The Role of Radiomics and AI Technologies in the Segmentation, Detection, and Management of Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is the most common primary hepatic neoplasm. Thanks to recent advances in computed tomography (CT) and magnetic resonance imaging (MRI), there is potential to improve detection, segmentation, discrimination from HCC mimics, and monitoring of therapeutic response. Radiomics, artificial intelligence (AI), and derived tools have already been applied in other areas of diagnostic imaging with promising results. In this review, we briefly discuss the current clinical applications of radiomics and AI in the detection, segmentation, and management of HCC. Moreover, we investigate their potential to reach a more accurate diagnosis of HCC and to guide proper treatment planning

Medical Image Analytics (Radiomics) with Machine/Deeping Learning for Outcome Modeling in Radiation Oncology

Image-based quantitative analysis (radiomics) has gained great attention recently. Radiomics possesses promising potentials to be applied in the clinical practice of radiotherapy and to provide personalized healthcare for cancer patients. However, there are several challenges along the way that this thesis will attempt to address. Specifically, this thesis focuses on the investigation of repeatability and reproducibility of radiomics features, the development of new machine/deep learning models, and combining these for robust outcomes modeling and their applications in radiotherapy. Radiomics features suffer from robustness issues when applied to outcome modeling problems, especially in head and neck computed tomography (CT) images. These images tend to contain streak artifacts due to patients’ dental implants. To investigate the influence of artifacts for radiomics modeling performance, we firstly developed an automatic artifact detection algorithm using gradient-based hand-crafted features. Then, comparing the radiomics models trained on ‘clean’ and ‘contaminated’ datasets. The second project focused on using hand-crafted radiomics features and conventional machine learning methods for the prediction of overall response and progression-free survival for Y90 treated liver cancer patients. By identifying robust features and embedding prior knowledge in the engineered radiomics features and using bootstrapped LASSO to select robust features, we trained imaging and dose based models for the desired clinical endpoints, highlighting the complementary nature of this information in Y90 outcomes prediction. Combining hand-crafted and machine learnt features can take advantage of both expert domain knowledge and advanced data-driven approaches (e.g., deep learning). Thus, we proposed a new variational autoencoder network framework that modeled radiomics features, clinical factors, and raw CT images for the prediction of intrahepatic recurrence-free and overall survival for hepatocellular carcinoma (HCC) patients in this third project. The proposed approach was compared with widely used Cox proportional hazard model for survival analysis. Our proposed methods achieved significant improvement in terms of the prediction using the c-index metric highlighting the value of advanced modeling techniques in learning from limited and heterogeneous information in actuarial prediction of outcomes. Advances in stereotactic radiation therapy (SBRT) has led to excellent local tumor control with limited toxicities for HCC patients, but intrahepatic recurrence still remains prevalent. As an extension of the third project, we not only hope to predict the time to intrahepatic recurrence, but also the location where the tumor might recur. This will be clinically beneficial for better intervention and optimizing decision making during the process of radiotherapy treatment planning. To address this challenging task, firstly, we proposed an unsupervised registration neural network to register atlas CT to patient simulation CT and obtain the liver’s Couinaud segments for the entire patient cohort. Secondly, a new attention convolutional neural network has been applied to utilize multimodality images (CT, MR and 3D dose distribution) for the prediction of high-risk segments. The results showed much improved efficiency for obtaining segments compared with conventional registration methods and the prediction performance showed promising accuracy for anticipating the recurrence location as well. Overall, this thesis contributed new methods and techniques to improve the utilization of radiomics for personalized radiotherapy. These contributions included new algorithm for detecting artifacts, a joint model of dose with image heterogeneity, combining hand-crafted features with machine learnt features for actuarial radiomics modeling, and a novel approach for predicting location of treatment failure.PHDApplied PhysicsUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/163092/1/liswei_1.pd

A Machine Learning Framework for Identifying Molecular Biomarkers from Transcriptomic Cancer Data

