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Methods to quantify and identify the sources of uncertainty for river basin water quality models.

Worldwide, the application of river basin water quality models is increasing, often imposed by law. It is, thus, important to know the degree of uncertainty associated with these models and their application to a specific watershed. These uncertainties lead to errors that are revealed when model outputs are compared to observations. Such uncertainty is typically described by calculating the residuals. However, residuals should not be seen as an estimate of total uncertainty, since through the calibration process, the residuals may be reduced by over-adjustment to the data, which is typically the case for over-parameterised models. Over-adjustment during a calibration period can also lead to highly biased results when the model is applied to other periods or environmental conditions. The total model uncertainties are, therefore, assessed by four components: the sum of the squares of the residuals (SSQ), parameter uncertainties (that can be ignored when their error is much smaller than SSQ), input data uncertainties, and an additional predictive uncertainty that is expressed when the model appears to be biased when it is applied for data other than the data used for calibration. The sources are ranked according to a quantification criterion (magnitude) as well as an identification criterion that depends on the number of observations that are covered by the confidence region. This approach is illustrated with SWAT2003 simulations for flow and sediment of Honey Creek, a tributary of the Sandusky River basin (Ohio). The results show the dominance of the model uncertainty. The input data uncertainty is less important.

Calibration↗

Dysmorphism of urinary red blood cells--value in diagnosis.

To aid investigation into the clinical problem of hematuria, assessment of abnormalities in the shape of red cells in the urine (dysmorphism) is gaining popularity in nephrology. However, there is uncertainty in the literature regarding both the number of red blood cells (RBC) in normal urine, as well as the quantification of dysmorphism. We have shown that in normal urine (N = 27) the number of RBC is less than 2,000/ml as assessed by scanning electron microscopy of filtered urine specimens from normal volunteers without known renal disease, which compared to less than 1,000/ml by centrifugation and phase contrast microscopy of the same specimen. To determine whether dysmorphism of urinary red blood cells was a significant predictor of glomerular disease we compared the number of dysmorphic cells in the urine of patients with biopsy proven glomerulonephritis (GN), before and immediately after renal biopsy. We also compared the number of dysmorphic cells in patients with glomerulonephritis to those with lower urinary tract bleeding. Renal biopsy caused significant dysmorphic hematuria, indicating that dysmorphism suggests renal rather than glomerular bleeding. Although patients with GN had significantly more dysmorphic urinary RBC when compared to those with lower tract urinary bleeding, the overlap was such that one could only be confident of renal hematuria if they accounted for greater than 75% of the total number of RBC. Non renal hematuria is present if number of dysmorphic cells is less than 17% of total RBC. Thus dysmorphism of urinary RBC is a useful diagnostic tool, but only if strict criteria established for each laboratory are adhered to.

Erythrocyte Count↗

Risk and uncertainty analysis in government safety decisions.

Probabilistic risk analysis (PRA) can be an effective tool to assess risks and uncertainties and to set priorities among safety policy options. Based on systems analysis and Bayesian probability, PRA has been applied to a wide range of cases, three of which are briefly presented here: the maintenance of the tiles of the space shuttle, the management of patient risk in anesthesia, and the choice of seismic provisions of building codes for the San Francisco Bay Area. In the quantification of a risk, a number of problems arise in the public sector where multiple stakeholders are involved. In this article, I describe different approaches to the treatments of uncertainties in risk analysis, their implications for risk ranking, and the role of risk analysis results in the context of a safety decision process. I also discuss the implications of adopting conservative hypotheses before proceeding to what is, in essence, a conditional uncertainty analysis, and I explore some implications of different levels of "conservatism" for the ranking of risk mitigation measures.

Journal Article↗

Metabolic engineering under uncertainty. I: framework development.

