Diseño y Desarrollo de un Sistema de Información para la Gestión de Información sobre Cáncer de Mama

Diagnosis, treatment and research about such complex diseases as breast cancer is an increasingly complex task due to the big quantity and diversity of involved data and the need of relating them properly to obtain relevant conclusions. Clinical data generation has to be followed by an efficient data management. So, the use of advanced information system technologies is essential to ensure a correct storage, management and exploitation of data. Following a deep study of domain and technologies used to store and manage clinical and biological data about the disease, the main goal of this thesis is to provide a methodological basis to design and implement software systems to manage breast cancer data in a trustable and efficient way. Using Conceptual Modelling techniques in an environment where their use is not as common as it should be, allows to create information systems perfectly adapted to the studied domain. Under this approach, in this thesis some tasks have been carried out among which are conceptual modelling of diagnosis, treatment and research of breast cancer's domain; archetypes' designing under ISO13606 standard to allow systems interoperability; breast cancer data integration from different data sources in a unified database; and designing a prototype of tool for managing and analysing clinical and genic expression data. In order to validate the proposal, a validation process in a real environment as Research Foundation INCLIVA in Valencia has been carried out. During this process, medical and biological researchers have use and assess the efficiency of solution proposed in this doctoral thesis.El diagnóstico, tratamiento e investigación sobre enfermedades tan complejas como el cáncer de mama es una tarea cada vez más complicada por la gran cantidad y diversidad de datos implicados y por la necesidad de relacionarlos adecuadamente para obtener conclusiones relevantes. La generación de los datos clínicos tiene que estar acompañada de una gestión eficiente de los mismos. Ello hace imprescindible la utilización de tecnologías avanzadas de Sistemas de Información que aseguren un correcto almacenamiento, gestión y explotación de los datos. Tras un profundo estudio del dominio y de las tecnologías utilizadas para el almacenamiento y gestión de datos clínicos y biológicos sobre la enfermedad, el objetivo principal de esta tesis es ofrecer una base metodológica que permita diseñar y desarrollar sistemas software para la manipulación eficiente y fiable de la información sobre el cáncer de mama. La utilización de técnicas de Modelado Conceptual en un entorno donde su uso no es tan habitual como debiera ser, permitirá disponer de un sistema de información perfectamente adaptado al dominio de aplicación. Bajo este planteamiento, en esta tesis se ha llevado a cabo el modelado conceptual del dominio del diagnóstico, tratamiento e investigación del cáncer de mama, el diseño de arquetipos bajo el estándar ISO13606 para ofrecer interoperabilidad entre sistemas, la integración de datos de distintos orígenes relacionados con el cáncer de mama en una base de datos unificadora y el diseño de un prototipo de herramienta de gestión y análisis de datos clínicos y de expresión génica. Para validar la idoneidad de esta propuesta, se ha llevado a cabo un proceso de validación en un entorno real como es la Fundación de Investigación INCLIVA de Valencia, donde investigadores clínicos y biólogos han probado y valorado la eficiencia de la solución planteada en esta tesis doctoral.El diagnòstic, tractament i investigació sobre malalties tan complexes com ara el càncer de mama és una tasca cada vegada més complexa per la gran quantitat i diversitat de dades implicades i per la necessitat de relacionar-les adequadament per a obtenir conclusions rellevants. La generació de dades clíniques ha d'estar acompanyada d'una gestió eficient de les mateixes. Açò fa imprescindible la utilització de tecnologies avançades de Sistemes d'Informació que asseguren un correcte emmagatzematge, gestió i explotació de les dades. Després d'un profund estudi del domini i de les tecnologies utilitzades per l'emmagatzematge i gestió de dades clíniques i biològiques sobre la malaltia, el principal objectiu d'aquesta tesi és oferir una base metodològica que permeta dissenyar i desenvolupar sistemes programaris per a la manipulació eficient i fiable de la informació sobre el càncer de mama. La utilització de tècniques de Modelat Conceptual en un entorn on el seu ús no és tan habitual com deuria ser, permetrà disposar d'un sistema d'informació perfectament adaptat al domini d'aplicació. Baix aquest plantejament, en aquesta tesi s'ha dut a terme el modelat conceptual del domini del diagnòstic, tractament i investigació del càncer de mama, el disseny d'arquetips baix l'estàndard ISO13606 per oferir interoperabilitat entre sistemes, la integració de dades de distints orígens sobre el càncer de mama en una base de dades unificadora i el disseny d'un prototip d'eina de gestió i anàlisi de dades clíniques i d'expressió gènica. Per a validar la idoneïtat d'aquesta proposta, s'ha dut a terme un procés de validació en un entorn real com és la Fundació d'Investigació INCLIVA de València, on investigadors clínics i biòlegs han provat i valorat l'eficiència de la solució plantejada en aquesta tesi doctoral.Burriel Coll, V. (2017). Diseño y Desarrollo de un Sistema de Información para la Gestión de Información sobre Cáncer de Mama [Tesis doctoral no publicada]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/86158TESI

An Application of an Electronic Health Record System in order to integrate clinical and molecular data and guide therapeutic strategy in Paraguay.

