A simplified method for calculating complex metabolic sensitivities by using matrix partitioning.
Ontology highlight
ABSTRACT:
SUBMITTER: Crabtree B
PROVIDER: S-EPMC1133422 | biostudies-other | 1989 Oct
REPOSITORIES: biostudies-other
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Project description:A simple and robust formulation of the path-independent confinement method for the calculation of free energies is presented. The simplified confinement method (SCM) does not require matrix diagonalization or switching off the molecular force field, and has a simple convergence criterion. The method can be readily implemented in molecular dynamics programs with minimal or no code modifications. Because the confinement method is a special case of thermodynamic integration, it is trivially parallel over the integration variable. The accuracy of the method is demonstrated using a model diatomic molecule, for which exact results can be computed analytically. The method is then applied to the alanine dipeptide in vacuum, and to the ?-helix ? ?-sheet transition in a 16-residue peptide modeled in implicit solvent. The SCM requires less effort for the calculation of free energy differences than previous formulations because it does not require computing normal modes. The SCM has a diminished advantage for determining absolute free energy values, because it requires decreasing the MD integration step to obtain accurate results. An approximate confinement procedure is introduced, which can be used to estimate directly the configurational entropy difference between two macrostates, without the need for additional computation of the difference in the free energy or enthalpy. The approximation has convergence properties similar to those of the standard confinement method for the calculation of free energies. The use of the approximation requires about 5 times less wall-clock simulation time than that needed to compute enthalpy differences to similar precision from an MD trajectory. For the biomolecular systems considered in this study, the errors in the entropy approximation are under 10%. Practical applications of the methods to proteins are currently limited to implicit solvent simulations.
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Project description:Estimating the lifespan of erythrocytes is useful for the differential diagnosis of anemia. However, measuring the lifespan of erythrocytes was very difficult; therefore, it was seldom measured. Erythrocyte creatine (EC) decreases reflecting erythrocyte age. We developed a method to obtain mean erythrocyte age (MRBC) from EC.We reanalyzed the previously published data from 21 patients with hemolytic anemia, which included EC and the half-life of 51Cr.MRBC and loge EC showed excellent significant linearity (r = -0.9475, p < 0.001), proving that it could be treated as a mono-exponential relationship within the studied range (EC: 1.45 - 11.76 ?mol/g Hb). We established an equation to obtain MRBC (days) from EC (?mol/g Hb): MRBC = -22.84loge EC + 65.83.This equation allowed calculation of MRBC based on EC which has practical applications such as the diagnosis of anemia.
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Project description:BackgroundIt is important to have an accurate count of physicians and a measurable understanding of their service provision for physician resource planning. Our objective was to compare 2 methods (income percentiles [IP] and service day activities [SVD]) for calculating the supply of full-time (FT) and part-time (PT) primary care physicians (PCPs) as measures of both physician supply counts and level of provider continuity.MethodsUsing an observational study design, we compared 2 methods of calculating the supply of PT and FT PCPs for 2011-2015. For the IP approach, the Canadian Institute for Health Information's method was applied to Alberta Health billing data. The SVD method calculated annual service days for fee-for-service PCPs. A simple descriptive analysis was conducted of the supply of PT and FT PCPs.ResultsThe 2 methods agreed on the FT versus PT status of 85.2% of PCPs in 2015 but disagreed on the status of 490 PCPs. A total of 239 PCPs were classified as working FT by the IP method but PT by the SVD method. Two hundred and fifty-one PCPs were classified as working PT according by the IP method but FT by the SVD method. The former group of 239 PCPs worked fewer days per week (3.22 v. 4.1) and fewer weekend days per year (8.6 v. 24.1), billed more per year ($300 327 v. $201 834) and saw more patients per day (26.8 v. 17.8) with less continuity of care (38.0% v. 72.0%) than the latter group of 251 PCPs.InterpretationThe SVD method provides a valid alternative to calculating GP supply that distinguishes groups of physicians that the standard IP methodology does not. Those groups provide very different service; policy-makers may benefit from distinguishing them.
