Communication: Iteration-free, weighted histogram analysis method in terms of intensive variables.
Ontology highlight
ABSTRACT:
SUBMITTER: Kim J
PROVIDER: S-EPMC3166335 | biostudies-other | 2011 Aug
REPOSITORIES: biostudies-other
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Project description:The weighted histogram analysis method (WHAM) for free energy calculations is a valuable tool to produce free energy differences with the minimal errors. Given multiple simulations, WHAM obtains from the distribution overlaps the optimal statistical estimator of the density of states, from which the free energy differences can be computed. The WHAM equations are often solved by an iterative procedure. In this work, we use a well-known linear algebra algorithm which allows for more rapid convergence to the solution. We find that the computational complexity of the iterative solution to WHAM and the closely-related multiple Bennett acceptance ratio (MBAR) method can be improved by using the method of direct inversion in the iterative subspace. We give examples from a lattice model, a simple liquid and an aqueous protein solution.
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Project description:Free energy perturbation (FEP) simulations have been widely applied to obtain predictions of the relative binding free energy for a series of congeneric ligands binding to the same receptor, which is an essential component for the lead optimization process in computer-aided drug discovery. In the case of several congeneric ligands forming a perturbation map involving a closed thermodynamic cycle, the summation of the estimated free energy change along each edge in the cycle using Bennett acceptance ratio (BAR) usually will deviate from zero due to systematic and random errors, which is the hysteresis of cycle closure. In this work, the advanced reweighting techniques binless weighted histogram analysis method (UWHAM) and locally weighted histogram analysis method (LWHAM) are applied to provide statistical estimators of the free energy change along each edge in order to eliminate the hysteresis effect. As an example, we analyze a closed thermodynamic cycle involving four congeneric ligands which bind to HIV-1 integrase, a promising target which has emerged for antiviral therapy. We demonstrate that, compared with FEP and BAR, more accurate and hysteresis-free estimates of free energy differences can be achieved by using UWHAM to find a single estimate of the density of states based on all of the data in the cycle. Furthermore, by comparison of LWHAM results obtained from the inclusion of different numbers of neighboring states with UWHAM estimation involving all the states, we show how to determine the optimal neighborhood size in the LWHAM analysis to balance the trade-offs between computational cost and accuracy of the free energy prediction. Even with the smallest neighborhood, LWHAM can improve the BAR free energy estimates using the same input data as BAR. We introduce an overlapping states matrix that is constructed by using the global jump formula of LWHAM and plot its heat map. The heat map provides a quantitative measure of the overlap between pairs of alchemical/thermodynamic states. We explain how to identify and improve the FEP calculations along the edges that most likely cause large systematic errors by using the heat map of the overlapping states matrix and by comparing the BAR and UWHAM estimates of the free energy change.
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Project description:Oligosaccharides and polysaccharides exert numerous functional roles in biology through their structural diversity and conformational properties. To investigate their conformational properties using computational methods, Hamiltonian replica exchange (H-REX) combined with two-dimensional grid-based correction maps as biasing potentials (bpCMAP) significantly improves the sampling efficiency about glycosidic linkages. In the current study, we extend the application of H-REX with bpCMAP to complex saccharides and establish systematic procedures for bpCMAP construction, determination of replica distribution, and data analysis. Our main findings are that (1) the bpCMAP for each type of glycosidic linkage can be constructed from the corresponding disaccharide using gas-phase umbrella sampling simulations, (2) the replica distribution can be conveniently determined following the exact definition of the average acceptance ratio based on the assigned distribution of biasing potentials, and (3) the extracted free energy surface (or potential of mean force (PMF)) can be improved using the weighted histogram analysis method (WHAM) allowing for the inclusion of data from the excited state replicas in the calculated probability distribution. The method is applied to a branched N-glycan found on the HIV gp120 protein, and a linear N-glycan. Considering the general importance of N-glycans and the wide appreciation of the sampling problem, the present method represents an efficient procedure for the conformational sampling of complex oligo- and polysaccharides under explicit solvent conditions. More generally, the use of WHAM is anticipated to be of general utility for the calculation of PMFs from H-REX simulations in a wide range of macromolecular systems.
