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PubMed2005

Using covariates to reduce uncertainty in the economic evaluation of clinical trial data.

As part of their practice, policymakers have to make economic evaluations using clinical trial data. Recent interest has been expressed in determining how cost-effectiveness analysis can be undertaken in a regression framework. In this respect, published research basically provides a general method for prognostic factor adjustment in the presence of imbalance, emphasizing sub-group analysis. In this paper, we present an alternative method from a Bayesian approach. We propose the use of covariates in Bayesian health technology assessment in order to reduce uncertainty about the effect of treatments. We show its advantages by comparison with another published method that do not adjust for covariates using simulated data.

Bayes Theorem↗
PubMed2006

Uncertainties of polynuclear aromatic hydrocarbon and carbonyl measurements in heavy-duty diesel emission.

In this note we describe the speciated particle-phase PM2.5 polynuclear aromatic hydrocarbon (PAH) and gas-phase carbonyl emissions as collected from a heavy-duty diesel bus outfitted with an oxidation catalyst for exhaust after-treatment. The vehicle was run on a chassis dynamometer during a transient cycle test reproducing a typical city bus route (Azienda Tramviaria Municipalizzata cycle). The diluted tailpipe emissions were sampled for PAH using a 2.5 microm cut size cyclone glass fiber filter assembly, while carbonyls were absorbed onto dinitrophenyl hydrazine-coated silica cartridges. The former compounds were analysed by CGC-MS, the latter by HPLC-UV. Combining the two sets of speciation data resulting from 15 identical dynamometer tests provided a profile of both unregulated organic emissions. PAH emission rates decreased with the number of benzene fused rings. Fluoranthene and pyrene amounted to 90% of total PAHs quantified; six-ring PAHs accounted only for 0.5%. Similarly, formaldehyde and acetaldehyde accounted for approximately 80% of the total carbonyl emissions. Uncertainties of the method in the determination of individual emission factors were calculated. Statistical data processing revealed that all the measurements were quite unaffected by systematic errors and repeatability percentages did not exceed 50% for the majority of components of both groups.

Air Pollutants↗
PubMed2005

Assessing uncertainty in reference intervals via tolerance intervals: application to a mixed model describing HIV infection.

We define the reference interval as the range between the 2.5th and 97.5th percentiles of a random variable. We use reference intervals to compare characteristics of a marker of disease progression between affected populations. We use a tolerance interval to assess uncertainty in the reference interval. Unlike the tolerance interval, the estimated reference interval does not contains the true reference interval with specified confidence (or credibility). The tolerance interval is easy to understand, communicate and visualize. We derive estimates of the reference interval and its tolerance interval for markers defined by features of a linear mixed model. Examples considered are reference intervals for time trends in HIV viral load, and CD4 per cent, in HIV-infected haemophiliac children and homosexual men. We estimate the intervals with likelihood methods and also develop a Bayesian model in which the parameters are estimated via Markov-chain Monte Carlo. The Bayesian formulation naturally overcomes some important limitations of the likelihood model.

Adult↗
PubMed2006

Proportional odds logistic regression--effective means of dealing with limited uncertainty in dichotomizing clinical outcomes.

Classifying a measurable clinical outcome as a dichotomous variable often involves difficulty with borderline cases that could fairly be assigned either of the two binary class memberships. In such situations the indicated class membership is often highly subjective and subject to, for instance, a measurement error. In other situations the intermediate level of a three-level ordinal factor may sometimes be explicitly reserved for cases which could likely belong to either of the two binary classes. Such indefinite readings are often eliminated from the statistical analysis. In this article we review conceptual and methodological aspects of employing proportional odds logistic regression for a three level ordinal factor as a suitable alternative to ordinary logistic regression when dealing with limited uncertainty in classifying clinical outcome as a binary variable.

Atherosclerosis↗
PubMedDate not supplied

Dose-interpolation of immunoassay data: uncertainties associated with curve-fitting.

Estimates of analyte concentrations, obtained by immunoassay, have error distributions which are generally underestimated. Better estimates, which take into account the distribution of the response metameter of the calibration curve and uncertainties associated with the location of the fitted curve, have been obtained by computer simulation using practical immunoassay data. The increased use of curve-fitting software in automated immunoassay equipment has prompted the investigation of reported analyte concentration distributions for three commonly used functions, namely the logit-log, the 4-parameter logistic and the four-parameter Amersham models. The stimulation model is of potential value for a variety of situations.

