Multimodal Data Fusion and Quantitative Analysis for Medical Applications

Medical big data is not only enormous in its size, but also heterogeneous and complex in its data structure, which makes conventional systems or algorithms difficult to process. These heterogeneous medical data include imaging data (e.g., Positron Emission Tomography (PET), Computerized Tomography (CT), Magnetic Resonance Imaging (MRI)), and non-imaging data (e.g., laboratory biomarkers, electronic medical records, and hand-written doctor notes). Multimodal data fusion is an emerging vital field to address this urgent challenge, aiming to process and analyze the complex, diverse and heterogeneous multimodal data. The fusion algorithms bring great potential in medical data analysis, by 1) taking advantage of complementary information from different sources (such as functional-structural complementarity of PET/CT images) and 2) exploiting consensus information that reflects the intrinsic essence (such as the genetic essence underlying medical imaging and clinical symptoms). Thus, multimodal data fusion benefits a wide range of quantitative medical applications, including personalized patient care, more optimal medical operation plan, and preventive public health. Though there has been extensive research on computational approaches for multimodal fusion, there are three major challenges of multimodal data fusion in quantitative medical applications, which are summarized as feature-level fusion, information-level fusion and knowledge-level fusion: • Feature-level fusion. The first challenge is to mine multimodal biomarkers from high-dimensional small-sample multimodal medical datasets, which hinders the effective discovery of informative multimodal biomarkers. Specifically, efficient dimension reduction algorithms are required to alleviate "curse of dimensionality" problem and address the criteria for discovering interpretable, relevant, non-redundant and generalizable multimodal biomarkers. • Information-level fusion. The second challenge is to exploit and interpret inter-modal and intra-modal information for precise clinical decisions. Although radiomics and multi-branch deep learning have been used for implicit information fusion guided with supervision of the labels, there is a lack of methods to explicitly explore inter-modal relationships in medical applications. Unsupervised multimodal learning is able to mine inter-modal relationship as well as reduce the usage of labor-intensive data and explore potential undiscovered biomarkers; however, mining discriminative information without label supervision is an upcoming challenge. Furthermore, the interpretation of complex non-linear cross-modal associations, especially in deep multimodal learning, is another critical challenge in information-level fusion, which hinders the exploration of multimodal interaction in disease mechanism. • Knowledge-level fusion. The third challenge is quantitative knowledge distillation from multi-focus regions on medical imaging. Although characterizing imaging features from single lesions using either feature engineering or deep learning methods have been investigated in recent years, both methods neglect the importance of inter-region spatial relationships. Thus, a topological profiling tool for multi-focus regions is in high demand, which is yet missing in current feature engineering and deep learning methods. Furthermore, incorporating domain knowledge with distilled knowledge from multi-focus regions is another challenge in knowledge-level fusion. To address the three challenges in multimodal data fusion, this thesis provides a multi-level fusion framework for multimodal biomarker mining, multimodal deep learning, and knowledge distillation from multi-focus regions. Specifically, our major contributions in this thesis include: • To address the challenges in feature-level fusion, we propose an Integrative Multimodal Biomarker Mining framework to select interpretable, relevant, non-redundant and generalizable multimodal biomarkers from high-dimensional small-sample imaging and non-imaging data for diagnostic and prognostic applications. The feature selection criteria including representativeness, robustness, discriminability, and non-redundancy are exploited by consensus clustering, Wilcoxon filter, sequential forward selection, and correlation analysis, respectively. SHapley Additive exPlanations (SHAP) method and nomogram are employed to further enhance feature interpretability in machine learning models. • To address the challenges in information-level fusion, we propose an Interpretable Deep Correlational Fusion framework, based on canonical correlation analysis (CCA) for 1) cohesive multimodal fusion of medical imaging and non-imaging data, and 2) interpretation of complex non-linear cross-modal associations. Specifically, two novel loss functions are proposed to optimize the discovery of informative multimodal representations in both supervised and unsupervised deep learning, by jointly learning inter-modal consensus and intra-modal discriminative information. An interpretation module is proposed to decipher the complex non-linear cross-modal association by leveraging interpretation methods in both deep learning and multimodal consensus learning. • To address the challenges in knowledge-level fusion, we proposed a Dynamic Topological Analysis framework, based on persistent homology, for knowledge distillation from inter-connected multi-focus regions in medical imaging and incorporation of domain knowledge. Different from conventional feature engineering and deep learning, our DTA framework is able to explicitly quantify inter-region topological relationships, including global-level geometric structure and community-level clusters. K-simplex Community Graph is proposed to construct the dynamic community graph for representing community-level multi-scale graph structure. The constructed dynamic graph is subsequently tracked with a novel Decomposed Persistence algorithm. Domain knowledge is incorporated into the Adaptive Community Profile, summarizing the tracked multi-scale community topology with additional customizable clinically important factors

