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Bayesian prediction bounds and comparisons of operating room times even for procedures with few or no historic data.

BACKGROUND: Lower prediction bounds (e.g., for fasting), upper prediction bounds (e.g., to schedule delays between sequential surgeons), comparisons of operating room (OR) times (e.g., when sequencing cases among ORs), and quantification of case uncertainty (e.g., for sequencing a surgeon's list of cases) can be done accurately for combinations of surgeon and scheduled procedure(s) by using historic OR times. The authors propose that when there are few or no historic data, the predictive distribution of the OR time of a future case be centered at the scheduled OR time, and its proportional uncertainty be based on that of other surgeons and procedures. When there are a moderate or large number of historic data, the historic data alone are used in the prediction. When there are a small number of historic data, a weighted combination is used. METHODS: This Bayesian method was tested with all 65,661 cases from a hospital. RESULTS: Bayesian prediction bounds were accurate to within 2% (e.g., the 5% lower bounds exceeded 4.9% of the actual OR times). The predicted probability of one case taking longer than another was estimated to within 0.7%. When sequencing a surgeon's list of cases to reduce patient waiting past scheduled start times, both the scheduled OR time and the variability in historic OR times should be used together when assessing which cases should be done first. CONCLUSIONS: The authors validated a practical way to calculate prediction bounds and compare the OR times of all cases, even those with few or no historic data for the surgeon and the scheduled procedure(s).

Algorithms↗

A resampling method for estimating the signal subspace of spatio-temporal EEG/MEG data.

Source localization using spatio-temporal electroencephalography (EEG) and magnetoencephalography (MEG) data is usually performed by means of signal subspace methods. The first step of these methods is the estimation of a set of vectors that spans a subspace containing as well as possible the signal of interest. This estimation is usually performed by means of a singular value decomposition (SVD) of the data matrix: The rank of the signal subspace (denoted by r) is estimated from a plot in which the singular values are plotted against their rank order, and the signal subspace itself is estimated by the first r singular vectors. The main problem with this method is that it is strongly affected by spatial covariance in the noise. Therefore, two methods are proposed that are much less affected by this spatial covariance, and old and a new method. The old method involves prewhitening of the data matrix, making use of an estimate of the spatial noise covariance matrix. The new method is based on the matrix product of two average data matrices, resulting from a random partition of a set of stochastically independent replications of the spatio-temporal data matrix. The estimated signal subspace is obtained by first filtering out the asymmetric and negative definite components of this matrix product and then retaining the eigenvectors that correspond to the r largest eigenvalues of this filtered data matrix. The main advantages of the partition-based eigen decomposition over prewhited SVD is that 1) it does not require an estimate of the spatial noise covariance matrix and 2b) that it allows one to make use of a resampling distribution (the so-called partitioning distribution) as a natural quantification of the uncertainty in the estimated rank. The performance of three methods (SVD with and without prewhitening, and the partition-based method) is compared in a simulation study. From this study, it could be concluded that prewhited SVD and the partition-based eigen decomposition perform equally well when the amplitude time series are constant, but that the partition-based method performs better when the amplitude time series are variable.

Algorithms↗

Geographic exposure modeling: a valuable extension of geographic information systems for use in environmental epidemiology.

Geographic modeling of individual exposures using air pollution modeling techniques can help in both the design of environmental epidemiologic studies and in the assignment of measures that delineate regions that receive the highest exposure in space and time. Geographic modeling can help in the interpretation of environmental sampling data associated with airborne concentration or deposition, and can act as a sophisticated interpolator for such data, allowing values to be assigned to locations between points where the data have actually been collected. Recent advances allow for quantification of the uncertainty in a geographic model and the resulting impact on estimates of association, variability, and study power. In this paper we present the terminology and methodology of geographic modeling, describe applications to date in the field of epidemiology, and evaluate the potential of this relatively new tool.

Calibration↗

Probabilistic environmental risk assessment of zinc in Dutch surface waters.