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Project description:PurposeTo assess the value of diffusion-weighted MRI (DW-MRI) in the non-invasive prediction of blastemal remnant after neoadjuvant chemotherapy in nephroblastoma.MethodsThis IRB-approved study included 32 pediatric patients with 35 tumors who underwent DW-MRI prior and after completion of neoadjuvant chemotherapy and subsequent surgical resection. Two blinded radiologists volumetrically assessed each tumor on pre- and post-neoadjuvant images and the parameters mean ADC, median ADC, 12.5th/25th/75th ADC percentile, skewness, and kurtosis were calculated. Blastemal remnant was determined per the pathology report. Associations between imaging features and blastemal remnant quartiles were examined using the Kruskal-Wallis test and adjusted for false discovery rate.ResultsInter-reader agreement was high for mean ADC, skewness, kurtosis, and volume (ICC: 0.76-0.998). Pre-therapeutic histogram parameters skewness and kurtosis were found to be higher in patients with a higher amount of blastemal remnant for reader 1 (overall p = 0.035) and for kurtosis in reader 2 (overall p = 0.032) with skewness not reaching the level of statistical significance (overall p = 0.055). Higher tumor volume on pre-treatment imaging was associated with a higher amount of blastemal remnant after therapy (overall p = 0.032 for both readers).ConclusionsPre-treatment skewness and kurtosis of ADC histogram analysis were significantly associated with a larger fraction of a blastemal remnant after neoadjuvant chemotherapy. These findings could be incorporated into a more personalized chemotherapeutic regime in these patients and offer prognostic information at the time of initial diagnosis.
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Project description:ObjectiveTo assess the utility and frequency of use of the Nightingale Communication method, during the early operational phase of the Nightingale Hospital London 4000-bed field hospital Intensive Care Unit.DesignSurvey based cross sectional assessment.SettingThe intensive care unit at the Nightingale London hospital.ParticipantsStaff working in the clinical area, and therefore requiring full personal protective equipment.InterventionSurvey of all staff members sampled from a single shift at the Nightingale Hospital. This investigated perceived utility and actual use of identification methods (name and role labels on visors and gowns, coloured role identification tapes) and formal hand signals as an adjunctive communication method.Main outcome measureSelf reported frequency of use and perceived utility of each communication and personnel identification adjunct.Results50 valid responses were received (72% response rate) covering all clinical professional groups. Prominent name/role identifications and colour-coded identification tapes were very frequently used and were perceived as being highly useful. Formal hand signals were infrequently used, and not perceived as being beneficial, with respondents citing use of single taught gestures only in specific circumstances.ConclusionPPE is highly depersonalising and interpersonal identification aids are very useful. Despite being difficult, verbal communication is not completely prohibited, which could explain the low utility of formal hand signals. The methods developed at the Nightingale hospital have enhanced communication in the critical care, field hospital setting. There is potential for wider application to a variety of healthcare settings, in both the current situation and future pandemic scenarios.
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Project description:PurposeGlioblastoma and anaplastic astrocytoma represent the most commonly encountered high-grade-glioma (HGG) in adults. Although both neoplasms are very distinct entities in context of epidemiology, clinical course and prognosis, their appearance in conventional magnetic resonance imaging (MRI) is very similar. In search for additional information aiding the distinction of potentially confusable neoplasms, histogram analysis of apparent diffusion coefficient (ADC) maps recently proved to be auxiliary in a number of entities. Therefore, our present exploratory retrospective study investigated whether ADC histogram profile parameters differ significantly between anaplastic astrocytoma and glioblastoma, reflect the proliferation index Ki-67, or are associated with the prognostic relevant MGMT (methylguanine-DNA methyl-transferase) promotor methylation status.MethodsPre-surgical ADC volumes of 56 HGG patients were analyzed by histogram-profiling. Association between extracted histogram parameters and neuropathology including WHO-grade, Ki-67 expression and MGMT promotor methylation status was investigated due to comparative and correlative statistics.ResultsGrade IV gliomas were more heterogeneous than grade III tumors. More specifically, ADCmin and the lowest percentile ADCp10 were significantly lower, whereas ADCmax, ADC standard deviation and Skewness were significantly higher in the glioblastoma group. ADCmin, ADCmax, ADC standard deviation, Kurtosis and Entropy of ADC histogram were significantly correlated with Ki-67 expression. No significant difference could be revealed by comparison of ADC histogram parameters between MGMT promotor methylated and unmethylated HGG.ConclusionsADC histogram parameters differ significantly between glioblastoma and anaplastic astrocytoma and show distinct associations with the proliferative activity in both HGG. Our results suggest ADC histogram profiling as promising biomarker for differentiation of both, however, further studies with prospective multicenter design are wanted to confirm and further elaborate this hypothesis.
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Project description:Measurement and calibration of an analog-to-digital converter (ADC) using a histogram-based method requires a large volume of data and a long test duration, especially for a high resolution ADC. A fast and accurate calibration method for pipelined ADCs is proposed in this research. The proposed calibration method composes histograms through the outputs of each stage and calculates error sources. The digitized outputs of a stage are influenced directly by the operation of the prior stage, so the results of the histogram provide the information of errors in the prior stage. The composed histograms reduce the required samples and thus calibration time being implemented by simple modules. For 14-bit resolution pipelined ADC, the measured maximum integral non-linearity (INL) is improved from 6.78 to 0.52 LSB, and the spurious-free dynamic range (SFDR) and signal-to-noise-and-distortion ratio (SNDR) are improved from 67.0 to 106.2dB and from 65.6 to 84.8dB, respectively.
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