Synergy-COPD: a systems approach for understanding and managing chronic diseases.

Chronic diseases (CD) are generating a dramatic societal burden worldwide that is expected to persist over the next decades. The challenges posed by the epidemics of CD have triggered a novel health paradigm with major consequences on the traditional concept of disease and with a profound impact on key aspects of healthcare systems. We hypothesized that the development of a systems approach to understand CD together with the generation of an ecosystem to transfer the acquired knowledge into the novel healthcare scenario may contribute to a cost-effective enhancement of health outcomes. To this end, we designed the Synergy-COPD project wherein the heterogeneity of chronic obstructive pulmonary disease (COPD) was addressed as a use case representative of CD. The current manuscript describes main features of the project design and the strategies put in place for its development, as well the expected outcomes during the project life-span. Moreover, the manuscript serves as introductory and unifying chapter of the different papers associated to the Supplement describing the characteristics, tools and the objectives of Synergy-COP

Genome-wide DNA methylation analysis for diabetic nephropathy in type 1 diabetes mellitus

BACKGROUND: Diabetic nephropathy is a serious complication of diabetes mellitus and is associated with considerable morbidity and high mortality. There is increasing evidence to suggest that dysregulation of the epigenome is involved in diabetic nephropathy. We assessed whether epigenetic modification of DNA methylation is associated with diabetic nephropathy in a case-control study of 192 Irish patients with type 1 diabetes mellitus (T1D). Cases had T1D and nephropathy whereas controls had T1D but no evidence of renal disease. METHODS: We performed DNA methylation profiling in bisulphite converted DNA from cases and controls using the recently developed Illumina Infinium(R) HumanMethylation27 BeadChip, that enables the direct investigation of 27,578 individual cytosines at CpG loci throughout the genome, which are focused on the promoter regions of 14,495 genes. RESULTS: Singular Value Decomposition (SVD) analysis indicated that significant components of DNA methylation variation correlated with patient age, time to onset of diabetic nephropathy, and sex. Adjusting for confounding factors using multivariate Cox-regression analyses, and with a false discovery rate (FDR) of 0.05, we observed 19 CpG sites that demonstrated correlations with time to development of diabetic nephropathy. Of note, this included one CpG site located 18 bp upstream of the transcription start site of UNC13B, a gene in which the first intronic SNP rs13293564 has recently been reported to be associated with diabetic nephropathy. CONCLUSION: This high throughput platform was able to successfully interrogate the methylation state of individual cytosines and identified 19 prospective CpG sites associated with risk of diabetic nephropathy. These differences in DNA methylation are worthy of further follow-up in replication studies using larger cohorts of diabetic patients with and without nephropathy

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

Developing Clinical Decision Support Systems for Sepsis Prediction Using Temporal and Non-Temporal Machine Learning Methods

In healthcare, diagnostic errors represent the biggest challenge to synthesize accurate treatments. In the United States, patient deaths due to misdiagnoses are estimated at 40,000 to 80,000 per year. It was also found that 30% of the annual healthcare spending was consumed on unnecessary services and other inefficiencies. The diagnostic errors could be reduced, and public health can be improved by applying machine learning and artificial intelligence in healthcare problems. This dissertation is an attempt to formulate clinical decision support systems and to develop new algorithms to reduce clinical errors.This dissertation aims at developing clinical decision support systems to diagnose sepsis in the early stages. The key feature of our work is that we captured the dynamics among body organs using Bayesian networks. The richness of the proposed model is measured not only by achieving high accuracy but also by utilizing fewer lab results.To further improve the accuracy of the clinical decision support system, we utilize longitudinal data to develop a mortality progression model. This part of the dissertation proposes a hidden Markov model (HMM) framework to model the mortality progression. In comparison to existing approaches, the proposed framework leverages the longitudinal data available in the electronic health records (EHR).In addition, this dissertation proposes an initialization procedure to train the parameters of HMM efficiently. The current HMM learning algorithms are sensitive to initialization. The proposed method computes an initial set of parameters by relaxing the time dependency in sequential time series data and incorporating the multinomial logistic regression.Finally, this dissertation compares the prognostic accuracy of two popularly used early sepsis diagnostic criteria: Systemic Inflammatory Response Syndrome (SIRS) and quick Sepsis-related Organ Failure Assessment (qSOFA). Using statistical and machine learning methods, we found that qSOFA is a better diagnostic criteria than SIRS. These findings will guide healthcare providers in selecting the best bedside diagnostic criteria

