Quantifying intra-tumoral genetic heterogeneity of glioblastoma toward precision medicine using MRI and a data-inclusive machine learning algorithm

Glioblastoma (GBM) is one of the most aggressive and lethal human cancers. Intra-tumoral genetic heterogeneity poses a significant challenge for treatment. Biopsy is invasive, which motivates the development of non-invasive, MRI-based machine learning (ML) models to quantify intra-tumoral genetic heterogeneity for each patient. This capability holds great promise for enabling better therapeutic selection to improve patient outcomes. We proposed a novel Weakly Supervised Ordinal Support Vector Machine (WSO-SVM) to predict regional genetic alteration status within each GBM tumor using MRI. WSO-SVM was applied to a unique dataset of 318 image-localized biopsies with spatially matched multiparametric MRI from 74 GBM patients. The model was trained to predict the regional genetic alteration of three GBM driver genes (EGFR, PDGFRA, and PTEN) based on features extracted from the corresponding region of five MRI contrast images. For comparison, a variety of existing ML algorithms were also applied. The classification accuracy of each gene was compared between the different algorithms. The SHapley Additive exPlanations (SHAP) method was further applied to compute contribution scores of different contrast images. Finally, the trained WSO-SVM was used to generate prediction maps within the tumoral area of each patient to help visualize the intra-tumoral genetic heterogeneity. This study demonstrated the feasibility of using MRI and WSO-SVM to enable non-invasive prediction of intra-tumoral regional genetic alteration for each GBM patient, which can inform future adaptive therapies for individualized oncology.Comment: 36 pages, 8 figures, 3 table

Joint learning from multiple information sources for biological problems

Thanks to technological advancements, more and more biological data havebeen generated in recent years. Data availability offers unprecedented opportunities to look at the same problem from multiple aspects. It also unveils a more global view of the problem that takes into account the intricated inter-play between the involved molecules/entities. Nevertheless, biological datasets are biased, limited in quantity, and contain many false-positive samples. Such challenges often drastically downgrade the performance of a predictive model on unseen data and, thus, limit its applicability in real biological studies. Human learning is a multi-stage process in which we usually start with simple things. Through the accumulated knowledge over time, our cognition ability extends to more complex concepts. Children learn to speak simple words before being able to formulate sentences. Similarly, being able to speak correct sentences supports our learning to speak correct and meaningful paragraphs, etc. Generally, knowledge acquired from related learning tasks would help boost our learning capability in the current task. Motivated by such a phenomenon, in this thesis, we study supervised machine learning models for bioinformatics problems that can improve their performance through exploiting multiple related knowledge sources. More specifically, we concern with ways to enrich the supervised models’ knowledge base with publicly available related data to enhance the computational models’ prediction performance. Our work shares commonality with existing works in multimodal learning, multi-task learning, and transfer learning. Nevertheless, there are certain differences in some cases. Besides the proposed architectures, we present large-scale experiment setups with consensus evaluation metrics along with the creation and release of large datasets to showcase our approaches’ superiority. Moreover, we add case studies with detailed analyses in which we place no simplified assumptions to demonstrate the systems’ utilities in realistic application scenarios. Finally, we develop and make available an easy-to-use website for non-expert users to query the model’s generated prediction results to facilitate field experts’ assessments and adaptation. We believe that our work serves as one of the first steps in bridging the gap between “Computer Science” and “Biology” that will open a new era of fruitful collaboration between computer scientists and biological field experts

Deep transfer learning for drug response prediction

The goal of precision oncology is to make accurate predictions for cancer patients via some omics data types of individual patients. Major challenges of computational methods for drug response prediction are that labeled clinical data is very limited, not publicly available, or has drug response for one or two drugs. These challenges have been addressed by generating large-scale pre-clinical datasets such as cancer cell lines or patient-derived xenografts (PDX). These pre-clinical datasets have multi-omics characterization of samples and are often screened with hundreds of drugs which makes them viable resources for precision oncology. However, they raise new questions: how can we integrate different data types? how can we handle data discrepancy between pre-clinical and clinical datasets that exist due to basic biological differences? and how can we make the best use of unlabeled samples in drug response prediction where labeling is extra challenging? In this thesis, we propose methods based on deep neural networks to answer these questions. First, we propose a method of multi-omics integration. Second, we propose a transfer learning method to address data discrepancy between cell lines, patients, and PDX models in the input and output space. Finally, we proposed a semi-supervised method of out-of-distribution generalization to predict drug response using labeled and unlabeled samples. The proposed methods have promising performance when compared to the state-of-the-art and may guide precision oncology more accurately

