Europe's Largest Research Infrastructure for Curated Medical Data Models with Semantic Annotations.

BACKGROUND: Structural metadata from the majority of clinical studies and routine health care systems is currently not yet available to the scientific community. OBJECTIVE: To provide an overview of available contents in the Portal of Medical Data Models (MDM Portal). METHODS: The MDM Portal is a registered European information infrastructure for research and health care, and its contents are curated and semantically annotated by medical experts. It enables users to search, view, discuss, and download existing medical data models. RESULTS: The most frequent keyword is "clinical trial" (n = 18,777), and the most frequent disease-specific keyword is "breast neoplasms" (n = 1,943). Most data items are available in English (n = 545,749) and German (n = 109,267). Manually curated semantic annotations are available for 805,308 elements (554,352 items, 58,101 item groups, and 192,855 code list items), which were derived from 25,257 data models. In total, 1,609,225 Unified Medical Language System (UMLS) codes have been assigned, with 66,373 unique UMLS codes. CONCLUSION: To our knowledge, the MDM Portal constitutes Europe's largest collection of medical data models with semantically annotated elements. As such, it can be used to increase compatibility of medical datasets and can be utilized as a large expert-annotated medical text corpus for natural language processing.

Architecture of the Mass Spectrometry Data Management Pipeline in the SMART-CARE Project.

In the SMART-CARE project- a systems medicine approach to stratification of cancer recurrence in Heidelberg, Germany - a streamlined mass-spectrometry (MS) workflow for identification of cancer relapse was developed. This project has multiple partners from clinics, laboratories and computational teams. For optimal collaboration, consistent documentation and centralized storage, the linked data repository was designed. Clinical, laboratory and computational group members interact with this platform and store meta- and raw-data. The specific architectural choices, such as pseudonymization service, uploading process and other technical specifications as well as lessons learned are presented in this work. Altogether, relevant information in order to provide other research groups with a head-start for tackling MS data management in the context of systems medicine research projects is described.

Next-generation study databases require FAIR, EHR-integrated, and scalable Electronic Data Capture for medical documentation and decision support.

Structured patient data play a key role in all types of clinical research. They are often collected in study databases for research purposes. In order to describe characteristics of a next-generation study database and assess the feasibility of its implementation a proof-of-concept study in a German university hospital was performed. Key characteristics identified include FAIR access to electronic case report forms (eCRF), regulatory compliant Electronic Data Capture (EDC), an EDC with electronic health record (EHR) integration, scalable EDC for medical documentation, patient generated data, and clinical decision support. In a local case study, we then successfully implemented a next-generation study database for 19 EDC systems (n = 2217 patients) that linked to i.s.h.med (Oracle Cerner) with the local EDC system called OpenEDC. Desiderata of next-generation study databases for patient data were identified from ongoing local clinical study projects in 11 clinical departments at Heidelberg University Hospital, Germany, a major tertiary referral hospital. We compiled and analyzed feature and functionality requests submitted to the OpenEDC team between May 2021 and July 2023. Next-generation study databases are technically and clinically feasible. Further research is needed to evaluate if our approach is feasible in a multi-center setting as well.

Proposing a Novel Hybrid Short-Term Exchange Program in Biomedical and Health Informatics Education.

International student exchange is a valuable opportunity for Biomedical and Health Informatics students to gain new perspectives and experiences. In the past, such exchanges have been made possible through international partnerships between universities. Unfortunately, numerous obstacles such as housing, financial concerns, and environmental implications related to travel, have made it difficult to continue international exchange. Experiences with hybrid and online education during covid-19 paved the way for a new approach that allows for short international exchange with a hybrid online-offline supervision model. This will be initiated with an exploration project between two international universities , each related to their respective institute's research focus.

Portal of Medical Data Models: Application in Federated Data Capture.

So far, the portal for medical data models allows its users to download medical forms in a standardized format. Importing data models into electronic data capture software involved a manual step of downloading and importing the files. Now, the portal was enhanced with a web services interface to allow electronic data capture systems to automatically download the forms. This mechanism can be used in federated studies to ensure that all partners are working with identical definitions of study forms.

Federated electronic data capture (fEDC): Architecture and prototype.

In clinical research as well as patient care, structured documentation of findings is an important task. In many cases, this is achieved by means of electronic case report forms (eCRF) using corresponding information technology systems. To avoid double data entry, eCRF systems can be integrated with electronic health records (EHR). However, when researchers from different institutions collaborate in collecting data, they often use a single joint eCRF system on the Internet. In this case, integration with EHR systems is not possible in most cases due to information security and data protection restrictions. To overcome this shortcoming, we propose a novel architecture for a federated electronic data capture system (fEDC). Four key requirements were identified for fEDC: Definitions of forms have to be available in a reliable and controlled fashion, integration with electronic health record systems must be possible, patient data should be under full local control until they are explicitly transferred for joint analysis, and the system must support data sharing principles accepted by the scientific community for both data model and data captured. With our approach, sites participating in a joint study can run their own instance of an fEDC system that complies with local standards (such as being behind a network firewall) while also being able to benefit from using identical form definitions by sharing metadata in the Operational Data Model (ODM) format published by the Clinical Data Interchange Standards Consortium (CDISC) throughout the collaboration. The fEDC architecture was validated with a working open-source prototype at five German university hospitals. The fEDC architecture provides a novel approach with the potential to significantly improve collaborative data capture: Efforts for data entry are reduced and at the same time, data quality is increased since barriers for integrating with local electronic health record systems are lowered. Further, metadata are shared and patient privacy is ensured at a high level.

