Chengsheng Mao

Chengsheng Mao, Jie Xu, Luke Rasmussen et al.

Objective: We develop a deep learning framework based on the pre-trained Bidirectional Encoder Representations from Transformers (BERT) model using unstructured clinical notes from electronic health records (EHRs) to predict the risk of disease progression from Mild Cognitive Impairment (MCI) to Alzheimer's Disease (AD). Materials and Methods: We identified 3657 patients diagnosed with MCI together with their progress notes from Northwestern Medicine Enterprise Data Warehouse (NMEDW) between 2000-2020. The progress notes no later than the first MCI diagnosis were used for the prediction. We first preprocessed the notes by deidentification, cleaning and splitting, and then pretrained a BERT model for AD (AD-BERT) based on the publicly available Bio+Clinical BERT on the preprocessed notes. The embeddings of all the sections of a patient's notes processed by AD-BERT were combined by MaxPooling to compute the probability of MCI-to-AD progression. For replication, we conducted a similar set of experiments on 2563 MCI patients identified at Weill Cornell Medicine (WCM) during the same timeframe. Results: Compared with the 7 baseline models, the AD-BERT model achieved the best performance on both datasets, with Area Under receiver operating characteristic Curve (AUC) of 0.8170 and F1 score of 0.4178 on NMEDW dataset and AUC of 0.8830 and F1 score of 0.6836 on WCM dataset. Conclusion: We developed a deep learning framework using BERT models which provide an effective solution for prediction of MCI-to-AD progression using clinical note analysis.

Yikuan Li, Chengsheng Mao, Kaixuan Huang et al.

Scarcity of health care resources could result in the unavoidable consequence of rationing. For example, ventilators are often limited in supply, especially during public health emergencies or in resource-constrained health care settings, such as amid the pandemic of COVID-19. Currently, there is no universally accepted standard for health care resource allocation protocols, resulting in different governments prioritizing patients based on various criteria and heuristic-based protocols. In this study, we investigate the use of reinforcement learning for critical care resource allocation policy optimization to fairly and effectively ration resources. We propose a transformer-based deep Q-network to integrate the disease progression of individual patients and the interaction effects among patients during the critical care resource allocation. We aim to improve both fairness of allocation and overall patient outcomes. Our experiments demonstrate that our method significantly reduces excess deaths and achieves a more equitable distribution under different levels of ventilator shortage, when compared to existing severity-based and comorbidity-based methods in use by different governments. Our source code is included in the supplement and will be released on Github upon publication.

Liang Yao, Jiazhen Peng, Chengsheng Mao et al.

Knowledge graphs play a vital role in numerous artificial intelligence tasks, yet they frequently face the issue of incompleteness. In this study, we explore utilizing Large Language Models (LLM) for knowledge graph completion. We consider triples in knowledge graphs as text sequences and introduce an innovative framework called Knowledge Graph LLM (KG-LLM) to model these triples. Our technique employs entity and relation descriptions of a triple as prompts and utilizes the response for predictions. Experiments on various benchmark knowledge graphs demonstrate that our method attains state-of-the-art performance in tasks such as triple classification and relation prediction. We also find that fine-tuning relatively smaller models (e.g., LLaMA-7B, ChatGLM-6B) outperforms recent ChatGPT and GPT-4.

Chengsheng Mao, Liang Yao, Yuan Luo

Acute kidney injury (AKI) is a common clinical syndrome characterized by a sudden episode of kidney failure or kidney damage within a few hours or a few days. Accurate early prediction of AKI for patients in ICU who are more likely than others to have AKI can enable timely interventions, and reduce the complications of AKI. Much of the clinical information relevant to AKI is captured in clinical notes that are largely unstructured text and requires advanced natural language processing (NLP) for useful information extraction. On the other hand, pre-trained contextual language models such as Bidirectional Encoder Representations from Transformers (BERT) have improved performances for many NLP tasks in general domain recently. However, few have explored BERT on disease-specific medical domain tasks such as AKI early prediction. In this paper, we try to apply BERT to specific diseases and present an AKI domain-specific pre-trained language model based on BERT (AKI-BERT) that could be used to mine the clinical notes for early prediction of AKI. AKI-BERT is a BERT model pre-trained on the clinical notes of patients having risks for AKI. Our experiments on Medical Information Mart for Intensive Care III (MIMIC-III) dataset demonstrate that AKI-BERT can yield performance improvements for early AKI prediction, thus expanding the utility of the BERT model from general clinical domain to disease-specific domain.

