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The uncertainty principle and industry-sponsored research.

BACKGROUND: Reporting of pharmaceutical-industry-sponsored randomised clinical trials often result in biased findings, either due to selective reporting of studies with non-equivalent arms or publication of low-quality papers, wherein unfavourable results are incompletely described. A randomised trial should be conducted only if there is substantial uncertainty about the relative value of one treatment versus another. Studies in which intervention and control are thought to be non-equivalent violates the uncertainty principle. METHODS: We examined the quality of 136 published randomised trials that focused on one disease category (multiple myeloma) and adherence to the uncertainty principle. To evaluate whether the uncertainty principle was upheld, we compared the number of studies favouring experimental treatments over standard ones. We analysed data according to the source of funding. FINDINGS: Trials funded solely or in part by 35 profit-making organisations had a trend toward higher quality scores (mean 2.94 [SD 1.3]; median 3) than randomised trials supported by 95 governmental or other non-profit organisations (2.4 [0.8]; 2; p=0.06). Overall, the uncertainty principle was upheld, with 44% of randomised trials favouring standard treatments and 56% innovative treatments (p=0.17); mean and median preference evaluation scores were 3.7 (1.0) and 4. However, when the analysis was done according to the source of funding, studies funded by non-profit organisations maintained equipoise favouring new therapies over standard ones (47% vs 53%; p=0.608) to a greater extent than randomised trials supported solely or in part by profit-making organisations (74% vs 26%; p=0.004). INTERPRETATION: The reported bias in research sponsored by the pharmaceutical industry may be a consequence of violations of the uncertainty principle. Sponsors of clinical trials should be encouraged to report all results and to choose appropriate comparative controls.

Bias↗

Spatial variability and uncertainty in ecological risk assessment: a case study on the potential risk of cadmium for the little owl in a Dutch river flood plain.

This paper outlines a procedure that quantifies the impact of different sources of spatial variability and uncertainty on ecological risk estimates. The procedure is illustrated in a case study that estimates the risks of cadmium for a little owl (Athene noctua vidalli) living in a Dutch river flood plain along the river Rhine. A geographical information system (GIS) was used to quantify spatial variability in contaminant concentrations and habitats. It was combined with an exposure and effect model that uses Monte Carlo simulation to quantify parameter uncertainty. Spatial model uncertainty was assessed by the application of two different spatial interpolation methods (classification and kriging) and foraging ranges. The results of the case study show that parameter uncertainty is the main type of uncertainty influencing the risk estimate, and to a lesser extent spatial variability, while spatial model uncertainty was of minor importance. Compared to the deterministically calculated hazard index for the little owl (0.9), inclusion of spatial variability resulted in a median hazard index that can vary between 0.8 and 1.4. It is concluded that a single estimator for a whole flood plain may over- or underestimate risks for specific parts within the flood plain. Further research that expands the procedure presented in this paper is necessary to improve the incorporation of spatial factors in ecological risk assessment.

Animals↗

Uncertainty analysis of a dynamic vapor sorption-fast gas chromatography-flame ionization detection method for the rapid analysis of volatile release from glassy matrices.

Uncertainty analysis was conducted with a dynamic vapor sorption-fast gas chromatography-flame ionization detection (DVS-fast GC-FID) method, developed to rapidly analyze the extent of volatile release that occurs from carbohydrate glasses due to humidification and temperature increases. Triplicate samples progressed through a two-step special automatic operation method in the DVS. Samples were exposed to relative humidities ranging from 40 to 90% (in 10% increments) at 15, 25, and 35 degrees C. Uncertainty analysis shows that the DVS-fast GC-FID method uncertainty is smaller than the natural sample uncertainty, indicating that the variability in a sample's physical properties has a dominant impact on the overall uncertainty of the volatile retention results obtained using the DVS-fast GC-FID method. Uncertainty analysis also indicates that the variance associated with the mass of benzaldehyde measured by the DVS-fast GC-FID is the largest contributor to the overall benzaldehyde retention variance when the cumulative mass of benzaldehyde measured is small.

Adsorption↗

Multi-analyte optimisation of uncertainty in infant food analysis.

