Degui Zhi

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

Shenghan Zhang, Haoxuan Li, Ruixiang Tang et al.

Detailed phenotype information is fundamental to accurate diagnosis and risk estimation of diseases. As a rich source of phenotype information, electronic health records (EHRs) promise to empower diagnostic variant interpretation. However, how to accurately and efficiently extract phenotypes from the heterogeneous EHR data remains a challenge. In this work, we present PheME, an Ensemble framework using Multi-modality data of structured EHRs and unstructured clinical notes for accurate Phenotype prediction. Firstly, we employ multiple deep neural networks to learn reliable representations from the sparse structured EHR data and redundant clinical notes. A multi-modal model then aligns multi-modal features onto the same latent space to predict phenotypes. Secondly, we leverage ensemble learning to combine outputs from single-modal models and multi-modal models to improve phenotype predictions. We choose seven diseases to evaluate the phenotyping performance of the proposed framework. Experimental results show that using multi-modal data significantly improves phenotype prediction in all diseases, the proposed ensemble learning framework can further boost the performance.

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, Haiyang Yu, Degui Zhi et al.

We consider the problem of predicting gene expressions from DNA sequences. A key challenge of this task is to find the regulatory elements that control gene expressions. Here, we introduce Seq2Exp, a Sequence to Expression network explicitly designed to discover and extract regulatory elements that drive target gene expression, enhancing the accuracy of the gene expression prediction. Our approach captures the causal relationship between epigenomic signals, DNA sequences and their associated regulatory elements. Specifically, we propose to decompose the epigenomic signals and the DNA sequence conditioned on the causal active regulatory elements, and apply an information bottleneck with the Beta distribution to combine their effects while filtering out non-causal components. Our experiments demonstrate that Seq2Exp outperforms existing baselines in gene expression prediction tasks and discovers influential regions compared to commonly used statistical methods for peak detection such as MACS3. The source code is released as part of the AIRS library (https://github.com/divelab/AIRS/).

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).

Laila Rasmy, Jie Zhu, Zhiheng Li et al.

Recently, there is great interest to investigate the application of deep learning models for the prediction of clinical events using electronic health records (EHR) data. In EHR data, a patient's history is often represented as a sequence of visits, and each visit contains multiple events. As a result, deep learning models developed for sequence modeling, like recurrent neural networks (RNNs) are common architecture for EHR-based clinical events predictive models. While a large variety of RNN models were proposed in the literature, it is unclear if complex architecture innovations will offer superior predictive performance. In order to move this field forward, a rigorous evaluation of various methods is needed. In this study, we conducted a thorough benchmark of RNN architectures in modeling EHR data. We used two prediction tasks: the risk for developing heart failure and the risk of early readmission for inpatient hospitalization. We found that simple gated RNN models, including GRUs and LSTMs, often offer competitive results when properly tuned with Bayesian Optimization, which is in line with similar to findings in the natural language processing (NLP) domain. For reproducibility, Our codebase is shared at https://github.com/ZhiGroup/pytorch_ehr.

Fan Ma, Yuntian Liu, Xiang Lan et al.

Evidence derived from large-scale real-world data (RWD) is increasingly informing regulatory evaluation and healthcare decision-making. Administrative claims provide population-scale, longitudinal records of healthcare utilization, expenditure, and detailed coding of diagnoses, procedures, and medications, yet their potential as a substrate for healthcare foundation models remains largely unexplored. Here we present ReClaim, a generative transformer trained from scratch on 43.8 billion medical events from more than 200 million enrollees in the MarketScan claims data spanning 2008-2022. ReClaim models longitudinal trajectories across diagnoses, procedures, medications, and expenditure, and was scaled to 140 million, 700 million, and 1.7 billion parameters. Across over 1,000 disease-onset prediction tasks, ReClaim achieved a mean AUC of 75.6%, substantially outperforming disease-specific LightGBM (66.3%) and the transformer-based Delphi model (69.4%), with the largest gains for rare diseases. These advantages held across retrospective and prospective evaluations and in external validation on two independent datasets. Performance improved monotonically with scale, and post-training added 13.8 percentage points over pre-training alone. Beyond disease prediction, ReClaim captured financial outcomes and improved real-world evidence (RWE) analyses: for healthcare expenditure forecasting it increased explained variance from 0.28 to 0.37 relative to LightGBM, and in a target trial emulation it reduced systematic bias by 72% on average relative to Delphi. Together, these results establish administrative claims as a scalable substrate for healthcare foundation models and show that learned representations generalize across time periods and data sources, supporting disease surveillance, expenditure forecasting, and RWE generation.