UNCERTAINTY MITIGATION IN IMAGE-BASED MACHINE LEARNING MODELS FOR PRECISION MEDICINE

Machine learning (ML) algorithms have been developed to build predictive models in medicine and healthcare. In most cases, the performance of ML models/algorithms is measured by predictive accuracy or accuracy-related measures only. In medicine, the model results are intended to guide physicians to make critical decisions regarding patient care. This means that quantifying and mitigating the uncertainty of the output is also very important as it will allow decision makers to know how much they can rely on the model output. My dissertation focuses on studying model uncertainty of image-based ML in the context of precision medicine of brain cancer. Specifically, I focus on developing ML models to predict intra-tumor heterogeneity of genomic and molecular markers based on multi-contrast magnetic resonance imaging (MRI) data for glioblastoma (GBM) – the most aggressive type of brain cancer. Intra-tumor heterogeneity has been found to be a leading cause of treatment failure of GBM. Devising a non-invasive approach to map out the molecular/genomic distribution using MRI helps develop treatment with high precision. My dissertation research addresses the model uncertainties due to high-dimensional and noisy features, sparsity of labeled data, and utility of domain knowledge. In the first study, we developed a Semi-supervised Gaussian Process with Uncertainty-minimizing Feature-selection (SGP-UF), which can incorporate selected unlabeled samples (i.e. unbiopsied regions of a tumor) in the model training, and integrate feature selection with a new criterion of seeking features that minimize the prediction uncertainty. In the second study, we developed a Knowledge-infused Global-Local data fusion (KGL) framework, which optimally fuses three sources of data/information including biopsy samples (labeled data, local/sparse), images (unlabeled data, global), and knowledge-driven mechanistic models. In the third study, we developed a Weakly Supervised Ordinal Support Vector Machine (WSO-SVM), which aims to leverage a combination of data sources including biopsy/labeled samples and unlabeled samples from the tumor and image data from the normal brain, as well as their intrinsic ordinal relationship. We demonstrate that these novel methods significantly reduce prediction uncertainty while at the same time achieving higher accuracy in precision medicine, which can inform personalized targeted treatment decisions that potentially improve clinical outcome.Ph.D

Learning by Fusing Heterogeneous Data

It has become increasingly common in science and technology to gather data about systems at different levels of granularity or from different perspectives. This often gives rise to data that are represented in totally different input spaces. A basic premise behind the study of learning from heterogeneous data is that in many such cases, there exists some correspondence among certain input dimensions of different input spaces. In our work we found that a key bottleneck that prevents us from better understanding and truly fusing heterogeneous data at large scales is identifying the kind of knowledge that can be transferred between related data views, entities and tasks. We develop interesting and accurate data fusion methods for predictive modeling, which reduce or entirely eliminate some of the basic feature engineering steps that were needed in the past when inferring prediction models from disparate data. In addition, our work has a wide range of applications of which we focus on those from molecular and systems biology: it can help us predict gene functions, forecast pharmacological actions of small chemicals, prioritize genes for further studies, mine disease associations, detect drug toxicity and regress cancer patient survival data. Another important aspect of our research is the study of latent factor models. We aim to design latent models with factorized parameters that simultaneously tackle multiple types of data heterogeneity, where data diversity spans across heterogeneous input spaces, multiple types of features, and a variety of related prediction tasks. Our algorithms are capable of retaining the relational structure of a data system during model inference, which turns out to be vital for good performance of data fusion in certain applications. Our recent work included the study of network inference from many potentially nonidentical data distributions and its application to cancer genomic data. We also model the epistasis, an important concept from genetics, and propose algorithms to efficiently find the ordering of genes in cellular pathways. A central topic of our Thesis is also the analysis of large data compendia as predictions about certain phenomena, such as associations between diseases and involvement of genes in a certain phenotype, are only possible when dealing with lots of data. Among others, we analyze 30 heterogeneous data sets to assess drug toxicity and over 40 human gene association data collections, the largest number of data sets considered by a collective latent factor model up to date. We also make interesting observations about deciding which data should be considered for fusion and develop a generic approach that can estimate the sensitivities between different data sets

