We propose a novel, efficient approach for obtaining high-quality experimental designs for event-related functional magnetic resonance imaging (ER-fMRI), a popular brain mapping technique. Our proposed approach combines a greedy hill-climbing algorithm and a cyclic permutation method. When searching for optimal ER-fMRI designs, the proposed approach focuses only on a promising restricted class of designs with equal frequency of occurrence across stimulus types. The computational time is significantly reduced. We demonstrate that our proposed approach is very efficient compared with a recently proposed genetic algorithm approach. We also apply our approach in obtaining designs that are robust against misspecification of error correlations.

We study the problem of controlling multiple 2-D directional sensors while maximizing an objective function based on the information gain corresponding to multiple target locations. We assume a joint prior Gaussian distribution for the target locations. A sensor generates a (noisy) measurement of a target only if the target lies within the field-of-view of the sensor, where the statistical properties of the measurement error depend on the location of the target with respect to the sensor and direction of the sensor. The measurements from the sensors are fused to form global estimates of target locations. This problem is combinatorial in nature-the computation time increases exponentially with the number of sensors. We develop heuristic methods to solve the problem approximately, and provide analytical results on performance guarantees. We then improve the performance of our heuristic approaches by applying an approximate dynamic programming approach called rollout. In addition, we address a variant of the above problem, where the goal is to map the sensors to the targets while maximizing the abovementioned objective function. This mapping problem also turns out to be combinatorial in nature, so we extend one of the above heuristics to solve this mapping problem approximately. We compare the performance of these heuristic approaches analytically and empirically.

Background: The binding of peptide fragments of antigens to class II MHC is a crucial step in initiating a helper T cell immune response. The identification of such peptide epitopes has potential applications in vaccine design and in better understanding autoimmune diseases and allergies. However, comprehensive experimental determination of peptide-MHC binding affinities is infeasible due to MHC diversity and the large number of possible peptide sequences. Computational methods trained on the limited experimental binding data can address this challenge. We present the MultiRTA method, an extension of our previous single-type RTA prediction method, which allows the prediction of peptide binding affinities for multiple MHC allotypes not used to train the model. Thus predictions can be made for many MHC allotypes for which experimental binding data is unavailable.

Results: We fit MultiRTA models for both HLA-DR and HLA-DP using large experimental binding data sets. The performance in predicting binding affinities for novel MHC allotypes, not in the training set, was tested in two different ways. First, we performed leave-one-allele-out cross-validation, in which predictions are made for one allotype using a model fit to binding data for the remaining MHC allotypes. Comparison of the HLA-DR results with those of two other prediction methods applied to the same data sets showed that MultiRTA achieved performance comparable to NetMHCIIpan and better than the earlier TEPITOPE method. We also directly tested model transferability by making leave-one-allele-out predictions for additional experimentally characterized sets of overlapping peptide epitopes binding to multiple MHC allotypes. In addition, we determined the applicability of prediction methods like MultiRTA to other MHC allotypes by examining the degree of MHC variation accounted for in the training set. An examination of predictions for the promiscuous binding CLIP peptide revealed variations in binding affinity among alleles as well as potentially distinct binding registers for HLA-DR and HLA-DP. Finally, we analyzed the optimal MultiRTA parameters to discover the most important peptide residues for promiscuous and allele-specific binding to HLA-DR and HLA-DP allotypes.

Conclusions: The MultiRTA method yields competitive performance but with a significantly simpler and physically interpretable model compared with previous prediction methods. A MultiRTA prediction webserver is available at http://bordnerlab.org/MultiRTA.

Background: The binding of peptide fragments of extracellular peptides to class II MHC is a crucial event in the adaptive immune response. Each MHC allotype generally binds a distinct subset of peptides and the enormous number of possible peptide epitopes prevents their complete experimental characterization. Computational methods can utilize the limited experimental data to predict the binding affinities of peptides to class II MHC.

Results: We have developed the Regularized Thermodynamic Average, or RTA, method for predicting the affinities of peptides binding to class II MHC. RTA accounts for all possible peptide binding conformations using a thermodynamic average and includes a parameter constraint for regularization to improve accuracy on novel data. RTA was shown to achieve higher accuracy, as measured by AUC, than SMM-align on the same data for all 17 MHC allotypes examined. RTA also gave the highest accuracy on all but three allotypes when compared with results from 9 different prediction methods applied to the same data. In addition, the method correctly predicted the peptide binding register of 17 out of 18 peptide-MHC complexes. Finally, we found that suboptimal peptide binding registers, which are often ignored in other prediction methods, made significant contributions of at least 50% of the total binding energy for approximately 20% of the peptides.

Conclusions: The RTA method accurately predicts peptide binding affinities to class II MHC and accounts for multiple peptide binding registers while reducing overfitting through regularization. The method has potential applications in vaccine design and in understanding autoimmune disorders. A web server implementing the RTA prediction method is available at http://bordnerlab.org/RTA/.