Biometry↗
PubMed2002

Age-related changes in task-switching components: the role of task uncertainty.

The present study examined age differences in executive functioning, using an externally cued task-switching paradigm. Two components of task switching were assessed: the ability to maintain and select among task sets (general switch costs) and the ability to switch between task sets (specific switch costs). In contrast to previous findings, we found large age-related differences in specific switch costs, especially when the number of potentially relevant task sets is increased from two to four. Age-related differences in general switch costs were absent when external task cues subserved executive processing in task switching. Generally, the findings suggest that age-related impairments in task-switching components vary as a function of task uncertainty, such as the presence of environmental prompts to behavior.

Adult↗
PubMed1996

Measures of uncertainty of pharmacokinetic and pharmacodynamic parameter estimates: a new computerized algorithm.

Numerous algorithms exist to fit data to nonlinear models of the type used in chemistry, pharmacology, physiology, etc. Most include modules that provide some measure of the reliability of the estimated model parameters. The variance-covariance matrix (VCM) is the common tabulation of information that is used to quantify the parameter uncertainty as well as correlations between parameters. The VCM has its mathematical foundation in the linear regression world, where the dependent variable is a linear function of the parameters. However, when the model is not linear in its parameters, then the VCM is no longer an absolute quantitative measure of reliability of the parameter estimates and should be interpreted with caution. If the goal is to obtain a realistic and quantitative rather than a qualitative measurement of the parameter reliability, then it is necessary to have an alternative approach to describe the parameter likelihood region. We present a computerized algorithm that fills that need, and we compare its performance with the traditional VCM approach for different data sets. We also discuss criteria that may be used to determine when the VCM approach should and should not be used.

Algorithms↗
PubMed2000

Uncertainty of the hazardous concentration and fraction affected for normal species sensitivity distributions.

Species in the environment vary according to their sensitivity to a toxicant. Because these differences in sensitivity are unique to the toxicant at consideration and laboratory data sets to assess this variability are very small due to cost, it is important to provide uncertainty estimates of (1) environmental quality objectives (hazardous concentrations) derived from these laboratory data and (2) fraction of species affected at given, or predicted, laboratory or environmental concentrations. This article focuses on the normal (Gaussian) distribution of species sensitivity. It examines and compares results of Problems (1) and (2) from two opposing statistical philosophies, Bayesian and Classical, leading to vastly different numerical approaches. For the normal model, both approaches lead to identical answers, numerically. Extrapolation factors for the lower, median, and upper estimates of the hazardous concentration at six levels of protection are derived. Furthermore, upper, median, and lower estimates of the fraction affected at given, standardized, logarithmic concentrations have been tabulated. This table can be used directly for risk assessment without reference to protection levels or hazardous concentrations. The confidence limits for hazardous concentration and fraction affected depend heavily on the number of species tested and are independent of the toxic substance involved (provided the model is right), due to correction for the mean and standard deviation of the toxicity data. The equivalence of confidence limits for hazardous concentration and fraction affected is captured in the law of extrapolation: the upper (median, lower) confidence limit for the fraction affected at the lower (median, upper) confidence limit of the hazardous concentration is equal to the fraction affected (e.g., 5%) used to define the hazardous concentration. The upper confidence limit for the fraction affected at the median estimate of the hazardous concentration for 5% of the species is a fixed number depending on the sample size of the toxicity data only. It amounts to 46% at n=3, down to 20% at n=10, and still 12% at n 30.

Animals↗
PubMed1998

Molecular phylogenetics of the avian genus Pipilo and a biogeographic argument for taxonomic uncertainty.

