Machine Learning and Integrative Analysis of Biomedical Big Data.

Recent developments in high-throughput technologies have accelerated the accumulation of massive amounts of omics data from multiple sources: genome, epigenome, transcriptome, proteome, metabolome, etc. Traditionally, data from each source (e.g., genome) is analyzed in isolation using statistical and machine learning (ML) methods. Integrative analysis of multi-omics and clinical data is key to new biomedical discoveries and advancements in precision medicine. However, data integration poses new computational challenges as well as exacerbates the ones associated with single-omics studies. Specialized computational approaches are required to effectively and efficiently perform integrative analysis of biomedical data acquired from diverse modalities. In this review, we discuss state-of-the-art ML-based approaches for tackling five specific computational challenges associated with integrative analysis: curse of dimensionality, data heterogeneity, missing data, class imbalance and scalability issues

Evaluation of colorectal cancer subtypes and cell lines using deep learning

Colorectal cancer (CRC) is a common cancer with a high mortality rate and a rising incidence rate in the developed world. Molecular profiling techniques have been used to better understand the variability between tumors and disease models such as cell lines. To maximize the translatability and clinical relevance of in vitro studies, the selection of optimal cancer models is imperative. We have developed a deep learning-based method to measure the similarity between CRC tumors and disease models such as cancer cell lines. Our method efficiently leverages multiomics data sets containing copy number alterations, gene expression, and point mutations and learns latent factors that describe data in lower dimensions. These latent factors represent the patterns that are clinically relevant and explain the variability of molecular profiles across tumors and cell lines. Using these, we propose refined CRC subtypes and provide best-matching cell lines to different subtypes. These findings are relevant to patient stratification and selection of cell lines for early-stage drug discovery pipelines, biomarker discovery, and target identification

Statistical Methods for Integrated Cancer Genomic Data Using a Joint Latent Variable Model

Inspired by the TCGA (The Cancer Genome Atlas), we explore multimodal genomic datasets with integrative methods using a joint latent variable approach. We use iCluster+, an existing clustering method for integrative data, to identify potential subtypes within TCGA sarcoma and mesothelioma tumors, and across a large cohort of 33 dierent TCGA cancer datasets. For classication, motivated to improve the prediction of platinum resistance in high grade serous ovarian cancer (HGSOC) treatment, we propose novel integrative methods, iClassify to perform classication using a joint latent variable model. iClassify provides eective data integration and classication while handling heterogeneous data types, while providing a natural framework to incorporate covariate risk factors and examine genomic driver by covariate risk factor interaction. Feature selection is performed through a thresholding parameter that combines both latent variable and feature coecients. We demonstrate increased accuracy in classication over methods that assume homogeneous data type, such as linear discriminant analysis and penalized logistic regression, and improved feature selection. We apply iClassify to a TCGA cohort of HGSOC patients with three types of genomic data and platinum response data. This methodology has broad applications beyond predicting treatment outcomes and disease progression in cancer, including predicting prognosis and diagnosis in other diseases with major public health implications

Statistical Methods for Integrating Genomics Data

This dissertation focuses on methodology to integrate multiplatform genomic data with cancer applications. Such integration facilitates the discovery of biological information crucial to the development of targeted treatments. We present iBAG (integrative Bayesian Analysis of Genomics data), a two-step hierarchical Bayesian model that uses the known biological relationships between genetic platforms to integrate an arbitrary number of platforms in a single model. This method identifies genes important to a clinical outcome, such as survival, and the integration approach also allows us to identify which platforms are modulating the important gene effects. A glioblastoma multiforme (GBM) data set publicly available from The Cancer Genome Atlas (TCGA) is analyzed with iBAG. We flag several genes as important to survival time, and we include a discussion of these genes in a biological context. We then present a nonlinear formulation of iBAG, which increases the flexibility of the model to accommodate nonlinear relationships among the data platforms. The TCGA GBM data is again analyzed, and we carefully compare the results from both the linear and nonlinear formulation. Next we present a pathway iBAG model, piBAG, which includes gene pathway membership information and utilizes hierarchical shrinkage to simultaneously select important genes and assign pathway scores. The integration of multiple genomic platforms again allows us to determine which platform is regulating each important gene, and it also provides insight as to through which platform each pathway is taking effect. We apply this method to a different subset of the TCGA GBM data. Finally, we present integrative heatmaps, a novel visualization tool for illustrating integrated data. We use a TCGA colorectal cancer data set to demonstrate the integrative heatmaps. Through the various simulation studies and data applications in this dissertation, we conclude that the methods presented achieve their respective goals and outperform standard methods. We demonstrate that our methods provide many advantages, including increased estimation efficiency, increased power, lower false discovery rates, and deeper biological insight into the genetic mechanics of cancer development and progression

Evaluation of colorectal cancer subtypes and cell lines using deep learning

Colorectal cancer (CRC) is a common cancer with a high mortality rate and rising incidence rate in the developed world. Molecular profiling techniques have been used to study the variability between tumours as well as cancer models such as cell lines, but their translational value is incomplete with current methods. Moreover, first generation computational methods for subtype classification do not make use of multi-omics data in full scale. Drug discovery programs use cell lines as a proxy for human cancers to characterize their molecular makeup and drug response, identify relevant indications and discover biomarkers. In order to maximize the translatability and the clinical relevance of in vitro studies, selection of optimal cancer models is imperative. We present a novel subtype classification method based on deep learning and apply it to classify CRC tumors using multi-omics data, and further to measure the similarity between tumors and disease models such as cancer cell lines. Multi-omics Autoencoder Integration (maui) efficiently leverages data sets containing copy number alterations, gene expression, and point mutations, and learns clinically important patterns (latent factors) across these data types. Using these latent factors, we propose a refinement of the gold-standard CRC subtypes, and propose best-matching cell lines for the different subtypes. These findings are relevant for patient stratification and selection of cell lines for drug discovery pipelines, biomarker discovery, and target identification

Pathway-Based Multi-Omics Data Integration for Breast Cancer Diagnosis and Prognosis.

