NETWORK ANALYTICS FOR THE MIRNA REGULOME AND MIRNA-DISEASE INTERACTIONS

miRNAs are non-coding RNAs of approx. 22 nucleotides in length that inhibit gene expression at the post-transcriptional level. By virtue of this gene regulation mechanism, miRNAs play a critical role in several biological processes and patho-physiological conditions, including cancers. miRNA behavior is a result of a multi-level complex interaction network involving miRNA-mRNA, TF-miRNA-gene, and miRNA-chemical interactions; hence the precise patterns through which a miRNA regulates a certain disease(s) are still elusive. Herein, I have developed an integrative genomics methods/pipeline to (i) build a miRNA regulomics and data analytics repository, (ii) create/model these interactions into networks and use optimization techniques, motif based analyses, network inference strategies and influence diffusion concepts to predict miRNA regulations and its role in diseases, especially related to cancers. By these methods, we are able to determine the regulatory behavior of miRNAs and potential causal miRNAs in specific diseases and potential biomarkers/targets for drug and medicinal therapeutics

Artificial intelligence in cancer target identification and drug discovery

Artificial intelligence is an advanced method to identify novel anticancer targets and discover novel drugs from biology networks because the networks can effectively preserve and quantify the interaction between components of cell systems underlying human diseases such as cancer. Here, we review and discuss how to employ artificial intelligence approaches to identify novel anticancer targets and discover drugs. First, we describe the scope of artificial intelligence biology analysis for novel anticancer target investigations. Second, we review and discuss the basic principles and theory of commonly used network-based and machine learning-based artificial intelligence algorithms. Finally, we showcase the applications of artificial intelligence approaches in cancer target identification and drug discovery. Taken together, the artificial intelligence models have provided us with a quantitative framework to study the relationship between network characteristics and cancer, thereby leading to the identification of potential anticancer targets and the discovery of novel drug candidates

MicroRNA Interaction Networks

La tesi di Giorgio Bertolazzi è incentrata sullo sviluppo di nuovi algoritmi per la predizione dei legami miRNA-mRNA. In particolare, un algoritmo di machine-learning viene proposto per l'upgrade del web tool ComiR; la versione originale di ComiR considerava soltanto i siti di legame dei miRNA collocati nella regione 3'UTR dell'RNA messaggero. La nuova versione di ComiR include nella ricerca dei legami la regione codificante dell'RNA messaggero.Bertolazzi’s thesis focuses on developing and applying computational methods to predict microRNA binding sites located on messenger RNA molecules. MicroRNAs (miRNAs) regulate gene expression by binding target messenger RNA molecules (mRNAs). Therefore, the prediction of miRNA binding is important to investigate cellular processes. Moreover, alterations in miRNA activity have been associated with many human diseases, such as cancer. The thesis explores miRNA binding behavior and highlights fundamental information for miRNA target prediction. In particular, a machine learning approach is used to upgrade an existing target prediction algorithm named ComiR; the original version of ComiR considers miRNA binding sites located on mRNA 3’UTR region. The novel algorithm significantly improves the ComiR prediction capacity by including miRNA binding sites located on mRNA coding regions

Modelling and inferring connections in complex networks

Network phenomena are of key importance in the majority of scientific disciplines. They motivate the desire to better understand the implications of interactions between connected entities. In the focus of this thesis are two of the most prominent tasks in the research of such phenomena: the modelling and the inference of connections within networks. In particular, I provide a systematic framework for using the topology and unifying characteristics of networks from fields as diverse as biology, sociology, and economics to predict and validate connections. I build on existing random graph models and node similarity measures, which I then employ in both unsupervised and supervised machine learning approaches. Furthermore, I present novel methods for identifying the statistically significant connections in network settings that involve multiple types of entities and connections — a crucial element of modelling, which most available methods fail to address. To demonstrate the potential of these new tools, I use them to filter networks that were constructed from large-scale noisy data generated by biological experiments as well as records of online social activity. Subsequently, I predict previously unobserved connections within these networks and evaluate the performance of the developed tools based on ground truth data. In further data sets without direct evidence for the connections in the network, a second, bipartite network serves as proxy for the analysis. Specifically, in an e-commerce setting I use connections between products and customers to deduce similarities between the products based on customer behaviour. In an analysis of high-throughput screening data on the other hand, I utilize relations between proteins and experimental conditions to identify potential functional affinities among the proteins. The findings presented here show that the computational prediction of connections can both help researchers gain a better understanding of costly large-scale data and guide further experimental design. The thesis demonstrates the potential of a network analytic approach to modelling and inference on multiple applications, such as the uncovering of possible privacy issues in the context of online social networking platforms and the optimization of drug development in cancer treatment