We sequenced 1709 base pairs (bp) of mitochondrial DNA including parts of cytochrome b, ND 2, and the control region (CR I, II) for seven members of the avian genus Pipilo (towhees), Melozone kieneri (rusty-crowned ground-sparrow), and Arremonops rufivirgatus (olive sparrow). A total of 457 bp was variable and 257 bp were potentially phylogenetically informative. All gene regions were similarly variable (20.2 to 28.4%) except for CR II (38.4%); third position transitions were as common as substitutions in the CR. Tree topology was sensitive to choice of outgroup(s) and individual sequences used as exemplars. Six trees were considered viable phylogenetic hypotheses based on maximum parsimony and maximum likelihood analyses. These trees generally supported two groups of towhees (rufous-sided group, brown towhee group), a sister taxon relationship for P. aberti and P. crissalis, and a sister taxon relationship for P. ocai and P. maculatus. The occurrence of M. kiernei within Pipilo in three trees challenges the monophyly of the latter; the other species of Melozone and other outgroups require study to resolve Pipilo monophyly. The relationships of P. albicollis and P. fuscus were ambiguous, as they were with previous data sets (allozymes, mtDNA restriction sites); they could be sister species or either one could be the basal species in the brown towhee group. We suggest that this taxonomic uncertainty obtains from the contemporaneous origin of P. fuscus, P. albicollis, and the ancestor of P. aberti/P. crissalis. We favor a "star" phylogeny because species in unrelated lineages found in the same region as P. albicollis are similarly difficult to resolve phylogenetically. Synapomorphies from coding genes and the CR did not preferentially support basal and terminal nodes, and hence did not provide different windows of taxonomic resolution, which might be expected from the apparent rapid rate of CR evolution. Phylogenetic trees inferred from allozymes, restriction sites, and mtDNA sequences were congruent, suggesting that each is a useful source of phylogenetic information.

Animals↗
PubMed1998

Negotiator Risk: Sources of Uncertainty and the Impact of Reference Points on Negotiated Agreements.

The settlement of a complex business negotiation inevitably requires the parties to assume substantial risks. Bargaining experiments, including those studying framing effects, have not. Two experiments examined the impact of reference points on negotiator tactics, concessions, and settlements in games with nondeterministic payoffs. In these experiments, subjects negotiated over chances to win a prize rather than directly over shares of the prize. In a reversal of the conventional findings with deterministic games, loss frame negotiators were more cooperative and more likely to settle. In the second experiment, subjects negotiated simultaneously over three linked lotteries, providing an opportunity to create value through risk spreading. In another reversal from deterministic games, loss frame negotiators created more integrative agreements. The impact of framing is clearly not uniform across all types of negotiations. It depends on the source of uncertainty confronting the parties. These experiments further establish and clarify the importance of variable risk preferences in understanding the negotiator framing effect. They also modify the conventional prescriptions given to negotiators and mediators regarding how to frame outcomes. Copyright 1998 Academic Press.

Journal Article↗
PubMed1995

Utilizing uncertainty factors in minimal risk levels derivation.

The Agency for Toxic Substances and Disease Registry (ATSDR) utilizes chemical-specific minimal risk levels (MRLs) to assist in evaluating public health risks associated with exposure to hazardous substances. During MRL derivation, uncertainty factors (UF) are used. Under current ATSDR methodology, default UFs of 10 are applied to extrapolate from a lowest-observed-adverse-effect level (LOAEL) to a no-observed-adverse-effect level (NOAEL), for interspecies extrapolation and for intraspecies variability. However, chemical-specific toxicity information has sometimes made it necessary and appropriate to deviate from using the standard UF of 10. Since its inception in January 1993 until December 1994, ATSDR's Inter-agency MRL Workgroup has derived 46 inhalation and 67 oral MRLs. When the substance-specific data permitted, the workgroup departed from the default UFs of 10 in 30 specific cases. Specific examples and rationales are presented in this paper.

Animals↗
PubMed2001

A biomathematical model of particle clearance and retention in the lungs of coal miners. II. Evaluation of variability and uncertainty.

The objective of this study is to investigate the sources of variability and uncertainty in a previously developed human lung dosimetry model. That three-compartment model describes the retention and clearance kinetics of respirable particles in the gas-exchange region of the lungs. It was calibrated using exposure histories and lung dust burden data in U.S. coal miners. A multivariate parameter estimation and optimization method was developed for fitting the dosimetry model to these human data. Models with various assumptions about overloading of alveolar clearance and interstitialization (sequestration) of particles were evaluated. Variability in the estimated clearance rate coefficients was assessed empirically by fitting the model to groups' and to each miner's data. Distributions of lung and lymph node particle burdens were computed at working lifetime exposures, using the variability in the estimated individual clearance rate coefficients. These findings confirm those of the earlier analysis; i.e., the best-fitting exposure-dose model to these data has substantial interstitialization/sequestration of particles and no dose-dependent decline in alveolar clearance. Among miners with different characteristics for smoking, disease, and race, the group median estimated alveolar clearance rate coefficients varied by a factor of approximately 4. Adjustment for these group differences provided some improvement in the dosimetry model fit to all miners (up to 25% reduction in MSE), although unexplained interindividual differences made up the largest source of variability. The predicted mean lung and lymph node particle burdens at age 75 after exposure to respirable coal mine dust at 2 mg/m(2) for a 45-year working lifetime were 12 g (5th and 95th percentiles, 3.0-26 g) and 1.9 g (0.26-5.3), respectively. This study provides quantitative information on variability in particle retention and clearance kinetics in humans. It is useful for risk assessment by providing estimated lung dust burdens associated with occupational exposure to respirable particles.

