Ramgopal R. Mettu

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, Yunbei Zhang et al.

T cell receptor (TCR)-epitope binding prediction is essential for understanding adaptive immunity and developing immunotherapies. Existing sequence- and structure-based models often generalize poorly to unseen epitopes and provide limited interpretability. Furthermore, the impact of generated structures on model learning remains unclear. We present TCR-SRIM, a structure-regularized interpretable-by-design model that combines protein language model embeddings with interpretable contact prototypes to capture residue-level TCR-epitope interactions. TCR-SRIM achieves state-of-the-art predictive performance and improved interpretation quality on the TCR-XAI benchmark. Using its inherent interpretability, we further evaluate the effect of generated structures on model learning. While structures predicted by AlphaFold3, TCRModel2, and tFold-TCR yield competitive performance, they lead to less accurate interaction patterns and reduced binding-site diversity than experimentally-resolved structures. Our results highlight limitations of current structure prediction models for TCR-epitope learning and demonstrate the value of interpretable-by-design models for studying generated biological structures.

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.

Chanyeol Yoo, Samuel Lensgraf, Robert Fitch et al.

The most widely used methods for toolpath planning in fused deposition 3D printing slice the input model into successive 2D layers in order to construct the toolpath. Unfortunately slicing-based methods can incur a substantial amount of wasted motion (i.e., the extruder is moving while not printing), particularly when features of the model are spatially separated. In recent years we have introduced a new paradigm that characterizes the space of feasible toolpaths using a dependency graph on the input model, along with several algorithms to search this space for toolpaths that optimize objective functions such as wasted motion or print time. A natural question that arises is, under what circumstances can we efficiently compute an optimal toolpath? In this paper, we give an algorithm for computing fused deposition modeling (FDM) toolpaths that utilizes Monte Carlo Tree Search (MCTS), a powerful general-purpose method for navigating large search spaces that is guaranteed to converge to the optimal solution. Under reasonable assumptions on printer geometry that allow us to compress the dependency graph, our MCTS-based algorithm converges to find the optimal toolpath. We validate our algorithm on a dataset of 75 models and show it performs on par with our previous best local search-based algorithm in terms of toolpath quality. In prior work we speculated that the performance of local search was near optimal, and we examine in detail the properties of the models and MCTS executions that lead to better or worse results than local search.

Umut A. Acar, Alexander T. Ihler, Ramgopal Mettu et al.

Many algorithms and applications involve repeatedly solving variations of the same inference problem; for example we may want to introduce new evidence to the model or perform updates to conditional dependencies. The goal of adaptive inference is to take advantage of what is preserved in the model and perform inference more rapidly than from scratch. In this paper, we describe techniques for adaptive inference on general graphs that support marginal computation and updates to the conditional probabilities and dependencies in logarithmic time. We give experimental results for an implementation of our algorithm, and demonstrate its potential performance benefit in the study of protein structure.