Ph.D. Thesis. University of Hawaiʻi at Mānoa 2017

Unsupervised multiple kernel learning approaches for integrating molecular cancer patient data

Cancer is the second leading cause of death worldwide. A characteristic of this disease is its complexity leading to a wide variety of genetic and molecular aberrations in the tumors. This heterogeneity necessitates personalized therapies for the patients. However, currently defined cancer subtypes used in clinical practice for treatment decision-making are based on relatively few selected markers and thus provide only a coarse classifcation of tumors. The increased availability in multi-omics data measured for cancer patients now offers the possibility of defining more informed cancer subtypes. Such a more fine-grained characterization of cancer subtypes harbors the potential of substantially expanding treatment options in personalized cancer therapy. In this thesis, we identify comprehensive cancer subtypes using multidimensional data. For this purpose, we apply and extend unsupervised multiple kernel learning methods. Three challenges of unsupervised multiple kernel learning are addressed: robustness, applicability, and interpretability. First, we show that regularization of the multiple kernel graph embedding framework, which enables the implementation of dimensionality reduction techniques, can increase the stability of the resulting patient subgroups. This improvement is especially beneficial for data sets with a small number of samples. Second, we adapt the objective function of kernel principal component analysis to enable the application of multiple kernel learning in combination with this widely used dimensionality reduction technique. Third, we improve the interpretability of kernel learning procedures by performing feature clustering prior to integrating the data via multiple kernel learning. On the basis of these clusters, we derive a score indicating the impact of a feature cluster on a patient cluster, thereby facilitating further analysis of the cluster-specific biological properties. All three procedures are successfully tested on real-world cancer data. Comparing our newly derived methodologies to established methods provides evidence that our work offers novel and beneficial ways of identifying patient subgroups and gaining insights into medically relevant characteristics of cancer subtypes.Krebs ist eine der häufigsten Todesursachen weltweit. Krebs ist gekennzeichnet durch seine Komplexität, die zu vielen verschiedenen genetischen und molekularen Aberrationen im Tumor führt. Die Unterschiede zwischen Tumoren erfordern personalisierte Therapien für die einzelnen Patienten. Die Krebssubtypen, die derzeit zur Behandlungsplanung in der klinischen Praxis verwendet werden, basieren auf relativ wenigen, genetischen oder molekularen Markern und können daher nur eine grobe Unterteilung der Tumoren liefern. Die zunehmende Verfügbarkeit von Multi-Omics-Daten für Krebspatienten ermöglicht die Neudefinition von fundierteren Krebssubtypen, die wiederum zu spezifischeren Behandlungen für Krebspatienten führen könnten. In dieser Dissertation identifizieren wir neue, potentielle Krebssubtypen basierend auf Multi-Omics-Daten. Hierfür verwenden wir unüberwachtes Multiple Kernel Learning, welches in der Lage ist mehrere Datentypen miteinander zu kombinieren. Drei Herausforderungen des unüberwachten Multiple Kernel Learnings werden adressiert: Robustheit, Anwendbarkeit und Interpretierbarkeit. Zunächst zeigen wir, dass die zusätzliche Regularisierung des Multiple Kernel Learning Frameworks zur Implementierung verschiedener Dimensionsreduktionstechniken die Stabilität der identifizierten Patientengruppen erhöht. Diese Robustheit ist besonders vorteilhaft für Datensätze mit einer geringen Anzahl von Proben. Zweitens passen wir die Zielfunktion der kernbasierten Hauptkomponentenanalyse an, um eine integrative Version dieser weit verbreiteten Dimensionsreduktionstechnik zu ermöglichen. Drittens verbessern wir die Interpretierbarkeit von kernbasierten Lernprozeduren, indem wir verwendete Merkmale in homogene Gruppen unterteilen bevor wir die Daten integrieren. Mit Hilfe dieser Gruppen definieren wir eine Bewertungsfunktion, die die weitere Auswertung der biologischen Eigenschaften von Patientengruppen erleichtert. Alle drei Verfahren werden an realen Krebsdaten getestet. Den Vergleich unserer Methodik mit etablierten Methoden weist nach, dass unsere Arbeit neue und nützliche Möglichkeiten bietet, um integrative Patientengruppen zu identifizieren und Einblicke in medizinisch relevante Eigenschaften von Krebssubtypen zu erhalten

Identifying Cancer Subtypes Using Unsupervised Deep Learning

Glioblastoma multiforme (GBM) is the most fatal malignant type of brain tumor with a very poor prognosis with a median survival of around one year. Numerous studies have reported tumor subtypes that consider different characteristics on individual patients, which may play important roles in determining the survival rates in GBM. In this study, we present a pathway-based clustering method using Restricted Boltzmann Machine (RBM), called R-PathCluster, for identifying unknown subtypes with pathway markers of gene expressions. In order to assess the performance of R-PathCluster, we conducted experiments with several clustering methods such as k-means, hierarchical clustering, and RBM models with different input data. R-PathCluster showed the best performance in clustering longterm and short-term survivals, although its clustering score was not the highest among them in experiments. R-PathCluster provides a solution to interpret the model in biological sense, since it takes pathway markers that represent biological process of pathways. We discussed that our findings from R-PathCluster are supported by many biological literatures. Keywords. Glioblastoma multiforme, tumor subtypes, clustering, Restricted Boltzmann Machin