In the framework of the European Union (EU) New and Existing Chemicals Policy, a regional risk assessment for Zn according to the current technical guidance documents and a probabilistic approach, by mathematically integrating both best-fitting exposure concentrations and species-sensitivity distributions into a probabilistic risk quotient distribution using Monte Carlo analysis, was explored for The Netherlands. Zinc is an essential element, and the current probability distributions may not adequately deal with this property. The threshold Pareto distribution provided the best fit to the chronic Zn toxicity data, resulting in a predicted-no-effect concentration (PNECadd) for dissolved Zn of 34.2 microg/L, whereas use of the conventional normal distribution resulted in a PNECadd for dissolved Zn of 14.6 microg/L. The extracted exposure data resulted in a regional predicted environmental concentration (PEC) for dissolved Zn in the Dutch surface waters of 20.1 microg/L and in PECadd values for dissolved Zn of between 15.5 and 17.3 microg/L, depending on the background correction used. The conventional deterministic risk characterization identified a regional risk for Zn in the Dutch surface waters. The more comprehensive probabilistic approach used in the present study, however, identified only very limited potential risks for the Dutch region. A probabilistic median risk, that the environmental concentration is greater than the no-observed-effect concentration of a species in Dutch surface waters (0.5-0.6%), depending on the inclusion of background correction, was obtained from the best-fitting distributions. Because probabilistic approaches provide a quantifiable and improved assessment of risk and quantification of the uncertainty associated with that assessment, these techniques may be considered as a way to improve the EU risk assessment procedures for data-rich substances.

Animals↗

The LYMFASIM simulation program for modeling lymphatic filariasis and its control.

The LYMFASIM modeling framework for the transmission and control of the tropical parasitic disease lymphatic filariasis is described and its use in the context of an endemic community in north-eastern Brazil is illustrated. Lymphatic filariasis is a disease with a complex natural history with many unknowns. This complicates decision making with respect to control strategies. With LYMFASIM, a variety of hypotheses can be tested about the life history of the parasite Wuchereria bancrofti, its transmission from man to man through mosquitoes, the role of the immune system in regulating parasite numbers, the development of disease symptoms, and the effects of control measures (drug treatment or mosquito control). The implications of alternative assumptions and uncertainty about the quantification of parameters for the effectiveness of control strategies can be investigated. Thanks to the use of stochastic microsimulation, LYMFASIM is highly flexible and can be adapted and extended as new knowledge emerges.

Adolescent↗

An assessment of sampling methods and microbiological hygiene indicators for process verification in poultry slaughterhouses.

Studies to determine the appropriateness of the use of populations of indicator bacteria on poultry carcasses for process verification were undertaken in commercial slaughterhouses. Samples were collected from neck skin by excision or from whole carcass rinses and were examined for a range of presumptive process hygiene indicator bacteria. Coefficients of variation were calculated for each bacterial indicator and were significantly lower in excised samples, indicating more reproducible bacterial recovery by this sampling method. Total viable counts of aerobic bacteria, Enterobacteriaceae, and Pseudomonas in samples collected by excision had the lowest coefficients of variation when compared with other indicators and were therefore used for further study. The uncertainties associated with the quantification of each bacterial indicator were calculated and were lowest overall for total viable counts of aerobic bacteria. In general, uncertainty was higher for lower bacterial numbers. Results of microbiological testing on pooled excised neck skin samples were not significantly different from the mean of individually analyzed samples. Bacterial numbers increased by 1 log unit when cultures were stored under chilled conditions typical of those used for transporting samples to external laboratories, but the increases were not significant for Pseudomonas and aerobic bacteria when storage time was less than 17 h. Weak relationships were identified between bacterial indicator numbers and duration of processing, although cleanliness of the processing environment diminished visibly during this time. In the plants visited for this study, there was a poor relationship between presumptive bacterial indicator numbers and process hygiene. Consequently, bacterial analyses for process verification purposes may be of limited value.

Abattoirs↗

Quantification of extrapulmonary translocation of intratracheal-instilled particles in vivo in rats: effect of lipopolysaccharide.

Particulate air pollution is associated with respiratory and cardiovascular morbidity and mortality. However, important uncertainties remain in the quantification of extrapulmonary translocation of ultrafine particles into blood circulation. Therefore, the widely used radioiodinated technique was applied to radiolabel polystyrene particles with an average diameter of 56.4 and 202 nm, respectively. The extrapulmonary distribution of these particles (3.7 x 10(5) Bq/rat) was quantified at 0.5, 2, 24 and 120 h after intratracheal instillation in rats. Moreover, we have taken into account the possible involvement of pulmonary inflammation in this process. Rats which received a single intratracheal instillation of free 125I or a single intravenous injection of labeled ultrafine particles served as control. The results indicated that the pulmonary deposition of radioactivity was almost unchanged for both sizes. Only small amounts of radioactivity (1.64-2.49%) were recovered in blood shortly after administration of both types of particle, in healthy rats. However, the extent of particle translocation into the blood of the ultrafine size following the pretreatment with lipopolysaccharides was significantly higher (from 1.96 +/- 0.67 to 4.73 +/- 0.31%) compared to larger particles (from 2.19 +/- 0.77 to 2.21 +/- 0.64%). In conclusion, our findings suggest that only a small fraction of intratracheal-instilled ultrafine particles can pass rapidly into systemic circulation, but this translocation is markedly increased following LPS pretreatment. Thus, pulmonary inflammation seems to play a major role in enhancing the extrapulmonary translocation of particles.