The Optimised Uncertainty (OU) methodology has been developed to optimise multi-analyte situations. It has then been applied to a retail survey of infant food for trace elements, classifying the food as compliant or non-compliant with the regulatory thresholds or specification limits that are appropriate for each element. The large-scale survey of infant foods was successfully adapted to allow the estimation of uncertainties, from both primary sampling and chemical analysis, for elemental concentrations in infant formula (milk) and wet meals. The analytes included in this investigation comprised both contaminants (Pb and Cd) and elements essential for child development (Zn and Cu). Optimisation of the measurement process for a 'single analyte' demonstrated the potential financial benefits of optimising future surveys for a false compliance scenario. Uncertainty estimates for the measurement of elemental concentrations in infant formula were dominated by uncertainty from the analytical method. Large potential savings (up to pounds 575,000 per batch) are predicted for both Pb and Zn by increasing the expenditure on chemical analysis to the optimal level. In comparison the uncertainty estimates for elemental concentration in wet meals showed a dominance of sampling as a source of uncertainty for Cd and Cu due to the increased heterogeneity. The feasibility of 'multi-analyte' optimisation is demonstrated for the case study of infant milk. Single analyte optimisation of the four analytes for a false compliance scenario indicated a decrease in expectations of financial loss of between 99% and 8%. An overall decrease in the total expectation of financial loss of 99% is indicated following multi-analyte optimisation.

Child, Preschool↗

Dielectric measurement: error analysis and assessment of uncertainty.

The advantages and limitations of using partial differential analysis to assess the methodological uncertainty associated with the measurement of the dielectric properties of a material are discussed and an alternative pragmatic approach is proposed. It relies on repeat measurements of the dielectric properties of reference liquids and an analysis to estimate random and systematic uncertainties. Examples of measurement uncertainty are provided for well-defined monomolecular materials and for less homogeneous materials at microwave frequencies. All examples relate to measurement with an open-ended coaxial probe but the methodology is not specific to this technique. Examination of the components of uncertainty in the dielectric properties of biological tissue shows that, where the system is free of methodological bias, random fluctuations originating from sampling and natural inhomogeneity dominate the uncertainty budget. In such cases, the mean value of the measured parameter and the standard error of the mean can be taken as a good measure of the true value and its associated uncertainty.

Biometry↗

Toxicology of micronutrients: adverse effects and uncertainty.

The establishment of safe upper intake levels for micronutrients must consider the intake-response relations for both deficiency and toxicity. Limited data are available on the toxicities of most micronutrients, and few studies that meet the criteria considered essential for the risk assessment of other chemicals in food, such as pesticides and food additives, have been performed. In some cases, the application of large uncertainty factors, which are used to establish the amount of a chemical that would be safe for daily intake throughout life, could result in nutritionally inadequate intakes of micronutrients. As a consequence, lower than normal uncertainty factors have been applied to determine safe or tolerable intakes of many micronutrients. There is no clear scientific rationale, on the basis of the metabolism and elimination of micronutrients or the nature of the adverse effects reported for high intakes, for the use of reduced uncertainty factors for micronutrient toxicity. A review of recent evaluations of selected vitamins and minerals shows little consistency in the application of uncertainty factors by different advisory groups, such as the Institute of Medicine in the United States and the Scientific Committee on Foods in the European Union. It is apparent that, in some cases, the uncertainty factor applied was selected largely to give a result that is compatible with nutritional requirements; therefore, the uncertainty factor represented part of risk management rather than hazard characterization. The usual risk assessment procedures for chemicals in food should be revised for micronutrients, so that the risks associated with intakes that are too low and too high are considered equally as part of a risk-benefit analysis.

Animals↗

Uncertainties evaluation for electrets based devices used in radon detection.

In recent years uncertainty evaluation in measurements has achieved great importance. National and international standards offer guidelines to evaluate uncertainties, but these procedures are, until now, not well understood by the operators. This is because of the fact that a detailed uncertainty evaluation is not an easy operation and a standard rule to apply in all cases is not available. Every measurement procedure has its own uncertainty evaluation. In this work, attention is focused upon the electret ion chambers (EIC), widely used in radon concentration measurements. Measurements of gamma radiation sensitivity are performed in a secondary standard calibration laboratory and measurement of radon concentration sensitivity is performed in a radon chamber 0.8 m3 in volume. Raw data are analysed to evaluate the calibration factors and the combined uncertainties are determined. The aim of the work is to give a practical method to assess the uncertainty of a radon measurement.

