The similar textures, diverse shapes and blurred boundaries of thyroid lesions in ultrasound images pose a significant challenge to accurate segmentation. Although several methods have been proposed to alleviate the aforementioned issues, their generalization is hindered by limited annotation data and insufficient ability to distinguish lesion from its surrounding tissues, especially in the presence of noise and outlier. Additionally, most existing methods lack uncertainty estimation which is essential for providing trustworthy results and identifying potential mispredictions. To this end, we propose knowledge-prompted trustworthy disentangled learning (KPTD) for thyroid ultrasound segmentation with limited annotations. The proposed method consists of three key components: 1) knowledge-aware prompt learning (KAPL) encodes TI-RADS reports into text features and introduces learnable prompts to extract contextual embeddings, which assist in generating region activation maps (serving as pseudo-labels for unlabeled images); 2) foreground-background disentangled learning (FBDL) leverages region activation maps to disentangle foreground and background representations, refining their prototype distributions through a contrastive learning strategy to enhance the model's discrimination and robustness; and 3) foreground-background trustworthy fusion (FBTF) integrates the foreground and background representations and estimates their uncertainty based on evidence theory, providing trustworthy segmentation results. Experimental results show that KPTD achieves superior segmentation performance under limited annotations, significantly outperforming state-of-the-art methods.

Longitudinal data with incomplete entries pose a significant challenge for clinical score regression over multiple time points. Although many methods primarily estimate longitudinal scores with complete baseline features (i.e., features collected at the initial time point), such snapshot features may overlook beneficial latent longitudinal traits for generalization. Alternatively, certain completion approaches (e.g., tensor decomposition technology) have been proposed to impute incomplete longitudinal data before score estimation, most of which, however, are transductive and cannot utilize label semantics. This work presents a tensor coupled learning (TCL) paradigm of incomplete longitudinal features and labels for clinical score regression. The TCL enjoys three advantages: 1) It drives semantic-aware factor matrices and collaboratively deals with incomplete longitudinal entries (of features and labels), during which a dynamic regularizer is designed for adaptive attribute selection. 2) It establishes a closed loop connecting baseline features and the coupled factor matrices, which enables inductive inference of longitudinal scores relying on only baseline features. 3) It reinforces the information encoding of baseline data by preserving the local manifold of longitudinal feature space and detecting the temporal alteration across multiple time points. Extensive experiments demonstrate the remarkable performance improvement of our method on clinical score regression with incomplete longitudinal data.

Computational methods for prediction of the dynamic and complex development of the infant cerebral cortex are critical and highly desired for a better understanding of early brain development in health and disease. Although a few methods have been proposed, they are limited to predicting cortical surface maps at predefined ages and require a large amount of strictly paired longitudinal data at these ages for model training. However, longitudinal infant images are typically acquired at highly irregular and nonuniform scanning ages, thus leading to limited training data for these methods and low flexibility and accuracy. To address these issues, we propose a flexible framework for individualized prediction of cortical surface maps at arbitrary ages during infancy. The central idea is that a cortical surface map can be considered as an entangled representation of two distinct components: 1) the identity-related invariant features, which preserve the individual identity and 2) the age-related features, which reflect the developmental patterns. Our framework, called intensive triplet autoencoder, extracts the mixed latent feature and further disentangles it into two components with an attention-based module. Identity recognition and age estimation tasks are introduced as supervision for a reliable disentanglement. Thus, we can obtain the target individualized cortical property maps with disentangled identity-related information with specific age-related information. Moreover, an adversarial learning strategy is integrated to achieve a vivid and realistic prediction. Extensive experiments validate our method's superior capability in predicting early developing cortical surface maps flexibly and precisely, in comparison with existing methods.

