The calculation of relative free energies that involve large reorganizations of the environment is one of the great challenges of condensed-phase simulation. Such calculations are of particular importance in protein−ligand free-energy calculations. To meet this challenge, we have developed new free-energy techniques that combine the advantages of the replica-exchange method with free-energy perturbation (FEP) and finite-difference thermodynamic integration (FDTI). These new techniques are tested and compared with FEP, FDTI, and the adaptive umbrella weighted histogram analysis method (AdUmWHAM) on the challenging calculation of the relative hydration free energy of methane and water. This calculation involves a large solvent configurational change. Through the use of replica-exchange moves along the λ-coordinate, the configurations sampled along λ are allowed to mix, which leads to dramatic improvements in solvent configurational sampling, an efficient reduction of random sampling error, and a reduction of general simulation error. This is achieved at effectively no extra computational cost, relative to standard FEP or FDTI.
The newly developed method of replica-exchange thermodynamic integration (RETI) was tested and compared with finite-difference thermodynamic integration (FDTI) on the calculation of the relative binding free energies of halides to a calix[4]pyrrole derivative. The calculation was challenging, because the dimethylsulfoxide solvent was contaminated by small amounts of water. The λ-swap move of RETI enabled more-complete sampling of the solvents and produced relative binding free energies that included the effect of the fluoride's higher affinity for water. In addition, the λ-swap move increased the quality of the configurational sampling of the host, because the system was able to escape from local minima. The results demonstrate that the sampling of RETI is superior to that of FDTI, at no additional computational expense.
Model and human observers have been compared in a series of localization receiver operating characteristic (LROC) studies involving single-slice and multislice image displays. The task was detection of Ga-avid lymphomas within single photon emission computed tomography (SPECT)-reconstructed transverse slices of a mathematical phantom, and the studies involved four reconstruction strategies: the filtered-backprojection (FBP) and ordered-subset expectation-maximization (OSEM) algorithms with two- and three-dimensional postreconstruction filtering. The human-observer data was drawn from studies performed by Wells et al. (2000), while multiclass versions of the nonprewhitening (NPW), channelized nonprewhitening (CNPW), and channelized Hotelling (CH) model observers, each capable of performing the tumor search task, were applied. The channelized observers were evaluated with multiple square-channel models and both with and without internal noise. For the multislice studies, two different capacities for integrating the slice information were also tested. The CH observer gave good quantitative agreement with the human data from both image-display studies when the internal-noise model was used. The CNPW observer performed similarly with the iterative strategies. Wells et al. had shown that human observers are imperfect integrators of multislice information, and this is characterized as increased internal noise with the model observers.
Purpose:One issue with amplitude binning list-mode studies in SPECT for respiratory motion correction is that variation in the patient's respiratory pattern will result in binned motion states with little or no counts at various projection angles. The reduced counts result in limited-angle reconstruction artifacts which can impact the accuracy of the necessary motion estimation needed to correct the images. In this work, the authors investigate a method to overcome the effect of limited-angle reconstruction artifacts in SPECT when estimating respiratory motion. Methods: In the first pass of the reconstruction method, only the projection angles with significant counts in common between the binned respiratory states are used in order to better estimate the motion between them. After motion estimation, the estimates are used to correct for motion within iterative reconstruction using all of the acquired projection data. Results: Using simulated SPECT studies based on the NCAT phantom, the authors demonstrate the problem caused by having data available for only a limited number of angles when estimating motion and the utility of the proposed method in diminishing this error. For NCAT data sets with a clinically appropriate level of Poisson noise, the average registration error for motion with the proposed method was always less with the use of their algorithm, the reduction being statistically significant ͑p Ͻ 0.05͒ in the majority of cases. The authors illustrate the ability of their method to correct the degradations caused by respiratory motion in short-axis slices and polar maps of the NCAT phantom for cases with 1 and 2 cm amplitudes of respiratory motion. In four cardiacperfusion patients acquired on the same day, the authors demonstrate the large variability of the number of counts in the amplitude-binned projections. Finally, the authors demonstrate a visual improvement in the slices and polar maps of patient studies with the algorithm for respiratory motion correction. Conclusions: The authors' method shows promise in reducing errors in respiratory motion estimation despite the presence of limited-angle reconstruction effects due to irregularity in respiration. Improvements in image quality were observed in both simulated and clinical studies.
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