scholarly journals Estimation of The Main Effect and Total Effect of a PBPK Model Based on The Uncertainty of Individual Parameter for Treatment Planning in PSMA Therapy

2021 ◽  
Vol 913 (1) ◽  
pp. 012101
Author(s):  
A. D. Widyanugraha ◽  
N. Atikah ◽  
D. Hardiansyah
Keyword(s):  
Blood Flow ◽  
Pbpk Model ◽  
Absorbed Dose ◽  
Sampling Strategy ◽  
Total Effect ◽  
Model Parameters ◽  
Receptor Density ◽  
Individual Parameter ◽  
Main Effect ◽  
Sensitivity Analysis Method

Abstract The purpose of this study was to identify the most important physiologically-based pharmacokinetic (PBPK) model parameters determining the absorbed dose (AD) in prostate-specific membrane antigen (PSMA) therapy. The extended-Sobol’ global sensitivity analysis method was used to analyze the sensitivity of the PBPK model parameters obtained from 3 patients. The investigated PBPK model parameters were the blood flow to the organs, PSMA binding rate, biological release rates, and density of organs receptor. The outputs of extended Sobol method were the main effect Si and the total effect STi of the parameter of interests for each ADs. The sampling strategy of extended Sobol has been implemented based on the mean and covariance matrix of the parameters. From the simulations, the most important parameters which determine the ADs to the kidney was the kidney receptor density (Si=0,4, STi=0,8). For tumors, it was shown that tumor receptor density was the most essential parameter (Si=0,7, STi=0,8). In conclusion, measurement of the blood flow and organ receptor densities might be of interest to improve individualized treatment of PSMA therapy.

246 Examining Melatonin-induced Changes in Uterine Blood Flow and Vaginal Temperatures in Nutrient Restricted Pregnant Heifers

2021 ◽  
Vol 99 (Supplement_3) ◽  
pp. 132-132
Author(s):  
Zully E Contreras-Correa ◽  
Riley D Messman ◽  
Hector Sanchez-Rodriguez ◽  
Caleb O Lemley
Keyword(s):  
Blood Flow ◽  
Repeated Measures ◽  
Farm Animals ◽  
Nutrient Restriction ◽  
Dependent Manner ◽  
Uterine Blood Flow ◽  
Time Interaction ◽  
Main Effect ◽  
Treatment Interaction ◽  
Induced Changes

Abstract The objectives were to examine melatonin mediated changes in temporal uterine blood flow (UBF) and vaginal temperatures (VT) in 54 Brangus heifers (Fall, n = 29; Summer, n = 25) during compromised pregnancy. At d160 of gestation, heifers were assigned to 1 of 4 groups consisting of adequately fed (ADQ-CON; 100% NRC; n=13), global nutrient restricted (RES-CON; 60% NRC; n = 13), and ADQ or RES supplemented with 20 mg of melatonin (ADQ-MEL, n = 13; RES-MEL, n = 15). In the morning (0500h) and afternoon (1300h) of d220 of gestation, temperature dataloggers (Onset Computer Corporation) attached to progesterone-free CIDRs were used to record VT, while UBF was determined via Doppler ultrasonography. Data were analyzed using repeated measures of ANOVA (SAS). Significant differences were found in UBF and VT between Fall and Summer groups (P< 0.05), therefore seasons were individually analyzed. In Fall, a nutrition by treatment interaction was significant, where the RES-CON heifers exhibited reduced total UBF compared to ADQ-CON (5.67±0.68 vs. 7.97±0.54 L/min; P = 0.012). In Summer, there was not a main effect of nutrition (P = 0.390); nevertheless, the MEL heifers exhibited increased total UBF compared to the CON counterparts (8.16±0.73 vs. 6.00±0.70 L/min; P = 0.048). Moreover, there was a nutrition by treatment by time interaction in VT for Fall and Summer heifers (P < 0.0001). In Fall, all groups had decreased VT in the morning compared to the afternoon (P < 0.0001). Whereas, in Summer, VT increased for ADQ-CON, RES-CON, and ADQ-MEL from morning to afternoon (P < 0.0001), while the RES-MEL remained constant throughout the day (P = 0.649). Furthermore, during the afternoon RES-MEL heifers exhibited decreased VT compared to ADQ-CON (38.91±0.09 vs. 39.26±0.09°C, respectively; P=0.039). In summary, nutrient restriction and melatonin supplementation altered UBF in a season dependent manner. Additionally, with the VT differences observed in Summer, future studies should evaluate the potential of melatonin supplementation for mitigating heat stress in farm animals.

