Zhanliang Wang

Hongzhuo Chen, Zhanliang Wang, Quan M. Nguyen et al.

Background: Medical Digital Twins (MDTs) are computational representations of individual patients that integrate clinical, genomic, and physiological data to support diagnosis, treatment planning, and outcome prediction. However, most MDTs remain static or passively updated, creating a critical synchronization gap, especially in rare genetic disorders where phenotypes, genomic interpretations, and care guidelines evolve over time. Methods: We propose an agent-orchestrated digital twin framework using OpenClaw's proactive "heartbeat" mechanism and modular Agent Skills. This Autonomous Agent-orchestrated Digital Twin (AADT) system continuously monitors local and external data streams (e.g., patient-reported phenotypes and updates in variant classification databases) and executes automated workflows for data ingestion, normalization, state updates, and trigger-based analysis. Results: A prototype implementation demonstrates that agent orchestration can continuously synchronize MDT states with both longitudinal phenotype updates and evolving genomic knowledge. In rare disease settings, this enables earlier diagnosis and more accurate modeling of disease progression. We present two case studies, including variant reinterpretation and longitudinal phenotype tracking, highlighting how AADTs support timely, auditable updates for both research and clinical care. Conclusion: The AADT framework addresses the key bottleneck of real-time synchronization in MDTs, enabling scalable and continuously updated patient models. We also discuss data security considerations and mitigation strategies through human-in-the-loop system design.

Zhanliang Wang, Hongzhuo Chen, Quan Minh Nguyen et al.

Long-tailed classification, where a small number of frequent classes dominate many rare ones, remains challenging because models systematically favor frequent classes at inference time. Existing post-hoc methods such as logit adjustment address this by adding a fixed classwise offset to the base-model logits. However, the correction required to restore the relative ranking of two classes need not be constant across inputs, and a fixed offset cannot adapt to such variation. We study this problem through Bayes-optimal reranking on a base-model top-k shortlist. The gap between the optimal score and the base score, the residual correction, decomposes into a classwise component that is constant within each class, and a pairwise component that depends on the input and competing labels. When the residual is purely classwise, a fixed offset suffices to recover the Bayes-optimal ordering. We further show that when the same label pair induces incompatible ordering constraints across contexts, no fixed offset can achieve this recovery. This decomposition leads to testable predictions regarding when pairwise correction can improve performance and when cannot. We develop REPAIR (Reranking via Pairwise residual correction), a lightweight post-hoc reranker that combines a shrinkage-stabilized classwise term with a linear pairwise term driven by competition features on the shortlist. Experiments on five benchmarks spanning image classification, species recognition, scene recognition, and rare disease diagnosis confirm that the decomposition explains where pairwise correction helps and where classwise correction alone suffices.

Zhanliang Wang, Kai Wang

Multimodal AI models have achieved impressive performance in tasks that require integrating information from multiple modalities, such as vision and language. However, their "black-box" nature poses a major barrier to deployment in high-stakes applications where interpretability and trustworthiness are essential. How to explain cross-modal interactions in multimodal AI models remains a major challenge. While existing model explanation methods, such as attention map and Grad-CAM, offer coarse insights into cross-modal relationships, they cannot precisely quantify the synergistic effects between modalities, and are limited to open-source models with accessible internal weights. Here we introduce MultiSHAP, a model-agnostic interpretability framework that leverages the Shapley Interaction Index to attribute multimodal predictions to pairwise interactions between fine-grained visual and textual elements (such as image patches and text tokens), while being applicable to both open- and closed-source models. Our approach provides: (1) instance-level explanations that reveal synergistic and suppressive cross-modal effects for individual samples - "why the model makes a specific prediction on this input", and (2) dataset-level explanation that uncovers generalizable interaction patterns across samples - "how the model integrates information across modalities". Experiments on public multimodal benchmarks confirm that MultiSHAP faithfully captures cross-modal reasoning mechanisms, while real-world case studies demonstrate its practical utility. Our framework is extensible beyond two modalities, offering a general solution for interpreting complex multimodal AI models.

Bojian Hou, Zhanliang Wang, Zhuoping Zhou et al.

Canonical correlation analysis (CCA) is a technique for finding correlations between different data modalities and learning low-dimensional representations. As fairness becomes crucial in machine learning, fair CCA has gained attention. However, previous approaches often overlook the impact on downstream classification tasks, limiting applicability. We propose a novel fair CCA method for fair representation learning, ensuring the projected features are independent of sensitive attributes, thus enhancing fairness without compromising accuracy. We validate our method on synthetic data and real-world data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), demonstrating its ability to maintain high correlation analysis performance while improving fairness in classification tasks. Our work enables fair machine learning in neuroimaging studies where unbiased analysis is essential. Code is available in https://github.com/ZhanliangAaronWang/FR-CCA-ADNI.

Zhanliang Wang, Jiancong Xiao, Ruochen Jin et al.