Standard bioprocess conditions have been widely applied for the microbial conversion of raw material to essential industrial products. Successful metabolic engineering (ME) strategies require a comprehensive framework to manage the complexity embedded in cellular metabolism, to explore the impacts of bioprocess conditions on the cellular responses, and to deal with the uncertainty of the physiochemical parameters. We have recently developed a computational and statistical framework that is based on Metabolic Control Analysis and uses a Monte Carlo method to simulate the uncertainty in the values of the system parameters [Wang, L., Birol, I., Hatzimanikatis, V., 2004. Metabolic control analysis under uncertainty: framework development and case studies. Biophys. J. 87(6), 3750-3763]. In this work, we generalize this framework to incorporate the central cellular processes, such as cell growth, and different bioprocess conditions, such as different types of bioreactors. The framework provides the mathematical basis for the quantification of the interactions between intracellular metabolism and extracellular conditions, and it is readily applicable to the identification of optimal ME targets for the improvement of industrial processes [Wang, L., Hatzimanikatis, V., 2005. Metabolic engineering under uncertainty. II: analysis of yeast metabolism. Submitted].

Bioreactors↗

High-sensitivity determination of birefringence in turbid media with enhanced polarization-sensitive optical coherence tomography.

Polarization-sensitive optical coherence tomography provides high-resolution cross-sectional characterization of birefringence in turbid media. Weakly birefringent biological tissues such as the retinal nerve fiber layer (RNFL) require advanced speckle noise reduction for high-sensitivity measurement of form birefringence. We present a novel method for high-sensitivity birefringence quantification by using enhanced polarization-sensitive optical coherence tomography (EPS-OCT) and introduce the polarimetric signal-to-noise ratio, a mathematical tool for analyzing speckle noise in polarimetry. Multiple incident polarization states and non-linear fitting of normalized Stokes vectors allow determination of retardation with +/-1 degrees uncertainty with invariance to unknown unitary polarization transformations. Results from a weakly birefringent turbid film and in vivo primate RNFL are presented. In addition, we discuss the potential of EPS-OCT for noninvasive quantification of intracellular filamentous nanostructures, such as neurotubules in the RNFL that are lost during the progression of glaucoma.

Algorithms↗

Uncertainty of inductively coupled plasma mass spectrometry based measurements: an application to the analysis of urinary barium, cesium, antimony and tungsten.

The wide use of barium (Ba), cesium (Cs), antimony (Sb) and tungsten (W) in many industrial and agricultural fields causes the increased release of these metals into the environment, laying the basis for health risk. To assess the exposure for the general population, the development of adequate and reliable analytical techniques becomes compulsory. This study refers to the quantification of urinary Ba, Cs, Sb and W levels by both quadrupole (Q) and sector field (SF) inductively coupled plasma mass spectrometry (ICP-MS). The two procedures were compared for their performances and their measurement uncertainties. The limits of detection were (Q and SF) 23.0 and 5.21 ng L(-1) for Ba; 21.1 and 7.52 ng L(-1) for Cs; 1.09 and 0.43 ng L(-1) for Sb; and 0.36 and 0.49 ng L(-1) for W. The trueness was better than 93.3% and the precision less than 12% for both techniques. Relative expanded uncertainties of the analytical procedures, at the median levels found in the general population, were below 5% for all the elements with both ICP-MS techniques. The uncertainties related to the calibration and repeatability were the parameters most influencing the final analytical performance. The urinary median values observed in healthy subjects from central Italy were 1146, 4301, 60.8 and 48.5 ng L(-1) for Ba, Cs, Sb and W, respectively.

Adult↗

Protein stabilization by salt bridges: concepts, experimental approaches and clarification of some misunderstandings.