An anatomic and physiological model of hepatic vascular system

1995 ◽  
Vol 79 (3) ◽  
pp. 1008-1026 ◽  
Author(s):  
D. R. Fine ◽  
D. Glasser ◽  
D. Hildebrandt ◽  
J. Esser ◽  
R. E. Lurie ◽  
...  
Keyword(s):  
Blood Flow ◽  
Transit Time ◽  
Vascular System ◽  
Model Parameters ◽  
Activity Time ◽  
Mathematical Relationship ◽  
Portal Flow ◽  
Splenic Blood Flow ◽  
Liver Activity ◽  
Transit Times

Hepatic function can be characterized by the activity/time curves obtained by imaging the aorta, spleen, and liver. Nonparametric deconvolution of the activity/time curves is clinically useful as a diagnostic tool in determining organ transit times and flow fractions. The use of this technique is limited, however, because of numerical and noise problems in performing deconvolution. Furthermore, the interaction of part of the tracer with the spleen and gastrointestinal tract, before it enters the liver, further obscures physiological information in the deconvolved liver curve. In this paper, a mathematical relationship is derived relating the liver activity/time curve to portal and hepatic behavior. The mathematical relationship is derived by using transit time spectrum/residence time density theory. Based on this theory, it is shown that the deconvolution of liver activity/time curves gives rise to a complex combination of splenic, gastrointestinal, and liver dependencies. An anatomically and physiologically plausible parametric model of the hepatic vascular system has been developed. This model is used in conjunction with experimental data to estimate portal, splenic, and hepatic physiological blood flow parameters for eight normal volunteers. These calculated parameters, which include the portal flow fraction, the splenic blood flow fraction, and blood transit times are shown to adequately correspond to published values. In particular, the model of the hepatic vascular system identifies the portal flow fraction as 0.752 +/- 0.022, the splenic blood flow fraction as 0.180 +/- 0.023, and the liver mean transit time as 13.4 +/- 1.71 s. The model has also been applied to two portal hypertensive patients. The variation in some of the model parameters is beyond normal limits and is consistent with the observed pathology.

scholarly journals Spatial Pattern Oriented Multi-Criteria Sensitivity Analysis of a Distributed Hydrologic Model

2018 ◽  
Author(s):  
Mehmet Cüneyd Demirel ◽  
Julian Koch ◽  
Gorka Mendiguren ◽  
Simon Stisen
Keyword(s):  
Sensitivity Analysis ◽  
Spatial Variability ◽  
Spatial Pattern ◽  
Spatial Patterns ◽  
Performance Measures ◽  
Sampling Strategy ◽  
Behavioral Model ◽  
Hydrologic Model ◽  
Actual Evapotranspiration ◽  
Model Parameters

Hydrologic models are conventionally constrained and evaluated using point measurements of streamflow, which represents an aggregated catchment measure. As a consequence of this single objective focus, model parametrization and model parameter sensitivity are typically not reflecting other aspects of catchment behavior. Specifically for distributed models, the spatial pattern aspect is often overlooked. Our paper examines the utility of multiple performance measures in a spatial sensitivity analysis framework to determine the key parameters governing the spatial variability of predicted actual evapotranspiration (AET). Latin hypercube one-at-a-time (LHS-OAT) sampling strategy with multiple initial parameter sets was applied using the mesoscale hydrologic model (mHM) and a total of 17 model parameters were identified as sensitive. The results indicate different parameter sensitivities for different performance measures focusing on temporal hydrograph dynamics and spatial variability of actual evapotranspiration. While spatial patterns were found to be sensitive to vegetation parameters, streamflow dynamics were sensitive to pedo-transfer function (PTF) parameters. Above all, our results show that behavioral model definition based only on streamflow metrics in the generalized likelihood uncertainty estimation (GLUE) type methods require reformulation by incorporating spatial patterns into the definition of threshold values to reveal robust hydrologic behavior in the analysis.

