Generation of Drug-Induced Cardiac Reactions towards Virtual Clinical Trials

Clinical trials are pivotal in cardiac drug development, yet they often fail due to inadequate efficacy and unexpected safety issues, leading to significant financial losses. Using in-silico trials to replace a part of physical clinical trials, e.g., leveraging advanced generative models to generate drug-influenced electrocardiograms (ECGs), seems an effective method to reduce financial risk and potential harm to trial participants. While existing generative models have demonstrated progress in ECG generation, they fall short in modeling drug reactions due to limited fidelity and inability to capture individualized drug response patterns. In this paper, we propose a Drug-Aware Diffusion Model (DADM), which could simulate individualized drug reactions while ensuring fidelity. To ensure fidelity, we construct a set of ordinary differential equations to provide external physical knowledge (EPK) of the realistic ECG morphology. The EPK is used to adaptively constrain the morphology of the generated ECGs through a dynamic cross-attention (DCA) mechanism. Furthermore, we propose an extension of ControlNet to incorporate demographic and drug data, simulating individual drug reactions. We compare DADM with the other eight state-of-the-art ECG generative models on two real-world databases covering 8 types of drug regimens. The results demonstrate that DADM can more accurately simulate drug-induced changes in ECGs, improving the accuracy by at least 5.79% and recall by 8%.

Take Your Steps: Hierarchically Efficient Pulmonary Disease Screening via CT Volume Compression

Deep learning models are widely used to process Computed Tomography (CT) data in the automated screening of pulmonary diseases, significantly reducing the workload of physicians. However, the three-dimensional nature of CT volumes involves an excessive number of voxels, which significantly increases the complexity of model processing. Previous screening approaches often overlook this issue, which undoubtedly reduces screening efficiency. Towards efficient and effective screening, we design a hierarchical approach to reduce the computational cost of pulmonary disease screening. The new approach re-organizes the screening workflows into three steps. First, we propose a Computed Tomography Volume Compression (CTVC) method to select a small slice subset that comprehensively represents the whole CT volume. Second, the selected CT slices are used to detect pulmonary diseases coarsely via a lightweight classification model. Third, an uncertainty measurement strategy is applied to identify samples with low diagnostic confidence, which are re-detected by radiologists. Experiments on two public pulmonary disease datasets demonstrate that our approach achieves comparable accuracy and recall while reducing the time by 50%-70% compared with the counterparts using full CT volumes. Besides, we also found that our approach outperforms previous cutting-edge CTVC methods in retaining important indications after compression.

S$^2$ALM: Sequence-Structure Pre-trained Large Language Model for Comprehensive Antibody Representation Learning

Antibodies safeguard our health through their precise and potent binding to specific antigens, demonstrating promising therapeutic efficacy in the treatment of numerous diseases, including COVID-19. Recent advancements in biomedical language models have shown the great potential to interpret complex biological structures and functions. However, existing antibody specific models have a notable limitation that they lack explicit consideration for antibody structural information, despite the fact that both 1D sequence and 3D structure carry unique and complementary insights into antibody behavior and functionality. This paper proposes Sequence-Structure multi-level pre-trained Antibody Language Model (S$^2$ALM), combining holistic sequential and structural information in one unified, generic antibody foundation model. We construct a hierarchical pre-training paradigm incorporated with two customized multi-level training objectives to facilitate the modeling of comprehensive antibody representations. S$^2$ALM's representation space uncovers inherent functional binding mechanisms, biological evolution properties and structural interaction patterns. Pre-trained over 75 million sequences and 11.7 million structures, S$^2$ALM can be adopted for diverse downstream tasks: accurately predicting antigen-antibody binding affinities, precisely distinguishing B cell maturation stages, identifying antibody crucial binding positions, and specifically designing novel coronavirus-binding antibodies. Remarkably, S$^2$ALM outperforms well-established and renowned baselines and sets new state-of-the-art performance across extensive antibody specific understanding and generation tasks. S$^2$ALM's ability to model comprehensive and generalized representations further positions its potential to advance real-world therapeutic antibody development, potentially addressing unmet academic, industrial, and clinical needs.