Calibration↗

Uncertainties in workplace external dosimetry--an analytical approach.

The uncertainties associated with external dosimetry measurements at workplaces depend on the type of dosemeter used together with its performance characteristics and the information available on the measurement conditions. Performance characteristics were determined in the course of a type test and information about the measurement conditions can either be general, e.g. 'research' and 'medicine', or specific, e.g. 'X-ray testing equipment for aluminium wheel rims'. This paper explains an analytical approach to determine the measurement uncertainty. It is based on the Draft IEC Technical Report IEC 62461 Radiation Protection Instrumentation-Determination of Uncertainty in Measurement. Both this paper and the report cannot eliminate the fact that the determination of the uncertainty requires a larger effort than performing the measurement itself. As a counterbalance, the process of determining the uncertainty results not only in a numerical value of the uncertainty but also produces the best estimate of the quantity to be measured, which may differ from the indication of the instrument. Thus it also improves the result of the measurement.

Calibration↗

Uncertainty reduction, self-enhancement, and ingroup identification.

Two experiments tested the prediction that uncertainty reduction and self-enhancement motivations have an interactive effect on ingroup identification. In Experiment 1 (N = 64), uncertainty and group status were manipulated, and the effect on ingroup identification was measured. As predicted, low-uncertainty participants identified more strongly with a high- than low-status group, whereas high-uncertainty participants showed no preference; and low-status group members identified more strongly under high than low uncertainty, whereas high-status group members showed no preference. Experiment 2 (N = 210) replicated Experiment 1, but with a third independent variable that manipulated how prototypical participants were of their group. As predicted, the effects obtained in Experiment 1 only emerged where participants were highly prototypical. Low prototypicality depressed identification with a low-status group under high uncertainty. The implications of these results for intergroup relations and the role of prototypicality in social identity processes are discussed.

Analysis of Variance↗

Uncertainty and quality of life of older men who undergo watchful waiting for prostate cancer.

PURPOSE/OBJECTIVES: To explore uncertainty, anxiety, and the personal manner in which uncertainty is understood, and explain the health-related and affective quality of life (QOL) of men who undergo watchful waiting for prostate cancer. DESIGN: Descriptive, quantitative, survey approach. SETTING: United States. SAMPLE: A national sample of 21 men diagnosed with prostate cancer (mean age = 76 years) who had elected to receive no treatment for their disease. METHODS: 19 subjects who met the criteria contacted the researcher and completed the mailed questionnaire. MAIN RESEARCH VARIABLES: Uncertainty and QOL. FINDINGS: Moderate yet significant relationships were found between each of the independent variables. Significant relationships were found among uncertainty, anxiety, and the perception of danger (a dimension of QOL). Using hierarchical multiple regression, a model was built to explain 60% of the variance in this QOL dimension. CONCLUSIONS: This study supports that men who undergo watchful waiting are uncertain and that this uncertainty results in their perception of danger and influences their affective health-functioning QOL. This study lends further support for the Uncertainty in Illness Model in the watchful waiting population. IMPLICATIONS FOR NURSING: The findings of this study imply that increased teaching and patient care management regarding watchful waiting are needed both before and after the treatment decision has been made. This study provides the framework for further study on interventions to improve the QOL of this population.

Aged↗

Age-related differences in susceptibility to carcinogenesis. II. Approaches for application and uncertainty analyses for individual genetically acting carcinogens.

In an earlier report we developed a quantitative likelihood-based analysis of the differences in sensitivity of rodents to mutagenic carcinogens across three life stages (fetal, birth to weaning, and weaning to 60 days) relative to exposures in adult life. Here we draw implications for assessing human risks for full lifetime exposures, taking into account three types of uncertainties in making projections from the rodent data: uncertainty in the central estimates of the life-stage-specific sensitivity factors estimated earlier, uncertainty from chemical-to-chemical differences in life-stage-specific sensitivities for carcinogenesis, and uncertainty in the mapping of rodent life stages to human ages/exposure periods. Among the uncertainties analyzed, the mapping of rodent life stages to human ages/exposure periods is most important quantitatively (a range of several-fold in estimates of the duration of the human equivalent of the highest sensitivity "birth to weaning" period in rodents). The combined effects of these uncertainties are estimated with Monte Carlo analyses. Overall, the estimated population arithmetic mean risk from lifetime exposures at a constant milligrams per kilogram body weight level to a generic mutagenic carcinogen is about 2.8-fold larger than expected from adult-only exposure with 5-95% confidence limits of 1.5- to 6-fold. The mean estimates for the 0- to 2-year and 2- to 15-year periods are about 35-55% larger than the 10- and 3-fold sensitivity factor adjustments recently proposed by the U.S. Environmental Protection Agency. The present results are based on data for only nine chemicals, including five mutagens. Risk inferences will be altered as data become available for other chemicals.