Cancer is a complex molecular process due to abnormal changes in the genome, such as mutation and copy number variation, and epigenetic aberrations such as dysregulations of long non-coding RNA (lncRNA). These abnormal changes are reflected in transcriptome by turning oncogenes on and tumor suppressor genes off, which are considered cancer biomarkers. However, transcriptomic data is high dimensional, and finding the best subset of genes (features) related to causing cancer is computationally challenging and expensive. Thus, developing a feature selection framework to discover molecular biomarkers for cancer is critical. Traditional approaches for biomarker discovery calculate the fold change for each gene, comparing expression profiles between tumor and healthy samples, thus failing to capture the combined effect of the whole gene set. Also, these approaches do not always investigate cancer-type prediction capabilities using discovered biomarkers. In this work, we proposed a machine learning-based framework to address all of the above challenges in discovering lncRNA biomarkers. First, we developed a machine learning pipeline that takes lncRNA expression profiles of cancer samples as input and outputs a small set of key lncRNAs that can accurately predict multiple cancer types. A significant innovation of our work is its ability to identify biomarkers without using healthy samples. However, this initial framework cannot identify cancer-specific lncRNAs. Second, we extended our framework to identify cancer type and subtype-specific lncRNAs. Third, we proposed to use a state-of-the-art deep learning algorithm concrete autoencoder (CAE) in an unsupervised setting, which efficiently identifies a subset of the most informative features. However, CAE does not identify reproducible features in different runs due to its stochastic nature. Thus, we proposed a multi-run CAE (mrCAE) to identify a stable set of features to address this issue. Our deep learning-based pipeline significantly extended the previous state-of-the-art feature selection techniques. Finally, we showed that discovered biomarkers are biologically relevant using literature review and prognostically significant using survival analyses. The discovered novel biomarkers could be used as a screening tool for different cancer diagnoses and as therapeutic targets

State of the Art in Artificial Intelligence and Radiomics in Hepatocellular Carcinoma

The most common liver malignancy is hepatocellular carcinoma (HCC), which is also associated with high mortality. Often HCC develops in a chronic liver disease setting, and early diagnosis as well as accurate screening of high-risk patients is crucial for appropriate and effective management of these patients. While imaging characteristics of HCC are well-defined in the diagnostic phase, challenging cases still occur, and current prognostic and predictive models are limited in their accuracy. Radiomics and machine learning (ML) offer new tools to address these issues and may lead to scientific breakthroughs with the potential to impact clinical practice and improve patient outcomes. In this review, we will present an overview of these technologies in the setting of HCC imaging across different modalities and a range of applications. These include lesion segmentation, diagnosis, prognostic modeling and prediction of treatment response. Finally, limitations preventing clinical application of radiomics and ML at the present time are discussed, together with necessary future developments to bring the field forward and outside of a purely academic endeavor

Deep learning for image-based liver analysis — A comprehensive review focusing on malignant lesions

Deep learning-based methods, in particular, convolutional neural networks and fully convolutional networks are now widely used in the medical image analysis domain. The scope of this review focuses on the analysis using deep learning of focal liver lesions, with a special interest in hepatocellular carcinoma and metastatic cancer; and structures like the parenchyma or the vascular system. Here, we address several neural network architectures used for analyzing the anatomical structures and lesions in the liver from various imaging modalities such as computed tomography, magnetic resonance imaging and ultrasound. Image analysis tasks like segmentation, object detection and classification for the liver, liver vessels and liver lesions are discussed. Based on the qualitative search, 91 papers were filtered out for the survey, including journal publications and conference proceedings. The papers reviewed in this work are grouped into eight categories based on the methodologies used. By comparing the evaluation metrics, hybrid models performed better for both the liver and the lesion segmentation tasks, ensemble classifiers performed better for the vessel segmentation tasks and combined approach performed better for both the lesion classification and detection tasks. The performance was measured based on the Dice score for the segmentation, and accuracy for the classification and detection tasks, which are the most commonly used metrics.publishedVersio

Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images

Beyond sample curation and basic pathologic characterization, the digitized H&E-stained images of TCGA samples remain underutilized. To highlight this resource, we present mappings of tumorinfiltrating lymphocytes (TILs) based on H&E images from 13 TCGA tumor types. These TIL maps are derived through computational staining using a convolutional neural network trained to classify patches of images. Affinity propagation revealed local spatial structure in TIL patterns and correlation with overall survival. TIL map structural patterns were grouped using standard histopathological parameters. These patterns are enriched in particular T cell subpopulations derived from molecular measures. TIL densities and spatial structure were differentially enriched among tumor types, immune subtypes, and tumor molecular subtypes, implying that spatial infiltrate state could reflect particular tumor cell aberration states. Obtaining spatial lymphocytic patterns linked to the rich genomic characterization of TCGA samples demonstrates one use for the TCGA image archives with insights into the tumor-immune microenvironment