Improve data management in two public hospitals in Paraguay - Hospital de Clínicas and Instituto Nacional del Cáncer (INCAN). Currently, data management in oncology department is complex and requires advanced Information System to process data where "omic" information should be integrated together with patient's clinical data to improve data analysis and decision-making process. Conceptual Modelling is an important and essential activity that helps us not only to design an abstract model of an advanced Information System but also facilitates the development process.CONACYT - Consejo Nacional de Ciencias y TecnologíaPROCIENCI

Design and Development of an Information System to Manage Clinical Data about Usher Syndrome Based on Conceptual Modeling

[EN] The inefficient management of clinical data in many research environments is a problem which slows down the service provided to patients. The benefits of an Information System created following the conceptual modeling rules have been proved in multiple environments with data management difficulties. The main hurdle to overcome is the large gap between the language and concepts employed by informaticians and the ones used by biologists. The work described in this paper shows how these technologies can also be applied to the clinical domain, after a long period of mutual approaching in order to understand each other. The research clinical data of an expert research group on Usher syndrome have been studied, analyzed and redesigned using conceptual modeling, helping this group to offer a better service.It is important to highlight that this work has been done under the framework of the Cátedra Tecnologías para la Salud of the Universitat Politècnica de València financed by INDRA Systems.Burriel Coll, V.; Pastor Cubillo, MÁ.; Celma Giménez, M.; Casamayor Rodenas, JC.; Mota Herranz, L. (2013). Design and Development of an Information System to Manage Clinical Data about Usher Syndrome Based on Conceptual Modeling. IARIA XPS Press. http://hdl.handle.net/10251/75237

An application of an EHR based on conceptual modeling to integrate clinical and genomic data and guide therapeutic strategy

Currently, data management in oncology department is complex and requires advanced Information Systems (ISs) to process data where “omic” information should be integrated together with patient’s clinical data to improve data analysis and decision-making process. This research paper reports a practical experience in this context. A Conceptual Model (CM) has been designed to develop an Information System (IS) in order to manage clinical, pathological, and molecular data in a holistic way at the oncology department of two main Hospitals in Paraguay. Additionally, model-based archetypes have been proposed to specify the selected user interaction strategy. The CM and its associated archetypes are the basis to develop a clinical IS in order to load -firstly- and manage -secondly- all the clinical data that the domain requires, showing how feasible the approach is in practice, and how much the corresponding clinical data management is improved. In this work, we want to reinforce with this real experience how using a CM along with archetypes correctly helps to design, develop and manage better information systems, emphasizing the relevance of the selected clinical domain

Molecular profile in Paraguayan colorectal cancer patients, towards to a precision medicine strategy

