Application of support vector machines for T-cell epitopes prediction

Motivation: The T-cell receptor, a major histocompatibility complex (MHC) molecule, and a bound antigenic peptide, play major roles in the process of antigen-specific T-cell activation. T-cell recognition was long considered exquisitely specific. Recent data also indicate that it is highly flexible, and one receptor may recognize thousands of different peptides. Deciphering the patterns of peptides that elicit a MHC restricted T-cell response is critical for vaccine development. Results: For the first time we develop a support vector machine (SVM) for T-cell epitope prediction with an MHC type I restricted T-cell clone. Using cross-validation, we demonstrate that SVMs can be trained on relatively small data sets to provide prediction more accurate than those based on previously published methods or on MHC binding. Supplementary information: Data for 203 synthesized peptides is available at http://linus.nci.nih.gov/Data/LAU203_Peptide.pd

An integrated approach of particle swarm optimization and support vector machine for gene signature selection and cancer prediction

To improve cancer diagnosis and drug development, the classification of tumor types based on genomic information is important. As DNA micro array studies produce a large amount of data, expression data are highly redundant and noisy, and most genes are believed to be uninformative with respect to the studied classes. Only a fraction of genes may present distinct profiles for different classes of samples. Classification tools to deal with these issues are thus important. These tools should learn to robustly identify a subset of informative genes embedded in a large dataset that is contaminated with high dimensional noises. In this paper, an integrated approach of support vector machine (SVM) and particle swarm optimization (PSO) is proposed for this purpose. The proposed approach can simultaneously optimize the selection of feature subset and the classifier through a common solution coding mechanism. As an illustration, the proposed approach is applied to search the combinational gene signatures for predicting histologic response to chemotherapy of osteosarcoma patients. Cross validation results show that the proposed approach outperforms other existing methods in terms of classification accuracy. Further validation using an independent dataset shows misclassification of only one out of fourteen patient samples, suggesting that the selected gene signatures can reflect the chemoresistance in osteosarcoma

A genetic approach for building different alphabets for peptide and protein classification

<p>Abstract</p> <p>Background</p> <p>In this paper, it is proposed an optimization approach for producing reduced alphabets for peptide classification, using a Genetic Algorithm. The classification task is performed by a multi-classifier system where each classifier (Linear or Radial Basis function Support Vector Machines) is trained using features extracted by different reduced alphabets. Each alphabet is constructed by a Genetic Algorithm whose objective function is the maximization of the area under the ROC-curve obtained in several classification problems.</p> <p>Results</p> <p>The new approach has been tested in three peptide classification problems: HIV-protease, recognition of T-cell epitopes and prediction of peptides that bind human leukocyte antigens. The tests demonstrate that the idea of training a pool classifiers by reduced alphabets, created using a Genetic Algorithm, allows an improvement over other state-of-the-art feature extraction methods.</p> <p>Conclusion</p> <p>The validity of the novel strategy for creating reduced alphabets is demonstrated by the performance improvement obtained by the proposed approach with respect to other reduced alphabets-based methods in the tested problems.</p

An Evolutionary Variable Neighborhood Search for Selecting Combinational Gene Signatures in Predicting Chemo-Response of Osteosarcoma

In genomic studies of cancers, identification of genetic biomarkers from analyzing microarray chip that interrogate thousands of genes is important for diagnosis and therapeutics. However, the commonly used statistical significance analysis can only provide information of each single gene, thus neglecting the intrinsic interactions among genes. Therefore, methods aiming at combinational gene signatures are highly valuable. Supervised classification is an effective way to assess the function of a gene combination in differentiating various groups of samples. In this paper, an evolutionary variable neighborhood search (EVNS) that integrated the approaches of evolutionary algorithm and variable neighborhood search (VNS) is introduced.It consists of a population of solutions that evolution is performed by a variable neighborhood search operator, instead of the more usual reproduction operators, crossover and mutation used in evolutionary algorithms. It is an efficient search algorithm especially suitable for tremendous solution space. The proposed EVNS can simultaneously optimize the feature subset and the classifier through a common solution coding mechanism. This method was applied in searching the combinational gene signatures for predicting histologic response of chemotherapy on osteosarcoma patients, which is the most common malignant bone tumor in children. Cross-validation results show that EVNS outperforms the other existing approaches in classifying initial biopsy samples