Adult↗
PubMed1996

"Don't think zebras": uncertainty, interpretation, and the place of paradox in clinical education.

Working retrospectively in an uncertain field of knowledge, physicians are engaged in an interpretive practice that is guided by counterweighted, competing, sometimes paradoxical maxims. "When you hear hoofbeats, don't think zebras," is the chief of these, the epitome of medicine's practical wisdom, its hermeneutic rule. The accumulated and contradictory wisdom distilled in clinical maxims arises necessarily from the case-based nature of medical practice and the narrative rationality that good practice requires. That these maxims all have their opposites enforces in students and physicians a practical skepticism that encourages them to question their expectations, interrupt patterns, and adjust to new developments as a case unfolds. Yet medicine resolutely ignores both the maxims and the tension between the practical reasoning they represent and the claim that medicine is a science. Indeed, resolute epistemological naivete is part of medicine's accommodation to uncertainty; counterweighted, competing, apparently paradoxical (but always situational) rules enable physicians simultaneously to express and to ignore the practical reason that characterizes their practice.

Art↗
PubMed1996

Strategies for managing uncertainty and complexity.

OBJECTIVES: To identify strategies involved in the diagnosis and treatment plans of primary care problems that are uncertain and complex. METHODS: In this exploratory study we observed primary care physicians encountering standardized patients who portrayed typical primary care problems involving uncertainty and complexity. First, we analyzed 10 tapes of nine physicians with a range of clinical experience (first-year residents through faculty physicians) interacting with four standardized patient cases (headache, back pain, hypertension, and abdominal pain). We analyzed the 10 tapes to determine the regular occurrence of physician behavior patterns that we later described as strategies. Then, using a written questionnaire, 19 general internal medicine faculty physicians from our hospital and from an affiliated hospital rated the perceived importance of these strategies for clinical practice in general. Finally, we checked the incidence of the strategies: (1) across a range of six cases (headache, back pain, hypertension, abdominal pain, fatigue, and well-adult care) using six first-year residents (a total of 19 encounters), and (2) across different levels of clinical experience using the standardized patient case of headache involving eight physicians (first-year residents through faculty physicians). RESULTS: Nine strategies were identified, and each was rated as important to primary care clinical practice. The strategies were: (1) defines the context of the diagnosis and explains the signs and symptoms as part of the expected spectrum of the disease; (2) eliminates alternative diagnoses by dealing with patient fears, giving reasons in the context of the patient's belief system; (3) describes the prognosis in terms of the likely course of the disease and expectations of treatment; (4) negotiates key problems or issues that are important to both patient and physician; (5) negotiates the plan and ensures patient understands, and is willing and able to comply, given his/her particular context; (6) keeps diagnostic options open by making provisional diagnoses while keeping alternatives in mind; (7) is circumspect and takes action to minimize the possibility of missing other critical diagnoses; (8) plays for time by allowing signs and symptoms to develop to help clarify the diagnosis; and (9) plans for contingencies by providing appropriate if/then statements concerning situations requiring further action. The strategies were used in each of the six cases, and by physicians with all levels of clinical experience. CONCLUSIONS: The nine strategies led to the generation of a construct we termed "strategic medical management," which refers to the management (diagnosis and proposed treatment) of uncertain and complex medical problems in primary care. The construct provides a more elaborated framework in which to view clinical decision making and integrates recent ideas concerning doctor-patient communication into this process. Strategic medical management appears to be based on tacit knowledge that is seldom explicity articulated or taught. It has potential implications for enhancing instruction and assessment in medical education.

Clinical Competence↗
PubMed2000

Nonlinear determination of Michaelis-Menten kinetics with model evaluation through estimation of uncertainties.

