945 research outputs found

    Automated benchmarking of peptide-MHC class I binding predictions

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    Motivation: Numerous in silico methods predicting peptide binding to major histocompatibility complex (MHC) class I molecules have been developed over the last decades. However, the multitude of available prediction tools makes it non-trivial for the end-user to select which tool to use for a given task. To provide a solid basis on which to compare different prediction tools, we here describe a framework for the automated benchmarking of peptide-MHC class I binding prediction tools. The framework runs weekly benchmarks on data that are newly entered into the Immune Epitope Database (IEDB), giving the public access to frequent, up-to-date performance evaluations of all participating tools. To overcome potential selection bias in the data included in the IEDB, a strategy was implemented that suggests a set of peptides for which different prediction methods give divergent predictions as to their binding capability. Upon experimental binding validation, these peptides entered the benchmark study. Results: The benchmark has run for 15 weeks and includes evaluation of 44 datasets covering 17 MHC alleles and more than 4000 peptide-MHC binding measurements. Inspection of the results allows the end-user to make educated selections between participating tools. Of the four participating servers, NetMHCpan performed the best, followed by ANN, SMM and finally ARB. Availability and implementation: Up-to-date performance evaluations of each server can be found online at http://tools.iedb.org/auto-bench/mhci/weekly. All prediction tool developers are invited to participate in the benchmark. Sign-up instructions are available at http://tools.iedb.org/auto-bench/mhci/join.Fil: Trolle, Thomas. Technical University of Denmark; DinamarcaFil: Metushi, Imir G.. La Jolla Institute for Allergy and Immunology; Estados UnidosFil: Greenbaum, Jason A.. La Jolla Institute for Allergy and Immunology; Estados UnidosFil: Kim, Yohan. La Jolla Institute for Allergy and Immunology; Estados UnidosFil: Sidney, John. La Jolla Institute for Allergy and Immunology; Estados UnidosFil: Lund, Ole. Technical University of Denmark; DinamarcaFil: Sette, Alessandro. La Jolla Institute for Allergy and Immunology; Estados UnidosFil: Peters, Bjoern. La Jolla Institute for Allergy and Immunology; Estados UnidosFil: Nielsen, Morten. Technical University of Denmark; Dinamarca. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Biotecnológicas. Universidad Nacional de San Martín. Instituto de Investigaciones Biotecnológicas; Argentin

    A Community Resource Benchmarking Predictions of Peptide Binding to MHC-I Molecules

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    Recognition of peptides bound to major histocompatibility complex (MHC) class I molecules by T lymphocytes is an essential part of immune surveillance. Each MHC allele has a characteristic peptide binding preference, which can be captured in prediction algorithms, allowing for the rapid scan of entire pathogen proteomes for peptide likely to bind MHC. Here we make public a large set of 48,828 quantitative peptide-binding affinity measurements relating to 48 different mouse, human, macaque, and chimpanzee MHC class I alleles. We use this data to establish a set of benchmark predictions with one neural network method and two matrix-based prediction methods extensively utilized in our groups. In general, the neural network outperforms the matrix-based predictions mainly due to its ability to generalize even on a small amount of data. We also retrieved predictions from tools publicly available on the internet. While differences in the data used to generate these predictions hamper direct comparisons, we do conclude that tools based on combinatorial peptide libraries perform remarkably well. The transparent prediction evaluation on this dataset provides tool developers with a benchmark for comparison of newly developed prediction methods. In addition, to generate and evaluate our own prediction methods, we have established an easily extensible web-based prediction framework that allows automated side-by-side comparisons of prediction methods implemented by experts. This is an advance over the current practice of tool developers having to generate reference predictions themselves, which can lead to underestimating the performance of prediction methods they are not as familiar with as their own. The overall goal of this effort is to provide a transparent prediction evaluation allowing bioinformaticians to identify promising features of prediction methods and providing guidance to immunologists regarding the reliability of prediction tools