Ziqing Wang, Chengsheng Mao, Xiaole Wen et al.

Medical Multimodal Large Language Models (Med-MLLMs) have shown great promise in medical visual question answering (Med-VQA). However, when deployed in low-resource settings where abundant labeled data are unavailable, existing Med-MLLMs commonly fail due to their medical reasoning capability bottlenecks: (i) the intrinsic reasoning bottleneck that ignores the details from the medical image; (ii) the extrinsic reasoning bottleneck that fails to incorporate specialized medical knowledge. To address those limitations, we propose AMANDA, a training-free agentic framework that performs medical knowledge augmentation via LLM agents. Specifically, our intrinsic medical knowledge augmentation focuses on coarse-to-fine question decomposition for comprehensive diagnosis, while extrinsic medical knowledge augmentation grounds the reasoning process via biomedical knowledge graph retrieval. Extensive experiments across eight Med-VQA benchmarks demonstrate substantial improvements in both zero-shot and few-shot Med-VQA settings. The code is available at https://github.com/REAL-Lab-NU/AMANDA.

Chengsheng Mao, Liang Yao, Yuan Luo

Image representation is a fundamental task in computer vision. However, most of the existing approaches for image representation ignore the relations between images and consider each input image independently. Intuitively, relations between images can help to understand the images and maintain model consistency over related images, leading to better explainability. In this paper, we consider modeling the image-level relations to generate more informative image representations, and propose ImageGCN, an end-to-end graph convolutional network framework for inductive multi-relational image modeling. We apply ImageGCN to chest X-ray images where rich relational information is available for disease identification. Unlike previous image representation models, ImageGCN learns the representation of an image using both its original pixel features and its relationship with other images. Besides learning informative representations for images, ImageGCN can also be used for object detection in a weakly supervised manner. The experimental results on 3 open-source x-ray datasets, ChestX-ray14, CheXpert and MIMIC-CXR demonstrate that ImageGCN can outperform respective baselines in both disease identification and localization tasks and can achieve comparable and often better results than the state-of-the-art methods.

Chengsheng Mao, Yuan Luo

Graph neural network (GNN) is effective to model graphs for distributed representations of nodes and an entire graph. Recently, research on the expressive power of GNN attracted growing attention. A highly-expressive GNN has the ability to generate discriminative graph representations. However, in the end-to-end training process for a certain graph learning task, a highly-expressive GNN risks generating graph representations overfitting the training data for the target task, while losing information important for the model generalization. In this paper, we propose Distribution Preserving GNN (DP-GNN) - a GNN framework that can improve the generalizability of expressive GNN models by preserving several kinds of distribution information in graph representations and node representations. Besides the generalizability, by applying an expressive GNN backbone, DP-GNN can also have high expressive power. We evaluate the proposed DP-GNN framework on multiple benchmark datasets for graph classification tasks. The experimental results demonstrate that our model achieves state-of-the-art performances.

Francisco Y Cai, Chengsheng Mao, Yuan Luo

Background: The increasing adoption of electronic health records (EHR) across the US has created troves of computable data, to which machine learning methods have been applied to extract useful insights. EHR data, represented as a three-dimensional analogue of a matrix (tensor), is decomposed into two-dimensional factors that can be interpreted as computational phenotypes. Methods: We apply constrained tensor factorization to derive computational phenotypes and predict mortality in cohorts of patients with breast, prostate, colorectal, or lung cancer in the Northwestern Medicine Enterprise Data Warehouse from 2000 to 2015. In our experiments, we examined using a supervised term in the factorization algorithm, filtering tensor co-occurrences by medical indication, and incorporating additional social determinants of health (SDOH) covariates in the factorization process. We evaluated the resulting computational phenotypes qualitatively and by assessing their ability to predict five-year mortality using the area under the curve (AUC) statistic. Results: Filtering by medical indication led to more concise and interpretable phenotypes. Mortality prediction performance (AUC) varied under the different experimental conditions and by cancer type (breast: 0.623 - 0.694, prostate: 0.603 - 0.750, colorectal: 0.523 - 0.641, and lung: 0.517 - 0.623). Generally, prediction performance improved with the use of a supervised term and the incorporation of SDOH covariates. Conclusion: Constrained tensor factorization, applied to sparse EHR data of patients with cancer, can discover computational phenotypes predictive of five-year mortality. The incorporation of SDOH variables into the factorization algorithm is an easy-to-implement and effective way to improve prediction performance.