EDMON - Electronic Disease Surveillance and Monitoring Network: A Personalized Health Model-based Digital Infectious Disease Detection Mechanism using Self-Recorded Data from People with Type 1 Diabetes

Through time, we as a society have been tested with infectious disease outbreaks of different magnitude, which often pose major public health challenges. To mitigate the challenges, research endeavors have been focused on early detection mechanisms through identifying potential data sources, mode of data collection and transmission, case and outbreak detection methods. Driven by the ubiquitous nature of smartphones and wearables, the current endeavor is targeted towards individualizing the surveillance effort through a personalized health model, where the case detection is realized by exploiting self-collected physiological data from wearables and smartphones. This dissertation aims to demonstrate the concept of a personalized health model as a case detector for outbreak detection by utilizing self-recorded data from people with type 1 diabetes. The results have shown that infection onset triggers substantial deviations, i.e. prolonged hyperglycemia regardless of higher insulin injections and fewer carbohydrate consumptions. Per the findings, key parameters such as blood glucose level, insulin, carbohydrate, and insulin-to-carbohydrate ratio are found to carry high discriminative power. A personalized health model devised based on a one-class classifier and unsupervised method using selected parameters achieved promising detection performance. Experimental results show the superior performance of the one-class classifier and, models such as one-class support vector machine, k-nearest neighbor and, k-means achieved better performance. Further, the result also revealed the effect of input parameters, data granularity, and sample sizes on model performances. The presented results have practical significance for understanding the effect of infection episodes amongst people with type 1 diabetes, and the potential of a personalized health model in outbreak detection settings. The added benefit of the personalized health model concept introduced in this dissertation lies in its usefulness beyond the surveillance purpose, i.e. to devise decision support tools and learning platforms for the patient to manage infection-induced crises

Diabetes Mellitus Glucose Prediction by Linear and Bayesian Ensemble Modeling

Diabetes Mellitus is a chronic disease of impaired blood glucose control due to degraded or absent bodily-specific insulin production, or utilization. To the affected, this in many cases implies relying on insulin injections and blood glucose measurements, in order to keep the blood glucose level within acceptable limits. Risks of developing short- and long-term complications, due to both too high and too low blood glucose concentrations are severalfold, and, generally, the glucose dynamics are not easy too fully comprehend for the affected individual—resulting in poor glucose control. To reduce the burden this implies to the patient and society, in terms of physiological and monetary costs, different technical solutions, based on closed or semi-closed loop blood glucose control, have been suggested. To this end, this thesis investigates simplified linear and merged models of glucose dynamics for the purpose of short-term prediction, developed within the EU FP7 DIAdvisor project. These models could, e.g., be used, in a decision support system, to alert the user of future low and high glucose levels, and, when implemented in a control framework, to suggest proactive actions. The simplified models were evaluated on 47 patient data records from the first DIAdvisor trial. Qualitatively physiological correct responses were imposed, and model-based prediction, up to two hours ahead, and specifically for low blood glucose detection, was evaluated. The glucose raising, and lowering effect of meals and insulin were estimated, together with the clinically relevant carbohydrate-to-insulin ratio. The model was further expanded to include the blood-to-interstitial lag, and tested for one patient data set. Finally, a novel algorithm for merging of multiple prediction models was developed and validated on both artificial data and 12 datasets from the second DIAdvisor trial

Machine Learning Methods To Identify Hidden Phenotypes In The Electronic Health Record

The widespread adoption of Electronic Health Records (EHRs) means an unprecedented amount of patient treatment and outcome data is available to researchers. Research is a tertiary priority in the EHR, where the priorities are patient care and billing. Because of this, the data is not standardized or formatted in a manner easily adapted to machine learning approaches. Data may be missing for a large variety of reasons ranging from individual input styles to differences in clinical decision making, for example, which lab tests to issue. Few patients are annotated at a research quality, limiting sample size and presenting a moving gold standard. Patient progression over time is key to understanding many diseases but many machine learning algorithms require a snapshot, at a single time point, to create a usable vector form. In this dissertation, we develop new machine learning methods and computational workflows to extract hidden phenotypes from the Electronic Health Record (EHR). In Part 1, we use a semi-supervised deep learning approach to compensate for the low number of research quality labels present in the EHR. In Part 2, we examine and provide recommendations for characterizing and managing the large amount of missing data inherent to EHR data. In Part 3, we present an adversarial approach to generate synthetic data that closely resembles the original data while protecting subject privacy. We also introduce a workflow to enable reproducible research even when data cannot be shared. In Part 4, we introduce a novel strategy to first extract sequential data from the EHR and then demonstrate the ability to model these sequences with deep learning