Survival prediction based on histopathological whole slide images (WSIs) is of great significance for risk-benefit assessment and clinical decision. However, complex microenvironments and heterogeneous tissue structures in WSIs bring challenges to learning informative prognosis-related representations. Additionally, previous studies mainly focus on modeling using mono-scale WSIs, which commonly ignore useful subtle differences existed in multi-zoom WSIs. To this end, we propose a deep multi-dictionary learning framework for cancer survival prediction with multi-zoom histopathological WSIs. The framework can recognize and learn discriminative clusters (i.e., microenvironments) based on multi-scale deep representations for survival analysis. Specifically, we learn multi-scale features based on multi-zoom tiles from WSIs via stacked deep autoencoders network followed by grouping different microenvironments by cluster algorithm. Based on multi-scale deep features of clusters, a multi-dictionary learning method with a post-pruning strategy is devised to learn discriminative representations from selected prognosis-related clusters in a task-driven manner. Finally, a survival model (i.e., EN-Cox) is constructed to estimate the risk index of an individual patient. The proposed model is evaluated on three datasets derived from The Cancer Genome Atlas (TCGA), and the experimental results demonstrate that it outperforms several state-of-the-art survival analysis approaches.

Accurate T-staging of nasopharyngeal carcinoma (NPC) holds paramount importance in guiding treatment decisions and prognosticating outcomes for distinct risk groups. Regrettably, the landscape of deep learning-based techniques for T-staging in NPC remains sparse, and existing methodologies often exhibit suboptimal performance due to their neglect of crucial domain-specific knowledge pertinent to primary tumor diagnosis. To address these issues, we propose a new cross-domain mutual-assistance learning framework for fully automated diagnosis of primary tumor using H&N MR images. Specifically, we tackle primary tumor diagnosis task with the convolutional neural network consisting of a 3D cross-domain knowledge perception network (CKP net) for excavated cross-domain-invariant features emphasizing tumor intensity variations and internal tumor heterogeneity, and a multi-domain mutual-information sharing fusion network (M2SF net), comprising a dual-pathway domain-specific representation module and a mutual information fusion module, for intelligently gauging and amalgamating multi-domain, multi-scale T-stage diagnosis-oriented features. The proposed 3D cross-domain mutual-assistance learning framework not only embraces task-specific multi-domain diagnostic knowledge but also automates the entire process of primary tumor diagnosis. We evaluate our model on an internal and an external MR images dataset in a three-fold cross-validation paradigm. Exhaustive experimental results demonstrate that our method outperforms the other algorithms, and obtains promising performance for tumor segmentation and T-staging. These findings underscore its potential for clinical application, offering valuable assistance to clinicians in treatment decision-making and prognostication for various risk groups.

Biomedical multi-modality data (also named multi-omics data) refer to data that span different types and derive from multiple sources in clinical practices (e.g. gene sequences, proteomics and histopathological images), which can provide comprehensive perspectives for cancers and generally improve the performance of survival models. However, the performance improvement of multi-modality survival models may be hindered by two key issues as follows: (1) how to learn and fuse modality-sharable and modality-individual representations from multi-modality data; (2) how to explore the potential risk-aware characteristics in each risk subgroup, which is beneficial to risk stratification and prognosis evaluation. Additionally, learning-based survival models generally refer to numerous hyper-parameters, which requires time-consuming parameter setting and might result in a suboptimal solution. In this paper, we propose an adaptive risk-aware sharable and individual subspace learning method for cancer survival analysis. The proposed method jointly learns sharable and individual subspaces from multi-modality data, whereas two auxiliary terms (i.e. intra-modality complementarity and inter-modality incoherence) are developed to preserve the complementary and distinctive properties of each modality. Moreover, it equips with a grouping co-expression constraint for obtaining risk-aware representation and preserving local consistency. Furthermore, an adaptive-weighted strategy is employed to efficiently estimate crucial parameters during the training stage. Experimental results on three public datasets demonstrate the superiority of our proposed model.

Current survival analysis of cancers confronts two key issues. While comprehensive perspectives provided by data from multiple modalities often promote the performance of survival models, data with inadequate modalities at the testing phase are more ubiquitous in clinical scenarios, which makes multi-modality approaches not applicable. Additionally, incomplete observations (i.e., censored instances) bring a unique challenge for survival analysis, to tackle which, some models have been proposed based on certain strict assumptions or attribute distributions that, however, may limit their applicability. In this paper, we present a mutual-assistance learning paradigm for standalone mono-modality survival analysis of cancers. The mutual assistance implies the cooperation of multiple components and embodies three aspects: 1) it leverages the knowledge of multi-modality data to guide the representation learning of an individual modality via mutual-assistance similarity and geometry constraints; 2) it formulates mutual-assistance regression and ranking functions independent of strong hypotheses to estimate the relative risk, in which a bias vector is introduced to efficiently cope with the censoring problem; 3) it integrates representation learning and survival modeling into a unified mutual-assistance framework for alleviating the requirement of attribute distributions. Extensive experiments on several datasets demonstrate our method can significantly improve the performance of mono-modality survival model.