Age Factors↗

Patients' perceptions of "uncertainty" in nurse practitioner consultations.

The aim of this qualitative study was to explore patients' perceptions of consulting with a nurse practitioner in situations of clinical uncertainty. Uncertainty in this context is defined as one where there is no obvious diagnosis, treatment or where the outcome of the consultation is not definite. Three general practice sites were recruited to participate. 43 patients who consulted with one of three nurse practitioners were interviewed using a semistructured schedule. The nurse practitioners identified uncertainty in 30 of these consultations; only two patients expressed any awareness of uncertainty with the consultation. The results showed that patients appear to accept that there will be a level of uncertainty in some consultations. Recognition of uncertainty within the consultation does not appear to have a negative effect on patients' perception of the nurse practitioner as they feel that the nurse will refer to a doctor if necessary.

Adolescent↗

Patient autonomy and the challenge of clinical uncertainty.

Bioethicists have articulated an ideal of shared decision making between physician and patient, but in doing so the role of clinical uncertainty has not been adequately confronted. In the face of uncertainty about the patient's prognosis and the best course of treatment, many physicians revert to a model of nondisclosure and nondiscussion, thus closing off opportunities for shared decision making. Empirical studies suggest that physicians find it more difficult to adhere to norms of disclosure in situations where there is substantial uncertainty. They may be concerned that acknowledging their own uncertainty will undermine patient trust and create additional confusion and anxiety for the patient. We argue, in contrast, that effective disclosure will protect patient trust in the long run and that patients can manage information about uncertainty. In situations where there is substantial uncertainty, extra vigilance is required to ensure that patients are given the tools and information they need to participate in cooperative decision making about their care.

Beneficence↗

Uncertainty calculation for calibrators and controls of laboratory diagnostic assays.

The uncertainty of the results from calibrators and controls is an important component of the overall uncertainty of the results of medical samples. The purpose of this note is to review procedures of standardization and to describe the respective calculation of the uncertainty components for calibrators and controls of commercial routine diagnostic assays. The authors hope that the laying out of the procedures for uncertainty calculation of routine calibrators and controls contributes (i) to the transparency on how this component of uncertainty is derived and (ii) to a better understanding and use of the uncertainty concept in the routine laboratory.

Algorithms↗

Incorporating known sources of uncertainty to determine precautionary harvests of saltwater crocodiles.

It has been demonstrated repeatedly that the degree to which regulation operates and the magnitude of environmental variation in an exploited population will together dictate the type of sustainable harvest achievable. Yet typically, harvest models fail to incorporate uncertainty in the underlying dynamics of the target population by assuming a particular (unknown) form of endogenous control. We use a novel approach to estimate the sustainable yield of saltwater crocodile (Crocodylus porosus) populations from major river systems in the Northern Territory, Australia, as an example of a system with high uncertainty. We used multimodel inference to incorporate three levels of uncertainty in yield estimation: (1) uncertainty in the choice of the underlying model(s) used to describe population dynamics, (2) the error associated with the precision and bias of model parameter estimation, and (3) environmental fluctuation (process error). We demonstrate varying strength of evidence for density regulation (1.3-96.7%) for crocodiles among 19 river systems by applying a continuum of five dynamical models (density-independent with and without drift and three alternative density-dependent models) to time series of density estimates. Evidence for density dependence increased with the number of yearly transitions over which each river system was monitored. Deterministic proportional maximum sustainable yield (PMSY) models varied widely among river systems (0.042-0.611), and there was strong evidence for an increasing PMSY as support for density dependence rose. However, there was also a large discrepancy between PMSY values and those produced by the full stochastic simulation projection incorporating all forms of uncertainty, which can be explained by the contribution of process error to estimates of sustainable harvest. We also determined that a fixed-quota harvest strategy (up to 0.2K, where K is the carrying capacity) reduces population size much more rapidly than proportional harvest (the latter strategy requiring temporal monitoring of population size to adjust harvest quotas) and greatly inflates the risk of resource depletion. Using an iconic species recovering from recent extreme overexploitation to examine the potential for renewed sustainable harvest, we have demonstrated that incorporating major forms of uncertainty into a single quantitative framework provides a robust approach to modeling the dynamics of exploited populations.

