Alzheimer's disease (AD) is a heterogeneous, multifactorial neurodegenerative disorder characterized by beta-amyloid, pathologic tau, and neurodegeneration. There are no effective treatments for Alzheimer's disease at a late stage, urging for early intervention. However, existing statistical inference approaches of AD subtype identification ignore the pathological domain knowledge, which could lead to ill-posed results that are sometimes inconsistent with the essential neurological principles. Integrating systems biology modeling with machine learning, we propose a novel pathology steered stratification network (PSSN) that incorporates established domain knowledge in AD pathology through a reaction-diffusion model, where we consider non-linear interactions between major biomarkers and diffusion along brain structural network. Trained on longitudinal multimodal neuroimaging data, the biological model predicts long-term trajectories that capture individual progression pattern, filling in the gaps between sparse imaging data available. A deep predictive neural network is then built to exploit spatiotemporal dynamics, link neurological examinations with clinical profiles, and generate subtype assignment probability on an individual basis. We further identify an evolutionary disease graph to quantify subtype transition probabilities through extensive simulations. Our stratification achieves superior performance in both inter-cluster heterogeneity and intra-cluster homogeneity of various clinical scores. Applying our approach to enriched samples of aging populations, we identify six subtypes spanning AD spectrum, where each subtype exhibits a distinctive biomarker pattern that is consistent with its clinical outcome. PSSN provides insights into pre-symptomatic diagnosis and practical guidance on clinical treatments, which may be further generalized to other neurodegenerative diseases.
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Background: Missing data is a common challenge in mass spectrometry-based metabolomics, which can lead to biased and incomplete analyses. The integration of whole-genome sequencing (WGS) data with metabolomics data has emerged as a promising approach to enhance the accuracy of data imputation in metabolomics studies. Method: In this study, we propose a novel method that leverages the information from WGS data and reference metabolites to impute unknown metabolites. Our approach utilizes a multi-view variational autoencoder to jointly model the burden score, polygenetic risk score (PGS), and linkage disequilibrium (LD) pruned single nucleotide polymorphisms (SNPs) for feature extraction and missing metabolomics data imputation. By learning the latent representations of both omics data, our method can effectively impute missing metabolomics values based on genomic information. Results: We evaluate the performance of our method on empirical metabolomics datasets with missing values and demonstrate its superiority compared to conventional imputation techniques. Using 35 template metabolites derived burden scores, PGS and LD-pruned SNPs, the proposed methods achieved r2-scores > 0.01 for 71.55% of metabolites. Conclusion: The integration of WGS data in metabolomics imputation not only improves data completeness but also enhances downstream analyses, paving the way for more comprehensive and accurate investigations of metabolic pathways and disease associations. Our findings offer valuable insights into the potential benefits of utilizing WGS data for metabolomics data imputation and underscore the importance of leveraging multi-modal data integration in precision medicine research.
MR-guided microwave ablation (MWA) has proven effective in treating hepatocellular carcinoma (HCC) with small-sized tumors, but the state-of-the-art technique suffers from sub-optimal workflow due to speed and accuracy of needle placement. This paper presents a compact body-mounted MR-conditional robot that can operate in closed-bore MR scanners for accurate needle guidance. The robotic platform consists of two stacked Cartesian XY stages, each with two degrees of freedom, that facilitate needle guidance. The robot is actuated using 3D-printed pneumatic turbines with MR-conditional bevel gear transmission systems. Pneumatic valves and control mechatronics are located inside the MRI control room and are connected to the robot with pneumatic transmission lines and optical fibers. Free space experiments indicated robot-assisted needle insertion error of 2.6$\pm$1.3 mm at an insertion depth of 80 mm. The MR-guided phantom studies were conducted to verify the MR-conditionality and targeting performance of the robot. Future work will focus on the system optimization and validations in animal trials.
