MLFLHMDA: predicting human microbe-disease association based on multi-view latent feature learning

IntroductionA growing body of research indicates that microorganisms play a crucial role in human health. Imbalances in microbial communities are closely linked to human diseases, and identifying potential relationships between microbes and diseases can help elucidate the pathogenesis of diseases. However, traditional methods based on biological or clinical experiments are costly, so the use of computational models to predict potential microbe-disease associations is of great importance.MethodsIn this paper, we present a novel computational model called MLFLHMDA, which is based on a Multi-View Latent Feature Learning approach to predict Human potential Microbe-Disease Associations. Specifically, we compute Gaussian interaction profile kernel similarity between diseases and microbes based on the known microbe-disease associations from the Human Microbe-Disease Association Database and perform a preprocessing step on the resulting microbe-disease association matrix, namely, weighting K nearest known neighbors (WKNKN) to reduce the sparsity of the microbe-disease association matrix. To obtain unobserved associations in the microbe and disease views, we extract different latent features based on the geometrical structure of microbes and diseases, and project multi-modal latent features into a common subspace. Next, we introduce graph regularization to preserve the local manifold structure of Gaussian interaction profile kernel similarity and add Lp,q-norms to the projection matrix to ensure the interpretability and sparsity of the model.ResultsThe AUC values for global leave-one-out cross-validation and 5-fold cross validation implemented by MLFLHMDA are 0.9165 and 0.8942+/−0.0041, respectively, which perform better than other existing methods. In addition, case studies of different diseases have demonstrated the superiority of the predictive power of MLFLHMDA. The source code of our model and the data are available on https://github.com/LiangzheZhang/MLFLHMDA_master

Predicting serious rare adverse reactions of novel chemicals

Motivation: Adverse drug reactions (ADRs) are one of the main causes of death and a major financial burden on the world\u27s economy. Due to the limitations of the animal model, computational prediction of serious and rare ADRs is invaluable. However, current state-of-the-art computational methods do not yield significantly better predictions of rare ADRs than random guessing. Results: We present a novel method, based on the theory of \u27compressed sensing\u27 (CS), which can accurately predict serious side-effects of candidate and market drugs. Not only is our method able to infer new chemical-ADR associations using existing noisy, biased and incomplete databases, but our data also demonstrate that the accuracy of CS in predicting a serious ADR for a candidate drug increases with increasing knowledge of other ADRs associated with the drug. In practice, this means that as the candidate drug moves up the different stages of clinical trials, the prediction accuracy of our method will increase accordingly. Availability and implementation: The program is available at https://github.com/poleksic/side-effects. Supplementary information: Supplementary data are available at Bioinformatics online

Time-Series Embedded Feature Selection Using Deep Learning: Data Mining Electronic Health Records for Novel Biomarkers

As health information technologies continue to advance, routine collection and digitisation of patient health records in the form of electronic health records present as an ideal opportunity for data-mining and exploratory analysis of biomarkers and risk factors indicative of a potentially diverse domain of patient outcomes. Patient records have continually become more widely available through various initiatives enabling open access whilst maintaining critical patient privacy. In spite of such progress, health records remain not widely adopted within the current clinical statistical analysis domain due to challenging issues derived from such “big data”.Deep learning based temporal modelling approaches present an ideal solution to health record challenges through automated self-optimisation of representation learning, able to man-ageably compose the high-dimensional domain of patient records into data representations able to model complex data associations. Such representations can serve to condense and reduce dimensionality to emphasise feature sparsity and importance through novel embedded feature selection approaches. Accordingly, application towards patient records enable complex mod-elling and analysis of the full domain of clinical features to select biomarkers of predictive relevance.Firstly, we propose a novel entropy regularised neural network ensemble able to highlight risk factors associated with hospitalisation risk of individuals with dementia. The application of which, was able to reduce a large domain of unique medical events to a small set of relevant risk factors able to maintain hospitalisation discrimination.Following on, we continue our work on ensemble architecture approaches with a novel cas-cading LSTM ensembles to predict severe sepsis onset within critical patients in an ICU critical care centre. We demonstrate state-of-the-art performance capabilities able to outperform that of current related literature.Finally, we propose a novel embedded feature selection application dubbed 1D convolu-tion feature selection using sparsity regularisation. Said methodology was evaluated on both domains of dementia and sepsis prediction objectives to highlight model capability and generalisability. We further report a selection of potential biomarkers for the aforementioned case study objectives highlighting clinical relevance and potential novelty value for future clinical analysis.Accordingly, we demonstrate the effective capability of embedded feature selection ap-proaches through the application of temporal based deep learning architectures in the discovery of effective biomarkers across a variety of challenging clinical applications