    Immunoinformatics: Predicting Peptide–MHC Binding

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    Immunoinformatics is a discipline that applies methods of computer science to study and model the immune system. A fundamental question addressed by immunoinformatics is how to understand the rules of antigen presentation by MHC molecules to T cells, a process that is central to adaptive immune responses to infections and cancer. In the modern era of personalized medicine, the ability to model and predict which antigens can be presented by MHC is key to manipulating the immune system and designing strategies for therapeutic intervention. Since the MHC is both polygenic and extremely polymorphic, each individual possesses a personalized set of MHC molecules with different peptide-binding specificities, and collectively they present a unique individualized peptide imprint of the ongoing protein metabolism. Mapping all MHC allotypes is an enormous undertaking that cannot be achieved without a strong bioinformatics component. Computational tools for the prediction of peptide?MHC binding have thus become essential in most pipelines for T cell epitope discovery and an inescapable component of vaccine and cancer research. Here, we describe the development of several such tools, from pioneering efforts to the current state-of-the-art methods, that have allowed for accurate predictions of peptide binding of all MHC molecules, even including those that have not yet been characterized experimentally.Fil: Nielsen, Morten. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Biotecnológicas. Universidad Nacional de San Martín. Instituto de Investigaciones Biotecnológicas; Argentina. Technical University of Denmark; DinamarcaFil: Andreatta, Massimo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Biotecnológicas. Universidad Nacional de San Martín. Instituto de Investigaciones Biotecnológicas; ArgentinaFil: Peters, Bjoern. La Jolla Institute for Allergy and Immunology; Estados UnidosFil: Buus, Søren. Universidad de Copenhagen; Dinamarc

    The Immune Epitope Database and Analysis Resource Program 2003–2018: reflections and outlook

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    The Immune Epitope Database and Analysis Resource (IEDB) contains information related to antibodies and T cells across an expansive scope of research fields (infectious diseases, allergy, autoimmunity, and transplantation). Capture and representation of the data to reflect growing scientific standards and techniques have required continual refinement of our rigorous curation and query and reporting processes beginning with the automated classification of over 28 million PubMed abstracts, and resulting in easily searchable data from over 20,000 published manuscripts. Data related to MHC binding and elution, nonpeptidics, natural processing, receptors, and 3D structure is first captured through manual curation and subsequently maintained through recuration to reflect evolving scientific standards. Upon promotion to the free, public database, users can query and export records of specific relevance via the online web portal which undergoes iterative development to best enable efficient data access. In parallel, the companion Analysis Resource site hosts a variety of tools that assist in the bioinformatic analyses of epitopes and related structures, which can be applied to IEDB-derived and independent datasets alike. Available tools are classified into two categories: analysis and prediction. Analysis tools include epitope clustering, sequence conservancy, and more, while prediction tools cover T and B cell epitope binding, immunogenicity, and TCR/BCR structures. In addition to these tools, benchmarking servers which allow for unbiased performance comparison are also offered. In order to expand and support the user-base of both the database and Analysis Resource, the research team actively engages in community outreach through publication of ongoing work, conference attendance and presentations, hosting of user workshops, and the provision of online help. This review provides a description of the IEDB database infrastructure, curation and recuration processes, query and reporting capabilities, the Analysis Resource, and our Community Outreach efforts, including assessment of the impact of the IEDB across the research community.Fil: Martini, Sheridan. La Jolla Institute for Allergy and Immunology; Estados UnidosFil: Nielsen, Morten. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Biotecnológicas. Universidad Nacional de San Martín. Instituto de Investigaciones Biotecnológicas; Argentina. Technical University of Denmark; DinamarcaFil: Peters, Bjoern. La Jolla Institute for Allergy and Immunology; Estados Unidos. University of California at San Diego; Estados UnidosFil: Sette, Alessandro. La Jolla Institute for Allergy and Immunology; Estados Unidos. University of California at San Diego; Estados Unido

    Machine learning-enhanced T cell neoepitope discovery for immunotherapy design

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    Immune responses mediated by T cells are aimed at specific peptides, designated T cell epitopes, that are recognized when bound to human leukocyte antigen (HLA) molecules. The HLA genes are remarkably polymorphic in the human population allowing a broad and fine-tuned capacity to bind a wide array of peptide sequences. Polymorphisms might generate neoepitopes by impacting the HLA-peptide interaction and potentially alter the level and type of generated T cell responses. Multiple algorithms and tools based on machine learning (ML) have been implemented and are able to predict HLA-peptide binding affinity with considerable accuracy. Challenges in this field include the availability of adequate epitope datasets for training and benchmarking and the development of fully integrated pipelines going from next-generation sequencing to neoepitope prediction and quality analysis metrics. Effectively predicting neoepitopes from in silico data is a demanding task that has been facilitated by ML and will be of great value for the future of personalized immunotherapies against cancer and other diseases.The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This research received funding from Fundação para a Ciência e a Tecnologia (FCT) contract IF/00474/2014; PhD scholarship SFRH/BD/132797/2017.info:eu-repo/semantics/publishedVersio

    Immune epitope database analysis resource (IEDB-AR)

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    We present a new release of the immune epitope database analysis resource (IEDB-AR, http://tools.immuneepitope.org), a repository of web-based tools for the prediction and analysis of immune epitopes. New functionalities have been added to most of the previously implemented tools, and a total of eight new tools were added, including two B-cell epitope prediction tools, four T-cell epitope prediction tools and two analysis tools

    Computational MHC-I epitope predictor identifies 95% of experimentally mapped HIV-1 clade A and D epitopes in a Ugandan cohort.

