical endpoint" approach in the interpretation of the maternal body burden that corresponds to the RfD, the use of central tendencies in a one-compartment pharmacokinetic model rather than the inclusion of the distributions of variables for the population of reproductive-age women, the assumption of unity for the ratio of fetal cord blood to maternal blood methylmercury concentrations, the choice of a total of 10 as an uncertainty factor, and the lack of dose-response analysis for other health effects such as cardiovascular disease. In addition, it may be argued that derivation of a RfD for methylmercury is inappropriate, given that there does not appear to be a threshold for adverse neuropsychological effects based on available data.

Adult↗

Optimal intervention for an epidemic model under parameter uncertainty.

We will be concerned with optimal intervention policies for a continuous-time stochastic SIR (susceptible-->infective-->removed) model for the spread of infection through a closed population. In previous work on such optimal policies, it is common to assume that model parameter values are known; in reality, uncertainty over parameter values exists. We shall consider the effect upon the optimal policy of changes in parameter estimates, and of explicitly taking into account parameter uncertainty via a Bayesian decision-theoretic framework. We consider policies allowing for (i) the isolation of any number of infectives, or (ii) the immunisation of all susceptibles (total immunisation). Numerical examples are given to illustrate our results.

Algorithms↗

Impact of setup uncertainty in the dosimetry of prostate and surrounding tissues in prostate cancer patients treated with Peacock/IMRT.

The purpose of this paper was to assess the effect of setup uncertainty on dosimetry of prostate, seminal vesicles, bladder, rectum, and colon in prostate cancer patients treated with Peacock intensity-modulated radiation therapy (IMRT). Ten patients underwent computed tomography (CT) scans using the "prostate box" for external, and an "endorectal balloon" for target immobilization devices, and treatment plans were generated (T1). A maximum of +/-5-mm setup error was chosen to model dosimetric effects. Isodose lines from the T1 treatment plan were then superimposed on each patient's CT anatomy shifted by 5 mm toward the cephalad and caudal direction, generating 2 more dosimetric plans (H1 and H2, respectively). Average mean doses ranged from 74.5 to 74.92 Gy for prostate and 73.65 to 74.94 Gy for seminal vesicles. Average percent target volume below 70 Gy increased significantly for seminal vesicles, from 0.53% to 6.26%, but minimally for prostate, from 2.08% to 4.4%. Dose statistics adhered to prescription limits for normal tissues. Setup uncertainty had minimum impact on target dose escalation and normal tissue dosing. The impact of target dose inhomogeneity is currently evaluated in clinical studies.

Colon↗

An uncertainty analysis of air pollution externalities from road transport in Belgium in 2010.

Although stricter standards for vehicles will reduce emissions to air significantly by 2010, a number of problems will remain, especially related to particulate concentrations in cities, ground-level ozone, and CO(2). To evaluate the impacts of new policy measures, tools need to be available that assess the potential benefits of these measures in terms of the vehicle fleet, fuel choice, modal choice, kilometers driven, emissions, and the impacts on public health and related external costs. The ExternE accounting framework offers the most up to date and comprehensive methodology to assess marginal external costs of energy-related pollutants. It combines emission models, air dispersion models at local and regional scales with dose-response functions and valuation rules. Vito has extended this accounting framework with data and models related to the future composition of the vehicle fleet and transportation demand to evaluate the impact of new policy proposals on air quality and aggregated (total) external costs by 2010. Special attention was given to uncertainty analysis. The uncertainty for more than 100 different parameters was combined in Monte Carlo simulations to assess the range of possible outcomes and the main drivers of these results. Although the impacts from emission standards and total fleet mileage look dominant at first, a number of other factors were found to be important as well. This includes the number of diesel vehicles, inspection and maintenance (high-emitter cars), use of air conditioning, and heavy duty transit traffic.

Air Pollutants↗

The Bayesian brain: the role of uncertainty in neural coding and computation.

To use sensory information efficiently to make judgments and guide action in the world, the brain must represent and use information about uncertainty in its computations for perception and action. Bayesian methods have proven successful in building computational theories for perception and sensorimotor control, and psychophysics is providing a growing body of evidence that human perceptual computations are "Bayes' optimal". This leads to the "Bayesian coding hypothesis": that the brain represents sensory information probabilistically, in the form of probability distributions. Several computational schemes have recently been proposed for how this might be achieved in populations of neurons. Neurophysiological data on the hypothesis, however, is almost non-existent. A major challenge for neuroscientists is to test these ideas experimentally, and so determine whether and how neurons code information about sensory uncertainty.

Animals↗