Martin Min NEC Labs America

Martin Renqiang Min

Department Head

Machine Learning


Disentangled Wasserstein Autoencoder for T-Cell Receptor Engineering

In protein biophysics, the separation between the functionally important residues (forming the active site or binding surface) and those that create the overall structure (the fold) is a well-established and fundamental concept. Identifying and modifying those functional sites is critical for protein engineering but computationally nontrivial, and requires significant domain knowledge. To automate this process from a data-driven perspective, we propose a disentangled Wasserstein autoencoder with an auxiliary classifier, which isolates the function-related patterns from the rest with theoretical guarantees. This enables one-pass protein sequence editing and improves the understanding of the resulting sequences and editing actionsinvolved. To demonstrate its effectiveness, we apply it to T-cell receptors (TCRs), a well-studied structure-function case. We show that our method can be used to alterthe function of TCRs without changing the structural backbone, outperforming several competing methods in generation quality and efficiency, and requiring only 10% of the running time needed by baseline models. To our knowledge, this is the first approach that utilizes disentangled representations for TCR engineering.

Few-Shot Video Classification via Representation Fusion and Promotion Learning

Recent few-shot video classification (FSVC) works achieve promising performance by capturing similarity across support and query samples with different temporal alignment strategies or learning discriminative features via Transformer block within each episode. However, they ignore two important issues: a) It is difficult to capture rich intrinsic action semantics from a limited number of support instances within each task. b) Redundant or irrelevant frames in videos easily weaken the positive influence of discriminative frames. To address these two issues, this paper proposes a novel Representation Fusion and Promotion Learning (RFPL) mechanism with two sub-modules: meta-action learning (MAL) and reinforced image representation (RIR). Concretely, during training stage, we perform online learning for seeking a task-shared meta-action bank to enrich task-specific action representation by injecting global knowledge. Besides, we exploit reinforcement learning to obtain the importance of each frame and refine the representation. This operation maximizes the contribution of discriminative frames to further capture the similarity of support and query samples from the same category. Our RFPL framework is highly flexible that it can be integrated with many existing FSVC methods. Extensive experiments show that RFPL significantly enhances the performance of existing FSVC models when integrated with them.

Conditional Image-to-Video Generation with Latent Flow Diffusion Models

Conditional image-to-video (cI2V) generation aims to synthesize a new plausible video starting from an image (e.g., a person’s face) and a condition (e.g., an action class label like smile). The key challenge of the cI2V task lies in the simultaneous generation of realistic spatial appearance and temporal dynamics corresponding to the given image and condition. In this paper, we propose an approach for cI2V using novel latent flow diffusion models (LFDM) that synthesize an optical flow sequence in the latent space based on the given condition to warp the given image. Compared to previous direct-synthesis-based works, our proposed LFDM can better synthesize spatial details and temporal motion by fully utilizing the spatial content of the given image and warping it in the latent space according to the generated temporally-coherent flow. The training of LFDM consists of two separate stages: (1) an unsupervised learning stage to train a latent flow auto-encoder for spatial content generation, including a flow predictor to estimate latent flow between pairs of video frames, and (2) a conditional learning stage to train a 3D-UNet-based diffusion model (DM) for temporal latent flow generation. Unlike previous DMs operating in pixel space or latent feature space that couples spatial and temporal information, the DM in our LFDM only needs to learn a low-dimensional latent flow space for motion generation, thus being more computationally efficient. We conduct comprehensive experiments on multiple datasets, where LFDM consistently outperforms prior arts. Furthermore, we show that LFDM can be easily adapted to new domains by simply finetuning the image decoder. Our code is available at

Source-Free Video Domain Adaptation with Spatial-Temporal-Historical Consistency Learning

Source-free domain adaptation (SFDA) is an emerging research topic that studies how to adapt a pretrained source model using unlabeled target data. It is derived from unsupervised domain adaptation but has the advantage of not requiring labeled source data to learn adaptive models. This makes it particularly useful in real-world applications where access to source data is restricted. While there has been some SFDA work for images, little attention has been paid to videos. Naively extending image-based methods to videos without considering the unique properties of videos often leads to unsatisfactory results. In this paper, we propose a simple and highly flexible method for Source-Free Video Domain Adaptation (SFVDA), which extensively exploits consistency learning for videos from spatial, temporal, and historical perspectives. Our method is based on the assumption that videos of the same action category are drawn from the same low-dimensional space, regardless of the spatio-temporal variations in the high-dimensional space that cause domain shifts. To overcome domain shifts, we simulate spatio-temporal variations by applying spatial and temporal augmentations on target videos, and encourage the model to make consistent predictions from a video and its augmented versions. Due to the simple design, our method can be applied to various SFVDA settings, and experiments show that our method achieves state-of-the-art performance for all the settings.

