Feature selection using a one dimensional naïve Bayes' classifier increases the accuracy of support vector machine classification of CDR3 repertoires.

MOTIVATION: Somatic DNA recombination, the hallmark of vertebrate adaptive immunity, has the potential to generate a vast diversity of antigen receptor sequences. How this diversity captures antigen specificity remains incompletely understood. In this study we use high throughput sequencing to compare the global changes in T cell receptor β chain complementarity determining region 3 (CDR3β) sequences following immunization with ovalbumin administered with complete Freund's adjuvant (CFA) or CFA alone. RESULTS: The CDR3β sequences were deconstructed into short stretches of overlapping contiguous amino acids. The motifs were ranked according to a one-dimensional Bayesian classifier score comparing their frequency in the repertoires of the two immunization classes. The top ranking motifs were selected and used to create feature vectors which were used to train a support vector machine. The support vector machine achieved high classification scores in a leave-one-out validation test reaching  : >90% in some cases. SUMMARY: The study describes a novel two-stage classification strategy combining a one-dimensional Bayesian classifier with a support vector machine. Using this approach we demonstrate that the frequency of a small number of linear motifs three amino acids in length can accurately identify a CD4 T cell response to ovalbumin against a background response to the complex mixture of antigens which characterize Complete Freund's Adjuvant. AVAILABILITY AND IMPLEMENTATION: The sequence data is available at www.ncbi.nlm.nih.gov/sra/?term¼SRP075893 The Decombinator package is available at github.com/innate2adaptive/Decombinator The R package e1071 is available at the CRAN repository https://cran.r-project.org/web/packages/e1071/index.html CONTACT: [email protected] information: Supplementary data are available at Bioinformatics online

Computational strategies for dissecting the high-dimensional complexity of adaptive immune repertoires

The adaptive immune system recognizes antigens via an immense array of antigen-binding antibodies and T-cell receptors, the immune repertoire. The interrogation of immune repertoires is of high relevance for understanding the adaptive immune response in disease and infection (e.g., autoimmunity, cancer, HIV). Adaptive immune receptor repertoire sequencing (AIRR-seq) has driven the quantitative and molecular-level profiling of immune repertoires thereby revealing the high-dimensional complexity of the immune receptor sequence landscape. Several methods for the computational and statistical analysis of large-scale AIRR-seq data have been developed to resolve immune repertoire complexity in order to understand the dynamics of adaptive immunity. Here, we review the current research on (i) diversity, (ii) clustering and network, (iii) phylogenetic and (iv) machine learning methods applied to dissect, quantify and compare the architecture, evolution, and specificity of immune repertoires. We summarize outstanding questions in computational immunology and propose future directions for systems immunology towards coupling AIRR-seq with the computational discovery of immunotherapeutics, vaccines, and immunodiagnostics.Comment: 27 pages, 2 figure

Identifying Phenotypes Based on TCR Repertoire Using Machine Learning Methods

The adaptive immune system can prevent human beings being infected by pathogens. T cells, a kind of lymphocytes in the adaptive immunity, recognise antigens by T cell receptors (TCRs) and then generate cell-mediated immune responses. After primary immune responses, the adaptive immunity can generate corresponding immunological memory. TCRs are generated by a process of somatic gene rearrangement and therefore have high diversity. An individual's TCR repertoire can reveal his pathogen exposure history, which can assist in biological studies such as disease diagnosis. This master thesis targets to make predictions about phenotype statuses based on high-throughput TCR sequencing data using machine learning approaches, to see how accurate the phenotype identification based on TCR repertoire can be. The raw TCR data is preprocessed in three different ways and then proceed the next steps separately. Several feature selection approaches are applied to obtain the most important TCRs. The machine learning algorithms including Beta-binomial model (baseline), Logistic regression, Random forest and a Boosting algorithm LightGBM are trained and evaluated. Two datasets, Cytomegalovirus (CMV) and rheumatoid arthritis (RA), are explored. For the CMV dataset, Random forest performs best, even though only a little bit better than the baseline model. However, the classification results of the RA dataset are not so good whatever models used, and the best classifier is LightGBM. The results imply that the TCR data needs to be large enough to make powerful predictions. Using a sufficiently large dataset, the prediction ability of the baseline model is great, and there may exist certain algorithms such as Random forest outperform it

