Ziqian Xie

Xingzhong Zhao, Ziqian Xie, Islam et al.

Motivation: Modern bioinformatics workflows, particularly in imaging and representation learning, can generate thousands to tens of thousands of quantitative phenotypes from a single cohort. In such settings, running genome-wide association analyses trait by trait rapidly becomes a computational bottleneck. While established GWAS tools are highly effective for individual traits, they are not optimized for phenotype-rich screening workflows in which the same genotype matrix is reused across a large phenotype panel. Results: We present TorchGWAS, a framework for high-throughput association testing of large phenotype panels through hardware acceleration. The current public release provides stable Python and command-line workflows for linear GWAS and multivariate phenotype screening, supports NumPy, PLINK, and BGEN genotype inputs, aligns phenotype and covariate tables by sample identifier, and performs covariate adjustment internally. In a benchmark with 8.9 million markers and 23,000 samples, fastGWA required approximately 100 second per phenotype on an AMD EPYC 7763 64-core CPU, whereas TorchGWAS completed 2,048 phenotypes in 10 minute and 20,480 phenotypes in 20 minutes on a single NVIDIA A100 GPU, corresponding to an approximately 300- to 1700-fold increase in phenotype throughput. TorchGWAS therefore makes large-scale GWAS screening practical in phenotype-rich settings where thousands of quantitative traits must be evaluated efficiently. Availability and implementation: TorchGWAS is implemented in Python and distributed as a documented source repository at https://github.com/ZhiGroup/TorchGWAS. The current release provides a command-line interface, packaged source code, tutorials, benchmark scripts, and example workflows.

Ming-Hsiu Wu, Ziqian Xie, Shuiwang Ji et al.

Advancements in AI for science unlocks capabilities for critical drug discovery tasks such as protein-ligand binding affinity prediction. However, current models overfit to existing oversimplified datasets that does not represent naturally occurring and biologically relevant proteins with modifications. In this work, we curate a complete and modification-aware version of the widely used DAVIS dataset by incorporating 4,032 kinase-ligand pairs involving substitutions, insertions, deletions, and phosphorylation events. This enriched dataset enables benchmarking of predictive models under biologically realistic conditions. Based on this new dataset, we propose three benchmark settings-Augmented Dataset Prediction, Wild-Type to Modification Generalization, and Few-Shot Modification Generalization-designed to assess model robustness in the presence of protein modifications. Through extensive evaluation of both docking-free and docking-based methods, we find that docking-based model generalize better in zero-shot settings. In contrast, docking-free models tend to overfit to wild-type proteins and struggle with unseen modifications but show notable improvement when fine-tuned on a small set of modified examples. We anticipate that the curated dataset and benchmarks offer a valuable foundation for developing models that better generalize to protein modifications, ultimately advancing precision medicine in drug discovery. The benchmark is available at: https://github.com/ZhiGroup/DAVIS-complete

Yaochen Xie, Ziqian Xie, Sheikh Muhammad Saiful Islam et al.

Genome-wide association studies (GWAS) are used to identify relationships between genetic variations and specific traits. When applied to high-dimensional medical imaging data, a key step is to extract lower-dimensional, yet informative representations of the data as traits. Representation learning for imaging genetics is largely under-explored due to the unique challenges posed by GWAS in comparison to typical visual representation learning. In this study, we tackle this problem from the mutual information (MI) perspective by identifying key limitations of existing methods. We introduce a trans-modal learning framework Genetic InfoMax (GIM), including a regularized MI estimator and a novel genetics-informed transformer to address the specific challenges of GWAS. We evaluate GIM on human brain 3D MRI data and establish standardized evaluation protocols to compare it to existing approaches. Our results demonstrate the effectiveness of GIM and a significantly improved performance on GWAS.

Xingyu Su, Xiner Li, Yuchao Lin et al.

We consider controllable DNA sequence design, where sequences are generated by conditioning on specific biological properties. While language models (LMs) such as GPT and BERT have achieved remarkable success in natural language generation, their application to DNA sequence generation remains largely underexplored. In this work, we introduce ATGC-Gen, an Automated Transformer Generator for Controllable Generation, which leverages cross-modal encoding to integrate diverse biological signals. ATGC-Gen is instantiated with both decoder-only and encoder-only transformer architectures, allowing flexible training and generation under either autoregressive or masked recovery objectives. We evaluate ATGC-Gen on representative tasks including promoter and enhancer sequence design, and further introduce a new dataset based on ChIP-Seq experiments for modeling protein binding specificity. Our experiments demonstrate that ATGC-Gen can generate fluent, diverse, and biologically relevant sequences aligned with the desired properties. Compared to prior methods, our model achieves notable improvements in controllability and functional relevance, highlighting the potential of language models in advancing programmable genomic design. The source code is released at (https://github.com/divelab/AIRS/blob/main/OpenBio/ATGC_Gen).