MET protein overexpression is a targetable event in non-small cell lung cancer (NSCLC) and is the subject of active drug development. Challenges in identifying patients for these therapies include lack of access to validated testing, such as standardized immunohistochemistry (IHC) assessment, and consumption of valuable tissue for a single gene/protein assay. Development of pre-screening algorithms using routinely available digitized hematoxylin and eosin (H&E)-stained slides to predict MET overexpression could promote testing for those who will benefit most. While assessment of MET expression using IHC is currently not routinely performed in NSCLC, next-generation sequencing is common and in some cases includes RNA expression panel testing. In this work, we leveraged a large database of matched H&E slides and RNA expression data to train a weakly supervised model to predict MET RNA overexpression directly from H&E images. This model was evaluated on an independent holdout test set of 300 over-expressed and 289 normal patients, demonstrating an ROC-AUC of 0.70 (95th percentile interval: 0.66 - 0.74) with stable performance characteristics across different patient clinical variables and robust to synthetic noise on the test set. These results suggest that H&E-based predictive models could be useful to prioritize patients for confirmatory testing of MET protein or MET gene expression status.
Biomarker detection is an indispensable part in the diagnosis and treatment of low-grade glioma (LGG). However, current LGG biomarker detection methods rely on expensive and complex molecular genetic testing, for which professionals are required to analyze the results, and intra-rater variability is often reported. To overcome these challenges, we propose an interpretable deep learning pipeline, a Multi-Biomarker Histomorphology Discoverer (Multi-Beholder) model based on the multiple instance learning (MIL) framework, to predict the status of five biomarkers in LGG using only hematoxylin and eosin-stained whole slide images and slide-level biomarker status labels. Specifically, by incorporating the one-class classification into the MIL framework, accurate instance pseudo-labeling is realized for instance-level supervision, which greatly complements the slide-level labels and improves the biomarker prediction performance. Multi-Beholder demonstrates superior prediction performance and generalizability for five LGG biomarkers (AUROC=0.6469-0.9735) in two cohorts (n=607) with diverse races and scanning protocols. Moreover, the excellent interpretability of Multi-Beholder allows for discovering the quantitative and qualitative correlations between biomarker status and histomorphology characteristics. Our pipeline not only provides a novel approach for biomarker prediction, enhancing the applicability of molecular treatments for LGG patients but also facilitates the discovery of new mechanisms in molecular functionality and LGG progression.
As Graph Neural Networks (GNNs) become increasingly prevalent in a variety of fields, from social network analysis to protein-protein interaction studies, growing concerns have emerged regarding the unauthorized utilization of personal data. Recent studies have shown that imperceptible poisoning attacks are an effective method of protecting image data from such misuse. However, the efficacy of this approach in the graph domain remains unexplored. To bridge this gap, this paper introduces GraphCloak to safeguard against the unauthorized usage of graph data. Compared with prior work, GraphCloak offers unique significant innovations: (1) graph-oriented, the perturbations are applied to both topological structures and descriptive features of the graph; (2) effective and stealthy, our cloaking method can bypass various inspections while causing a significant performance drop in GNNs trained on the cloaked graphs; and (3) stable across settings, our methods consistently perform effectively under a range of practical settings with limited knowledge. To address the intractable bi-level optimization problem, we propose two error-minimizing-based poisoning methods that target perturbations on the structural and feature space, along with a subgraph injection poisoning method. Our comprehensive evaluation of these methods underscores their effectiveness, stealthiness, and stability. We also delve into potential countermeasures and provide analytical justification for their effectiveness, paving the way for intriguing future research.
Prostate cancer (PCa) is a severe disease among men globally. It is important to identify PCa early and make a precise diagnosis for effective treatment. For PCa diagnosis, Multi-parametric magnetic resonance imaging (mpMRI) emerged as an invaluable imaging modality that offers a precise anatomical view of the prostate gland and its tissue structure. Deep learning (DL) models can enhance existing clinical systems and improve patient care by locating regions of interest for physicians. Recently, DL techniques have been employed to develop a pipeline for segmenting and classifying different cancer types. These studies show that DL can be used to increase diagnostic precision and give objective results without variability. This work uses well-known DL models for the classification and segmentation of mpMRI images to detect PCa. Our implementation involves four pipelines; Semantic DeepSegNet with ResNet50, DeepSegNet with recurrent neural network (RNN), U-Net with RNN, and U-Net with a long short-term memory (LSTM). Each segmentation model is paired with a different classifier to evaluate the performance using different metrics. The results of our experiments show that the pipeline that uses the combination of U-Net and the LSTM model outperforms all other combinations, excelling in both segmentation and classification tasks.