Calibration measures whether a model's predicted confidence aligns with its empirical accuracy, and is central to the reliable deployment of large language models (LLMs) in high-stakes domains such as medicine and law. While much recent work focuses on improving LLM calibration, the equally important question of how to evaluate it in realistic settings remains underdeveloped. Open-ended question answering (QA), the most common deployment setting for modern LLMs, is where existing evaluation methods fall short: logit-based metrics need restricted output formats and internal probabilities; verbalized confidence is self-reported and often overconfident; and sampling-based methods rely on task-specific extraction rules without a clear finite-sample target. We introduce Sem-ECE (Semantic-Sampling Expected Calibration Error), a calibration evaluation framework for open-ended QA that samples answers from the model, groups them into semantic classes, and uses the resulting frequencies as confidence. We study two estimators within this framework: Sem$_1$-ECE, the same-sample self-consistency score, and Sem$_2$-ECE, a held-out variant that separates answer selection from confidence evaluation. We prove both are asymptotically unbiased, and further show that they agree on easy questions but diverge on hard ones with Sem$_2$ achieving strictly smaller calibration error, so their gap also serves as a diagnostic for question difficulty. Experiments on three open-ended QA benchmarks across five leading commercial LLMs match our theoretical predictions and show that Sem-ECE outperforms verbalized confidence and existing sampling-based methods, while complementing logit-based evaluation when internal probabilities are unavailable.

Jiancong Xiao, Bojian Hou, Zhanliang Wang et al.

One of the key technologies for the success of Large Language Models (LLMs) is preference alignment. However, a notable side effect of preference alignment is poor calibration: while the pre-trained models are typically well-calibrated, LLMs tend to become poorly calibrated after alignment with human preferences. In this paper, we investigate why preference alignment affects calibration and how to address this issue. For the first question, we observe that the preference collapse issue in alignment undesirably generalizes to the calibration scenario, causing LLMs to exhibit overconfidence and poor calibration. To address this, we demonstrate the importance of fine-tuning with domain-specific knowledge to alleviate the overconfidence issue. To further analyze whether this affects the model's performance, we categorize models into two regimes: calibratable and non-calibratable, defined by bounds of Expected Calibration Error (ECE). In the calibratable regime, we propose a calibration-aware fine-tuning approach to achieve proper calibration without compromising LLMs' performance. However, as models are further fine-tuned for better performance, they enter the non-calibratable regime. For this case, we develop an EM-algorithm-based ECE regularization for the fine-tuning loss to maintain low calibration error. Extensive experiments validate the effectiveness of the proposed methods.

Da Wu, Zhanliang Wang, Quan Nguyen et al.

Background: Several studies show that large language models (LLMs) struggle with phenotype-driven gene prioritization for rare diseases. These studies typically use Human Phenotype Ontology (HPO) terms to prompt foundation models like GPT and LLaMA to predict candidate genes. However, in real-world settings, foundation models are not optimized for domain-specific tasks like clinical diagnosis, yet inputs are unstructured clinical notes rather than standardized terms. How LLMs can be instructed to predict candidate genes or disease diagnosis from unstructured clinical notes remains a major challenge. Methods: We introduce RAG-driven CoT and CoT-driven RAG, two methods that combine Chain-of-Thought (CoT) and Retrieval Augmented Generation (RAG) to analyze clinical notes. A five-question CoT protocol mimics expert reasoning, while RAG retrieves data from sources like HPO and OMIM (Online Mendelian Inheritance in Man). We evaluated these approaches on rare disease datasets, including 5,980 Phenopacket-derived notes, 255 literature-based narratives, and 220 in-house clinical notes from Childrens Hospital of Philadelphia. Results: We found that recent foundations models, including Llama 3.3-70B-Instruct and DeepSeek-R1-Distill-Llama-70B, outperformed earlier versions such as Llama 2 and GPT-3.5. We also showed that RAG-driven CoT and CoT-driven RAG both outperform foundation models in candidate gene prioritization from clinical notes; in particular, both methods with DeepSeek backbone resulted in a top-10 gene accuracy of over 40% on Phenopacket-derived clinical notes. RAG-driven CoT works better for high-quality notes, where early retrieval can anchor the subsequent reasoning steps in domain-specific evidence, while CoT-driven RAG has advantage when processing lengthy and noisy notes.

Da Wu, Zhanliang Wang, Quan Nguyen et al.

The scarcity of high-quality multimodal biomedical data limits the ability to effectively fine-tune pretrained Large Language Models (LLMs) for specialized biomedical tasks. To address this challenge, we introduce MINT (Multimodal Integrated kNowledge Transfer), a framework that aligns unimodal large decoder models with domain-specific decision patterns from multimodal biomedical data through preference optimization. While MINT supports different optimization techniques, we primarily implement it with the Odds Ratio Preference Optimization (ORPO) framework as its backbone. This strategy enables the aligned LLMs to perform predictive tasks using text-only or image-only inputs while retaining knowledge learnt from multimodal data. MINT leverages an upstream multimodal machine learning (MML) model trained on high-quality multimodal data to transfer domain-specific insights to downstream text-only or image-only LLMs. We demonstrate its effectiveness through two key applications: (1) Rare genetic disease prediction from texts, where MINT uses a multimodal encoder model, trained on facial photos and clinical notes, to generate a preference dataset for aligning a lightweight Llama 3.2-3B-Instruct. Despite relying on text input only, the MINT-derived model outperforms models trained with SFT, RAG, or DPO, and even outperforms Llama 3.1-405B-Instruct. (2) Tissue type classification using cell nucleus images, where MINT uses a vision-language foundation model as the preference generator, containing knowledge learnt from both text and histopathological images to align downstream image-only models. The resulting MINT-derived model significantly improves the performance of Llama 3.2-Vision-11B-Instruct on tissue type classification. In summary, MINT provides an effective strategy to align unimodal LLMs with high-quality multimodal expertise through preference optimization.