Administration, Inhalation↗

A stochastic regression approach to analyzing thermodynamic uncertainty in chemical speciation modeling.

Chemical speciation modeling is a vital tool for assessing the bioavailability of inorganic species, yet significant uncertainties in thermodynamic parameters and model form limit its potential for decision-making. In this paper we present a novel method for the quantification of thermodynamic parameter uncertainty and ionic strength correction model uncertainty using Bayesian Markov Chain Monte Carlo (MCMC) estimation methods. These methods allow for the inclusion of correlation modeling, which has not been present in previous work. The MCMC simulations are used to model a natural river water to determine the uncertainty in the calculated environmental speciation of ethylenediamenetetraacetate, a chelating agent that has attracted considerable environmental interest. The results indicate that incorporating correlation among related thermodynamic parameters into the uncertainty model is necessary to correctly quantify the overall system uncertainty. This result indicates the superiority of MCMC estimation methods overtraditional Monte Carlo methods when available data are used to estimate parameter uncertainty in systems with closely related model parameters.

Bayes Theorem↗

Reduced transit-time sensitivity in noninvasive magnetic resonance imaging of human cerebral blood flow.

Herein, we present a theoretical framework and experimental methods to more accurately account for transit effects in quantitative human perfusion imaging using endogenous magnetic resonance imaging (MRI) contrast. The theoretical transit time sensitivities of both continuous and pulsed inversion spin tagging experiments are demonstrated. We propose introducing a delay following continuous labeling, and demonstrate theoretically that introduction of a delay dramatically reduces the transit time sensitivity of perfusion imaging. The effects of magnetization transfer saturation on this modified continuous labeling experiment are also derived, and the assumption that the perfusion signal resides entirely within tissue rather than the arterial microvasculature is examined. We present results demonstrating the implementation of the continuous tagging experiment with delay on an echoplanar scanner for measuring cerebral blood flow (CBF) in normal volunteers. By varying the delay, we estimate transit times in the arterial system, values that are necessary for assessing the accuracy of our quantification. The effect of uncertainties in the transit time from the tagging plane to the arterial microvasculature and the transit time to the tissue itself on the accuracy of perfusion quantification is discussed and found to be small in gray matter but still potentially significant in white matter. A novel method for measuring T1, which is fast, insensitive to contamination by cerebrospinal fluid, and compatible with the application of magnetization transfer saturation, is also presented. The methods are combined to produce quantitative maps of resting and hypercarbic CBF.

Cerebrovascular Circulation↗

Statistical issues in the estimation of assigned shares for carcinogenesis liability.

Congress is currently considering adopting a mathematical formula to assign shares in cancer causation to specific doses of radiation, for use in establishing liability and compensation awards. The proposed formula, if it were sound, would allow difficult problems in tort law and public policy to be resolved by reference to tabulated "probabilities of causation." This article examines the statistical and conceptual bases for the proposed methodology. We find that the proposed formula is incorrect as an expression for "probability and causation," that it implies hidden, debatable policy judgments in its treatment of factor interactions and uncertainties, and that it can not in general be quantified with sufficient precision to be useful. Three generic sources of statistical uncertainty are identified--sampling variability, population heterogeneity, and error propagation--that prevent accurate quantification of "assigned shares." These uncertainties arise whenever aggregate epidemiological or risk data are used to draw causal inferences about individual cases.

Disease Susceptibility↗

Quantification of regional extravascular lung water in dogs with positron emission tomography, using constant infusion of 15O-labeled water.

Continuous infusion of 15O-labeled water allows a quantitative measurement of the total water pool in the chest region by positron emission tomography (PET). By subsequent inhalation of 11CO the intravascular space (blood pool) can be quantitated as well. After a suitable normalization of the intravascular activities the extravascular water can be determined by subtraction of the blood pool from the water pool. The regional extravascular lung water distribution can be visualized in tomographic slices. The method was validated in an animal experiment using five dogs. They were measured before and after induction of a lung edema by IV injection of oleic acid. The increase of extravascular lung water was monitored by the thermo-dye-dilution method (TDD). The correlation of extravascular lung water as measured by TDD with PET measurements is good (r = 0.94). The PET values agree also with gravimetric lung water determinations. An absolute quantitation of regional extravascular lung water is possible after absorption correction of the PET data via transmission measurements and calibration of the camera system. The uncertainty in the absolute quantification is +/- 20%. In the experiments described here the mean extravascular lung water was 0.13 g/cm3 before and 0.25 g/cm3 after induction of lung edema.