A novel structure-based encoding for machine-learning applied to the inference of SH3 domain specificity

MOTIVATION: Unravelling the rules underlying protein-protein and protein-ligand interactions is a crucial step in understanding cell machinery. Peptide recognition modules (PRMs) are globular protein domains which focus their binding targets on short protein sequences and play a key role in the frame of protein-protein interactions. High-throughput techniques permit the whole proteome scanning of each domain, but they are characterized by a high incidence of false positives. In this context, there is a pressing need for the development of in silico experiments to validate experimental results and of computational tools for the inference of domain-peptide interactions. RESULTS: We focused on the SH3 domain family and developed a machine-learning approach for inferring interaction specificity. SH3 domains are well-studied PRMs which typically bind proline-rich short sequences characterized by the PxxP consensus. The binding information is known to be held in the conformation of the domain surface and in the short sequence of the peptide. Our method relies on interaction data from high-throughput techniques and benefits from the integration of sequence and structure data of the interacting partners. Here, we propose a novel encoding technique aimed at representing binding information on the basis of the domain-peptide contact residues in complexes of known structure. Remarkably, the new encoding requires few variables to represent an interaction, thus avoiding the 'curse of dimension'. Our results display an accuracy >90% in detecting new binders of known SH3 domains, thus outperforming neural models on standard binary encodings, profile methods and recent statistical predictors. The method, moreover, shows a generalization capability, inferring specificity of unknown SH3 domains displaying some degree of similarity with the known data

Epitope Discovery with Phylogenetic Hidden Markov Models

Existing methods for the prediction of immunologically active T-cell epitopes are based on the amino acid sequence or structure of pathogen proteins. Additional information regarding the locations of epitopes may be acquired by considering the evolution of viruses in hosts with different immune backgrounds. In particular, immune-dependent evolutionary patterns at sites within or near T-cell epitopes can be used to enhance epitope identification. We have developed a mutation–selection model of T-cell epitope evolution that allows the human leukocyte antigen (HLA) genotype of the host to influence the evolutionary process. This is one of the first examples of the incorporation of environmental parameters into a phylogenetic model and has many other potential applications where the selection pressures exerted on an organism can be related directly to environmental factors. We combine this novel evolutionary model with a hidden Markov model to identify contiguous amino acid positions that appear to evolve under immune pressure in the presence of specific host immune alleles and that therefore represent potential epitopes. This phylogenetic hidden Markov model provides a rigorous probabilistic framework that can be combined with sequence or structural information to improve epitope prediction. As a demonstration, we apply the model to a data set of HIV-1 protein-coding sequences and host HLA genotypes

SITC cancer immunotherapy resource document: a compass in the land of biomarker discovery.

Since the publication of the Society for Immunotherapy of Cancer\u27s (SITC) original cancer immunotherapy biomarkers resource document, there have been remarkable breakthroughs in cancer immunotherapy, in particular the development and approval of immune checkpoint inhibitors, engineered cellular therapies, and tumor vaccines to unleash antitumor immune activity. The most notable feature of these breakthroughs is the achievement of durable clinical responses in some patients, enabling long-term survival. These durable responses have been noted in tumor types that were not previously considered immunotherapy-sensitive, suggesting that all patients with cancer may have the potential to benefit from immunotherapy. However, a persistent challenge in the field is the fact that only a minority of patients respond to immunotherapy, especially those therapies that rely on endogenous immune activation such as checkpoint inhibitors and vaccination due to the complex and heterogeneous immune escape mechanisms which can develop in each patient. Therefore, the development of robust biomarkers for each immunotherapy strategy, enabling rational patient selection and the design of precise combination therapies, is key for the continued success and improvement of immunotherapy. In this document, we summarize and update established biomarkers, guidelines, and regulatory considerations for clinical immune biomarker development, discuss well-known and novel technologies for biomarker discovery and validation, and provide tools and resources that can be used by the biomarker research community to facilitate the continued development of immuno-oncology and aid in the goal of durable responses in all patients