Advancing efficiency and robustness of neural networks for imaging

Enabling machines to see and analyze the world is a longstanding research objective. Advances in computer vision have the potential of influencing many aspects of our lives as they can enable machines to tackle a variety of tasks. Great progress in computer vision has been made, catalyzed by recent progress in machine learning and especially the breakthroughs achieved by deep artificial neural networks. Goal of this work is to alleviate limitations of deep neural networks that hinder their large-scale adoption for real-world applications. To this end, it investigates methodologies for constructing and training deep neural networks with low computational requirements. Moreover, it explores strategies for achieving robust performance on unseen data. Of particular interest is the application of segmenting volumetric medical scans because of the technical challenges it imposes, as well as its clinical importance. The developed methodologies are generic and of relevance to a broader computer vision and machine learning audience. More specifically, this work introduces an efficient 3D convolutional neural network architecture, which achieves high performance for segmentation of volumetric medical images, an application previously hindered by high computational requirements of 3D networks. It then investigates sensitivity of network performance on hyper-parameter configuration, which we interpret as overfitting the model configuration to the data available during development. It is shown that ensembling a set of models with diverse configurations mitigates this and improves generalization. The thesis then explores how to utilize unlabelled data for learning representations that generalize better. It investigates domain adaptation and introduces an architecture for adversarial networks tailored for adaptation of segmentation networks. Finally, a novel semi-supervised learning method is proposed that introduces a graph in the latent space of a neural network to capture relations between labelled and unlabelled samples. It then regularizes the embedding to form a compact cluster per class, which improves generalization.Open Acces

Automated Recommender Systems

Recommender systems have been existing accompanying by web development, driving personalized experience for billions of users. They play a vital role in the information retrieval process, overcome the information overload by facilitating the communication between business people and the public, and boost the business world. Powered by the advances of machine learning techniques, modern recommender systems enable tremendous automation on the data preprocessing, information distillations, and contextual inferences. It allows us to mine patterns and relationships from massive datasets and various data resources to make inferences. Moreover, the fast evolvement of deep learning techniques brings vast vitality and improvements dived in both academic research and industry applications. Despite the prominence achieved in the recent recommender systems, the automation they have been achieved is still limited in a narrow scope. On the one hand, beyond the static setting, real-world recommendation tasks are often imbued with high-velocity streaming data. On the other hand, with the increasing complexity of model structure and system architecture, the handcrafted design and tuning process is becoming increasingly complicated and time-consuming. With these challenges in mind, this dissertation aims to enable advanced automation in recommender systems. In particular, we discuss how to update factorization-based recommendation models adaptively and how to automatically design and tune recommendation models with automated machine learning techniques. Four main contributions are made via tackling the challenges: (1) The first contribution of this research dissertation is the development of a tensor-based algorithm for streaming recommendation tasks. (2) As deep learning techniques have shown their superiority in recommendation tasks and become dominant in both academia and industry applications, the second contribution is exploring and developing advanced deep learning algorithms to tackle the recommendation problem with the streaming dataset. (3) To alleviate the burden of human efforts, we explore adopting automated machine learning in designing and tuning recommender systems. The third contribution of this dissertation is the development of a novel neural architecture search approaches for discovering useful features interactions and designing better models for the click-through rate prediction problem. (4) Considering a large number of recommendation tasks in industrial applications and their similarities, in the last piece of work work, we focus on the hyperparameter tuning problem in the transfer-learning setting and develop a transferable framework for meta-level tuning of machine learning models