Animals↗

Application of micellar electrokinetic capillary chromatography for quantitative analysis of quercetin in plant materials.

A simple method for the routine determination of quercetin in biological samples was developed. The method consists of hydrolysis of bonded quercetin, its isolation and preconcentration on solid-phase extraction (SPE) column and a final analytical step using micellar electrokinetic capillary chromatography. The working range, linear range, the limit of quantification, and the measurement uncertainty were tested in validation. The method is suitable for quercetin determination in fruit and vegetable samples.

Brassica↗

Analysis of myocardial perfusion MRI.

Rapid MR imaging (MRI) during the first pass of an injected tracer is used to assess myocardial perfusion with a spatial resolution of 2-3 mm, and to detect any regional impairments of myocardial blood flow (MBF) that may lead to ischemia. The spatial resolution is sufficient to detect flow reductions that are limited to the subendocardial layer. The capacity of the coronary system to increase MBF severalfold in response to vasodilation can be quantified by analysis of the myocardial contrast enhancement. The myocardial perfusion reserve (MPR) is a useful concept for quantifying the vasodilator response. The perfusion reserve can be estimated from the ratio of MBFs during vasodilation and at baseline, in units identical to those used for invasive measurements with labeled microspheres, or from dimensionless flow indices normalized by their value for autoregulated flow at rest. The perfusion reserve can be reduced as a result of a blunted hyperemic response and/or an abnormal resting blood flow. The absolute quantification of MBF removes uncertainties in the evaluation of the vasodilator response, and can be achieved without the use of complex tracer kinetic models; therefore, its application to clinical studies is feasible.

Coronary Circulation↗

An integrated multiscale air quality modelling framework for industrial park pollution: Linking local emissions to regional transport.

Capturing the spatiotemporal distribution of pollutants in industrial parks remains challenging for regional air quality models because of their coarse resolution (3 km), resulting in uncertainties in local emission quantification. To address this, we developed the Integrated Multiscale Air Quality Modelling System for Industry (IAQMS-Industry), coupling the regional Nested Air Quality Prediction Modelling System (NAQPMS) with a city-scale chemical transport model. This framework integrates point-source locations and Gaussian plume dispersion to simulate particulate matter with a diameter smaller than 2.5 micrometres (PM2.5) at 100 m resolution. Applied to the Beijing Yi Zhuang and Tangshan industrial parks and evaluated against observations. The coupled model achieved a normalized mean bias (NMB) ranging from 3.1 % to 6.2 %, improving upon NAQPMS (-16.9 % to -7.7 %). Spatial analysis revealed that coarse regional grids underestimated the PM2.5​ concentrations at industrial sites by smoothing gradients, whereas IAQMS-Industry successfully resolved spatial patterns. Industrial point emissions accounted for 22.9 %-26.4 % of PM2.5 in the coupled model, which was significantly greater than the regional model estimates of 1.6 %-13.7 %. These findings indicate that regional models overestimate pollutant dispersion processes in industrial parks while underestimating local industrial impacts. By explicitly resolving point-source dynamics and linking them to regional transport, IAQMS-Industry provides a robust tool for designing targeted emission controls in industrial cities and balancing local air quality improvements with minimized regional pollution outflow. This study underscores the necessity of multiscale modelling for accurate source apportionment and informed environmental governance in industrial zones.

Air Pollution↗

Factors affecting quantitative analysis in laser desorption/laser ionization mass spectrometry.

Microprobe laser desorption/laser ionization mass spectrometry (microL(2)MS) is a sensitive and selective technique that has proven useful in the qualitative and semiquantitative detection of trace organic compounds, particularly polycyclic aromatic hydrocarbons (PAHs). Recent efforts have focused on developing microL(2)MS as a quantitative method, often by measuring the ratio of signal strength of an analyte to an internal standard. Here, we present evidence of factors that affect these ratios and thus create uncertainty and irreproducibility in quantification. The power and wavelength of the desorption laser, the delay time between the desorption and ionization steps, the power of the ionization laser, and the ionization laser alignment are all shown to change PAH ratios, in some cases by up to a factor of 24. Although changes in the desorption laser parameters and the delay time cause the largest effects, the ionization laser power and alignment are the most difficult parameters to control and thus provide the most practical limitations for quantitative microL(2)MS. Variation in ratios is seen in both synthetic poly(vinyl chloride) membranes and in "real-life" samples of Murchison meteorite powder. Ratios between similar PAHs vary less than those between PAHs that differ greatly in mass and structure. This finding indicates that multiple internal standards may be needed for quantification of samples containing diverse PAHs.