Progresses and Challenges in Link Prediction

Link prediction is a paradigmatic problem in network science, which aims at estimating the existence likelihoods of nonobserved links, based on known topology. After a brief introduction of the standard problem and metrics of link prediction, this Perspective will summarize representative progresses about local similarity indices, link predictability, network embedding, matrix completion, ensemble learning and others, mainly extracted from thousands of related publications in the last decade. Finally, this Perspective will outline some long-standing challenges for future studies.Comment: 45 pages, 1 tabl

Understanding regulatory mechanisms underlying stem cells helps to identify cancer biomarkers

Detection of biomarker genes play a crucial role in disease detection and treatment. Bioinformatics offers a variety of approaches for identification of biomarker genes which play key roles in complex diseases. These computational approaches enhance the insight derived from experiments and reduce the efforts of biologists and experimentalists. This is essentially achieved through prioritizing a set of genes with certain attributes. In this thesis, we show that understanding the regulatory mechanisms underlying stem cells helps to identify cancer biomarkers. We got inspired by the regulatory mechanisms of the pluripotency network in mouse embryonic stem cells and formulated the problem where a set of master regulatory genes in regulatory networks is identified with two combinatorial optimization problems namely as minimum dominating set and minimum connected dominating set in weakly and strongly connected components. Then we applied the developed methods to regulatory cancer networks to identify disease-associated genes and anti-cancer drug targets in breast cancer and hepatocellular carcinoma. As not all the nodes in the solutions are critical, we developed a prioritization method to rank a set of candidate genes which are related to a certain disease based on systematic analysis of the genes that are differentially expressed in tumor and normal conditions. Moreover, we demonstrated that the topological features in regulatory networks surrounding differentially expressed genes are highly consistent in terms of using the output of several analysis tools. We compared two randomization strategies for TF-miRNA co-regulatory networks to infer significant network motifs underlying cellular identity. We showed that the edge-type conserving method surpasses the non-conserving method in terms of biological relevance and centrality overlap. We presented several web servers and software packages that are publicly available at no cost. The Cytoscape plugin of minimum connected dominating set identifies a set of key regulatory genes in a user provided regulatory network based on a heuristic approach. The ILP formulations of minimum dominating set and minimum connected dominating set return the optimal solutions for the aforementioned problems. Our source code is publicly available. The web servers TFmiR and TFmiR2 construct disease-, tissue-, process-specific networks for the sets of deregulated genes and miRNAs provided by a user. They highlight topological hotspots and offer detection of three- and four-node FFL motifs as a separate web service for both organisms mouse and human.Die Gendetektion von Biomarkern spielt eine wesentliche Rolle bei der Erkennung und Behandlung von Krankheiten. Die Bioinformatik bietet eine Vielzahl von Ansätzen zur Identifizierung von Biomarker-Genen, die bei komplizierten Erkrankungen eine Schlüsselrolle spielen. Diese computerbasierten Ansätze verbessern die Erkenntnisse aus Experimenten und reduzieren den Aufwand von Biologen und Forschern. Dies wird hauptsächlich erreicht durch die Priorisierung einer Reihe von Genen mit bestimmten Attributen. In dieser Arbeit zeigen wir, dass die Identifizierung von Krebs-Biomarkern leichter gelingt, wenn wir die den Stammzellen zugrunde liegenden regulatorischen Mechanismen verstehen. Dazu angeregt wurden wir durch die regulatorischen Mechanismen des Pluripotenz-Netzwerks in embryonalen Maus-Stammzellen. Wir formulierten und haben das Problem der Identifizierung einer Reihe von Master-Regulator-Genen in regulatorischen Netzwerken mit zwei kombinatorischen Optimierungsproblemen, nämlich als minimal dominierende Menge und als minimal zusammenhängende dominierende Menge in schwach und stark verbundenen Komponenten. Die entwickelten Methoden haben wir dann auf regulatorische Krebsnetzwerke angewandt, um krankheitsassoziierte Gene und Zielproteine für Medikamenten gegen Brustkrebs und hepatozelluläres Karzinom zu identifizieren. Im Hinblick darauf, dass nicht alle Knoten in den Lösungen wesentlich sind, haben wir basierend auf der systematischen Analyse von Genen, die unterschiedlich bei Tumor- und Normalbedingungen reagieren, eine Priorisierungsmethode entwickelt, um einen Satz von Kandidatengenen in eine Reihenfolge zu bringen, die einer bestimmten Krankheit zugeordnet sind. Darüber hinaus haben wir gezeigt, dass die topologischen Eigenschaften in regulatorischen Netzwerken, die die deregulierte Gene umgeben, sehr einheitlich in Bezug auf den Einsatz verschiedener Analysewerkzeuge sind. Wir haben zwei Randomisierungsstrategien für TF-miRNA-Co-regulatorische Netzwerke verglichen, um signifikante Netzwerkmotive herauszufinden, welche zellulärer Identität zugrunde liegen. Wir haben gezeigt, dass die Edge-Type-Erhaltungsmethode, die nicht-erhaltende Methode in Bezug auf biologische Relevanz und zentrale Überlappung übertrifft. Wir haben mehrere Softwarepakete und Webserver vorgestellt, die allgemein und kostenlos zugänglich sind. Das Cytoscape Plugin für die Identififizierung, der minimal verbundener dominierenden Mengen identifiziert einen Satz von regulatorischen Schlüsselgenen in einem vom Benutzer bereitgestellten regulatorischen Netzwerk basierend auf einem heuristischen Ansatz. Die ILP Formulierungen, der minimal dominierenden Menge und der minimal verbundenen dominierenden Menge liefern die optimalen Lösungen für die oben vorgenannten Probleme. Unser Quellcode hierfür ist öffentlich verfügbar. Die Webserver TFmiR und TFmiR2 erzeugen Krankheits-, Gewebe- und prozessspezifische Netzwerke für die von einem Benutzer bereitgestellten deregulierten Gene und miRNAs. Außerdem verwenden die Webserver topologische Merkmale, um Hotspot-Knoten hervorzuheben und bieten die Erkennung von drei und vier Knoten FFL Motiven als separaten Web-Service für beide Organismen, Maus und Mensch