[EN] Somatic mutation analysis and evaluation of microsatellite instability (MSI) have become mandatory for selecting personalized therapy strategies for advanced colorectal cancer and are not available as routine methods in Paraguay. The aims of this study were to analyze the molecular profile as well as the microsatellite status in a series of advanced colorectal patients from two public hospitals from Paraguay, to introduce these methodologies in the routine practice to guide the therapeutic decisions. Thirty-six patients diagnosed with advanced colorectal cancer from two referent public hospitals from Paraguay were recruited from May 2017 to February 2018. Sequenom Mass spectrometry, Oncocarta Panel V.1 was applied to analyze the mutational profile from formalin-fixed paraffin-embedded samples. The microsatellite status was tested by immunohistochemistry (IHC). The mean age of the patients was 52 years with a range from 20 to 74 years. Eighty-three percent of the patients included in the study have advanced-stage tumors at the moment of the diagnosis. Sixteen patients (44.4%) were wild-type for all the oncogene regions analyzed with the Oncocarta panel. Thirty-two hot-spot pathogenic variants on seven oncogenes, among 20 patients (55.6%), were identified, including KRAS, NRAS, BRAF, PI3KCA, FGFR, epidermal growth factor receptor, and PDGFRA. Moreover, 14 (38.8%) of these patients presented pathogenic variants in KRAS/NRAS or BRAF genes that have implications in the clinical practice decisions. Five patients (14%) presented MSI. The IHC study for microsatellite status and the molecular profile analysis through Sequenom mass spectrometry are feasible and useful methods, due to identify those patient candidates for targeted therapies and for the budgetary calculations of the National Health PlansCONACYT Paraguay, Grant/Award Number: PINV-156/2015; INSTITUTO CARLOS III, Grant/Award Number: 17/00026 and CD15/00153; FONDOS FEDER; BankiaFleitas-Kanonnikoff, T.; Martinez-Ciarpaglini, C.; Ayala, J.; Gauna, C.; Denis, R.; Yoffe, I.; Sforza, S.... (2019). Molecular profile in Paraguayan colorectal cancer patients, towards to a precision medicine strategy. Wiley Interdisciplinary Reviews. Computational Molecular Science (Online). 8(6):3120-3130. https://doi.org/10.1002/cam4.2191S3120313086Bray, F., Ferlay, J., Soerjomataram, I., Siegel, R. L., Torre, L. A., & Jemal, A. (2018). Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer Journal for Clinicians, 68(6), 394-424. doi:10.3322/caac.21492Bray, F., & Piñeros, M. (2016). Cancer patterns, trends and projections in Latin America and the Caribbean: a global context. Salud Pública de México, 58(2), 104-117. doi:10.21149/spm.v58i2.7779Bohorquez, M., Sahasrabudhe, R., Criollo, A., Sanabria-Salas, M. C., Vélez, A., Castro, J. M., … Carvajal-Carmona, L. G. (2016). Clinical manifestations of colorectal cancer patients from a large multicenter study in Colombia. Medicine, 95(40), e4883. doi:10.1097/md.0000000000004883Sartore-Bianchi, A., Trusolino, L., Martino, C., Bencardino, K., Lonardi, S., Bergamo, F., … Siena, S. (2016). Dual-targeted therapy with trastuzumab and lapatinib in treatment-refractory, KRAS codon 12/13 wild-type, HER2-positive metastatic colorectal cancer (HERACLES): a proof-of-concept, multicentre, open-label, phase 2 trial. The Lancet Oncology, 17(6), 738-746. doi:10.1016/s1470-2045(16)00150-9Martinez-Ciarpaglini, C., Oltra, S., Roselló, S., Roda, D., Mongort, C., Carrasco, F., … Cervantes, A. (2018). Low miR200c expression in tumor budding of invasive front predicts worse survival in patients with localized colon cancer and is related to PD-L1 overexpression. Modern Pathology, 32(2), 306-313. doi:10.1038/s41379-018-0124-5Gao, J., Aksoy, B. A., Dogrusoz, U., Dresdner, G., Gross, B., Sumer, S. O., … Schultz, N. (2013). Integrative Analysis of Complex Cancer Genomics and Clinical Profiles Using the cBioPortal. Science Signaling, 6(269), pl1-pl1. doi:10.1126/scisignal.2004088Chakravarty, D., Gao, J., Phillips, S., Kundra, R., Zhang, H., Wang, J., … Schultz, N. (2017). OncoKB: A Precision Oncology Knowledge Base. JCO Precision Oncology, (1), 1-16. doi:10.1200/po.17.00011Arnold, M., Sierra, M. S., Laversanne, M., Soerjomataram, I., Jemal, A., & Bray, F. (2016). Global patterns and trends in colorectal cancer incidence and mortality. Gut, 66(4), 683-691. doi:10.1136/gutjnl-2015-310912Ohhara, Y., Fukuda, N., Takeuchi, S., Honma, R., Shimizu, Y., Kinoshita, I., & Dosaka-Akita, H. (2016). Role of targeted therapy in metastatic colorectal cancer. World Journal of Gastrointestinal Oncology, 8(9), 642. doi:10.4251/wjgo.v8.i9.64

Molecular profile in Paraguayan colorectal cancer patients, towards to a precision medicine strategy

Somatic mutation analysis and evaluation of microsatellite instability (MSI) have become mandatory for selecting personalized therapy strategies for advanced colorectal cancer and are not available as routine methods in Paraguay. The aims of this study were to analyze the molecular profile as well as the microsatellite status in a series of advanced colorectal patients from two public hospitals from Paraguay, to introduce these methodologies in the routine practice to guide the therapeutic decisions.CONACYT – Consejo Nacional de Ciencia y TecnologíaPROCIENCI

Una Aplicación de una Historia Clínica Electrónica (HCE) Basado en Modelos Conceptuales para Integrar Datos Clínicos y Genómicos y Orientar la Estrategia Terapéutica