Alligators and Crocodiles↗

Surveillance of Barrett's oesophagus: exploring the uncertainty through systematic review, expert workshop and economic modelling.

OBJECTIVES: To assess what is known about the effectiveness, safety, affordability, cost-effectiveness and organisational impact of endoscopic surveillance in preventing morbidity and mortality from adenocarcinoma in patients with Barrett's oesophagus. In addition, to identify important areas of uncertainty in current knowledge for these programmes and to identify areas for further research. DATA SOURCES: Electronic databases up to March 2004. Experts in Barrett's oesophagus from the UK. REVIEW METHODS: A systematic review of the effectiveness of endoscopic surveillance of Barrett's oesophagus was carried out following methodological guidelines. Experts in Barrett's oesophagus from the UK were invited to contribute to a workshop held in London in May 2004 on surveillance of Barrett's oesophagus. Small group discussion, using a modified nominal group technique, identified key areas of uncertainty and ranked them for importance. A Markov model was developed to assess the cost-effectiveness of a surveillance programme for patients with Barrett's oesophagus compared with no surveillance and to quantify important areas of uncertainty. The model estimates incremental cost--utility and expected value of perfect information for an endoscopic surveillance programme compared with no surveillance. A cohort of 1000 55-year-old men with a diagnosis of Barrett's oesophagus was modelled for 20 years. The base case used costs in 2004 and took the perspective of the UK NHS. Estimates of expected value of information were included. RESULTS: No randomised controlled trials (RCTs) or well-designed non-randomised controlled studies were identified, although two comparative studies and numerous case series were found. Reaching clear conclusions from these studies was impossible owing to lack of RCT evidence. In addition, there was incomplete reporting of data particularly about cause of death, and changes in surveillance practice over time were mentioned but not explained in several studies. Three cost--utility analyses of surveillance of Barrett's oesophagus were identified, of which one was a further development of a previous study by the same group. Both sets of authors used Markov modelling and confined their analysis to 50- or 55-year-old white men with gastro-oesophageal reflux disease (GORD) symptoms. The models were run either for 30 years or to age 75 years. As these models are American, there are almost certainly differences in practice from the UK and possible underlying differences in the epidemiology and natural history of the disease. The costs of the procedures involved are also likely to be very different. The expert workshop identified the following key areas of uncertainty that needed to be addressed: the contribution of risk factors for the progression of Barrett's oesophagus to the development of high-grade dysplasia (HGD) and adenocarcinoma of the oesophagus; possible techniques for use in the general population to identify patients with high risk of adenocarcinoma; effectiveness of treatments for Barrett's oesophagus in altering cancer incidence; how best to identify those at risk in order to target treatment; whether surveillance programmes should take place at all; and whether there are clinical subgroups at higher risk of adenocarcinoma. Our Markov model suggests that the base case scenario of endoscopic surveillance of Barrett's oesophagus at 3-yearly intervals, with low-grade dysplasia surveyed yearly and HGD 3-monthly, does more harm than good when compared with no surveillance. Surveillance produces fewer quality-adjusted life-years (QALYs) for higher cost than no surveillance, therefore it is dominated by no surveillance. The cost per cancer identified approaches pound 45,000 in the surveillance arm and there is no apparent survival advantage owing to high recurrence rates and increased mortality due to more oesophagectomies in this arm. Non-surveillance continues to cost less and result in better quality of life whatever the surveillance intervals for Barrett's oesophagus and dysplastic states and whatever the costs (including none) attached to endoscopy and biopsy as the surveillance test. The probabilistic analyses assess the overall uncertainty in the model. According to this, it is very unlikely that surveillance will be cost-effective even at relatively high levels of willingness to pay. The simulation showed that, in the majority of model runs, non-surveillance continued to cost less and result in better quality of life than surveillance. At the population level (i.e. people with Barrett's oesophagus in England and Wales), a value of pound 6.5 million is placed on acquiring perfect information about surveillance for Barrett's oesophagus using expected value of perfect information (EVPI) analyses, if the surveillance is assumed to be relevant over 10 years. As with the one-way sensitivity analyses, the partial EVPI highlighted recurrence of adenocarcinoma of the oesophagus (ACO) after surgery and time taken for ACO to become symptomatic as particularly important parameters in the model. CONCLUSIONS: The systematic review concludes that there is insufficient evidence available to assess the clinical effectiveness of surveillance programmes of Barrett's oesophagus. There are numerous gaps in the evidence, of which the lack of RCT data is the major one. The expert workshop reflected these gaps in the range of topics raised as important in answering the question of the effectiveness of surveillance. Previous models of cost-effectiveness have most recently shown that surveillance programmes either do more harm than good compared with no surveillance or are unlikely to be cost-effective at usual levels of willingness to pay. Our cost--utility model has shown that, across a range of values for the various parameters that have been chosen to reflect uncertainty in the inputs, it is likely that surveillance programmes do more harm than good -- costing more and conferring lower quality of life than no surveillance. Probabilistic analysis shows that, in most cases, surveillance does more harm and costs more than no surveillance. It is unlikely, but still possible, that surveillance may prove to be cost-effective. The cost-effectiveness acceptability curve, however, shows that surveillance is unlikely to be cost-effective at either the 'usual' level of willingness to pay ( pound 20,000-30,000 per QALY) or at much higher levels. The expected value of perfect information at the population level is pound 6.5 million. Future research should target both the overall effectiveness of surveillance and the individual elements that contribute to a surveillance programme, particularly the performance of the test and the effectiveness of treatment for both Barrett's oesophagus and ACO. In addition, of particular importance is the clarification of the natural history of Barrett's oesophagus.