Deep learning approaches to multimodal MRI brain age estimation

Brain ageing remains an intricate, multifaceted process, marked not just by chronological time but by a myriad of structural, functional, and microstructural changes that often lead to discrepancies between actual age and the age inferred from neuroimaging. Machine learning methods, and especially Convolutional Neural Networks (CNNs), have proven adept in capturing patterns relating to ageing induced changes in the brain. The differences between the predicted and chronological ages, referred to as brain age deltas, have emerged as useful biomarkers for exploring those factors which promote accelerated ageing or resilience, such as pathologies or lifestyle factors. However, previous studies relied overwhelmingly on structural neuroimaging for predictions, overlooking rich details inherent in other MRI modalities, such as potentially informative functional and microstructural changes. This research, utilising the extensive UK Biobank dataset, reveals that 57 different maps spanning structural, susceptibility-weighted, diffusion, and functional MRI modalities can not only predict an individual's chronological age, but also encode unique ageing-related details. Through the use of both 3D CNNs and the novel 3D Shifted Window (SWIN) Transformers, this work uncovered associations between brain age deltas and 191 different non-imaging derived phenotypes (nIDPs), offering a valuable insight into factors influencing brain ageing. Moreover, this work found that ensembling data from multiple maps results in higher prediction accuracies. After a thorough comparison of both linear and non-linear multi-modal ensembling methods, including deep fusion networks, it was found that linear methods, such as ElasticNet, generally outperform their more complex non-linear counterparts. In addition, while ensembling was found to strengthen age prediction accuracies, it was found to weaken nIDP associations in certain circumstances where ensembled maps might have opposing sensitivities to a particular nIDP, thus reinforcing the need for guided selections of the ensemble components. Finally, while both CNNs and SWINs show comparable brain age prediction precision, SWIN networks stand out for their robustness against data corruption, while also proving a degree of inherent explainability. Overall, the results presented herein demonstrate that other 3D maps and modalities, which have not been considered previously for the task of brain age prediction, encode different information about the ageing brain. This research lays the foundation for further explorations into how different factors, such as off-target drug effects, impact brain ageing. It also ushers in possibilities for enhanced clinical trial design, diagnostic approaches, and therapeutic monitoring grounded in refined brain age prediction models