The visual examination of tissue biopsy sections is fundamental for cancer diagnosis, with pathologists analyzing sections at multiple magnifications to discern tumor cells and their subtypes. However, existing attention-based multiple instance learning (MIL) models, used for analyzing Whole Slide Images (WSIs) in cancer diagnostics, often overlook the contextual information of tumor and neighboring tiles, leading to misclassifications. To address this, we propose the Context-Aware Multiple Instance Learning (CAMIL) architecture. CAMIL incorporates neighbor-constrained attention to consider dependencies among tiles within a WSI and integrates contextual constraints as prior knowledge into the MIL model. We evaluated CAMIL on subtyping non-small cell lung cancer (TCGA-NSCLC) and detecting lymph node (CAMELYON16) metastasis, achieving test AUCs of 0.959\% and 0.975\%, respectively, outperforming other state-of-the-art methods. Additionally, CAMIL enhances model interpretability by identifying regions of high diagnostic value.
Dengue is a vector-borne disease transmitted by Aedes mosquitoes. The worldwide spread of these mosquitoes and the increasing disease burden have emphasized the need for a spatio-temporal risk map capable of assessing dengue outbreak conditions and quantifying the outbreak risk. Given that the life cycle of Aedes mosquitoes is strongly influenced by habitat temperature, numerous studies have utilized temperature-dependent development rates of these mosquitoes to construct virus transmission and outbreak risk models. In this study, we advance existing research by developing a mechanistic model for the mosquito life cycle that accurately accounts for the non-Markovian nature of the process. By fitting the model to data on human dengue cases, we estimate several model parameters, allowing the development of a global spatiotemporal dengue risk map. This risk model employs temperature and precipitation data to assess the environmental suitability for dengue outbreaks in a given area. Furthermore, we demonstrate how to reduce the model to the corresponding differential equations, enabling us to utilize existing methods for analyzing the system and fitting the model to observations. This approach can be further applied to similar non-Markovian processes that are currently described with less accurate Markovian models.
Clinical Named Entity Recognition (CNER) aims to identify and classify clinical terms such as diseases, symptoms, treatments, exams, and body parts in electronic health records, which is a fundamental and crucial task for clinical and translational research. In recent years, deep neural networks have achieved significant success in named entity recognition and many other Natural Language Processing (NLP) tasks. Most of these algorithms are trained end to end, and can automatically learn features from large scale labeled datasets. However, these data-driven methods typically lack the capability of processing rare or unseen entities. Previous statistical methods and feature engineering practice have demonstrated that human knowledge can provide valuable information for handling rare and unseen cases. In this paper, we address the problem by incorporating dictionaries into deep neural networks for the Chinese CNER task. Two different architectures that extend the Bi-directional Long Short-Term Memory (Bi-LSTM) neural network and five different feature representation schemes are proposed to handle the task. Computational results on the CCKS-2017 Task 2 benchmark dataset show that the proposed method achieves the highly competitive performance compared with the state-of-the-art deep learning methods.
Object tracking is challenging as target objects often undergo drastic appearance changes over time. Recently, adaptive correlation filters have been successfully applied to object tracking. However, tracking algorithms relying on highly adaptive correlation filters are prone to drift due to noisy updates. Moreover, as these algorithms do not maintain long-term memory of target appearance, they cannot recover from tracking failures caused by heavy occlusion or target disappearance in the camera view. In this paper, we propose to learn multiple adaptive correlation filters with both long-term and short-term memory of target appearance for robust object tracking. First, we learn a kernelized correlation filter with an aggressive learning rate for locating target objects precisely. We take into account the appropriate size of surrounding context and the feature representations. Second, we learn a correlation filter over a feature pyramid centered at the estimated target position for predicting scale changes. Third, we learn a complementary correlation filter with a conservative learning rate to maintain long-term memory of target appearance. We use the output responses of this long-term filter to determine if tracking failure occurs. In the case of tracking failures, we apply an incrementally learned detector to recover the target position in a sliding window fashion. Extensive experimental results on large-scale benchmark datasets demonstrate that the proposed algorithm performs favorably against the state-of-the-art methods in terms of efficiency, accuracy, and robustness.
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