Exploring Compositional Visual Generation with Latent Classifier Guidance

Diffusion probabilistic models have achieved enormous success in the field of image generation and manipulation. In this paper, we explore a novel paradigm of using the diffusion model and classifier guidance in the latent semantic space for compositional visual tasks. Specifically, we train latent diffusion models and auxiliary latent classifiers to facilitate non-linear navigation of latent representation generation for any pre-trained generative model with a semantic latent space. We demonstrate that such conditional generation achieved by latent classifier guidance provably maximizes a lower bound of the conditional log probability during training. To maintain the original semantics during manipulation, we introduce a new guidance term, which we show is crucial for achieving compositionality. With additional assumptions, we show that the non-linear manipulation reduces to a simple latent arithmetic approach. We show that this paradigm based on latent classifier guidance is agnostic to pre-trained generative models, and present competitive results for both image generation and sequential manipulation of real and synthetic images. Our findings suggest that latent classifier guidance is a promising approach that merits further exploration, even in the presence of other strong competing methods.

T-Cell Receptor Optimization with Reinforcement Learning and Mutation Polices for Precision Immunotherapy

T cells monitor the health status of cells by identifying foreign peptides displayed on their surface. T-cell receptors (TCRs), which are protein complexes found on the surface of T cells, are able to bind to these peptides. This process is known as TCR recognition and constitutes a key step for immune response. Optimizing TCR sequences for TCR recognition represents a fundamental step towards the development of personalized treatments to trigger immune responses killing cancerous or virus-infected cells. In this paper, we formulated the search for these optimized TCRs as a reinforcement learning (RL) problem and presented a framework TCRPPO with a mutation policy using proximal policy optimization. TCRPPO mutates TCRs into effective ones that can recognize given peptides. TCRPPO leverages a reward function that combines the likelihoods of mutated sequences being valid TCRs measured by a new scoring function based on deep autoencoders, with the probabilities of mutated sequences recognizing peptides from a peptide-TCR interaction predictor. We compared TCRPPO with multiple baseline methods and demonstrated that TCRPPO significantly outperforms all the baseline methods to generate positive binding and valid TCRs. These results demonstrate the potential of TCRPPO for both precision immunotherapy and peptide-recognizing TCR motif discovery.

Binding Peptide Generation for MHC Class I Proteins with Deep Reinforcement Learning

Motivation: MHC Class I protein plays an important role in immunotherapy by presenting immunogenic peptides to anti-tumor immune cells. The repertoires of peptides for various MHC Class I proteins are distinct, which can be reflected by their diverse binding motifs. To characterize binding motifs for MHC Class I proteins, in vitro experiments have been conducted to screen peptides with high binding affinities to hundreds of given MHC Class I proteins. However, considering tens of thousands of known MHC Class I proteins, conducting in vitro experiments for extensive MHC proteins is infeasible, and thus a more efficient and scalable way to characterize binding motifs is needed.Results: We presented a de novo generation framework, coined PepPPO, to characterize binding motif for any given MHC Class I proteins via generating repertoires of peptides presented by them. PepPPO leverages a reinforcement learning agent with a mutation policy to mutate random input peptides into positive presented ones. Using PepPPO, we characterized binding motifs for around 10 000 known human MHC Class I proteins with and without experimental for the rapid screening of neoantigens at a much lower time cost than previous deep-learning methods.

On TCR Binding Predictors Failing to Generalize to Unseen Peptides

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.

Attentive Variational Information Bottleneck for TCR–peptide interaction prediction

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.

T-Cell Receptor-Peptide Interaction Prediction with Physical Model Augmented Pseudo-Labeling

Predicting the interactions between T-cell receptors (TCRs) and peptides is crucial for the development of personalized medicine and targeted vaccine in immunotherapy. Current datasets for training deep learning models of this purpose remain constrained without diverse TCRs and peptides. To combat the data scarcity issue presented in the current datasets, we propose to extend the training dataset by physical modeling of TCR-peptide pairs. Specifically, we compute the docking energies between auxiliary unknown TCR-peptide pairs as surrogate training labels. Then, we use these extended example-label pairs to train our model in a supervised fashion. Finally, we find that the AUC score for the prediction of the model can be further improved by pseudo-labeling of such unknown TCR-peptide pairs (by a trained teacher model), and re-training the model with those pseudo-labeled TCR-peptide pairs. Our proposed method that trains the deep neural network with physical modeling and data-augmented pseudo-labeling improves over baselines in the available two datasets. We also introduce a new dataset that contains over 80,000 unknown TCR-peptide pairs with docking energy scores.