진료 내역 데이터를 활용한 딥러닝 기반의 건강보험 남용 탐지

학위논문 (박사) -- 서울대학교 대학원 : 공과대학 산업공학과, 2020. 8. 조성준.As global life expectancy increases, spending on healthcare grows in accordance in order to improve quality of life. However, due to expensive price of medical care, the bare cost of healthcare services would inevitably places great financial burden to individuals and households. In this light, many countries have devised and established their own public healthcare insurance systems to help people receive medical services at a lower price. Since reimbursements are made ex-post, unethical practices arise, exploiting the post-payment structure of the insurance system. The archetypes of such behavior are overdiagnosis, the act of manipulating patients diseases, and overtreatments, prescribing unnecessary drugs for the patient. These abusive behaviors are considered as one of the main sources of financial loss incurred in the healthcare system. In order to detect and prevent abuse, the national healthcare insurance hires medical professionals to manually examine whether the claim filing is medically legitimate or not. However, the review process is, unquestionably, very costly and time-consuming. In order to address these limitations, data mining techniques have been employed to detect problematic claims or abusive providers showing an abnormal billing pattern. However, these cases only used coarsely grained information such as claim-level or provider-level data. This extracted information may lead to degradation of the model's performance. In this thesis, we proposed abuse detection methods using the medical treatment data, which is the lowest level information of the healthcare insurance claim. Firstly, we propose a scoring model based on which abusive providers are detected and show that the review process with the proposed model is more efficient than that with the previous model which uses the provider-level variables as input variables. At the same time, we devise the evaluation metrics to quantify the efficiency of the review process. Secondly, we propose the method of detecting overtreatment under seasonality, which reflects more reality to the model. We propose a model embodying multiple structures specific to DRG codes selected as important for each given department. We show that the proposed method is more robust to the seasonality than the previous method. Thirdly, we propose an overtreatment detection model accounting for heterogeneous treatment between practitioners. We proposed a network-based approach through which the relationship between the diseases and treatments is considered during the overtreatment detection process. Experimental results show that the proposed method classify the treatment well which does not explicitly exist in the training set. From these works, we show that using treatment data allows modeling abuse detection at various levels: treatment, claim, and provider-level.사람들의 기대수명이 증가함에 따라 삶의 질을 향상시키기 위해 보건의료에 소비하는 금액은 증가하고 있다. 그러나, 비싼 의료 서비스 비용은 필연적으로 개인과 가정에게 큰 재정적 부담을 주게된다. 이를 방지하기 위해, 많은 국가에서는 공공 의료 보험 시스템을 도입하여 사람들이 적절한 가격에 의료서비스를 받을 수 있도록 하고 있다. 일반적으로, 환자가 먼저 서비스를 받고 나서 일부만 지불하고 나면, 보험 회사가 사후에 해당 의료 기관에 잔여 금액을 상환을 하는 제도로 운영된다. 그러나 이러한 제도를 악용하여 환자의 질병을 조작하거나 과잉진료를 하는 등의 부당청구가 발생하기도 한다. 