The Cox proportional hazard model has been widely applied to cancer prognosis prediction. Nowadays, multi-modal data, such as histopathological images and gene data, have advanced this field by providing histologic phenotype and genotype information. However, how to efficiently fuse and select the complementary information of high-dimensional multi-modal data remains challenging for Cox model, as it generally does not equip with feature fusion/selection mechanism. Many previous studies typically perform feature fusion/selection in the original feature space before Cox modeling. Alternatively, learning a latent shared feature space that is tailored for Cox model and simultaneously keeps sparsity is desirable. In addition, existing Cox-based models commonly pay little attention to the actual length of the observed time that may help to boost the model's performance. In this article, we propose a novel Cox-driven multi-constraint latent representation learning framework for prognosis analysis with multi-modal data. Specifically, for efficient feature fusion, a multi-modal latent space is learned via a bi-mapping approach under ranking and regression constraints. The ranking constraint utilizes the log-partial likelihood of Cox model to induce learning discriminative representations in a task-oriented manner. Meanwhile, the representations also benefit from regression constraint, which imposes the supervision of specific survival time on representation learning. To improve generalization and alleviate overfitting, we further introduce similarity and sparsity constraints to encourage extra consistency and sparseness. Extensive experiments on three datasets acquired from The Cancer Genome Atlas (TCGA) demonstrate that the proposed method is superior to state-of-the-art Cox-based models.

The multi-instance learning (MIL) has advanced cancer prognosis analysis with whole slide images (WSIs). However, current MIL methods for WSI analysis still confront unique challenges. Previous methods typically generate instance representations via a pre-trained model or a model trained by the instances with bag-level annotations, which, however, may not generalize well to the downstream task due to the introduction of excessive label noises and the lack of fine-grained information across multi-magnification WSIs. Additionally, existing methods generally aggregate instance representations as bag ones for prognosis prediction and have no consideration of intra-bag redundancy and inter-bag discrimination. To address these issues, we propose a dual-curriculum contrastive MIL method for cancer prognosis analysis with WSIs. The proposed method consists of two curriculums, i.e., saliency-guided weakly-supervised instance encoding with cross-scale tiles and contrastive-enhanced soft-bag prognosis inference. Extensive experiments on three public datasets demonstrate that our method outperforms state-of-the-art methods in this field. The code is available at https://github.com/YuZhang-SMU/Cancer-Prognosis-Analysis/tree/main/DC_MIL%20Code.

The integrative analysis of complementary phenotype information contained in multi-modality data (e.g., histopathological images and genomic data) has advanced the prognostic evaluation of cancers. However, multi-modality based prognosis analysis confronts two challenges: (1) how to explore underlying relations inherent in different modalities data for learning compact and discriminative multi-modality representations; (2) how to take full consideration of incomplete multi-modality data for constructing accurate and robust prognostic model, since a host of complete multi-modality data are not always available. Additionally, many existing multi-modality based prognostic methods commonly ignore relevant clinical variables (e.g., grade and stage), which, however, may provide supplemental information to promote the performance of model. In this paper, we propose a relation-aware shared representation learning method for prognosis analysis of cancers, which makes full use of clinical information and incomplete multi-modality data. The proposed method learns multi-modal shared space tailored for prognostic model via a dual mapping. Within the shared space, it equips with relational regularizers to explore the potential relations (i.e., feature-label and feature-feature relations) among multi-modality data for inducing discriminatory representations and simultaneously obtaining extra sparsity for alleviating overfitting. Moreover, it regresses and incorporates multiple auxiliary clinical attributes with dynamic coefficients to meliorate performance. Furthermore, in training stage, a partial mapping strategy is employed to extend and train a more reliable model with incomplete multi-modality data. We have evaluated our method on three public datasets derived from The Cancer Genome Atlas (TCGA) project, and the experimental results demonstrate the superior performance of the proposed method.