scholarly journals A Population Modelling Approach to Studying Age-Related Effects on Excitation-Contraction Coupling in Human Cardiomyocytes

2019 ◽  
Author(s):  
Arsenii Dokuchaev ◽  
Svyatoslav Khamzin ◽  
Olga Solovyova
Keyword(s):  
Experimental Data ◽  
Transient Outward Current ◽  
Model Parameters ◽  
Maximal Velocity ◽  
Population Modelling ◽  
Individual Parameter ◽  
Human Cardiomyocytes ◽  
Age Related ◽  
Age Related Changes ◽  
Modelling Approach

AbstractAgeing is the dominant risk factor for cardiovascular diseases. A great body of experimental data has been gathered on cellular remodelling in the Ageing myocardium from animals. Very few experimental data are available on age-related changes in the human cardiomyocyte. We have used our combined electromechanical model of the human cardiomyocyte and the population modelling approach to investigate the variability in the response of cardiomyocytes to age-related changes in the model parameters. To generate the model population, we varied nine model parameters and excluded model samples with biomarkers falling outside of the physiological ranges. We evaluated the response to age-related changes in four electrophysiological model parameters reported in the literature: reduction in the density of the K+ transient outward current, maximal velocity of SERCA, and an increase in the density of NaCa exchange current and CaL-type current. The sensitivity of the action potential biomarkers to individual parameter variations was assessed. Each parameter modulation caused an increase in APD, while the sensitivity of the model to changes in GCaL and Vmax_up was much higher than to those in the effects of Gto and KNaCa. Then 60 age-related sets of the four parameters were randomly generated and each set was applied to every model in the control population. We calculated the frequency of model samples with repolarisation anomalies (RA) and the shortening of the electro-mechanical window in the ageing model populations as an arrhythmogenic ageing score. The linear dependence of the score on the deviation of the parameters showed a high determination coefficient with the most significant impact due to the age-related change in the CaL current. The population-based approach allowed us to classify models with low and high risk of age-related RA and to predict risks based on the control biomarkers.

Optimal constant-stress ADDT plan with one main effect and one interaction effect

2020 ◽  
Vol ahead-of-print (ahead-of-print) ◽  
Author(s):  
Preeti Wanti Srivastava ◽  
Manisha Manisha ◽  
Manju Agarwal
Keyword(s):  
Interaction Effect ◽  
High Reliability ◽  
Stress Factor ◽  
Operating Conditions ◽  
Constant Stress ◽  
Stress Factors ◽  
Inspection Time ◽  
Model Parameters ◽  
Content Type ◽  
Main Effect

PurposeDegradation measurement of some products requires destructive inspection; that is, the degradation of each unit can be observed only once. For example, observation on the mechanical strength of interconnection bonds or on the dielectric strength of insulators requires destruction of the unit. Testing high-reliability items under normal operating conditions yields a small amount of degradation in a reasonable length of time. To overcome this problem, the items are tested at higher than normal stress level – an approach called an accelerated destructive degradation test (ADDT). The present paper deals with formulation of constant-stress ADDT (CSADDT) plan with the test specimens subject to stress induced by temperature and voltage.Design/methodology/approachThe stress–life relationship between temperature and voltage is described using Zhurkov–Arrhenius model. The fractional factorial experiment has been used to determine optimal number of stress combinations. The product's degradation path follows Wiener process. The model parameters are estimated using method of maximum likelihood. The optimum plan consists in finding out optimum allocations at each inspection time corresponding to each stress combination by using variance optimality criterion.FindingsThe method developed has been explained using a numerical example wherein point estimates and confidence intervals for the model parameters have been obtained and likelihood ratio test has been used to test for the presence of interaction effect. It has been found that both the temperature and the interaction between temperature and voltage influence the quantile lifetime of the product. Sensitivity analysis is also carried out.Originality/valueMost of the work in the literature on the design of ADDT plans focusses on only a single stress factor. An interaction exists among two or more stress factors if the effect of one factor on a response depends on the levels of other factors. In this paper, an optimal CSADDT plan is studied with one main effect and one interaction effect. The method developed can help engineers study the effect of elevated temperature and its interaction with another stress factor, say, voltage on quantile lifetime of a high-reliability unit likely to last for several years.