KA$^2$ER: Knowledge Adaptive Amalgamation of ExpeRts for Medical Images Segmentation

Recently, many foundation models for medical image analysis such as MedSAM, SwinUNETR have been released and proven to be useful in multiple tasks. However, considering the inherent heterogeneity and inhomogeneity of real-world medical data, directly applying these models to specific medical image segmentation tasks often leads to negative domain shift effects, which can severely weaken the model's segmentation capabilities. To this end, we propose an adaptive amalgamation knowledge framework that aims to train a versatile foundation model to handle the joint goals of multiple expert models, each specialized for a distinct task. Specifically, we first train an nnUNet-based expert model for each task, and reuse the pre-trained SwinUNTER as the target foundation model. Then, the input data for all challenging tasks are encoded in the foundation model and the expert models, respectively, and their backbone features are jointly projected into the adaptive amalgamation layer. Within the hidden layer, the hierarchical attention mechanisms are designed to achieve adaptive merging of the target model to the hidden layer feature knowledge of all experts, which significantly reduces the domain shift arising from the inter-task differences. Finally, the gold amalgamated features and the prompt features are fed into the mask decoder to obtain the segmentation results. Extensive experiments conducted in these challenging tasks demonstrate the effectiveness and adaptability of our foundation model for real-world medical image segmentation.

Enhancing Semi-Supervised Learning via Representative and Diverse Sample Selection

Semi-Supervised Learning (SSL) has become a preferred paradigm in many deep learning tasks, which reduces the need for human labor. Previous studies primarily focus on effectively utilising the labelled and unlabeled data to improve performance. However, we observe that how to select samples for labelling also significantly impacts performance, particularly under extremely low-budget settings. The sample selection task in SSL has been under-explored for a long time. To fill in this gap, we propose a Representative and Diverse Sample Selection approach (RDSS). By adopting a modified Frank-Wolfe algorithm to minimise a novel criterion $\alpha$-Maximum Mean Discrepancy ($\alpha$-MMD), RDSS samples a representative and diverse subset for annotation from the unlabeled data. We demonstrate that minimizing $\alpha$-MMD enhances the generalization ability of low-budget learning. Experimental results show that RDSS consistently improves the performance of several popular SSL frameworks and outperforms the state-of-the-art sample selection approaches used in Active Learning (AL) and Semi-Supervised Active Learning (SSAL), even with constrained annotation budgets.

MambaCapsule: Towards Transparent Cardiac Disease Diagnosis with Electrocardiography Using Mamba Capsule Network

Cardiac arrhythmia, a condition characterized by irregular heartbeats, often serves as an early indication of various heart ailments. With the advent of deep learning, numerous innovative models have been introduced for diagnosing arrhythmias using Electrocardiogram (ECG) signals. However, recent studies solely focus on the performance of models, neglecting the interpretation of their results. This leads to a considerable lack of transparency, posing a significant risk in the actual diagnostic process. To solve this problem, this paper introduces MambaCapsule, a deep neural networks for ECG arrhythmias classification, which increases the explainability of the model while enhancing the accuracy.Our model utilizes Mamba for feature extraction and Capsule networks for prediction, providing not only a confidence score but also signal features. Akin to the processing mechanism of human brain, the model learns signal features and their relationship between them by reconstructing ECG signals in the predicted selection. The model evaluation was conducted on MIT-BIH and PTB dataset, following the AAMI standard. MambaCapsule has achieved a total accuracy of 99.54% and 99.59% on the test sets respectively. These results demonstrate the promising performance of under the standard test protocol.

Multi-Modal CLIP-Informed Protein Editing

Proteins govern most biological functions essential for life, but achieving controllable protein discovery and optimization remains challenging. Recently, machine learning-assisted protein editing (MLPE) has shown promise in accelerating optimization cycles and reducing experimental workloads. However, current methods struggle with the vast combinatorial space of potential protein edits and cannot explicitly conduct protein editing using biotext instructions, limiting their interactivity with human feedback. To fill these gaps, we propose a novel method called ProtET for efficient CLIP-informed protein editing through multi-modality learning. Our approach comprises two stages: in the pretraining stage, contrastive learning aligns protein-biotext representations encoded by two large language models (LLMs), respectively. Subsequently, during the protein editing stage, the fused features from editing instruction texts and original protein sequences serve as the final editing condition for generating target protein sequences. Comprehensive experiments demonstrated the superiority of ProtET in editing proteins to enhance human-expected functionality across multiple attribute domains, including enzyme catalytic activity, protein stability and antibody specific binding ability. And ProtET improves the state-of-the-art results by a large margin, leading to significant stability improvements of 16.67% and 16.90%. This capability positions ProtET to advance real-world artificial protein editing, potentially addressing unmet academic, industrial, and clinical needs.