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    BACKGROUND: Identifying immunogens that induce HIV-1-specific immune responses is a lengthy process that can benefit from computational methods, which predict T-cell epitopes for various HLA types. METHODS: We tested the performance of the NetMHCpan4.0 computational neural network in re-identifying 93 T-cell epitopes that had been previously independently mapped using the whole proteome IFN-γ ELISPOT assays in 6 HLA class I typed Ugandan individuals infected with HIV-1 subtypes A1 and D. To provide a benchmark we compared the predictions for NetMHCpan4.0 to MHCflurry1.2.0 and NetCTL1.2. RESULTS: NetMHCpan4.0 performed best correctly predicting 88 of the 93 experimentally mapped epitopes for a set length of 9-mer and matched HLA class I alleles. Receiver Operator Characteristic (ROC) analysis gave an area under the curve (AUC) of 0.928. Setting NetMHCpan4.0 to predict 11-14mer length did not improve the prediction (37-79 of 93 peptides) with an inverse correlation between the number of predictions and length set. Late time point peptides were significantly stronger binders than early peptides (Wilcoxon signed rank test: p = 0.0000005). MHCflurry1.2.0 similarly predicted all but 2 of the peptides that NetMHCpan4.0 predicted and NetCTL1.2 predicted only 14 of the 93 experimental peptides. CONCLUSION: NetMHCpan4.0 class I epitope predictions covered 95% of the epitope responses identified in six HIV-1 infected individuals, and would have reduced the number of experimental confirmatory tests by > 80%. Algorithmic epitope prediction in conjunction with HLA allele frequency information can cost-effectively assist immunogen design through minimizing the experimental effort

    NetMHCpan-3.0; improved prediction of binding to MHC class I molecules integrating information from multiple receptor and peptide length datasets

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    Allele-specific length preference for 24 MHC molecules characterized by 20 or more ligand data points for the allmer and 9mer prediction methods compared to the length preference in the SYFPEITHI data. Length profiles for the allmer and 9mer methods were estimated as described in the text. (XLSX 50 kb

    EpiTOP—a proteochemometric tool for MHC class II binding prediction

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    Motivation: T-cell epitope identification is a critical immunoinformatic problem within vaccine design. To be an epitope, a peptide must bind an MHC protein. Results: Here, we present EpiTOP, the first server predicting MHC class II binding based on proteochemometrics, a QSAR approach for ligands binding to several related proteins. EpiTOP uses a quantitative matrix to predict binding to 12 HLA-DRB1 alleles. It identifies 89% of known epitopes within the top 20% of predicted binders, reducing laboratory labour, materials and time by 80%. EpiTOP is easy to use, gives comprehensive quantitative predictions and will be expanded and updated with new quantitative matrices over time

    Best practices for bioinformatic characterization of neoantigens for clinical utility

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    Neoantigens are newly formed peptides created from somatic mutations that are capable of inducing tumor-specific T cell recognition. Recently, researchers and clinicians have leveraged next generation sequencing technologies to identify neoantigens and to create personalized immunotherapies for cancer treatment. To create a personalized cancer vaccine, neoantigens must be computationally predicted from matched tumor-normal sequencing data, and then ranked according to their predicted capability in stimulating a T cell response. This candidate neoantigen prediction process involves multiple steps, including somatic mutation identification, HLA typing, peptide processing, and peptide-MHC binding prediction. The general workflow has been utilized for many preclinical and clinical trials, but there is no current consensus approach and few established best practices. In this article, we review recent discoveries, summarize the available computational tools, and provide analysis considerations for each step, including neoantigen prediction, prioritization, delivery, and validation methods. In addition to reviewing the current state of neoantigen analysis, we provide practical guidance, specific recommendations, and extensive discussion of critical concepts and points of confusion in the practice of neoantigen characterization for clinical use. Finally, we outline necessary areas of development, including the need to improve HLA class II typing accuracy, to expand software support for diverse neoantigen sources, and to incorporate clinical response data to improve neoantigen prediction algorithms. The ultimate goal of neoantigen characterization workflows is to create personalized vaccines that improve patient outcomes in diverse cancer types
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