scholarly journals Aerosol and physical atmosphere model parameters are both important sources of uncertainty in aerosol ERF

2018 ◽  
Vol 18 (13) ◽  
pp. 9975-10006 ◽  
Author(s):  
Leighton A. Regayre ◽  
Jill S. Johnson ◽  
Masaru Yoshioka ◽  
Kirsty J. Pringle ◽  
David M. H. Sexton ◽  
...  
Keyword(s):  
Model Uncertainty ◽  
Radiative Forcing ◽  
Computational Cost ◽  
Short Wave ◽  
Sensitivity Analyses ◽  
Model Parameters ◽  
Large Set ◽  
Individual Parameter ◽  
Cloud Water Content ◽  
Atmosphere Model

Abstract. Changes in aerosols cause a change in net top-of-the-atmosphere (ToA) short-wave and long-wave radiative fluxes; rapid adjustments in clouds, water vapour and temperature; and an effective radiative forcing (ERF) of the planetary energy budget. The diverse sources of model uncertainty and the computational cost of running climate models make it difficult to isolate the main causes of aerosol ERF uncertainty and to understand how observations can be used to constrain it. We explore the aerosol ERF uncertainty by using fast model emulators to generate a very large set of aerosol–climate model variants that span the model uncertainty due to 27 parameters related to atmospheric and aerosol processes. Sensitivity analyses shows that the uncertainty in the ToA flux is dominated (around 80 %) by uncertainties in the physical atmosphere model, particularly parameters that affect cloud reflectivity. However, uncertainty in the change in ToA flux caused by aerosol emissions over the industrial period (the aerosol ERF) is controlled by a combination of uncertainties in aerosol (around 60 %) and physical atmosphere (around 40 %) parameters. Four atmospheric and aerosol parameters account for around 80 % of the uncertainty in short-wave ToA flux (mostly parameters that directly scale cloud reflectivity, cloud water content or cloud droplet concentrations), and these parameters also account for around 60 % of the aerosol ERF uncertainty. The common causes of uncertainty mean that constraining the modelled planetary brightness to tightly match satellite observations changes the lower 95 % credible aerosol ERF value from −2.65 to −2.37 W m−2. This suggests the strongest forcings (below around −2.4 W m−2) are inconsistent with observations. These results show that, regardless of the fact that the ToA flux is 2 orders of magnitude larger than the aerosol ERF, the observed flux can constrain the uncertainty in ERF because their values are connected by constrainable process parameters. The key to reducing the aerosol ERF uncertainty further will be to identify observations that can additionally constrain individual parameter ranges and/or combined parameter effects, which can be achieved through sensitivity analysis of perturbed parameter ensembles.

scholarly journals Parameter Optimization of the 3PG Model Based on Sensitivity Analysis and a Bayesian Method

Forests ◽  
2020 ◽  
Vol 11 (12) ◽  
pp. 1369
Author(s):  
Chenjian Liu ◽  
Xiaoman Zheng ◽  
Yin Ren
Keyword(s):  
Sensitivity Analysis ◽  
Parameter Optimization ◽  
Bayesian Method ◽  
Growth Models ◽  
Probability Distributions ◽  
Model Parameters ◽  
Simulation Accuracy ◽  
Sensitivity Analysis Method ◽  
Improved Model ◽  
Posterior Estimation