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Project description:Application of artificial intelligence (AI) in precision oncology typically involves predicting whether the cancer cells of a patient (previously unseen by AI models) will respond to any of a set of existing anticancer drugs, based on responses of previous training cell samples to those drugs. To expand the repertoire of anticancer drugs, AI has also been used to repurpose drugs that have not been tested in an anticancer setting, i.e., predicting the anticancer effects of a new drug on previously unseen cancer cells de novo. Here, we report a computational model that addresses both of the above tasks in a unified AI framework. Our model, referred to as deep learning-based graph regularized matrix factorization (DeepGRMF), integrates neural networks, graph models, and matrix-factorization techniques to utilize diverse information from drug chemical structures, their impact on cellular signaling systems, and cancer cell cellular states to predict cell response to drugs. DeepGRMF learns embeddings of drugs so that drugs sharing similar structures and mechanisms of action (MOAs) are closely related in the embedding space. Similarly, DeepGRMF also learns representation embeddings of cells such that cells sharing similar cellular states and drug responses are closely related. Evaluation of DeepGRMF and competing models on Genomics of Drug Sensitivity in Cancer (GDSC) and Cancer Cell Line Encyclopedia (CCLE) datasets show its superiority in prediction performance. Finally, we show that the model is capable of predicting effectiveness of a chemotherapy regimen on patient outcomes for the lung cancer patients in The Cancer Genome Atlas (TCGA) dataset*.
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Project description:There is demand for safer and bio-based solvents, brought on by legislation and sustainability objectives. The prediction of physical properties is highly desirable to help design new molecules. Here we present an in silico approach to obtain calculated Kamlet-Abboud-Taft solvatochromic parameters using virtual experiments. The tautomerisation equilibrium of methyl acetoacetate and dimedone was calculated in different solvents with COSMO-RS theory and converted into estimates of solvent dipolarity and hydrogen bond accepting ability, respectively. Hydrogen bond donating ability was calculated as a function of the electron deficient surface area on protic solvents. These polarity descriptors correlate with rate constants and equilibria, and so ability of calculated Kamlet-Abboud-Taft solvatochromic parameters to recreate experimental free energy relationships was tested with sixteen case studies taken from the literature. The accuracy of the calculated parameters was also satisfactory for solvent selection, as demonstrated with a 1,4-addition reaction and a multicomponent heterocycle synthesis.
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Project description:PurposeThe multiplier method is a technique to predict limb length discrepancy (LLD) at maturity in pediatric patients. Various tools have been developed for performing the multiplier calculations to predict LLD and timing of epiphysiodesis. These include multiplier/growth applications (apps) and a spreadsheet which have helped to facilitate LLC calculations in an efficient and easy manner. We have updated the spreadsheet to improve features for making LLD calculations and facilitate pasting data into electronic medical records (EMRs).MethodsTools currently in use were critically examined for features that limited their function, created possible sources of error or could be more user-friendly. These features were modified and recreated in an improved Excel spreadsheet that uses patient age, sex, limb lengths, and previous lengthening surgeries as inputs to predict LLD at maturity and offer options for timing of epiphysiodesis for both congenital and developmental LLD. Our multiplier spreadsheet function was then compared to manual calculations and other multiplier tools for accuracy and ease of use.ResultsOur spreadsheet accurately calculates LLD at maturity and timing of epiphysiodesis when compared to other methods. It contains a function to calculate predicted leg lengths after previous lengthenings, and concise single-page worksheets for developmental LLD, congenital LLD, and height prediction.ConclusionsThis spreadsheet was developed to provide a more efficient and user-friendly method of calculating LLD at maturity and timing of epiphysiodesis. It can easily be pasted into the EMR for ease of documentation. We recommend this method for both clinical practice and educational use.
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Project description:We estimate and partition genetic variation for height, body mass index (BMI), von Willebrand factor and QT interval (QTi) using 586,898 SNPs genotyped on 11,586 unrelated individuals. We estimate that ?45%, ?17%, ?25% and ?21% of the variance in height, BMI, von Willebrand factor and QTi, respectively, can be explained by all autosomal SNPs and a further ?0.5-1% can be explained by X chromosome SNPs. We show that the variance explained by each chromosome is proportional to its length, and that SNPs in or near genes explain more variation than SNPs between genes. We propose a new approach to estimate variation due to cryptic relatedness and population stratification. Our results provide further evidence that a substantial proportion of heritability is captured by common SNPs, that height, BMI and QTi are highly polygenic traits, and that the additive variation explained by a part of the genome is approximately proportional to the total length of DNA contained within genes therein.
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