Yu Deng, Jennifer A. Pacheco, Anh Chung et al.

Systemic lupus erythematosus (SLE) is a rare autoimmune disorder characterized by an unpredictable course of flares and remission with diverse manifestations. Lupus nephritis, one of the major disease manifestations of SLE for organ damage and mortality, is a key component of lupus classification criteria. Accurately identifying lupus nephritis in electronic health records (EHRs) would therefore benefit large cohort observational studies and clinical trials where characterization of the patient population is critical for recruitment, study design, and analysis. Lupus nephritis can be recognized through procedure codes and structured data, such as laboratory tests. However, other critical information documenting lupus nephritis, such as histologic reports from kidney biopsies and prior medical history narratives, require sophisticated text processing to mine information from pathology reports and clinical notes. In this study, we developed algorithms to identify lupus nephritis with and without natural language processing (NLP) using EHR data. We developed four algorithms: a rule-based algorithm using only structured data (baseline algorithm) and three algorithms using different NLP models. The three NLP models are based on regularized logistic regression and use different sets of features including positive mention of concept unique identifiers (CUIs), number of appearances of CUIs, and a mixture of three components respectively. The baseline algorithm and the best performed NLP algorithm were external validated on a dataset from Vanderbilt University Medical Center (VUMC). Our best performing NLP model incorporating features from both structured data, regular expression concepts, and mapped CUIs improved F measure in both the NMEDW (0.41 vs 0.79) and VUMC (0.62 vs 0.96) datasets compared to the baseline lupus nephritis algorithm.

Yuan Luo, Chengsheng Mao

Genetic pathways usually encode molecular mechanisms that can inform targeted interventions. It is often challenging for existing machine learning approaches to jointly model genetic pathways (higher-order features) and variants (atomic features), and present to clinicians interpretable models. In order to build more accurate and better interpretable machine learning models for genetic medicine, we introduce Pathway Augmented Nonnegative Tensor factorization for HighER-order feature learning (PANTHER). PANTHER selects informative genetic pathways that directly encode molecular mechanisms. We apply genetically motivated constrained tensor factorization to group pathways in a way that reflects molecular mechanism interactions. We then train a softmax classifier for disease types using the identified pathway groups. We evaluated PANTHER against multiple state-of-the-art constrained tensor/matrix factorization models, as well as group guided and Bayesian hierarchical models. PANTHER outperforms all state-of-the-art comparison models significantly (p<0.05). Our experiments on large scale Next Generation Sequencing (NGS) and whole-genome genotyping datasets also demonstrated wide applicability of PANTHER. We performed feature analysis in predicting disease types, which suggested insights and benefits of the identified pathway groups.

Chengsheng Mao, Liang Yao, Yuan Luo

Graph Neural Network (GNN) aggregates the neighborhood of each node into the node embedding and shows its powerful capability for graph representation learning. However, most existing GNN variants aggregate the neighborhood information in a fixed non-injective fashion, which may map different graphs or nodes to the same embedding, reducing the model expressiveness. We present a theoretical framework to design a continuous injective set function for neighborhood aggregation in GNN. Using the framework, we propose expressive GNN that aggregates the neighborhood of each node with a continuous injective set function, so that a GNN layer maps similar nodes with similar neighborhoods to similar embeddings, different nodes to different embeddings and the equivalent nodes or isomorphic graphs to the same embeddings. Moreover, the proposed expressive GNN can naturally learn expressive representations for graphs with continuous node attributes. We validate the proposed expressive GNN (ExpGNN) for graph classification on multiple benchmark datasets including simple graphs and attributed graphs. The experimental results demonstrate that our model achieves state-of-the-art performances on most of the benchmarks.

Liang Yao, Chengsheng Mao, Yuan Luo

Knowledge graphs are important resources for many artificial intelligence tasks but often suffer from incompleteness. In this work, we propose to use pre-trained language models for knowledge graph completion. We treat triples in knowledge graphs as textual sequences and propose a novel framework named Knowledge Graph Bidirectional Encoder Representations from Transformer (KG-BERT) to model these triples. Our method takes entity and relation descriptions of a triple as input and computes scoring function of the triple with the KG-BERT language model. Experimental results on multiple benchmark knowledge graphs show that our method can achieve state-of-the-art performance in triple classification, link prediction and relation prediction tasks.