이러한 행위들은 의료 시스템에서 발생하는 주요 재정 손실의 이유 중 하나로, 이를 방지하기 위해, 보험회사에서는 의료 전문가를 고용하여 의학적 정당성여부를 일일히 검사한다. 그러나, 이러한 검토과정은 매우 비싸고 많은 시간이 소요된다. 이러한 검토과정을 효율적으로 하기 위해, 데이터마이닝 기법을 활용하여 문제가 있는 청구서나 청구 패턴이 비정상적인 의료 서비스 공급자를 탐지하는 연구가 있어왔다. 그러나, 이러한 연구들은 데이터로부터 청구서 단위나 공급자 단위의 변수를 유도하여 모델을 학습한 사례들로, 가장 낮은 단위의 데이터인 진료 내역 데이터를 활용하지 못했다. 이 논문에서는 청구서에서 가장 낮은 단위의 데이터인 진료 내역 데이터를 활용하여 부당청구를 탐지하는 방법론을 제안한다. 첫째, 비정상적인 청구 패턴을 갖는 의료 서비스 제공자를 탐지하는 방법론을 제안하였다. 이를 실제 데이터에 적용하였을 때, 기존의 공급자 단위의 변수를 사용한 방법보다 더 효율적인 심사가 이루어 짐을 확인하였다. 이 때, 효율성을 정량화하기 위한 평가 척도도 제안하였다. 둘째로, 청구서의 계절성이 존재하는 상황에서 과잉진료를 탐지하는 방법을 제안하였다. 이 때, 진료 과목단위로 모델을 운영하는 대신 질병군(DRG) 단위로 모델을 학습하고 평가하는 방법을 제안하였다. 그리고 실제 데이터에 적용하였을 때, 제안한 방법이 기존 방법보다 계절성에 더 강건함을 확인하였다. 셋째로, 동일 환자에 대해서 의사간의 상이한 진료 패턴을 갖는 환경에서의 과잉진료 탐지 방법을 제안하였다. 이는 환자의 질병과 진료내역간의 관계를 네트워크 기반으로 모델링하는것을 기반으로 한다. 실험 결과 제안한 방법이 학습 데이터에서 나타나지 않는 진료 패턴에 대해서도 잘 분류함을 알 수 있었다. 그리고 이러한 연구들로부터 진료 내역을 활용하였을 때, 진료내역, 청구서, 의료 서비스 제공자 등 다양한 레벨에서의 부당 청구를 탐지할 수 있음을 확인하였다.Chapter 1 Introduction 1 Chapter 2 Detection of Abusive Providers by department with Neural Network 9 2.1 Background 9 2.2 Literature Review 12 2.2.1 Abnormality Detection in Healthcare Insurance with Datamining Technique 12 2.2.2 Feed-Forward Neural Network 17 2.3 Proposed Method 21 2.3.1 Calculating the Likelihood of Abuse for each Treatment with Deep Neural Network 22 2.3.2 Calculating the Abuse Score of the Provider 25 2.4 Experiments 26 2.4.1 Data Description 27 2.4.2 Experimental Settings 32 2.4.3 Evaluation Measure (1): Relative Efficiency 33 2.4.4 Evaluation Measure (2): Precision at k 37 2.5 Results 38 2.5.1 Results in the test set 38 2.5.2 The Relationship among the Claimed Amount, the Abused Amount and the Abuse Score 40 2.5.3 The Relationship between the Performance of the Treatment Scoring Model and Review Efficiency 41 2.5.4 Treatment Scoring Model Results 42 2.5.5 Post-deployment Performance 44 2.6 Summary 45 Chapter 3 Detection of overtreatment by Diagnosis-related Group with Neural Network 48 3.1 Background 48 3.2 Literature review 51 3.2.1 Seasonality in disease 51 3.2.2 Diagnosis related group 52 3.3 Proposed method 54 3.3.1 Training a deep neural network model for treatment classi fication 55 3.3.2 Comparing the Performance of DRG-based Model against the department-based Model 57 3.4 Experiments 60 3.4.1 Data Description and Preprocessing 60 3.4.2 Performance Measures 64 3.4.3 Experimental Settings 65 3.5 Results 65 3.5.1 Overtreatment Detection 65 3.5.2 Abnormal Claim Detection 67 3.6 Summary 68 Chapter 4 Detection of overtreatment with graph embedding of disease-treatment pair 70 4.1 Background 70 4.2 Literature review 72 4.2.1 Graph embedding methods 73 4.2.2 Application of graph embedding methods to biomedical data analysis 79 4.2.3 Medical concept embedding methods 87 4.3 Proposed method 88 4.3.1 Network construction 89 4.3.2 Link Prediction between the Disease and the Treatment 90 4.3.3 Overtreatment Detection 93 4.4 Experiments 96 4.4.1 Data Description 97 4.4.2 Experimental Settings 99 4.5 Results 102 4.5.1 Network Construction 102 4.5.2 Link Prediction between the Disease and the Treatment 104 4.5.3 Overtreatment Detection 105 4.6 Summary 106 Chapter 5 Conclusion 108 5.1 Contribution 108 5.2 Future Work 110 Bibliography 112 국문초록 129Docto