Deep learning methods, especially convolutional neural networks, have been successfully applied to lesion segmentation in breast ultrasound (BUS) images. However, pattern complexity and intensity similarity between the surrounding tissues (i.e., background) and lesion regions (i.e., foreground) bring challenges for lesion segmentation. Considering that such rich texture information is contained in background, very few methods have tried to explore and exploit background-salient representations for assisting foreground segmentation. Additionally, other characteristics of BUS images, i.e., 1) low-contrast appearance and blurry boundary, and 2) significant shape and position variation of lesions, also increase the difficulty in accurate lesion segmentation. In this paper, we present a saliency-guided morphology-aware U-Net (SMU-Net) for lesion segmentation in BUS images. The SMU-Net is composed of a main network with an additional middle stream and an auxiliary network. Specifically, we first propose generation of saliency maps which incorporate both low-level and high-level image structures, for foreground and background. These saliency maps are then employed to guide the main network and auxiliary network for respectively learning foreground-salient and background-salient representations. Furthermore, we devise an additional middle stream which basically consists of background-assisted fusion, shape-aware, edge-aware and position-aware units. This stream receives the coarse-to-fine representations from the main network and auxiliary network for efficiently fusing the foreground-salient and background-salient features and enhancing the ability of learning morphological information for network. Extensive experiments on five datasets demonstrate higher performance and superior robustness to the scale of dataset than several state-of-the-art deep learning approaches in breast lesion segmentation in ultrasound image.

The fusion of multi-modal data (e.g., magnetic resonance imaging (MRI) and positron emission tomography (PET)) has been prevalent for accurate identification of Alzheimer's disease (AD) by providing complementary structural and functional information. However, most of the existing methods simply concatenate multi-modal features in the original space and ignore their underlying associations which may provide more discriminative characteristics for AD identification. Meanwhile, how to overcome the overfitting issue caused by high-dimensional multi-modal data remains appealing. To this end, we propose a relation-induced multi-modal shared representation learning method for AD diagnosis. The proposed method integrates representation learning, dimension reduction, and classifier modeling into a unified framework. Specifically, the framework first obtains multi-modal shared representations by learning a bi-directional mapping between original space and shared space. Within this shared space, we utilize several relational regularizers (including feature-feature, feature-label, and sample-sample regularizers) and auxiliary regularizers to encourage learning underlying associations inherent in multi-modal data and alleviate overfitting, respectively. Next, we project the shared representations into the target space for AD diagnosis. To validate the effectiveness of our proposed approach, we conduct extensive experiments on two independent datasets (i.e., ADNI-1 and ADNI-2), and the experimental results demonstrate that our proposed method outperforms several state-of-the-art methods.

To better understand early brain development in health and disorder, it is critical to accurately segment infant brain magnetic resonance (MR) images into white matter (WM), gray matter (GM), and cerebrospinal fluid (CSF). Deep learning-based methods have achieved state-of-the-art performance; h owever, one of the major limitations is that the learning-based methods may suffer from the multi-site issue, that is, the models trained on a dataset from one site may not be applicable to the datasets acquired from other sites with different imaging protocols/scanners. To promote methodological development in the community, the iSeg-2019 challenge (http://iseg2019.web.unc.edu) provides a set of 6-month infant subjects from multiple sites with different protocols/scanners for the participating methods. T raining/validation subjects are from UNC (MAP) and testing subjects are from UNC/UMN (BCP), Stanford University, and Emory University. By the time of writing, there are 30 automatic segmentation methods participated in the iSeg-2019. In this article, 8 top-ranked methods were reviewed by detailing their pipelines/implementations, presenting experimental results, and evaluating performance across different sites in terms of whole brain, regions of interest, and gyral landmark curves. We further pointed out their limitations and possible directions for addressing the multi-site issue. We find that multi-site consistency is still an open issue. We hope that the multi-site dataset in the iSeg-2019 and this review article will attract more researchers to address the challenging and critical multi-site issue in practice.