Contributions to interoperability, scalability and formalization of personal health systems

The ageing of the world's population combined with unhealthy lifestyles are contributing to a major prevalence of chronic diseases. This scenario poses the challenge of providing good healthcare services to that people affected by chronic illnesses, but without increasing its costs. A prominent way to face this challenge is through pervasive healthcare. Research in pervasive healthcare tries to shift the current centralized healthcare delivery model focused on the doctors, to a more distributed model focused on the patients. In this context Personal Health Systems (PHSs) consists on approaching sampling technologies into the hands of the patients, without disturbing its activities of the daily life, to monitor patient's physiological parameters and providing feedback on their state. The use of PHSs involves the patients in the management of their illness and in their own well being too. The development of PHSs has to face technological issues in order to be accepted by our society. Within them it is important to ensure interoperability between different systems in order to make them work together. Scalability it is also a concern, as their performance must not decrease when increasing the number of users. Another issue is how to formalize the medical knowledge for each patient, as different patients may have different target goals. Security and privacy are a must feature because of the sensitive nature of medical data. Other issues involve the the integration with legacy systems, and the usability of graphical user interfaces in order to encourage old people with the use these technologies. The aim of this PhD thesis is to contribute into the state-of-the-art of PHSs by tackling together different of the above-mentioned challenges. First, to achieve interoperability we use the CDA standard as a format to encode and exchange health data and alerts related with the status of the patient. We show how these documents can be generated automatically through the use of XML templates. Second, we address the scalability by distributing the computations needed to monitor the patients over their devices, rather than performing them in a centralized server. In this context we develop the MAGPIE agent platform, which runs on Android devices, as a framework able to provide intelligence to PHSs, and generate alerts that can be of interest for the patients and the medical doctors. Third, we focus on the formalization of PHSs by providing a tool for the practitioners where they can define, in a graphical way, monitoring rules related with chronic diseases that are integrated with the MAGPIE agent platform. The thesis also explores different ways to share the data collected with PHSs in order to improve the outcomes obtained with the use of this technology. Data is shared between individuals following a Distributed Event-Based System (DEBS) approach, where different people can subscribe to the alerts produced by the patient. Data is also shared between institutions with a network protocol called MOSAIC, and we focus on the security aspects of this protocol. The research in this PhD focuses in the use case of Diabetes Mellitus; and it has been developed in the context of the projects MONDAINE, MAGPIE, COMMODITY12 and TAMESIS.L'envelliment de la població mundial combinat amb uns estils de vida no saludables contribueixen a una major prevalença d'enfermetats cròniques. Aquest escenari presenta el repte de proporcionar uns bons serveis sanitaris a les persones afectades per aquestes enfermetats, sense incrementar-ne els costos. Una solució prometedora a aquest repte és mitjançant l'aplicació del que en anglès s'anomena "pervasive healthcare". L'investigació en aquesta camp tracta de canviar l'actual model centralitzat de serveis sanitaris enfocat en el personal sanitari, per un model de serveis distribuït enfocat en els pacients. En aquest context, els Personal Health Systems (PHSs) consisteixen en posar a l'abast dels pacients les tecnologies de monitorització, i proporcionar-los informació sobre el seu estat. L'ús de PHSs involucra els pacients en la gestió de la seva enfermetat i del seu propi benestar. L'acceptació dels PHSs per part de la societat implica certs reptes tecnològics en el seu desenvolupament. És important garantir la seva interoperabilitat per tal de que puguin treballar conjuntament. La seva escalabilitat també s'ha de tenir en compte, ja que el seu rendiment no s'ha de veure afectat al incrementar-ne el número d'usuaris. Un altre aspecte a considerar és com formalitzar el coneixement mèdic per cada pacient, ja que cada un d'ells pot tenir objectius diferents. La seguretat i privacitat són característiques desitjades degut a la naturalesa sensible de les dades mèdiques. Altres problemàtiques impliquen la integració amb sistemes heretats, i la usabilitat de les interfícies gràfiques per fomentar-ne