Chengsheng Mao, Liang Yao, Yuan Luo

Laboratory testing and medication prescription are two of the most important routines in daily clinical practice. Developing an artificial intelligence system that can automatically make lab test imputations and medication recommendations can save costs on potentially redundant lab tests and inform physicians of a more effective prescription. We present an intelligent medical system (named MedGCN) that can automatically recommend the patients' medications based on their incomplete lab tests, and can even accurately estimate the lab values that have not been taken. In our system, we integrate the complex relations between multiple types of medical entities with their inherent features in a heterogeneous graph. Then we model the graph to learn a distributed representation for each entity in the graph based on graph convolutional networks (GCN). By the propagation of graph convolutional networks, the entity representations can incorporate multiple types of medical information that can benefit multiple medical tasks. Moreover, we introduce a cross regularization strategy to reduce overfitting for multi-task training by the interaction between the multiple tasks. In this study, we construct a graph to associate 4 types of medical entities, i.e., patients, encounters, lab tests, and medications, and applied a graph neural network to learn node embeddings for medication recommendation and lab test imputation. we validate our MedGCN model on two real-world datasets: NMEDW and MIMIC-III. The experimental results on both datasets demonstrate that our model can outperform the state-of-the-art in both tasks. We believe that our innovative system can provide a promising and reliable way to assist physicians to make medication prescriptions and to save costs on potentially redundant lab tests.

Chengsheng Mao, Lijuan Lu, Bin Hu

In Bayesian classification, it is important to establish a probabilistic model for each class for likelihood estimation. Most of the previous methods modeled the probability distribution in the whole sample space. However, real-world problems are usually too complex to model in the whole sample space; some fundamental assumptions are required to simplify the global model, for example, the class conditional independence assumption for naive Bayesian classification. In this paper, with the insight that the distribution in a local sample space should be simpler than that in the whole sample space, a local probabilistic model established for a local region is expected much simpler and can relax the fundamental assumptions that may not be true in the whole sample space. Based on these advantages we propose establishing local probabilistic models for Bayesian classification. In addition, a Bayesian classifier adopting a local probabilistic model can even be viewed as a generalized local classification model; by tuning the size of the local region and the corresponding local model assumption, a fitting model can be established for a particular classification problem. The experimental results on several real-world datasets demonstrate the effectiveness of local probabilistic models for Bayesian classification.

Chengsheng Mao, Bin Hu, Lei Chen et al.

The k-nearest-neighbor method performs classification tasks for a query sample based on the information contained in its neighborhood. Previous studies into the k-nearest-neighbor algorithm usually achieved the decision value for a class by combining the support of each sample in the neighborhood. They have generally considered the nearest neighbors separately, and potentially integral neighborhood information important for classification was lost, e.g. the distribution information. This article proposes a novel local learning method that organizes the information in the neighborhood through local distribution. In the proposed method, additional distribution information in the neighborhood is estimated and then organized; the classification decision is made based on maximum posterior probability which is estimated from the local distribution in the neighborhood. Additionally, based on the local distribution, we generate a generalized local classification form that can be effectively applied to various datasets through tuning the parameters. We use both synthetic and real datasets to evaluate the classification performance of the proposed method; the experimental results demonstrate the dimensional scalability, efficiency, effectiveness and robustness of the proposed method compared to some other state-of-the-art classifiers. The results indicate that the proposed method is effective and promising in a broad range of domains.

Yikuan Li, Liang Yao, Chengsheng Mao et al.

Acute kidney injury (AKI) in critically ill patients is associated with significant morbidity and mortality. Development of novel methods to identify patients with AKI earlier will allow for testing of novel strategies to prevent or reduce the complications of AKI. We developed data-driven prediction models to estimate the risk of new AKI onset. We generated models from clinical notes within the first 24 hours following intensive care unit (ICU) admission extracted from Medical Information Mart for Intensive Care III (MIMIC-III). From the clinical notes, we generated clinically meaningful word and concept representations and embeddings, respectively. Five supervised learning classifiers and knowledge-guided deep learning architecture were used to construct prediction models. The best configuration yielded a competitive AUC of 0.779. Our work suggests that natural language processing of clinical notes can be applied to assist clinicians in identifying the risk of incident AKI onset in critically ill patients upon admission to the ICU.

