Anja Mosch works at NEC Laboratories Europe.

Posts

On TCR Binding Predictors Failing to Generalize to Unseen Peptides

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Several recent studies investigate TCR-peptide/-pMHC binding prediction using machine learning or deep learning approaches. Many of these methods achieve impressive results on test sets, which include peptide sequences that are also included in the training set. In this work, we investigate how state of the-art deep learning models for TCR-peptide/-pMHC binding prediction generalize to unseen peptides. We create a dataset including positive samples from IEDB, VDJdb, McPAS-TCR, and the MIRA set, as well as negative samples from both randomization and 10X Genomics assays. We name this collection of samples TChard. We propose the hard split, a simple heuristic for training/test split, which ensures that test samples exclusively present peptides that do not belong to the training set. We investigate the effect of different training/test splitting techniques on the models’ test performance, as well as the effect of training and testing the models using mismatched negative samples generated randomly, in addition to the negative samples derived from assays. Our results show that modern deep learning methods fail to generalize to unseen peptides. We provide an explanation why this happens and verify our hypothesis on the TChard dataset. We then conclude that robust prediction of TCR recognition is still far for being solved.

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Attentive Variational Information Bottleneck for TCR–peptide interaction prediction

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We present a multi-sequence generalization of Variational Information Bottleneck and call the resulting model Attentive Variational Information Bottleneck (AVIB). Our AVIB model leverages multi-head self-attention to implicitly approximate a posterior distribution over latent encodings conditioned on multiple input sequences. We apply AVIB to a fundamental immuno-oncology problem: predicting the interactions between T-cell receptors (TCRs) and peptides.ResultsExperimental results on various datasets show that AVIB significantly outperforms state-of-the-art methods for TCR–peptide interaction prediction. Additionally, we show that the latent posterior distribution learned by AVIB is particularly effective for the unsupervised detection of out-of-distribution amino acid sequences.

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