el seu ús entre les persones grans. L'objectiu d'aquesta tesi és contribuir a l'estat de l'art dels PHSs tractant de manera conjunta varis dels reptes mencionats. Per abordar l'interoperabilitat s'utilitza l'estàndard CDA com a format per codificar les dades mèdiques i alertes relacionades amb el pacient. A més es mostra com aquests documents poden generar-se de forma automàtica mitjançant l' ús de plantilles XML. Per tractar l'escalabilitat es distribueixen les computacions per monitoritzar els pacients entre els seus terminals mòbils, en comptes de realitzar-les en un servidor central. En aquest context es desenvolupa la plataforma d'agents MAGPIE com a framework per proporcionar intelligència als PHSs i generar alertes d'interès per al metge i el pacient. La formalització s'aborda mitjançant una eina que permet als metges definir de manera gràfica regles de monitorització relacionades amb enfermetats cròniques, que a més estan integrades amb la plataforma d'agents MAGPIE. La tesi també explora diferents maneres de compartir les dades recol·lectades amb un PHS, amb l'objectiu de millorar els resultats obtinguts amb aquesta tecnologia. Les dades es comparteixen entre individus seguint un enfoc de sistemes distribuïts basats en events (DEBS), on diferents usuaris poden subscriure's a les alertes produïdes per el pacient. Les dades també es comparteixen entre institucions mitjançant un protocol de xarxa anomenat MOSAIC. A la tesi es desenvolupen els aspectes de seguretat d'aquest protocol. La test es centra en la Diabetis Mellitus com a cas d'ús, i s'ha realitzat en el context dels projectes MONDAINE, MAGPIE, COMMODITY12 i TAMESIS.El envejecimiento de la población mundial combinado con unos estilos de vida no saludables contribuyen a una mayor prevalencia de enfermedades crónicas. Este escenario presenta el reto de proporcionar unos buenos servicios sanitarios a las personas afectadas por estas enfermedades, sin incrementar sus costes. Una solución prometedora a este reto es mediante la aplicación de lo que en inglés se denomina "pervasive healthcare". La investigación en este campo trata de cambiar el actual modelo centralizado de servicios sanitarios enfocado hacia el personal sanitario, por un modelo distribuido enfocado hacia los pacientes. En este contexto, los Personal Health Systems (PHSs) consisten en poner al alcance de los pacientes las tecnologías de monitorización, y proporcionarles información sobre su estado. El uso de PHSs involucra a los pacientes en la gestión de su enfermedad y en su propio bienestar. La aceptación de los PHSs por parte de la sociedad implica ciertos retos tecnológicos en su desarrollo. Es importante garantizar su interoperabilidad para que puedan trabajar conjuntamente. Su escalabilidad también se debe tener en cuenta, ya que su rendimiento no tiene que verse afectado al incrementar su número de usuarios. Otro aspecto a considerar es cómo formalizar el conocimiento médico para cada paciente, ya que cada uno puede tener objetivos distintos. La seguridad y privacidad son características deseadas debido a la naturaleza sensible de los datos médicos. Otras problemáticas implican la integración con sistemas heredados, y la usabilidad de las interfaces gráficas para fomentar su uso entre las personas mayores. El objetivo de esta tesis es contribuir al estado del arte de los PHSs tratando de manera conjunta varios de los retos mencionados. Para abordar la interoperabilidad se usa el estándar CDA como formato para codificar los datos médicos y alertas relacionados con el paciente. Además se muestra como estros documentos pueden generarse de forma automática mediante el uso de plantillas XML. Para tratar la escalabilidad se distribuye la computación para monitorizar a los pacientes en sus terminales móbiles, en lugar de realizarla en un servidor central. En este contexto se desarrolla la plataforma de agentes MAGPIE como framework para proporcionar inteligencia a los PHSs y generar alertas de interés para el médico y el paciente. La formalización se aborda mediante una herramienta que permite a los médicos definir de manera gráfica reglas de monitorización relacionadas con enfermedades crónicas, que ademas están integradas con la plataforma de agentes MAGPIE. La tesis también explora distintas formas de compartir los datos recolectados con un PHS, con el fin de mejorar los resultados obtenidos mediante esta tecnología. Los datos se comparten entre individuos siguiendo un enfoque de sistemas distribuidos basados en eventos (DEBS), donde distintos usuarios pueden suscribirse a las alertas producidas por el paciente. Los datos también se comparten entre instituciones mediante un protocolo dered llamado MOSAIC. En la tesis se desarrollan los aspectos de seguridad de este protocolo. La tesis se centra en la Diabetes Mellitus como caso de uso, y se ha realizado en el contexto de los proyectos MONDAINE, MAGPIE, COMMODITY12 y TAMESIS.Postprint (published version