A structured analytic approach was developed to evaluate enzyme kinetic parameters using non-linear least-squares fitting. The approach was implemented in a software package called KinSim and designed to run on Windows 95, 98, and NT platforms. The software and the theoretical approach were tested using kinetic data obtained using citrate synthase with acetyl CoA as a substrate and octanoyl CoA as an inhibitor. Using the software, the data were evaluated for statistical certainty of the presence of competitive and non-competitive inhibition of the enzyme. Given the determination of the presence of both components of inhibition in the experimental setup, the software was used to determine the inhibitory kinetics from the experimental data, including non-normal distributions of uncertainty. Finally, the software was used to evaluate the sensitivities of the experiment design at each concentration of substrate used. The theoretical approach as implemented in the user-friendly software allows investigators to use a structured procedure for evaluating and planning enzyme kinetic and related metabolic studies.

Acetyl Coenzyme A↗
PubMedDate not supplied

Prediction and control as determinants of behavioural uncertainty: effects on task performance and heart rate reactivity.

Control or control-belief is often viewed as being directly instrumental in facilitating coping mechanisms in aversive situations, and yet the empirical evidence for the beneficial effects of control is inconclusive. In this study we investigated the role of predictability in determining the effects of perceived control during an aversive reaction time task. Fifty-six subjects were allocated to one of four groups; predictable-control, predictable-no control, unpredictable-control, unpredictable-no control. In the predictable conditions, subjects could temporally predict the occurrence of an aversive noise. In the perceived control conditions, duration of the aversive tone was contingent on subject's performance. All subjects were matched in terms of the nature of the task and in the number and time of receipt of both the warning signal and noise. Heart rate reactivity and two performance parameters were measured, reaction time and performance increase. Both predictability and control-belief led to a reduction in heart rate reactivity, although they appeared to function independently and at different points in the sequence of events. That is, predictability or perceived control was sufficient to mitigate the effects of an aversive situation. Neither perception of control or predictability led to better task performance. These results are discussed in terms of behavioural uncertainty explanations.

Acoustic Stimulation↗
PubMed2001

Determination of tolerance dose uncertainties and optimal design of dose response experiments with small animal numbers.

BACKGROUND: Dose response experiments aim to determine the complication probability as a function of dose. Adjusting the parameters of the frequently used dose response model P(D) = 1/[1 + (D50/D)k] to the experimental data, 2 intuitive quantities are obtained: the tolerance dose D50 and the slope parameter k. For mathematical reasons, however, standard statistic software uses a different set of parameters. Therefore, the resulting fit parameters of the statistic software as well as their standard errors have to be transformed to obtain D50 and k as well as their standard errors. MATERIAL AND METHODS: The influence of the number of dose levels on the uncertainty of the fit parameters is studied by a simulation for a fixed number of animals. For experiments with small animal numbers, statistical artifacts may prevent the determination of the standard errors of the fit parameters. Consequences on the design of dose response experiments are investigated. RESULTS: Explicit formulas are presented, which allow to calculate the parameters D50 and k as well as their standard errors from the output of standard statistic software. The simulation shows, that the standard errors of the resulting parameters are independent of the number of dose levels, as long as the total number of animals involved in the experiment, remains constant. CONCLUSION: Statistical artifacts in experiments containing small animal numbers may be prevented by an adequate design of the experiment. For this, it is suggested to select a higher number of dose levels, rather than using a higher number of animals per dose level.

Animals↗
PubMed2002

Determination of endocrine-disrupting pesticides and polychlorinated biphenyls in human serum by GC-ECD and GC-MS-MS and evaluation of contributions to the uncertainty of the results.

The chemicals endosulfan-alpha, endosulfan-beta, endosulfan sulfate, endosulfan ether, endosulfan lactone, PCB-21, PCB-48, PCB-61, and PCB-136 have been determined in 100 serum samples from women living in agricultural areas of Almería (Spain). The study includes a surgically treated breast cancer patient and a matching group of women with no sign of estrogenic-dependent disease. The determination was performed by gas chromatography with electron capture detection (GC-ECD) and tandem mass spectrometry (GC-MS-MS). Recovery, precision, linear range, detection limit (LOD), and quantification limit (LOQ) were calculated for each pesticide as was the expanded uncertainty (U). The method was evaluated for our laboratory and could be applied to subsequent results with relevant quality-control data. Comparison of the results was performed. The advantage of MS-MS over ECD for determination of endocrine-disrupting compounds in complex matrices is presented. The most commonly encountered pesticide was endosulfan-alpha. Endosulfan-beta and the PCB-48 congener were detected at concentrations lower than their LOQ. Endosulfan sulfate, endosulfan ether, endosulfan lactone, PCB-21, PCB-61 and PCB-136 were not found in any of the serum samples analysed.

Breast Neoplasms↗