MOTIVATION: As a highly heterogeneous disease, clear cell renal cell carcinoma (ccRCC) has quite variable clinical behaviors. The prognostic biomarkers play a crucial role in stratifying patients suffering from ccRCC to avoid over- and under-treatment. Researches based on hand-crafted features and single-modal data have been widely conducted to predict the prognosis of ccRCC. However, these experience-dependent methods, neglecting the synergy among multimodal data, have limited capacity to perform accurate prediction. Inspired by complementary information among multimodal data and the successful application of convolutional neural networks (CNNs) in medical image analysis, a novel framework was proposed to improve prediction performance. RESULTS: We proposed a cross-modal feature-based integrative framework, in which deep features extracted from computed tomography/histopathological images by using CNNs were combined with eigengenes generated from functional genomic data, to construct a prognostic model for ccRCC. Results showed that our proposed model can stratify high- and low-risk subgroups with significant difference (P-value < 0.05) and outperform the predictive performance of those models based on single-modality features in the independent testing cohort [C-index, 0.808 (0.728-0.888)]. In addition, we also explored the relationship between deep image features and eigengenes, and make an attempt to explain deep image features from the view of genomic data. Notably, the integrative framework is available to the task of prognosis prediction of other cancer with matched multimodal data. AVAILABILITY AND IMPLEMENTATION: https://github.com/zhang-de-lab/zhang-lab? from=singlemessage. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Accurate segmentation of organs at risk (OARs) from head and neck (H&N) CT images is crucial for effective H&N cancer radiotherapy. However, the existing deep learning methods are often not trained in an end-to-end fashion, i.e., they independently predetermine the regions of target organs before organ segmentation, causing limited information sharing between related tasks and thus leading to suboptimal segmentation results. Furthermore, when conventional segmentation network is used to segment all the OARs simultaneously, the results often favor big OARs over small OARs. Thus, the existing methods often train a specific model for each OAR, ignoring the correlation between different segmentation tasks. To address these issues, we propose a new multi-view spatial aggregation framework for joint localization and segmentation of multiple OARs using H&N CT images. The core of our framework is a proposed region-of-interest (ROI)-based fine-grained representation convolutional neural network (CNN), which is used to generate multi-OAR probability maps from each 2D view (i.e., axial, coronal, and sagittal view) of CT images. Specifically, our ROI-based fine-grained representation CNN (1) unifies the OARs localization and segmentation tasks and trains them in an end-to-end fashion, and (2) improves the segmentation results of various-sized OARs via a novel ROI-based fine-grained representation. Our multi-view spatial aggregation framework then spatially aggregates and assembles the generated multi-view multi-OAR probability maps to segment all the OARs simultaneously. We evaluate our framework using two sets of H&N CT images and achieve competitive and highly robust segmentation performance for OARs of various sizes.

Predicting malignant potential is one of the most critical components of a computer-aided diagnosis system for gastrointestinal stromal tumors (GISTs). These tumors have been studied only on the basis of subjective computed tomography findings. Among various methodologies, radiomics, and deep learning algorithms, specifically convolutional neural networks (CNNs), have recently been confirmed to achieve significant success by outperforming the state-of-the-art performance in medical image pattern classification and have rapidly become leading methodologies in this field. However, the existing methods generally use radiomics or deep convolutional features independently for pattern classification, which tend to take into account only global or local features, respectively. In this paper, we introduce and evaluate a hybrid structure that includes different features selected with radiomics model and CNNs and integrates these features to deal with GISTs classification. The Radiomics model and CNNs are constructed for global radiomics and local convolutional feature selection, respectively. Subsequently, we utilize distinct radiomics and deep convolutional features to perform pattern classification for GISTs. Specifically, we propose a new pooling strategy to assemble the deep convolutional features of 54 three-dimensional patches from the same case and integrate these features with the radiomics features for independent case, followed by random forest classifier. Our method can be extensively evaluated using multiple clinical datasets. The classification performance (area under the curve (AUC): 0.882; 95% confidence interval (CI): 0.816-0.947) consistently outperforms those of independent radiomics (AUC: 0.807; 95% CI: 0.724-0.892) and CNNs (AUC: 0.826; 95% CI: 0.795-0.856) approaches.