Salt bridges in proteins are bonds between oppositely charged residues that are sufficiently close to each other to experience electrostatic attraction. They contribute to protein structure and to the specificity of interaction of proteins with other biomolecules, but in doing so they need not necessarily increase a protein's free energy of unfolding. The net electrostatic free energy of a salt bridge can be partitioned into three components: charge-charge interactions, interactions of charges with permanent dipoles, and desolvation of charges. Energetically favorable Coulombic charge-charge interaction is opposed by often unfavorable desolvation of interacting charges. As a consequence, salt bridges may destabilize the structure of the folded protein. There are two ways to estimate the free energy contribution of salt bridges by experiment: the pK(a) approach and the mutation approach. In the pK(a) approach, the contribution of charges to the free energy of unfolding of a protein is obtained from the change of pK(a) of ionizable groups caused by altered electrostatic interactions upon folding of the protein. The pK(a) approach provides the relative free energy gained or lost when ionizable groups are being charged. In the mutation approach, the coupling free energy between interacting charges is obtained from a double mutant cycle. The coupling free energy is an indirect and approximate measure of the free energy of charge-charge interaction. Neither the pK(a) approach nor the mutation approach can provide the net free energy of a salt bridge. Currently, this is obtained only by computational methods which, however, are often prone to large uncertainties due to simplifying assumptions and insufficient structural information on which calculations are based. This state of affairs makes the precise thermodynamic quantification of salt bridge energies very difficult. This review is focused on concepts and on the assessment of experimental methods and does not cover the vast literature.

Animals↗

Nickel quantification in serum by a validated sector-field inductively coupled plasma mass spectrometry method: Assessment of tentative reference values for an Italian population.

The daily exposure to Ni from food, industrial processes, jewellery and coins makes the determination of Ni in human serum an important way to monitor the health status in non-occupationally exposed subjects. To this end, a method based on sector-field inductively coupled plasma mass spectrometry was developed and validated. The limits of detection (LoD) and quantification (LoQ), sensitivity, linearity range, trueness, repeatability, within-laboratory reproducibility and robustness were the considered issues of the validation process. The uncertainty associated with the measurements was also calculated, according to the Eurachem/Citac Guide. The method LoD and LoQ were 0.03 and 0.09 ng mL(-1), linearity was over two order of magnitude, trueness was -3.57%, and the repeatability and reproducibility showed relative standard deviations equal to 4.56% and 6.52%, respectively. The relative expanded uncertainty was 21.8% at the Ni levels found in the general population. The tentative reference value for serum Ni was 0.466 +/- 0.160 ng mL(-1) with a related interval between 0.226 and 1.026 ng mL(-1).

Adult↗

Error in estimation of rate and time inferred from the early amniote fossil record and avian molecular clocks.

The best reconstructions of the history of life will use both molecular time estimates and fossil data. Errors in molecular rate estimation typically are unaccounted for and no attempts have been made to quantify this uncertainty comprehensively. Here, focus is primarily on fossil calibration error because this error is least well understood and nearly universally disregarded. Our quantification of errors in the synapsid-diapsid calibration illustrates that although some error can derive from geological dating of sedimentary rocks, the absence of good stem fossils makes phylogenetic error the most critical. We therefore propose the use of calibration ages that are based on the first undisputed synapsid and diapsid. This approach yields minimum age estimates and standard errors of 306.1 +/- 8.5 MYR for the divergence leading to birds and mammals. Because this upper bound overlaps with the recent use of 310 MYR, we do not support the notion that several metazoan divergence times are significantly overestimated because of serious miscalibration (sensuLee 1999). However, the propagation of relevant errors reduces the statistical significance of the pre-K-T boundary diversification of many bird lineages despite retaining similar point time estimates. Our results demand renewed investigation into suitable loci and fossil calibrations for constructing evolutionary timescales.

Animals↗

Global disparities in COVID-19 vaccine coverage associated with trajectories of SARS-CoV-2 adaptation.