MACHINE LEARNING APPROACHES FOR BIOMARKER IDENTIFICATION AND SUBGROUP DISCOVERY FOR POST-TRAUMATIC STRESS DISORDER

Post-traumatic stress disorder (PTSD) is a psychiatric disorder caused by environmental and genetic factors resulting from alterations in genetic variation, epigenetic changes and neuroimaging characteristics. There is a pressing need to identify reliable molecular and physiological biomarkers for accurate diagnosis, prognosis, and treatment, as well to deepen the understanding of PTSD pathophysiology. Machine learning methods are widely used to infer patterns from biological data, identify biomarkers, and make predictions. The objective of this research is to apply machine learning methods for the accurate classification of human diseases from genome-scale datasets, focusing primarily on PTSD.The DoD-funded Systems Biology of PTSD Consortium has recruited combat veterans with and without PTSD for measurement of molecular and physiological data from blood or urine samples with the goal of identifying accurate and specific PTSD biomarkers. As a member of the Consortium with access to these PTSD multiple omics datasets, we first completed a project titled Clinical Subgroup-Specific PTSD Classification and Biomarker Discovery. We applied machine learning approaches to these data to build classification models consisting of molecular and clinical features to predict PTSD status. We also identified candidate biomarkers for diagnosis, which improves our understanding of PTSD pathogenesis. In a second project, entitled Multi-Omic PTSD Subgroup Identification and Clinical Characterization, we applied methods for integrating multiple omics datasets to investigate the complex, multivariate nature of the biological systems underlying PTSD. We identified an optimal 2 PTSD subgroups using two different machine learning approaches from 82 PTSD positive samples, and we found that the subgroups exhibited different remitting behavior as inferred from subjects recalled at a later time point. The results from our association, differential expression, and classification analyses demonstrated the distinct clinical and molecular features characterizing these subgroups.Taken together, our work has advanced our understanding of PTSD biomarkers and subgroups through the use of machine learning approaches. Results from our work should strongly contribute to the precise diagnosis and eventual treatment of PTSD, as well as other diseases. Future work will involve continuing to leverage these results to enable precision medicine for PTSD

Validation of volatile organic compounds for the assessment of liver disease

Chronic liver disease is one of the few conditions with increasing morbidity and mortality rates. Up to 75% of individuals with cirrhosis are diagnosed during a decompensation episode, at which point the prognosis is poor. Cirrhotic patients also have an annual risk of 2 to 4% of developing hepatocellular carcinoma (HCC). HCC is currently the fourth leading cause of cancer-related mortality worldwide, which is at least in part due to late diagnosis and inadequate screening. Gas chromatography-mass spectrometry (GC-MS) analysis of volatile organic compounds (VOCs) in breath has the potential to form the basis of a non-invasive diagnostic test for chronic liver disease and HCC. However, exhaled VOCs can be influenced by multiple confounding factors and the equipment used to collect and analyse breath can be cost prohibitive. The aims of my PhD were four-fold. Firstly, to develop and validate a novel, cost-effective breath collection device and to formulate a standard operating procedure for its use in clinical studies. Secondly, to analyse the VOC profile of background room air within common clinical sampling locations and to assess their potential impact upon the collection of breath samples. Thirdly, to investigate a methodology for sample splitting using GC-MS as a way of facilitating sample analysis across multiple mass spectrometry platforms. With the information garnered from this methodology work, my final aim was to perform a clinical study to profile the VOCs in the exhaled breath of patients with cirrhosis, HCC, and normal liver parenchyma. Prior to this, I also performed a critical analysis of the pre-existing literature on VOCs for assessment of liver disease to help guide my study design. Analysis of the novel breath collection device revealed acceptable repeatability for a wide range of VOCs and optimum settings for flow rates and volumes of breath were determined and included within a standard operating procedure. Profiling the background air volatiles in sampling locations identified specific VOC signatures for each location. Breath samples did not separate by location but monitoring of background volatiles in parallel to breath sampling remains important for identification of contaminant VOCs. Splitting of desorbed breath samples via GC-MS and recollection of two samples back on to one thermal desorption tube provides the best discrimination between samples. For my main clinical study, breath samples of 149 patients were analysed using GC-MS. Elevated levels of limonene and 2-pentanone were identified in those with hepatopathology, validating the results of previous studies. Additional VOCs were also discovered as candidate biomarkers and further studies are required to validate these findings. The results of my clinical study have added to the existing literature that specific VOCs in exhaled breath have the potential to form a non-invasive diagnostic test for hepatopathology that could potentially help enhance earlier diagnosis of liver disease and reverse the trend in mortality rates.Open Acces