Guoqing Chao, Chengsheng Mao, Fei Wang et al.

ICU mortality risk prediction is a tough yet important task. On one hand, due to the complex temporal data collected, it is difficult to identify the effective features and interpret them easily; on the other hand, good prediction can help clinicians take timely actions to prevent the mortality. These correspond to the interpretability and accuracy problems. Most existing methods lack of the interpretability, but recently Subgraph Augmented Nonnegative Matrix Factorization (SANMF) has been successfully applied to time series data to provide a path to interpret the features well. Therefore, we adopted this approach as the backbone to analyze the patient data. One limitation of the raw SANMF method is its poor prediction ability due to its unsupervised nature. To deal with this problem, we proposed a supervised SANMF algorithm by integrating the logistic regression loss function into the NMF framework and solved it with an alternating optimization procedure. We used the simulation data to verify the effectiveness of this method, and then we applied it to ICU mortality risk prediction and demonstrated its superiority over other conventional supervised NMF methods.

Chengsheng Mao, Yiheng Pan, Zexian Zeng et al.

Thoracic diseases are very serious health problems that plague a large number of people. Chest X-ray is currently one of the most popular methods to diagnose thoracic diseases, playing an important role in the healthcare workflow. However, reading the chest X-ray images and giving an accurate diagnosis remain challenging tasks for expert radiologists. With the success of deep learning in computer vision, a growing number of deep neural network architectures were applied to chest X-ray image classification. However, most of the previous deep neural network classifiers were based on deterministic architectures which are usually very noise-sensitive and are likely to aggravate the overfitting issue. In this paper, to make a deep architecture more robust to noise and to reduce overfitting, we propose using deep generative classifiers to automatically diagnose thorax diseases from the chest X-ray images. Unlike the traditional deterministic classifier, a deep generative classifier has a distribution middle layer in the deep neural network. A sampling layer then draws a random sample from the distribution layer and input it to the following layer for classification. The classifier is generative because the class label is generated from samples of a related distribution. Through training the model with a certain amount of randomness, the deep generative classifiers are expected to be robust to noise and can reduce overfitting and then achieve good performances. We implemented our deep generative classifiers based on a number of well-known deterministic neural network architectures, and tested our models on the chest X-ray14 dataset. The results demonstrated the superiority of deep generative classifiers compared with the corresponding deep deterministic classifiers.

Chengsheng Mao, Liang Yao, Yuan Luo

In open set learning, a model must be able to generalize to novel classes when it encounters a sample that does not belong to any of the classes it has seen before. Open set learning poses a realistic learning scenario that is receiving growing attention. Existing studies on open set learning mainly focused on detecting novel classes, but few studies tried to model them for differentiating novel classes. In this paper, we recognize that novel classes should be different from each other, and propose distribution networks for open set learning that can model different novel classes based on probability distributions. We hypothesize that, through a certain mapping, samples from different classes with the same classification criterion should follow different probability distributions from the same distribution family. A deep neural network is learned to map the samples in the original feature space to a latent space where the distributions of known classes can be jointly learned with the network. We additionally propose a distribution parameter transfer and updating strategy for novel class modeling when a novel class is detected in the latent space. By novel class modeling, the detected novel classes can serve as known classes to the subsequent classification. Our experimental results on image datasets MNIST and CIFAR10 show that the distribution networks can detect novel classes accurately, and model them well for the subsequent classification tasks.

Liang Yao, Chengsheng Mao, Yuan Luo

Text classification is an important and classical problem in natural language processing. There have been a number of studies that applied convolutional neural networks (convolution on regular grid, e.g., sequence) to classification. However, only a limited number of studies have explored the more flexible graph convolutional neural networks (convolution on non-grid, e.g., arbitrary graph) for the task. In this work, we propose to use graph convolutional networks for text classification. We build a single text graph for a corpus based on word co-occurrence and document word relations, then learn a Text Graph Convolutional Network (Text GCN) for the corpus. Our Text GCN is initialized with one-hot representation for word and document, it then jointly learns the embeddings for both words and documents, as supervised by the known class labels for documents. Our experimental results on multiple benchmark datasets demonstrate that a vanilla Text GCN without any external word embeddings or knowledge outperforms state-of-the-art methods for text classification. On the other hand, Text GCN also learns predictive word and document embeddings. In addition, experimental results show that the improvement of Text GCN over state-of-the-art comparison methods become more prominent as we lower the percentage of training data, suggesting the robustness of Text GCN to less training data in text classification.