Xu Pan, Aaron Philip, Ziqian Xie et al.

Self-attention in vision transformers is often thought to perform perceptual grouping where tokens attend to other tokens with similar embeddings, which could correspond to semantically similar features of an object. However, attending to dissimilar tokens can be beneficial by providing contextual information. We propose to analyze the query-key interaction by the singular value decomposition of the interaction matrix (i.e. ${\textbf{W}_q}^\top\textbf{W}_k$). We find that in many ViTs, especially those with classification training objectives, early layers attend more to similar tokens, while late layers show increased attention to dissimilar tokens, providing evidence corresponding to perceptual grouping and contextualization, respectively. Many of these interactions between features represented by singular vectors are interpretable and semantic, such as attention between relevant objects, between parts of an object, or between the foreground and background. This offers a novel perspective on interpreting the attention mechanism, which contributes to understanding how transformer models utilize context and salient features when processing images.

Xu Pan, Ely Hahami, Jingxuan Fan et al.

Despite autoregressive large language models (arLLMs) being the current dominant paradigm in language modeling, they resist knowledge injection via fine-tuning due to inherent shortcomings such as the "reversal curse" -- the challenge of answering questions that reverse the original information order in the training sample. Masked diffusion large language models (dLLMs) are rapidly emerging as a powerful alternative to the arLLM paradigm, with evidence of better data efficiency and free of the "reversal curse" in pre-training. However, it is unknown whether these advantages extend to the post-training phase, i.e. whether pre-trained dLLMs can easily acquire new knowledge through fine-tuning. On three diverse datasets, we fine-tune arLLMs and dLLMs, evaluating them with forward and backward style Question Answering (QA) to probe knowledge generalization and the reversal curse. Our results confirm that arLLMs critically rely on extensive data augmentation via paraphrases for QA generalization, and paraphrases are only effective when their information order matches the QA style. Conversely, dLLMs achieve high accuracies on both forward and backward QAs without paraphrases; adding paraphrases yields only marginal gains. Lastly, inspired by the dLLM's performance, we introduce a novel masked fine-tuning paradigm for knowledge injection into pre-trained arLLMs. This proposed method successfully and drastically improves the data efficiency of arLLM fine-tuning, effectively closing the performance gap with dLLMs.

Xu Pan, Jingxuan Fan, Zidi Xiong et al.

Large language models (LLMs) can bias towards relying on their own or the user's information in chat history, leading to overly stubborn or agreeable behaviors in multi-turn conversations. In this paper, we formalize this model characteristic as user-assistant bias and introduce an 8k multi-turn conversation dataset $\textbf{UserAssist}$, which we use to benchmark, understand and manipulate the user-assistant bias in frontier LLMs. Leveraging $\textbf{UserAssist-test}$, we first benchmark the user-assistant bias of 26 commercial and 26 open-weight models. Commercial models show various levels of user bias. Evaluation on open-weight models reveals significant user bias in the instruction-tuned models, and weak user bias in reasoning (or reasoning-distilled) models. We then perform controlled fine-tuning experiments to pinpoint the post-training recipe contributing to these bias shifts: human preference alignment increases user bias, while training on chain-of-thought reasoning traces decreases it. Finally, we demonstrate that user-assistant bias can be bidirectionally adjusted by performing direct preference optimization (DPO) on $\textbf{UserAssist-train}$, and generalizes well to both in-domain and out-of-domain conversations. Our results provide insights into how the LLM integrates information from different sources, and also a viable way to detect and control model abnormalities.

Laila Rasmy, Yang Xiang, Ziqian Xie et al.

Deep learning (DL) based predictive models from electronic health records (EHR) deliver impressive performance in many clinical tasks. Large training cohorts, however, are often required to achieve high accuracy, hindering the adoption of DL-based models in scenarios with limited training data size. Recently, bidirectional encoder representations from transformers (BERT) and related models have achieved tremendous successes in the natural language processing domain. The pre-training of BERT on a very large training corpus generates contextualized embeddings that can boost the performance of models trained on smaller datasets. We propose Med-BERT, which adapts the BERT framework for pre-training contextualized embedding models on structured diagnosis data from 28,490,650 patients EHR dataset. Fine-tuning experiments are conducted on two disease-prediction tasks: (1) prediction of heart failure in patients with diabetes and (2) prediction of pancreatic cancer from two clinical databases. Med-BERT substantially improves prediction accuracy, boosting the area under receiver operating characteristics curve (AUC) by 2.02-7.12%. In particular, pre-trained Med-BERT substantially improves the performance of tasks with very small fine-tuning training sets (300-500 samples) boosting the AUC by more than 20% or equivalent to the AUC of 10 times larger training set. We believe that Med-BERT will benefit disease-prediction studies with small local training datasets, reduce data collection expenses, and accelerate the pace of artificial intelligence aided healthcare.