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

Previsão e análise da estrutura e dinâmica de redes biológicas

Increasing knowledge about the biological processes that govern the dynamics of living organisms has fostered a better understanding of the origin of many diseases as well as the identification of potential therapeutic targets. Biological systems can be modeled through biological networks, allowing to apply and explore methods of graph theory in their investigation and characterization. This work had as main motivation the inference of patterns and rules that underlie the organization of biological networks. Through the integration of different types of data, such as gene expression, interaction between proteins and other biomedical concepts, computational methods have been developed so that they can be used to predict and study diseases. The first contribution, was the characterization a subsystem of the human protein interactome through the topological properties of the networks that model it. As a second contribution, an unsupervised method using biological criteria and network topology was used to improve the understanding of the genetic mechanisms and risk factors of a disease through co-expression networks. As a third contribution, a methodology was developed to remove noise (denoise) in protein networks, to obtain more accurate models, using the network topology. As a fourth contribution, a supervised methodology was proposed to model the protein interactome dynamics, using exclusively the topology of protein interactions networks that are part of the dynamic model of the system. The proposed methodologies contribute to the creation of more precise, static and dynamic biological models through the identification and use of topological patterns of protein interaction networks, which can be used to predict and study diseases.O conhecimento crescente sobre os processos biológicos que regem a dinâmica dos organismos vivos tem potenciado uma melhor compreensão da origem de muitas doenças, assim como a identificação de potenciais alvos terapêuticos. Os sistemas biológicos podem ser modelados através de redes biológicas, permitindo aplicar e explorar métodos da teoria de grafos na sua investigação e caracterização. Este trabalho teve como principal motivação a inferência de padrões e de regras que estão subjacentes à organização de redes biológicas. Através da integração de diferentes tipos de dados, como a expressão de genes, interação entre proteínas e outros conceitos biomédicos, foram desenvolvidos métodos computacionais, para que possam ser usados na previsão e no estudo de doenças. Como primeira contribuição, foi proposto um método de caracterização de um subsistema do interactoma de proteínas humano através das propriedades topológicas das redes que o modelam. Como segunda contribuição, foi utilizado um método não supervisionado que utiliza critérios biológicos e topologia de redes para, através de redes de co-expressão, melhorar a compreensão dos mecanismos genéticos e dos fatores de risco de uma doença. Como terceira contribuição, foi desenvolvida uma metodologia para remover ruído (denoise) em redes de proteínas, para obter modelos mais precisos, utilizando a topologia das redes. Como quarta contribuição, propôs-se uma metodologia supervisionada para modelar a dinâmica do interactoma de proteínas, usando exclusivamente a topologia das redes de interação de proteínas que fazem parte do modelo dinâmico do sistema. As metodologias propostas contribuem para a criação de modelos biológicos, estáticos e dinâmicos, mais precisos, através da identificação e uso de padrões topológicos das redes de interação de proteínas, que podem ser usados na previsão e no estudo doenças.Programa Doutoral em Engenharia Informátic

Analysing functional genomics data using novel ensemble, consensus and data fusion techniques

Motivation: A rapid technological development in the biosciences and in computer science in the last decade has enabled the analysis of high-dimensional biological datasets on standard desktop computers. However, in spite of these technical advances, common properties of the new high-throughput experimental data, like small sample sizes in relation to the number of features, high noise levels and outliers, also pose novel challenges. Ensemble and consensus machine learning techniques and data integration methods can alleviate these issues, but often provide overly complex models which lack generalization capability and interpretability. The goal of this thesis was therefore to develop new approaches to combine algorithms and large-scale biological datasets, including novel approaches to integrate analysis types from different domains (e.g. statistics, topological network analysis, machine learning and text mining), to exploit their synergies in a manner that provides compact and interpretable models for inferring new biological knowledge. Main results: The main contributions of the doctoral project are new ensemble, consensus and cross-domain bioinformatics algorithms, and new analysis pipelines combining these techniques within a general framework. This framework is designed to enable the integrative analysis of both large- scale gene and protein expression data (including the tools ArrayMining, Top-scoring pathway pairs and RNAnalyze) and general gene and protein sets (including the tools TopoGSA , EnrichNet and PathExpand), by combining algorithms for different statistical learning tasks (feature selection, classification and clustering) in a modular fashion. Ensemble and consensus analysis techniques employed within the modules are redesigned such that the compactness and interpretability of the resulting models is optimized in addition to the predictive accuracy and robustness. The framework was applied to real-word biomedical problems, with a focus on cancer biology, providing the following main results: (1) The identification of a novel tumour marker gene in collaboration with the Nottingham Queens Medical Centre, facilitating the distinction between two clinically important breast cancer subtypes (framework tool: ArrayMining) (2) The prediction of novel candidate disease genes for Alzheimer’s disease and pancreatic cancer using an integrative analysis of cellular pathway definitions and protein interaction data (framework tool: PathExpand, collaboration with the Spanish National Cancer Centre) (3) The prioritization of associations between disease-related processes and other cellular pathways using a new rule-based classification method integrating gene expression data and pathway definitions (framework tool: Top-scoring pathway pairs) (4) The discovery of topological similarities between differentially expressed genes in cancers and cellular pathway definitions mapped to a molecular interaction network (framework tool: TopoGSA, collaboration with the Spanish National Cancer Centre) In summary, the framework combines the synergies of multiple cross-domain analysis techniques within a single easy-to-use software and has provided new biological insights in a wide variety of practical settings

