Dataset Information

Optimized Threshold Inference for Partitioning of Clones From High-Throughput B Cell Repertoire Sequencing Data.

ABSTRACT: During adaptive immune responses, activated B cells expand and undergo somatic hypermutation of their B cell receptor (BCR), forming a clone of diversified cells that can be related back to a common ancestor. Identification of B cell clones from high-throughput Adaptive Immune Receptor Repertoire sequencing (AIRR-seq) data relies on computational analysis. Recently, we proposed an automated method to partition sequences into clonal groups based on single-linkage hierarchical clustering of the BCR junction region with length-normalized Hamming distance metric. This method could identify clonal sequences with high confidence on several benchmark experimental and simulated data sets. However, determining the threshold to cut the hierarchy, a key step in the method, is computationally expensive for large-scale repertoire sequencing data sets. Moreover, the methodology was unable to provide estimates of accuracy for new data. Here, a new method is presented that addresses this computational bottleneck and also provides a study-specific estimation of performance, including sensitivity and specificity. The method uses a finite mixture model fitting procedure for learning the parameters of two univariate curves which fit the bimodal distribution of the distance vector between pairs of sequences. These distributions are used to estimate the performance of different threshold choices for partitioning sequences into clones. These performance estimates are validated using simulated and experimental data sets. With this method, clones can be identified from AIRR-seq data with sensitivity and specificity profiles that are user-defined based on the overall goals of the study.

SUBMITTER: Nouri N

PROVIDER: S-EPMC6070604 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Publications

Optimized Threshold Inference for Partitioning of Clones From High-Throughput B Cell Repertoire Sequencing Data.

Nouri Nima N Kleinstein Steven H SH

Frontiers in immunology 20180726

During adaptive immune responses, activated B cells expand and undergo somatic hypermutation of their B cell receptor (BCR), forming a clone of diversified cells that can be related back to a common ancestor. Identification of B cell clones from high-throughput Adaptive Immune Receptor Repertoire sequencing (AIRR-seq) data relies on computational analysis. Recently, we proposed an automated method to partition sequences into clonal groups based on single-linkage hierarchical clustering of the BC ...[more]

PMID: 30093903

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Project description:Motivation:B cells derive their antigen-specificity through the expression of Immunoglobulin (Ig) receptors on their surface. These receptors are initially generated stochastically by somatic re-arrangement of the DNA and further diversified following antigen-activation by a process of somatic hypermutation, which introduces mainly point substitutions into the receptor DNA at a high rate. Recent advances in next-generation sequencing have enabled large-scale profiling of the B cell Ig repertoire from blood and tissue samples. A key computational challenge in the analysis of these data is partitioning the sequences to identify descendants of a common B cell (i.e. a clone). Current methods group sequences using a fixed distance threshold, or a likelihood calculation that is computationally-intensive. Here, we propose a new method based on spectral clustering with an adaptive threshold to determine the local sequence neighborhood. Validation using simulated and experimental datasets demonstrates that this method has high sensitivity and specificity compared to a fixed threshold that is optimized for these measures. In addition, this method works on datasets where choosing an optimal fixed threshold is difficult and is more computationally efficient in all cases. The ability to quickly and accurately identify members of a clone from repertoire sequencing data will greatly improve downstream analyses. Clonally-related sequences cannot be treated independently in statistical models, and clonal partitions are used as the basis for the calculation of diversity metrics, lineage reconstruction and selection analysis. Thus, the spectral clustering-based method here represents an important contribution to repertoire analysis. Availability and implementation:Source code for this method is freely available in the SCOPe (Spectral Clustering for clOne Partitioning) R package in the Immcantation framework: www.immcantation.org under the CC BY-SA 4.0 license. Supplementary information:Supplementary data are available at Bioinformatics online.

Dataset Information

Optimized Threshold Inference for Partitioning of Clones From High-Throughput B Cell Repertoire Sequencing Data.

Publications

Optimized Threshold Inference for Partitioning of Clones From High-Throughput B Cell Repertoire Sequencing Data.

Similar Datasets

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