Zixiang Yin

Jiarui Li, Zixiang Yin, Samuel J Landry et al.

Deep learning models achieve remarkable predictive performance, yet their black-box nature limits transparency and trustworthiness. Although numerous explainable artificial intelligence (XAI) methods have been proposed, they primarily provide saliency maps or concepts (i.e., unstructured interpretability). Existing approaches often rely on auxiliary models (\eg, GPT, CLIP) to describe model behavior, thereby compromising faithfulness to the original models. We propose Interpretability to Explainability (I2X), a framework that builds structured explanations directly from unstructured interpretability by quantifying progress at selected checkpoints during training using prototypes extracted from post-hoc XAI methods (e.g., GradCAM). I2X answers the question of "why does it look there" by providing a structured view of both intra- and inter-class decision making during training. Experiments on MNIST and CIFAR10 demonstrate effectiveness of I2X to reveal prototype-based inference process of various image classification models. Moreover, we demonstrate that I2X can be used to improve predictions across different model architectures and datasets: we can identify uncertain prototypes recognized by I2X and then use targeted perturbation of samples that allows fine-tuning to ultimately improve accuracy. Thus, I2X not only faithfully explains model behavior but also provides a practical approach to guide optimization toward desired targets.

Jiarui Li, Zixiang Yin, Haley Smith et al.

CD8+ "killer" T cells and CD4+ "helper" T cells play a central role in the adaptive immune system by recognizing antigens presented by Major Histocompatibility Complex (pMHC) molecules via T Cell Receptors (TCRs). Modeling binding between T cells and the pMHC complex is fundamental to understanding basic mechanisms of human immune response as well as in developing therapies. While transformer-based models such as TULIP have achieved impressive performance in this domain, their black-box nature precludes interpretability and thus limits a deeper mechanistic understanding of T cell response. Most existing post-hoc explainable AI (XAI) methods are confined to encoder-only, co-attention, or model-specific architectures and cannot handle encoder-decoder transformers used in TCR-pMHC modeling. To address this gap, we propose Quantifying Cross-Attention Interaction (QCAI), a new post-hoc method designed to interpret the cross-attention mechanisms in transformer decoders. Quantitative evaluation is a challenge for XAI methods; we have compiled TCR-XAI, a benchmark consisting of 274 experimentally determined TCR-pMHC structures to serve as ground truth for binding. Using these structures we compute physical distances between relevant amino acid residues in the TCR-pMHC interaction region and evaluate how well our method and others estimate the importance of residues in this region across the dataset. We show that QCAI achieves state-of-the-art performance on both interpretability and prediction accuracy under the TCR-XAI benchmark.

Jiarui Li, Zixiang Yin, Zhengming Ding et al.

T cell receptor (TCR) recognition of peptide-MHC (pMHC) complexes is a central component of adaptive immunity, with implications for vaccine design, cancer immunotherapy, and autoimmune disease. While recent advances in machine learning have improved prediction of TCR-pMHC binding, the most effective approaches are black-box transformer models that cannot provide a rationale for predictions. Post-hoc explanation methods can provide insight with respect to the input but do not explicitly model biochemical mechanisms (e.g. known binding regions), as in TCR-pMHC binding. ``Explain-by-design'' models (i.e., with architectural components that can be examined directly after training) have been explored in other domains, but have not been used for TCR-pMHC binding. We propose explainable model layers (TCR-EML) that can be incorporated into protein-language model backbones for TCR-pMHC modeling. Our approach uses prototype layers for amino acid residue contacts drawn from known TCR-pMHC binding mechanisms, enabling high-quality explanations for predicted TCR-pMHC binding. Experiments of our proposed method on large-scale datasets demonstrate competitive predictive accuracy and generalization, and evaluation on the TCR-XAI benchmark demonstrates improved explainability compared with existing approaches.