BACKGROUND: Vaccination serves as an effective intervention for health promotion and disease prevention across the socioecological systems and has played an important role during the COVID-19 pandemic. However, global disparities in vaccine coverage have increased uncertainty about the trajectories of viral adaptation, and the potential interplay between SARS-CoV-2 adaptation and vaccine rollout warrants further quantification. METHODS: Using over 13 million SARS-CoV-2 genomes across 86 countries from March 2020 to September 2022, we analyzed nonlinear associations between SARS-CoV-2 adaptation and vaccination coverage, considering public health and social measures, international travel, and infection dynamics, before and after the emergence of Omicron. Additionally, we examined the relationship between SARS-CoV-2 adaptation and COVID-19 mortality. RESULTS: During the pre-Omicron period, we found positive associations between nonsynonymous to synonymous divergence (dN/dS) ratios in the S1 subunit and medium levels of adjusted vaccine coverage (effect size: 0.96 [95% CI 0.47, 1.45]), while the association became insignificant at high levels (effect size: -1.89 [95% CI -4.20, 0.43]). However, no significant associations were found when Omicron dominated, possibly due to the immune escape ability of Omicron variants and the complex immune landscape shaped by mass hybrid immunity. Moreover, we observed evidence of dynamic interdependence and positive correlations between COVID-19 mortality and SARS-CoV-2 adaptation, with COVID-19 mortality interpreted as a proxy for uncontrolled viral spread. CONCLUSIONS: Our findings suggest a complex nonlinear relationship between vaccine-induced immunity and SARS-CoV-2 adaptation, with high vaccine coverage potentially linked to lower positive selection. We also observed directional coupling between COVID-19 mortality and SARS-CoV-2 adaptation. This may have implications for fair and fast vaccination in pandemic preparedness and response. CLINICAL TRIAL NUMBER: Not applicable.

Humans↗

Occurrence of ochratoxin A in cocoa beans: effect of shelling.

The aim of this study was to investigate the influence of the shelling process on the presence of ochratoxin A (OTA) in cocoa samples. Twenty-two cocoa samples were analysed for the determination of OTA before (cocoa bean) and after undergoing manual shelling process (cocoa nib). In order to determine OTA contamination in cocoa samples, a validated high-performance liquid chromatography (HPLC) method with fluorescence detection was used for the quantitative analysis of ochratoxin A (OTA). In both types of samples, OTA was extracted with methanol-3% sodium hydrogen carbonate solution and then purified using immunoaffinity columns prior to HPLC analysis. Due to the fact that different recovery values were obtained for OTA from both types of samples, a revalidation of the method in the case of cocoa nibs was needed. Revalidation was based on the following criteria: Selectivity, limits of detection and quantification (0.03 and 0.1 microg kg(-1), respectively), precision (within-day and between-day variability) and recovery 84.2% (RSD = 7.1%), and uncertainty (30%). Fourteen of the twenty-two cocoa bean samples (64%) suffered a loss of OTA of more than 95% due to shelling, six samples suffered a loss of OTA in the range 65-95%, and only one sample presented a reduction of less than 50%. The principal conclusion derived from this study is that OTA contamination in cocoa beans is concentrated in the shell; therefore, improvements of the industrial shelling process could prevent OTA occurrence in cocoa final products.

Cacao↗

The regulation of ammonium translocation in plants.

Much controversy exists about whether or not NH(+)(4) is translocated in the xylem from roots to shoots. In this paper it is shown that such translocation can indeed take place, but that interference from other metabolites such as amino acids and amines may give rise to large uncertainties about the magnitude of xylem NH(+)(4) concentrations. Elimination of interference requires sample stabilization by, for instance, formic acid or methanol. Subsequent quantification of NH(+)(4) should be done by the OPA-fluorometric method at neutral pH with 2-mercaptoethanol as the reducing agent since this method is sensitive and reliable. Colorimetric methods based on the Berthelot reaction should never be used, as they are prone to give erroneous results. Significant concentrations of NH(+)(4), exceeding 1 mM, were measured in both xylem sap and leaf apoplastic solution of oilseed rape and tomato plants growing with NO(-)(3) as the sole N source. When NO(-)(3) was replaced by NH(+)(4), xylem sap NH(+)(4) concentrations increased with increasing external concentrations and with time of exposure to NH(+)(4). Up to 11% of the translocated N was constituted by NH(+)(4). Glutamine synthetase (GS) incorporates NH(+)(4) into glutamine, but root GS activity and expression were repressed when high levels of NH(+)(4) were supplied. Ammonium concentrations measured in xylem sap sampled just above the stem base were highly correlated with NH(+)(4) concentrations in apoplastic solution from the leaves. Young leaves tended to have higher apoplastic NH(+)(4) concentrations than older non-senescing leaves. The flux of NH(+)(4) (concentration multiplied by transpirational water flow) increased with temperature despite a decline in xylem NH(+)(4) concentration. Retrieval of leaf apoplastic NH(+)(4) involves both high and low affinity transporters in the plasma membrane of mesophyll cells. Current knowledge about these transporters and their regulation is discussed.