Quantifying changes in the T cell receptor repertoire during thymic development

One of the feats of adaptive immunity is its ability to recognize foreign pathogens while sparing the self. During maturation in the thymus, T cells are selected through the binding properties of their antigen-specific T-cell receptor (TCR), through the elimination of both weakly (positive selection) and strongly (negative selection) self-reactive receptors. However, the impact of thymic selection on the TCR repertoire is poorly understood. Here, we use transgenic Nur77-mice expressing a T-cell activation reporter to study the repertoires of thymic T cells at various stages of their development, including cells that do not pass selection. We combine high-throughput repertoire sequencing with statistical inference techniques to characterize the selection of the TCR in these distinct subsets. We find small but significant differences in the TCR repertoire parameters between the maturation stages, which recapitulate known differentiation pathways leading to the CD4+ and CD8+ subtypes. These differences can be simulated by simple models of selection acting linearly on the sequence features. We find no evidence of specific sequences or sequence motifs or features that are suppressed by negative selection. These results favour a collective or statistical model for T-cell self non-self discrimination, where negative selection biases the repertoire away from self recognition, rather than ensuring lack of self-reactivity at the single-cell level

Predicting T Cell Receptor Antigen Specificity From Structural Features Derived From Homology Models of Receptor-Peptide-Major Histocompatibility Complexes

The physical interaction between the T cell receptor (TCR) and its cognate antigen causes T cells to activate and participate in the immune response. Understanding this physical interaction is important in predicting TCR binding to a target epitope, as well as potential cross-reactivity. Here, we propose a way of collecting informative features of the binding interface from homology models of T cell receptor-peptide-major histocompatibility complex (TCR-pMHC) complexes. The information collected from these structures is sufficient to discriminate binding from non-binding TCR-pMHC pairs in multiple independent datasets. The classifier is limited by the number of crystal structures available for the homology modelling and by the size of the training set. However, the classifier shows comparable performance to sequence-based classifiers requiring much larger training sets

Applications of deep learning and statistical methods for a systems understanding of convergence in immune repertoires

Deep learning and adaptive immune receptor repertoire (AIRR) biology are two emerging fields that are highly compatible due to the inherent complexity of the immune systems and the enormous amount of data produced in AIRR-sequencing research combined with the revolutionary success of deep learning technology to make predictions about high dimensional complex systems/data. We took steps towards the effective utilisation of and statistical methods in repertoire immunology by undertaking one of the central problems in immunology, i.e. immune repertoire convergence. First, we took part in developing and testing an array of summary statistics for immune repertoires to gain insights into the descriptive features of immune repertoires and grant us the ability to compare repertoires. We collected the deepest sequencing datasets to address whether the population-wide genomic convergence of immunoglobulin molecules can be predicted. The immunoglobulin molecules were labelled with their “degree of commonality” (DoC), defined as the number of times an immunoglobulin V3J clonotype is observed in a population, where a V3J clonotype is defined by its V and J genes and CDR3 sequence. We developed various bespoke data analytics methods, informed at different stages by the summary statistics we had previously implemented. Importantly, we demonstrated that machine learning (ML) predictions for immune repertoires could lead to misleadingly positive outcomes if data is processed inappropriately due to “data leakage” and addressed this issue by implementing a leak-free data processing pipeline. Here, data leakage refers to immunoglobulin sequences with the same clonotype definition spreading across the train-validation-test splits in the ML task. We designed a multitude of bespoke deep neural network architectures, implemented under various modelling approaches, including a customised squeeze-and-excitation temporal convolutional neural network (SE-TCN) and a Transformer model. Unsurprisingly, given the continuous spectrum of DoCs, regression modelling proved to be the best approach, both in the granularity of predictions and error distribution. Finally, we report that our SE-TCN architecture under the regression modelling framework achieves state-of-the-art performance by achieving an overall mean absolute error (MAE) score of 0.083 and per-DoC error distributions with reasonably small standard deviations