Adenocarcinoma↗

[Estimate of uncertainty of measurements in clinical laboratories and in environmental, occupational, and preventive medicine].

According to recently issued (UNI CEI EN ISO/IEC 17025, UNI CEI ENV 13005 and prEN ISO 15189) standards, to assure the quality of analytical results and their comparability in time and in different places, testing and clinical laboratories must demonstrate to use validated methods, guarantee the traceability of their measurements and state the measurement uncertainty associated with each result. For some SI quantities, such as the mass, the traceability to SI and the estimate of measurement uncertainty are warranted by established methods. In the clinical laboratory and especially in preventive, environmental and occupational laboratory medicine, specific difficulties arise to warrant the traceability to the mole. On one hand, the whole concept of measurement uncertainty is new in laboratory medicine, on the other hand, its application faces practical difficulties, because of the wideness and the complexity of the analytical repertory, the lack of officially validated methods and matrix-specific reference materials traceable to SI. In this paper we discuss briefly the concept of measurement uncertainty and its meaning in comparison with other parameters used to define the performance of analytical methods. In addition, we describe the procedures recommended by international organisations for estimating measurement uncertainty and interpreting analytical results with an associated measurement uncertainty in comparison with limit values.

Clinical Laboratory Techniques↗

Propagation of uncertainty in diffuse pollution into water quality predictions: application to the River Dender in Flanders, Belgium.

The uncertainty of water quality predictions caused by uncertainty in the inputs related to emissions of diffuse pollution is analysed. An uncertainty analysis of the effects of diffuse pollution is essential to compare the cost and benefits of measures to lower those emissions. We focus on diffuse nitrate pollution due to fertiliser use. Using an efficient Monte Carlo method and Latin Hypercube sampling, the contribution to the overall uncertainty by each of the inputs is calculated. The modelling environment is ESWAT, an extension of SWAT, which allows for integral modelling of the water quantity and quality processes in river basins. The diffuse pollution sources are assessed by considering crop and soil processes. The crop simulations include growth, uptake of water and nutrients and several land management practices. The in-stream water quality model is based on QUAL2E. The spatial variability of the terrain strongly affects the non-point source pollution processes. The methodology is applied to the Dender basin in Belgium. Eight inputs have significant influence on the time that the nitrate content in the river is higher than 3 mg/l. The uncertainty analysis indicated wide uncertainty bounds (95% percentile bounds differ up to +/-50% from the average NO3 predictions).

Belgium↗