Amines↗

Optimization of technetium-99m Sestamibi single-photon emission tomography to define multidrug resistance with confidence.

BACKGROUND: The efflux rate of technetium-99m Sestamibi (99mTc-Sestamibi) is a kinetic phenomenon related to the response of cancer cells to chemotherapy, and may be used to determine drug resistance. Measurement of the efflux rate requires accurate quantitative single-photon emission tomography (SPET) imaging within the time constraints imposed by the kinetics of the process. METHODS: A phantom study, at activity concentrations typically found with 99mTc-Sestamibi in vivo, was undertaken to optimize the SPET parameters and, in particular, to determine whether 180 degrees acquisition arcs with heads in 'L' configuration could be used for accurate quantification. Following the development of the most appropriate SPET protocol, a small patient pilot study was undertaken. RESULTS: Studies designed to evaluate statistical uncertainty (noise), contrast restitution and spatial resolution of the data sets, using different acquisition and reconstruction parameters, showed that 180 degrees SPET using a 64 x 64 matrix, 6 degrees angular sampling and iterative reconstruction was optimal. Finer linear and/or angular sampling afforded negligible improvement in resolution, but markedly increased the statistical uncertainty. Comparison of 360 degrees and 180 degrees acquisitions, utilizing conventional filtered backprojection and iterative reconstruction algorithms, demonstrated that the statistical uncertainty was reduced to a greater extent for 180 degrees data collection. For 360 degrees (64 x 64) data acquisition, statistical uncertainty decreased from 15% to 11% using the iterative algorithm, whilst the 180 degrees (64 x 64) data showed a reduction from 20% to 7%, and approached values obtained by planar imaging. The efflux measurements obtained in the patient pilot study were consistent with the observed chemotherapy response. CONCLUSION: Our study shows that 180 degrees acquisition arcs are a practical option for accurate quantitative SPET kinetic imaging for potential studies of chemotherapy response in patients with lung cancer.

Algorithms↗

Quantitative assessment of liver fibrosis: a novel automated image analysis method.

BACKGROUND: Semiquantitative staging of liver fibrosis is a highly subjective procedure and may lead to an uncertainty in judgment regarding the degree of severity and hence the progression of the disease. AIM: In this work, we present an automated quantification system (AQS) for evaluating the degree of severity of fibrosis in liver biopsies based on Ishak et al.'s classification. Accordingly, liver fibrosis is classified into six classes depending on its severity and progression. The described system is of special value in accurately assessing the prognosis of chronic liver disease. METHODS: In our method, we tried to approximate the architecture of the fibrosis in the subject sample using texture features and shape representation of the fibrosis structural expansion with an overall accuracy of about 98%. RESULTS AND CONCLUSION: The presented AQS is considered to be a novel approach in the domain of automatic liver fibrosis quantification. It is a true quantification and intelligent approach that attempts to utilize the current semiquantitative methods of liver fibrosis assessment to turn them into real quantitative ones with significant reduction in variability and subjectivity. We propose that our method can be adopted by a panel of expert liver pathologists and software to be developed and used on a wide scale.

Biopsy↗

Cancer risks related to electricity production.

The International Agency for Research on Cancer has previously evaluated the cancer risks associated with fossil fuel-based industrial processes such as coal gastification and coke production, substances and mixtures such as coal tars, coal tar pitch and mineral oils, and a number of substances emitted from fossil-fuelled plants such as benzo[a]pyrene and other polycyclic aromatic hydrocarbons, arsenic, beryllium, cadmium, chromium, nickel, lead and formaldehyde. Based on these evaluations and other evidence from the literature, the carcinogenic risks to the general population and occupational groups from the fossil fuel cycle, the nuclear fuel cycle and renewable cycles are reviewed. Cancer risks from waste disposal, accidents and misuses, and electricity distribution are also considered. No cycle appears to be totally free from cancer risk, but the quantification of the effects of such exposures (in particular of those involving potential exposure to large amounts of carcinogens, such as coal, oil and nuclear) requires the application of methods which are subject to considerable margins of error. Uncertainties due to inadequate data and unconfirmed assumptions are discussed. Cancer risks related to the operation of renewable energy sources are negligible, although there may be some risks from construction of such installations. The elements of knowledge at our disposal do not encourage any attempt toward a quantitative comparative risk assessment. However, even in the absence of an accurate quantification of risk, qualitative indication of carcinogenic hazards should lead to preventive measures.