Polycyclic Aromatic Hydrocarbons↗

BagBoosting for tumor classification with gene expression data.

MOTIVATION: Microarray experiments are expected to contribute significantly to the progress in cancer treatment by enabling a precise and early diagnosis. They create a need for class prediction tools, which can deal with a large number of highly correlated input variables, perform feature selection and provide class probability estimates that serve as a quantification of the predictive uncertainty. A very promising solution is to combine the two ensemble schemes bagging and boosting to a novel algorithm called BagBoosting. RESULTS: When bagging is used as a module in boosting, the resulting classifier consistently improves the predictive performance and the probability estimates of both bagging and boosting on real and simulated gene expression data. This quasi-guaranteed improvement can be obtained by simply making a bigger computing effort. The advantageous predictive potential is also confirmed by comparing BagBoosting to several established class prediction tools for microarray data. AVAILABILITY: Software for the modified boosting algorithms, for benchmark studies and for the simulation of microarray data are available as an R package under GNU public license at http://stat.ethz.ch/~dettling/bagboost.html.

Algorithms↗

In search of power and significance: issues in the design and analysis of stochastic cost-effectiveness studies in health care.

Application of techniques such as cost-effectiveness analysis (CEA) is growing rapidly in health care. There are two general approaches to analysis: deterministic models based upon assumptions and secondary analysis of retrospective data, and prospective stochastic analyses in which the design of a clinical experiment such as randomised controlled trial is adapted to collect patient-specific data on costs and effects. An important methodological difference between these two approaches is in the quantification and analysis of uncertainty. Whereas the traditional CEA model utilizes sensitivity analysis, the mean-variance data on costs and effects from a prospective trial presents the opportunity to analyze cost-effectiveness using conventional inferential statistical methods. In this study we explored some of the implications of moving economic appraisal away from deterministic models and toward the experimental paradigm. Our specific focus was on the feasibility and desirability of constructing statistical tests of economic hypotheses and estimation of cost-effectiveness ratios with associated 95% confidence intervals. We show how relevant variances can be estimated for this task and discuss the implications for the design and analysis of prospective economic studies.

Confidence Intervals↗

Geostatistical analysis of disease data: estimation of cancer mortality risk from empirical frequencies using Poisson kriging.

BACKGROUND: Cancer mortality maps are used by public health officials to identify areas of excess and to guide surveillance and control activities. Quality of decision-making thus relies on an accurate quantification of risks from observed rates which can be very unreliable when computed from sparsely populated geographical units or recorded for minority populations. This paper presents a geostatistical methodology that accounts for spatially varying population sizes and spatial patterns in the processing of cancer mortality data. Simulation studies are conducted to compare the performances of Poisson kriging to a few simple smoothers (i.e. population-weighted estimators and empirical Bayes smoothers) under different scenarios for the disease frequency, the population size, and the spatial pattern of risk. A public-domain executable with example datasets is provided. RESULTS: The analysis of age-adjusted mortality rates for breast and cervix cancers illustrated some key features of commonly used smoothing techniques. Because of the small weight assigned to the rate observed over the entity being smoothed (kernel weight), the population-weighted average leads to risk maps that show little variability. Other techniques assign larger and similar kernel weights but they use a different piece of auxiliary information in the prediction: global or local means for global or local empirical Bayes smoothers, and spatial combination of surrounding rates for the geostatistical estimator. Simulation studies indicated that Poisson kriging outperforms other approaches for most scenarios, with a clear benefit when the risk values are spatially correlated. Global empirical Bayes smoothers provide more accurate predictions under the least frequent scenario of spatially random risk. CONCLUSION: The approach presented in this paper enables researchers to incorporate the pattern of spatial dependence of mortality rates into the mapping of risk values and the quantification of the associated uncertainty, while being easier to implement than a full Bayesian model. The availability of a public-domain executable makes the geostatistical analysis of health data, and its comparison to traditional smoothers, more accessible to common users. In future papers this methodology will be generalized to the simulation of the spatial distribution of risk values and the propagation of the uncertainty attached to predicted risks in local cluster analysis.

Journal Article↗