TrialBench: Multi-Modal Artificial Intelligence-Ready Clinical Trial Datasets

Clinical trials are pivotal for developing new medical treatments, yet they typically pose some risks such as patient mortality, adverse events, and enrollment failure that waste immense efforts spanning over a decade. Applying artificial intelligence (AI) to forecast or simulate key events in clinical trials holds great potential for providing insights to guide trial designs. However, complex data collection and question definition requiring medical expertise and a deep understanding of trial designs have hindered the involvement of AI thus far. This paper tackles these challenges by presenting a comprehensive suite of meticulously curated AIready datasets covering multi-modal data (e.g., drug molecule, disease code, text, categorical/numerical features) and 8 crucial prediction challenges in clinical trial design, encompassing prediction of trial duration, patient dropout rate, serious adverse event, mortality rate, trial approval outcome, trial failure reason, drug dose finding, design of eligibility criteria. Furthermore, we provide basic validation methods for each task to ensure the datasets' usability and reliability. We anticipate that the availability of such open-access datasets will catalyze the development of advanced AI approaches for clinical trial design, ultimately advancing clinical trial research and accelerating medical solution development. The curated dataset, metrics, and basic models are publicly available at https://github.com/ML2Health/ML2ClinicalTrials/tree/main/AI4Trial.

Multi-rater Prompting for Ambiguous Medical Image Segmentation

Multi-rater annotations commonly occur when medical images are independently annotated by multiple experts (raters). In this paper, we tackle two challenges arisen in multi-rater annotations for medical image segmentation (called ambiguous medical image segmentation): (1) How to train a deep learning model when a group of raters produces a set of diverse but plausible annotations, and (2) how to fine-tune the model efficiently when computation resources are not available for re-training the entire model on a different dataset domain. We propose a multi-rater prompt-based approach to address these two challenges altogether. Specifically, we introduce a series of rater-aware prompts that can be plugged into the U-Net model for uncertainty estimation to handle multi-annotation cases. During the prompt-based fine-tuning process, only 0.3% of learnable parameters are required to be updated comparing to training the entire model. Further, in order to integrate expert consensus and disagreement, we explore different multi-rater incorporation strategies and design a mix-training strategy for comprehensive insight learning. Extensive experiments verify the effectiveness of our new approach for ambiguous medical image segmentation on two public datasets while alleviating the heavy burden of model re-training.

TWIN-GPT: Digital Twins for Clinical Trials via Large Language Model

Recently, there has been a burgeoning interest in virtual clinical trials, which simulate real-world scenarios and hold the potential to significantly enhance patient safety, expedite development, reduce costs, and contribute to the broader scientific knowledge in healthcare. Existing research often focuses on leveraging electronic health records (EHRs) to support clinical trial outcome prediction. Yet, trained with limited clinical trial outcome data, existing approaches frequently struggle to perform accurate predictions. Some research has attempted to generate EHRs to augment model development but has fallen short in personalizing the generation for individual patient profiles. Recently, the emergence of large language models has illuminated new possibilities, as their embedded comprehensive clinical knowledge has proven beneficial in addressing medical issues. In this paper, we propose a large language model-based digital twin creation approach, called TWIN-GPT. TWIN-GPT can establish cross-dataset associations of medical information given limited data, generating unique personalized digital twins for different patients, thereby preserving individual patient characteristics. Comprehensive experiments show that using digital twins created by TWIN-GPT can boost clinical trial outcome prediction, exceeding various previous prediction approaches. Besides, we also demonstrate that TWIN-GPT can generate high-fidelity trial data that closely approximate specific patients, aiding in more accurate result predictions in data-scarce situations. Moreover, our study provides practical evidence for the application of digital twins in healthcare, highlighting its potential significance.