[EN] Currently, data management in oncology department is complex and requires advanced Information Systems (ISs) to process data where "omic" information should be integrated together with patient's clinical data to improve data analysis and decision-making process. This research paper reports a practical experience in this context. A Conceptual Model (CM) has been designed to develop an Information System (IS) in order to manage clinical, pathological, and molecular data in a holistic way at the oncology department of two main Hospitals in Paraguay. Additionally, model-based archetypes have been proposed to specify the selected user interaction strategy. The CM and its associated archetypes are the basis to develop a clinical IS in order to load -firstly- and manage -secondly- all the clinical data that the domain requires, showing how feasible the approach is in practice, and how much the corresponding clinical data management is improved. In this work, we want to reinforce with this real experience how using a CM along with archetypes correctly helps to design, develop and manage better information systems, emphasizing the relevance of the selected clinical domain.[ES] Actualmente, la gestión de datos en el departamento de oncología es compleja y requiere sistemas de información avanzados para procesar datos donde la información "ómica" debe integrarse junto con los datos clínicos del paciente para mejorar el análisis de datos y el proceso de toma de decisiones. Este trabajo de investigación presenta una experiencia práctica en este contexto. Se ha diseñado un Modelo Conceptual (MC) para desarrollar un Sistema de Información (SI) con el fin de gestionar datos clínicos, patológicos y moleculares de manera integral en el departamento de oncología de dos hospitales principales en Paraguay. Además, se han propuesto arquetipos basados en modelos para especificar la estrategia de interacción del usuario. El MC y los arquetipos asociados son la base para desarrollar un SI clínico con el fin de cargar -primero- y gestionar -segundo- todos los datos clínicos que requiere el dominio, mostrando cuán factible es el enfoque en la práctica y cuánto se mejora la gestión de datos. En este trabajo, queremos reforzar con esta experiencia real, cómo el uso correcto de un MC junto con los arquetipos ayuda a diseñar, desarrollar y administrar mejores sistemas de información, enfatizando la relevancia del dominio clínico seleccionado.This work has been developed in the framework of the project PINV115-149 with the financial support of the Consejo Nacional de Ciencia y Tecnología (CONACYT)- Paraguay, with resources del FEEI and with the financial support of the Spanish State Research Agency, the Generalitat Valenciana and "Multicenter Project of Multidisciplinary Training in Cancer and Application of Electronic Health Record (EHR)", and co-financed with ERDF.Arevshatyan, S.; Burriel, V.; Boscá, D.; Reyes Román, JF.; Pastor López, O.; Yoffe, I.; Denis, RMC.... (2020). An Application of an EHR Based on Conceptual Modeling to Integrate Clinical and Genomic Data and Guide Therapeutic Strategy. Anales de la Facultad de Ciencias Médicas. 53(1):17-30. https://doi.org/10.18004/anales/2020.053.01.17-030S173053

Gestión de mutaciones en ambientes genómicos: una perspectiva basada en Modelos Conceptuales

La creación de un modelo conceptual que contenga información relacionada con el genoma humano y la carga de su correspondiente base de datos con los contenidos apropiados extraidos de bases de datos genómicas actuales, hace posible la explotación de esos datos en la realización de informes de ayuda al diagnóstico de enfermedades genéticas.Burriel Coll, V. (2010). Gestión de mutaciones en ambientes genómicos: una perspectiva basada en Modelos Conceptuales. http://hdl.handle.net/10251/14623Archivo delegad

Coeliac disease case-control study: Has the time come to explore beyond patients at risk?

The worldwide prevalence of asymptomatic coeliac disease (CD) is increasing, which is in part due to the routine screening of children with risk factors. Both symptomatic and asymptomatic patients with CD are at risk of long-term complications. The objective of this study was to compare the clinical characteristics of asymptomatic and symptomatic children at the time of CD diagnosis. A case-control study was conducted using data from a cohort of 4838 CD patients recruited from 73 centers across Spain between 2011 and 2017. A total of 468 asymptomatic patients (cases) were selected and matched by age and sex with 468 symptomatic patients (controls). Clinical data, including any reported symptoms, as well as serologic, genetic, and histopathologic data were collected. No significant differences were found between the two groups in most clinical variables, nor in the degree of intestinal lesion. However, the asymptomatic patients were taller (height z-score -0.12 (1.06) vs. -0.45 (1.19), p < 0.001) and were less likely to have anti transglutaminase IgA antibodies 10 times the upper normal limit (66.2% vs. 758.4%, p = 0.002). Among the 37.1% of asymptomatic patients who were not screened for CD due to the absence of risk factors, only 34% were truly asymptomatic, while the remaining 66% reported non-specific CD-related symptoms. Therefore, expanding CD screening to any child who undergoes a blood test could reduce the burden of care for some children, as many of those considered asymptomatic reported non-specific CD-related symptom