A Novel computer assisted genomic test method to detect breast cancer in reduced cost and time using ensemble technique

Breast cancer is the leading cause of death among women around the world. It is a primary malignancy for which genetic markers have revealed the ability for clinical decision making. It is a genetic disease that generates due to gene mutations, but the cost of a genetic test is relatively high for a number of patients in developing nations like India. The results of a genetic test can take a few weeks to determine cancer. This time duration influences the prognosis of genes since certain patients suffer from a high rate of malignant cell proliferation. Therefore, a computer-assisted genetic test method (CAGT) is proposed to detect breast cancer. This test method will predict the gene expressions and convert these expressions in the state of mutation (under-expression (-1), transition (0) overexpression (1)) and afterwards perform the classification to get the benign and malignant class in reduced time and cost. In the research work, machine learning techniques are applied to identify the most responsive genes of breast cancer on the premises of the clinical report of a patient and generated a CAGT. In the research work, the hard voting ensemble approach is applied to detect breast cancer on the basis of most responsive genes by CAGT which leads to improving 3.5% accuracy in cancer classification

Investigating the Role of the T-Cell Receptor Using Targeted Capture and High-Throughput Sequencing

Maintaining a diverse immune repertoire is crucial for protection against a wide range of pathogens. Until recently, it has been difficult to quantify this diversity and define the range of a repertoire in a healthy individual. The rise of massively parallel highthroughput sequencing has enabled researchers to gather more information than ever before, but many published works concentrate on describing individual T-cell and immunoglobulin chains. This report introduces a novel method for sequencing all a, b, g and d chains of the T-cell receptor and all immunoglobulin chains simultaneously, using high-throughput sequencing and targeted capture. Data was obtained through this method using two sequencing platforms, the Illumina MiSeq and the Ion Torrent Personal Genome Machine, and the analysis of data focused on the T-cell receptor using diversity measures borrowed from other scientific fields. This work demonstrated the successes and limitations of the capture technique and suggests that immune repertoire sequencing could have dramatic impact on the understanding of the immune system across a range of disease states. Therefore, a preliminary investigation was carried out into the reconstitution of the immune repertoires following paediatric haematopoeitic stem cell transplants in the treatment of acute myeloid leukaemia

Quantitative Immunology for Physicists

The adaptive immune system is a dynamical, self-organized multiscale system that protects vertebrates from both pathogens and internal irregularities, such as tumours. For these reason it fascinates physicists, yet the multitude of different cells, molecules and sub-systems is often also petrifying. Despite this complexity, as experiments on different scales of the adaptive immune system become more quantitative, many physicists have made both theoretical and experimental contributions that help predict the behaviour of ensembles of cells and molecules that participate in an immune response. Here we review some recent contributions with an emphasis on quantitative questions and methodologies. We also provide a more general methods section that presents some of the wide array of theoretical tools used in the field.Comment: 78 page revie

Pacific Symposium on Biocomputing 2023

The Pacific Symposium on Biocomputing (PSB) 2023 is an international, multidisciplinary conference for the presentation and discussion of current research in the theory and application of computational methods in problems of biological significance. Presentations are rigorously peer reviewed and are published in an archival proceedings volume. PSB 2023 will be held on January 3-7, 2023 in Kohala Coast, Hawaii. Tutorials and workshops will be offered prior to the start of the conference.PSB 2023 will bring together top researchers from the US, the Asian Pacific nations, and around the world to exchange research results and address open issues in all aspects of computational biology. It is a forum for the presentation of work in databases, algorithms, interfaces, visualization, modeling, and other computational methods, as applied to biological problems, with emphasis on applications in data-rich areas of molecular biology.The PSB has been designed to be responsive to the need for critical mass in sub-disciplines within biocomputing. For that reason, it is the only meeting whose sessions are defined dynamically each year in response to specific proposals. PSB sessions are organized by leaders of research in biocomputing's 'hot topics.' In this way, the meeting provides an early forum for serious examination of emerging methods and approaches in this rapidly changing field