Liang Yao, Chengsheng Mao, Yuan Luo

Clinical text classification is an important problem in medical natural language processing. Existing studies have conventionally focused on rules or knowledge sources-based feature engineering, but only a few have exploited effective feature learning capability of deep learning methods. In this study, we propose a novel approach which combines rule-based features and knowledge-guided deep learning techniques for effective disease classification. Critical Steps of our method include identifying trigger phrases, predicting classes with very few examples using trigger phrases and training a convolutional neural network with word embeddings and Unified Medical Language System (UMLS) entity embeddings. We evaluated our method on the 2008 Integrating Informatics with Biology and the Bedside (i2b2) obesity challenge. The results show that our method outperforms the state of the art methods.

Himanshu Sharma, Chengsheng Mao, Yizhen Zhang et al.

This paper presents a portable phenotyping system that is capable of integrating both rule-based and statistical machine learning based approaches. Our system utilizes UMLS to extract clinically relevant features from the unstructured text and then facilitates portability across different institutions and data systems by incorporating OHDSI's OMOP Common Data Model (CDM) to standardize necessary data elements. Our system can also store the key components of rule-based systems (e.g., regular expression matches) in the format of OMOP CDM, thus enabling the reuse, adaptation and extension of many existing rule-based clinical NLP systems. We experimented with our system on the corpus from i2b2's Obesity Challenge as a pilot study. Our system facilitates portable phenotyping of obesity and its 15 comorbidities based on the unstructured patient discharge summaries, while achieving a performance that often ranked among the top 10 of the challenge participants. This standardization enables a consistent application of numerous rule-based and machine learning based classification techniques downstream.

Chengsheng Mao, Yuan Zhao, Mengxin Sun et al.

Privacy is a major concern in sharing human subject data to researchers for secondary analyses. A simple binary consent (opt-in or not) may significantly reduce the amount of sharable data, since many patients might only be concerned about a few sensitive medical conditions rather than the entire medical records. We propose event-level privacy protection, and develop a feature ablation method to protect event-level privacy in electronic medical records. Using a list of 13 sensitive diagnoses, we evaluate the feasibility and the efficacy of the proposed method. As feature ablation progresses, the identifiability of a sensitive medical condition decreases with varying speeds on different diseases. We find that these sensitive diagnoses can be divided into 3 categories: (1) 5 diseases have fast declining identifiability (AUC below 0.6 with less than 400 features excluded); (2) 7 diseases with progressively declining identifiability (AUC below 0.7 with between 200 and 700 features excluded); and (3) 1 disease with slowly declining identifiability (AUC above 0.7 with 1000 features excluded). The fact that the majority (12 out of 13) of the sensitive diseases fall into the first two categories suggests the potential of the proposed feature ablation method as a solution for event-level record privacy protection.

Yuan Luo, Chengsheng Mao, Yiben Yang et al.

Hypertension is a heterogeneous syndrome in need of improved subtyping using phenotypic and genetic measurements so that patients in different subtypes share similar pathophysiologic mechanisms and respond more uniformly to targeted treatments. Existing machine learning approaches often face challenges in integrating phenotype and genotype information and presenting to clinicians an interpretable model. We aim to provide informed patient stratification by introducing Hybrid Non-negative Matrix Factorization (HNMF) on phenotype and genotype matrices. HNMF simultaneously approximates the phenotypic and genetic matrices using different appropriate loss functions, and generates patient subtypes, phenotypic groups and genetic groups. Unlike previous methods, HNMF approximates phenotypic matrix under Frobenius loss, and genetic matrix under Kullback-Leibler (KL) loss. We propose an alternating projected gradient method to solve the approximation problem. Simulation shows HNMF converges fast and accurately to the true factor matrices. On real-world clinical dataset, we used the patient factor matrix as features to predict main cardiac mechanistic outcomes. We compared HNMF with six different models using phenotype or genotype features alone, with or without NMF, or using joint NMF with only one type of loss. HNMF significantly outperforms all comparison models. HNMF also reveals intuitive phenotype-genotype interactions that characterize cardiac abnormalities.