Network-driven strategies to integrate and exploit biomedical data

[eng] In the quest for understanding complex biological systems, the scientific community has been delving into protein, chemical and disease biology, populating biomedical databases with a wealth of data and knowledge. Currently, the field of biomedicine has entered a Big Data era, in which computational-driven research can largely benefit from existing knowledge to better understand and characterize biological and chemical entities. And yet, the heterogeneity and complexity of biomedical data trigger the need for a proper integration and representation of this knowledge, so that it can be effectively and efficiently exploited. In this thesis, we aim at developing new strategies to leverage the current biomedical knowledge, so that meaningful information can be extracted and fused into downstream applications. To this goal, we have capitalized on network analysis algorithms to integrate and exploit biomedical data in a wide variety of scenarios, providing a better understanding of pharmacoomics experiments while helping accelerate the drug discovery process. More specifically, we have (i) devised an approach to identify functional gene sets associated with drug response mechanisms of action, (ii) created a resource of biomedical descriptors able to anticipate cellular drug response and identify new drug repurposing opportunities, (iii) designed a tool to annotate biomedical support for a given set of experimental observations, and (iv) reviewed different chemical and biological descriptors relevant for drug discovery, illustrating how they can be used to provide solutions to current challenges in biomedicine.[cat] En la cerca d’una millor comprensió dels sistemes biològics complexos, la comunitat científica ha estat aprofundint en la biologia de les proteïnes, fàrmacs i malalties, poblant les bases de dades biomèdiques amb un gran volum de dades i coneixement. En l’actualitat, el camp de la biomedicina es troba en una era de “dades massives” (Big Data), on la investigació duta a terme per ordinadors se’n pot beneficiar per entendre i caracteritzar millor les entitats químiques i biològiques. No obstant, la heterogeneïtat i complexitat de les dades biomèdiques requereix que aquestes s’integrin i es representin d’una manera idònia, permetent així explotar aquesta informació d’una manera efectiva i eficient. L’objectiu d’aquesta tesis doctoral és desenvolupar noves estratègies que permetin explotar el coneixement biomèdic actual i així extreure informació rellevant per aplicacions biomèdiques futures. Per aquesta finalitat, em fet servir algoritmes de xarxes per tal d’integrar i explotar el coneixement biomèdic en diferents tasques, proporcionant un millor enteniment dels experiments farmacoòmics per tal d’ajudar accelerar el procés de descobriment de nous fàrmacs. Com a resultat, en aquesta tesi hem (i) dissenyat una estratègia per identificar grups funcionals de gens associats a la resposta de línies cel·lulars als fàrmacs, (ii) creat una col·lecció de descriptors biomèdics capaços, entre altres coses, d’anticipar com les cèl·lules responen als fàrmacs o trobar nous usos per fàrmacs existents, (iii) desenvolupat una eina per descobrir quins contextos biològics corresponen a una associació biològica observada experimentalment i, finalment, (iv) hem explorat diferents descriptors químics i biològics rellevants pel procés de descobriment de nous fàrmacs, mostrant com aquests poden ser utilitzats per trobar solucions a reptes actuals dins el camp de la biomedicina