TTMFN: Two-stream Transformer-based Multimodal Fusion Network for Survival Prediction

Survival prediction plays a crucial role in assisting clinicians with the development of cancer treatment protocols. Recent evidence shows that multimodal data can help in the diagnosis of cancer disease and improve survival prediction. Currently, deep learning-based approaches have experienced increasing success in survival prediction by integrating pathological images and gene expression data. However, most existing approaches overlook the intra-modality latent information and the complex inter-modality correlations. Furthermore, existing modalities do not fully exploit the immense representational capabilities of neural networks for feature aggregation and disregard the importance of relationships between features. Therefore, it is highly recommended to address these issues in order to enhance the prediction performance by proposing a novel deep learning-based method. We propose a novel framework named Two-stream Transformer-based Multimodal Fusion Network for survival prediction (TTMFN), which integrates pathological images and gene expression data. In TTMFN, we present a two-stream multimodal co-attention transformer module to take full advantage of the complex relationships between different modalities and the potential connections within the modalities. Additionally, we develop a multi-head attention pooling approach to effectively aggregate the feature representations of the two modalities. The experiment results on four datasets from The Cancer Genome Atlas demonstrate that TTMFN can achieve the best performance or competitive results compared to the state-of-the-art methods in predicting the overall survival of patients

Cross-Modality Deep Feature Learning for Brain Tumor Segmentation

Recent advances in machine learning and prevalence of digital medical images have opened up an opportunity to address the challenging brain tumor segmentation (BTS) task by using deep convolutional neural networks. However, different from the RGB image data that are very widespread, the medical image data used in brain tumor segmentation are relatively scarce in terms of the data scale but contain the richer information in terms of the modality property. To this end, this paper proposes a novel cross-modality deep feature learning framework to segment brain tumors from the multi-modality MRI data. The core idea is to mine rich patterns across the multi-modality data to make up for the insufficient data scale. The proposed cross-modality deep feature learning framework consists of two learning processes: the cross-modality feature transition (CMFT) process and the cross-modality feature fusion (CMFF) process, which aims at learning rich feature representations by transiting knowledge across different modality data and fusing knowledge from different modality data, respectively. Comprehensive experiments are conducted on the BraTS benchmarks, which show that the proposed cross-modality deep feature learning framework can effectively improve the brain tumor segmentation performance when compared with the baseline methods and state-of-the-art methods.Comment: published on Pattern Recognition 202

Ordinal Multi-modal Feature Selection for Survival Analysis of Early-Stage Renal Cancer

Existing studies have demonstrated that combining genomic data and histopathological images can better stratify cancer patients with distinct prognosis than using single biomarker, for different biomarkers may provide complementary information. However, these multi-modal data, most high-dimensional, may contain redundant features that will deteriorate the performance of the prognosis model, and therefore it has become a challenging problem to select the informative features for survival analysis from the redundant and heterogeneous feature groups. Existing feature selection methods assume that the survival information of one patient is independent to another, and thus miss the ordinal relationship among the survival time of different patients. To solve this issue, we make use of the important ordinal survival information among different patients and propose an ordinal sparse canonical correlation analysis (i.e., OSCCA) framework to simultaneously identify important image features and eigengenes for survival analysis. Specifically, we formulate our framework basing on sparse canonical correlation analysis model, which aims at finding the best linear projections so that the highest correlation between the selected image features and eigengenes can be achieved. In addition, we also add constrains to ensure that the ordinal survival information of different patients is preserved after projection. We evaluate the effectiveness of our method on an early-stage renal cell carcinoma dataset. Experimental results demonstrate that the selected features correlated strongly with survival, by which we can achieve better patient stratification than the comparing methods

Deep Learning for Survival Analysis: A Review

The influx of deep learning (DL) techniques into the field of survival analysis in recent years, coupled with the increasing availability of high-dimensional omics data and unstructured data like images or text, has led to substantial methodological progress; for instance, learning from such high-dimensional or unstructured data. Numerous modern DL-based survival methods have been developed since the mid-2010s; however, they often address only a small subset of scenarios in the time-to-event data setting - e.g., single-risk right-censored survival tasks - and neglect to incorporate more complex (and common) settings. Partially, this is due to a lack of exchange between experts in the respective fields. In this work, we provide a comprehensive systematic review of DL-based methods for time-to-event analysis, characterizing them according to both survival- and DL-related attributes. In doing so, we hope to provide a helpful overview to practitioners who are interested in DL techniques applicable to their specific use case as well as to enable researchers from both fields to identify directions for future investigation. We provide a detailed characterization of the methods included in this review as an open-source, interactive table: https://survival-org.github.io/DL4Survival. As this research area is advancing rapidly, we encourage the research community to contribute to keeping the information up to date.Comment: 24 pages, 6 figures, 2 tables, 1 interactive tabl