Accidents, Occupational↗

[New methods for the diagnosis of cytomegalovirus].

Despite remarkable progress made in the fields of antiviral therapy and virological laboratory diagnosis, infections with the human cytomegalovirus (CMV) still pose considerable problems in certain patient groups. The variety of available test methods - mostly not standardised - with their different test characteristics, sample types etc. is often confusing for the clinician. There is often great uncertainty as to whether a given laboratory result is pathognomonic. In addition, not only is the diagnostic repertoire growing constantly - for instance through genome quantification and measurement of virus-specific T lymphocytes - but also the available antiviral therapeutic options with the need for adequate surveillance. This paper gives an up-to-date overview about the available diagnostic means with their specific advantages and disadvantages. Concrete recommendations regarding a rational and comprehensive, yet economic approach to CMV diagnosis have to be targeted at the individual patient group and specific diagnostic problem; this is beyond the scope of this paper and the reader is referred to the pertinent expert groups' publications. This review article deals with general and fundamental aspects.

Age Distribution↗

Three-dimensional echocardiography: assessment of inter- and intra-operator variability and accuracy in the measurement of left ventricular cavity volume and myocardial mass.

Accurate left ventricular (LV) volume and mass estimation is a strong predictor of cardiovascular morbidity and mortality. We propose that our technique of 3D echocardiography provides an accurate quantification of LV volume and mass by the reconstruction of 2D images into 3D volumes, thus avoiding the need for geometric assumptions. We compared the accuracy and variability in LV volume and mass measurement using 3D echocardiography with 2D echocardiography, using in vitro studies. Six operators measured the LV volume and mass of seven porcine hearts, using both 3D and 2D techniques. Regression analysis was used to test the accuracy of results and an ANOVA test was used to compute variability in measurement. LV volume measurement accuracy was 9.8% (3D) and 18.4% (2D); LV mass measurement accuracy was 5% (3D) and 9.2% (2D). Variability in LV volume quantification with 3D echocardiography was %SEMinter = 13.5%, %SEMintra = 11.4%, and for 2D echocardiography was %SEMinter = 21.5%, %SEMintra = 19.1%. We derived an equation to predict uncertainty in measurement of LV volume and mass using 3D echocardiography, the results of which agreed with our experimental results to within 13%. 3D echocardiography provided twice the accuracy for LV volume and mass measurement and half the variability for LV volume measurement as compared with 2D echocardiography.

Analysis of Variance↗

Quantifying and reporting uncertainty from systematic errors.

Optimal use of epidemiologic findings in decision making requires more information than standard analyses provide. It requires calculating and reporting the total uncertainty in the results, which in turn requires methods for quantifying the uncertainty introduced by systematic error. Quantified uncertainty can improve policy and clinical decisions, better direct further research, and aid public understanding, and thus enhance the contributions of epidemiology. The error quantification approach proposed here is based on estimating a probability distribution for a bias-corrected effect measure based on externally-derived distributions of bias levels. Using Monte Carlo simulation, corrections for multiple biases are combined by identifying the steps through which true causal effects become data, and (in reverse order) correcting for the errors introduced by each step. The bias-correction calculations are the same as those used in sensitivity analysis, but the resulting distribution of possible true values is more than a sensitivity analysis; it is a more complete reporting of the actual study results. The approach is illustrated with an application to a recent study that resulted in the drug, phenylpropanolamine, being removed from the market.

Appetite Depressants↗