Sensitivity analysis and parameter optimization of stand models can improve their efficiency and accuracy, and increase their applicability. In this study, the sensitivity analysis, screening, and optimization of 63 model parameters of the Physiological Principles in Predicting Growth (3PG) model were performed by combining a sensitivity analysis method and the Markov chain Monte Carlo (MCMC) method of Bayesian posterior estimation theory. Additionally, a nine-year observational dataset of Chinese fir trees felled in the Shunchang Forest Farm, Nanping, was used to analyze, screen, and optimize the 63 model parameters of the 3PG model. The results showed the following: (1) The parameters that are most sensitive to stand stocking and diameter at breast height (DBH) are nWs(power in stem mass vs. diameter relationship), aWs(constant in stem mass vs. diameter relationship), alphaCx(maximum canopy quantum efficiency), k(extinction coefficient for PAR absorption by canopy), pRx(maximum fraction of NPP to roots), pRn(minimum fraction of NPP to roots), and CoeffCond(defines stomatal response to VPD); (2) MCMC can be used to optimize the parameters of the 3PG model, in which the posterior probability distributions of nWs, aWs, alphaCx, pRx, pRn, and CoeffCond conform to approximately normal or skewed distributions, and the peak value is prominent; and (3) compared with the accuracy before sensitivity analysis and a Bayesian method, the biomass simulation accuracy of the stand model was increased by 13.92%, and all indicators show that the accuracy of the improved model is superior. This method can be used to calibrate the parameters and analyze the uncertainty of multi-parameter complex stand growth models, which are important for the improvement of parameter estimation and simulation accuracy.

Biological consequences of the spatial-differentiated level of the 131I accumulation in sheep thyroid after Chernobyl accident

2020 ◽  
Author(s):  
Elvira Denisova ◽  
Alexander Zenkin ◽  
Alexey Snegirev ◽  
Yuri Kurachenko ◽  
Gennady Kozmin ◽  
...  
Keyword(s):  
Radiation Transport ◽  
Biological Effects ◽  
Venous Blood ◽  
Absorbed Dose ◽  
Theoretical Data ◽  
Iodine Content ◽  
Model Parameters ◽  
Average Dose ◽  
Practical Result ◽  
Stable Iodine

<p>The aim of this work is to study the <sup>131</sup>I biological effects on sheep at different concentrations of stable iodine in the diet. The problem of the absorbed dose estimation in the sheep thyroid gland (TG) after a radiation accident at the Chernobyl NPP in the conditions of natural micronutrient deficiency is considered. To determine the <sup>131</sup>I critical dose in the sheep TG, leading to its dysfunction and subsequent destruction, complex laboratory studies were performed to refine the compartmental model parameters, based on reliable experimental and theoretical data. Modern technologies are used to model the TG area. The solution of the radiation transport equation is performed by the Monte Carlo technique, which takes into account both the γ - and β-radiation of the <sup>131</sup>I immanent source and the contribution of all secondary radiations.</p><p>The studies were carried out on 64 sheep, divided into 10 groups based on the general clinical condition and body weight. The first 5 groups included animals from the Gomel region (32 sheep, iodine content in the daily diet was 0.08 mg/kg ), in the 6–10th groups (32 sheep; 0.43 mg/kg ) – from the Vladimir region. Tests for iodine content in feed and water were performed in the Belarusian Institute of Experimental Veterinary Medicine, Minsk, 1989). For sheep 1–3rd  , 6–8th  groups (9 sheep in the group) once peroral the <sup>131</sup>I was injected with activity: for the 1st  and 6th  groups  3 µCi, for the 2nd  and 7th 15 µCi, from the 3rd  and 8th  – 72 µCi  per capita. The surviving sheep were vaccinated against Rift Valley fever and then exposed to infection with an epizootic strain of the virus of this disease.</p><p>The main theoretical result is the conversion factor of the <sup>131</sup>I activity to the average dose rate in thyroid. The main practical result is the evaluation of the lower limit of absorbed dose in the TG (~ 300 Gy), which leads to its destruction. Animals with a reduced content of stable iodine in the diet were characterized by an increased number of cells in venous blood, reduced levels of thyroxine in the serum, altered structure and functional activity of the thyroid and liver. In animals with low levels of iodine nutrition, a large capture of the isotope by the TG was noted, which provided larger (2–5 times) doses. In sheep with iodine deficiency, a decrease in the number of leukocytes, thyroxine levels; survival is reduced. After the <sup>131</sup>I intake, sheep developed a radiation-induced immunodeficiency, but the main mechanisms of the infectious process in animals remained: post-vaccination reactions proceeded without complications, were characterized by antibody formation and immune development.</p>

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