Xingyu Su, Xiner Li, Masatoshi Uehara et al. · princeton

We address the problem of fine-tuning diffusion models for reward-guided generation in biomolecular design. While diffusion models have proven highly effective in modeling complex, high-dimensional data distributions, real-world applications often demand more than high-fidelity generation, requiring optimization with respect to potentially non-differentiable reward functions such as physics-based simulation or rewards based on scientific knowledge. Although RL methods have been explored to fine-tune diffusion models for such objectives, they often suffer from instability, low sample efficiency, and mode collapse due to their on-policy nature. In this work, we propose an iterative distillation-based fine-tuning framework that enables diffusion models to optimize for arbitrary reward functions. Our method casts the problem as policy distillation: it collects off-policy data during the roll-in phase, simulates reward-based soft-optimal policies during roll-out, and updates the model by minimizing the KL divergence between the simulated soft-optimal policy and the current model policy. Our off-policy formulation, combined with KL divergence minimization, enhances training stability and sample efficiency compared to existing RL-based methods. Empirical results demonstrate the effectiveness and superior reward optimization of our approach across diverse tasks in protein, small molecule, and regulatory DNA design.

Jianping He, Laila Rasmy, Degui Zhi et al.

Background: Recently, numerous foundation models pretrained on extensive data have demonstrated efficacy in disease prediction using Electronic Health Records (EHRs). However, there remains some unanswered questions on how to best utilize such models especially with very small fine-tuning cohorts. Methods: We utilized Med-BERT, an EHR-specific foundation model, and reformulated the disease binary prediction task into a token prediction task and a next visit mask token prediction task to align with Med-BERT's pretraining task format in order to improve the accuracy of pancreatic cancer (PaCa) prediction in both few-shot and fully supervised settings. Results: The reformulation of the task into a token prediction task, referred to as Med-BERT-Sum, demonstrates slightly superior performance in both few-shot scenarios and larger data samples. Furthermore, reformulating the prediction task as a Next Visit Mask Token Prediction task (Med-BERT-Mask) significantly outperforms the conventional Binary Classification (BC) prediction task (Med-BERT-BC) by 3% to 7% in few-shot scenarios with data sizes ranging from 10 to 500 samples. These findings highlight that aligning the downstream task with Med-BERT's pretraining objectives substantially enhances the model's predictive capabilities, thereby improving its effectiveness in predicting both rare and common diseases. Conclusion: Reformatting disease prediction tasks to align with the pretraining of foundation models enhances prediction accuracy, leading to earlier detection and timely intervention. This approach improves treatment effectiveness, survival rates, and overall patient outcomes for PaCa and potentially other cancers.

Jianping He, Laila Rasmy, Haifang Li et al.

Objective: This paper aims to prompt large language models (LLMs) for clinical temporal relation extraction (CTRE) in both few-shot and fully supervised settings. Materials and Methods: This study utilizes four LLMs: Encoder-based GatorTron-Base (345M)/Large (8.9B); Decoder-based LLaMA3-8B/MeLLaMA-13B. We developed full (FFT) and parameter-efficient (PEFT) fine-tuning strategies and evaluated these strategies on the 2012 i2b2 CTRE task. We explored four fine-tuning strategies for GatorTron-Base: (1) Standard Fine-Tuning, (2) Hard-Prompting with Unfrozen LLMs, (3) Soft-Prompting with Frozen LLMs, and (4) Low-Rank Adaptation (LoRA) with Frozen LLMs. For GatorTron-Large, we assessed two PEFT strategies-Soft-Prompting and LoRA with Frozen LLMs-leveraging Quantization techniques. Additionally, LLaMA3-8B and MeLLaMA-13B employed two PEFT strategies: LoRA strategy with Quantization (QLoRA) applied to Frozen LLMs using instruction tuning and standard fine-tuning. Results: Under fully supervised settings, Hard-Prompting with Unfrozen GatorTron-Base achieved the highest F1 score (89.54%), surpassing the SOTA model (85.70%) by 3.74%. Additionally, two variants of QLoRA adapted to GatorTron-Large and Standard Fine-Tuning of GatorTron-Base exceeded the SOTA model by 2.36%, 1.88%, and 0.25%, respectively. Decoder-based models with frozen parameters outperformed their Encoder-based counterparts in this setting; however, the trend reversed in few-shot scenarios. Discussions and Conclusions: This study presented new methods that significantly improved CTRE performance, benefiting downstream tasks reliant on CTRE systems. The findings underscore the importance of selecting appropriate models and fine-tuning strategies based on task requirements and data availability. Future work will explore larger models and broader CTRE applications.

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.