Conducting an accurate motion correction of liver dynamic contrast-enhanced magnetic resonance (DCE-MR) imaging remains challenging because of intensity variations caused by contrast agents. Such variations lead to the failure of the traditional intensity-based registration method. To address this problem, we propose a correlation-weighted sparse representation framework to separate the contrast agent from original liver DCE-MR images. This framework allows the robust registration of motion components over time without intensity variances. Existing sparse coding techniques recover a 3D image containing only contrast agents (named contrast enhancement component) from a manually labeled dictionary, whose column has the same size with the original 3D volume (3D-t mode). The high dimension of the recovery target (3D volume) and the indistinguishability between the unenhanced and enhanced images make accurate coding difficult. In this paper, we predefine an ideal time-intensity curve containing only contrast agents (named contrast agent curve) and recover it from the transpose dictionary (t-3D mode), whose column has been updated into the original time-intensity curves. The low dimension of the target (1D curve) and the significant intergroup difference between contrast agent curves and non-contrast agent curves can estimate a series of pure contrast agent curves. A "correlation-weighted" constraint is introduced for the selection of a coding subset with more contrast agent curves, leading to an efficient and accurate sparse recovery process. Then, the contrast enhancement component can be estimated by the solved sparse coefficients' map and the ideal curve and subtracted from the original DCE-MRI. Finally, we register the de-enhanced images and apply the obtained deformation fields for the original DCE-MRI to achieve the goal of motion correction. We conduct the experiments on both simulated and real liver DCE-MRI data. Compared with other state-of-the-art DCE-MRI registration methods, the experimental results show that our method achieves a better registration performance with less computational efficiency.

4D-CT plays an important role in lung cancer treatment. However, due to the inherent high-dose exposure associated with CT, dense sampling along superior-inferior direction is often not practical. As a result, artifacts such as lung vessel discontinuity and partial volume are typical in 4D-CT images and might mislead dose administration in radiation therapy. In this paper, we present a novel patch-based technique for super-resolution enhancement of the 4D-CT images along the superior-inferior direction. Our working premise is that the anatomical information that is missing at one particular phase can be recovered from other phases. Based on this assumption, we employ a patch-based mechanism for guided reconstruction of super-resolution axial slices. Specifically, to reconstruct each targeted super-resolution slice for a CT image at a particular phase, we agglomerate a dictionary of patches from images of all other phases in the 4D-CT sequence. Then we perform a sparse combination of the patches in this dictionary to reconstruct details of a super-resolution patch, under constraint of similarity to the corresponding patches in the neighboring slices. By iterating this procedure over all possible patch locations, a superresolution 4D-CT image sequence with enhanced anatomical details can be eventually reconstructed. Our method was extensively evaluated using a public dataset. In all experiments, our method outperforms the conventional linear and cubic-spline interpolation methods in terms of preserving image details and suppressing misleading artifacts.

4D-CT plays an important role in lung cancer treatment because of its capability in providing a comprehensive characterization of respiratory motion for high-precision radiation therapy. However, due to the inherent high-dose exposure associated with CT, dense sampling along superior-inferior direction is often not practical, thus resulting in an inter-slice thickness that is much greater than in-plane voxel resolutions. As a consequence, artifacts such as lung vessel discontinuity and partial volume effects are often observed in 4D-CT images, which may mislead dose administration in radiation therapy. In this paper, we present a novel patch-based technique for resolution enhancement of 4D-CT images along the superior-inferior direction. Our working premise is that anatomical information that is missing in one particular phase can be recovered from other phases. Based on this assumption, we employ a hierarchical patch-based sparse representation mechanism to enhance the superior-inferior resolution of 4D-CT by reconstructing additional intermediate CT slices. Specifically, for each spatial location on an intermediate CT slice that we intend to reconstruct, we first agglomerate a dictionary of patches from images of all other phases in the 4D-CT. We then employ a sparse combination of patches from this dictionary, with guidance from neighboring (upper and lower) slices, to reconstruct a series of patches, which we progressively refine in a hierarchical fashion to reconstruct the final intermediate slices with significantly enhanced anatomical details. Our method was extensively evaluated using a public dataset. In all experiments, our method outperforms the conventional linear and cubic-spline interpolation methods in preserving image details and also in suppressing misleading artifacts, indicating that our proposed method can potentially be applied to better image-guided radiation therapy of lung cancer in the future.