Gradient Boosting Decision Tree-Based Method for Predicting Interactions Between Target Genes and Drugs

Determining the target genes that interact with drugs—drug–target interactions—plays an important role in drug discovery. Identification of drug–target interactions through biological experiments is time consuming, laborious, and costly. Therefore, using computational approaches to predict candidate targets is a good way to reduce the cost of wet-lab experiments. However, the known interactions (positive samples) and the unknown interactions (negative samples) display a serious class imbalance, which has an adverse effect on the accuracy of the prediction results. To mitigate the impact of class imbalance and completely exploit the negative samples, we proposed a new method, named DTIGBDT, based on gradient boosting decision trees, for predicting candidate drug–target interactions. We constructed a drug–target heterogeneous network that contains the drug similarities based on the chemical structures of drugs, the target similarities based on target sequences, and the known drug–target interactions. The topological information of the network was captured by random walks to update the similarities between drugs or targets. The paths between drugs and targets could be divided into multiple categories, and the features of each category of paths were extracted. We constructed a prediction model based on gradient boosting decision trees. The model establishes multiple decision trees with the extracted features and obtains the interaction scores between drugs and targets. DTIGBDT is a method of ensemble learning, and it effectively reduces the impact of class imbalance. The experimental results indicate that DTIGBDT outperforms several state-of-the-art methods for drug–target interaction prediction. In addition, case studies on Quetiapine, Clozapine, Olanzapine, Aripiprazole, and Ziprasidone demonstrate the ability of DTIGBDT to discover potential drug–target interactions

Integration of multi-scale protein interactions for biomedical data analysis

With the advancement of modern technologies, we observe an increasing accumulation of biomedical data about diseases. There is a need for computational methods to sift through and extract knowledge from the diverse data available in order to improve our mechanistic understanding of diseases and improve patient care. Biomedical data come in various forms as exemplified by the various omics data. Existing studies have shown that each form of omics data gives only partial information on cells state and motivated jointly mining multi-omics, multi-modal data to extract integrated system knowledge. The interactome is of particular importance as it enables the modelling of dependencies arising from molecular interactions. This Thesis takes a special interest in the multi-scale protein interactome and its integration with computational models to extract relevant information from biomedical data. We define multi-scale interactions at different omics scale that involve proteins: pairwise protein-protein interactions, multi-protein complexes, and biological pathways. Using hypergraph representations, we motivate considering higher-order protein interactions, highlighting the complementary biological information contained in the multi-scale interactome. Based on those results, we further investigate how those multi-scale protein interactions can be used as either prior knowledge, or auxiliary data to develop machine learning algorithms. First, we design a neural network using the multi-scale organization of proteins in a cell into biological pathways as prior knowledge and train it to predict a patient's diagnosis based on transcriptomics data. From the trained models, we develop a strategy to extract biomedical knowledge pertaining to the diseases investigated. Second, we propose a general framework based on Non-negative Matrix Factorization to integrate the multi-scale protein interactome with multi-omics data. We show that our approach outperforms the existing methods, provide biomedical insights and relevant hypotheses for specific cancer types