Proteogenomics refines the molecular classification of chronic lymphocytic leukemia.

Cancer heterogeneity at the proteome level may explain differences in therapy response and prognosis beyond the currently established genomic and transcriptomic-based diagnostics. The relevance of proteomics for disease classifications remains to be established in clinically heterogeneous cancer entities such as chronic lymphocytic leukemia (CLL). Here, we characterize the proteome and transcriptome alongside genetic and ex-vivo drug response profiling in a clinically annotated CLL discovery cohort (n = 68). Unsupervised clustering of the proteome data reveals six subgroups. Five of these proteomic groups are associated with genetic features, while one group is only detectable at the proteome level. This new group is characterized by accelerated disease progression, high spliceosomal protein abundances associated with aberrant splicing, and low B cell receptor signaling protein abundances (ASB-CLL). Classifiers developed to identify ASB-CLL based on its characteristic proteome or splicing signature in two independent cohorts (n = 165, n = 169) confirm that ASB-CLL comprises about 20% of CLL patients. The inferior overall survival in ASB-CLL is also independent of both TP53- and IGHV mutation status. Our multi-omics analysis refines the classification of CLL and highlights the potential of proteomics to improve cancer patient stratification beyond genetic and transcriptomic profiling.

Towards Data Analysis Environment for Multi-Partner Clinical Research Project - SMART-CARE.

A Systems Medicine Approach to Stratification of Cancer Recurrence (SMART-CARE) establishes mass spectrometry-based systems medicine technologies and data analysis pipelines employing expertise of the multiple partners from Heidelberg biomedical campus. We have established a central linked data repository that links clinical, mass spectrometry, and data analysis teams to enable a full cycle of data management. Other questions of setting up the data analysis environment for the multi-partner clinical research project are addressed in this work, too.

Large-File Raw Data Synchronization for openBIS Research Repositories.

In a systems medicine research consortium, openBIS is used as a research data repository. To facilitate efficient upload of large files, openBIS is complemented by a Nextcloud data cloud system. Using a Nextcloud client, raw mass spectrometry data is automatically imported into the repository in the background, enabling comprehensive data provenance.

Data Management for Systems Medicine: The SMART-CARE Joint Environment.

For a research project on mass spectrometry, a streamlined, harmonized and robust analytical pipeline is built to predict tumor recurrence. By means of standardization all steps from sample collection, analysis, proteome, and metabolome analysis are harmonized. Challenges like non-central identificators and distributed data are overcome with a centralized high-performant IT-platform in combination with a pseudonymization service and harmonization.

On the Construction of Multilingual Corpora for Clinical Text Mining.

The amount of digital data derived from healthcare processes have increased tremendously in the last years. This applies especially to unstructured data, which are often hard to analyze due to the lack of available tools to process and extract information. Natural language processing is often used in medicine, but the majority of tools used by researchers are developed primarily for the English language. For developing and testing natural language processing methods, it is important to have a suitable corpus, specific to the medical domain that covers the intended target language. To improve the potential of natural language processing research, we developed tools to derive language specific medical corpora from publicly available text sources. n order to extract medicine-specific unstructured text data, openly available pub-lications from biomedical journals were used in a four-step process: (1) medical journal databases were scraped to download the articles, (2) the articles were parsed and consolidated into a single repository, (3) the content of the repository was de-scribed, and (4) the text data and the codes were released. In total, 93 969 articles were retrieved, with a word count of 83 868 501 in three different languages (German, English, and Spanish) from two medical journal databases Our results show that unstructured text data extraction from openly available medical journal databases for the construction of unified corpora of medical text data can be achieved through web scraping techniques.

vivaGen - a survival data set generator for software testing.

An amendment to this paper has been published and can be accessed via the original article.

Graph-Representation of Patient Data: a Systematic Literature Review.

Graph theory is a well-established theory with many methods used in mathematics to study graph structures. In the field of medicine, electronic health records (EHR) are commonly used to store and analyze patient data. Consequently, it seems straight-forward to perform research on modeling EHR data as graphs. This systematic literature review aims to investigate the frontiers of the current research in the field of graphs representing and processing patient data. We want to show, which areas of research in this context need further investigation. The databases MEDLINE, Web of Science, IEEE Xplore and ACM digital library were queried by using the search terms health record, graph and related terms. Based on the "Preferred Reporting Items for Systematic Reviews and Meta-Analysis" (PRISMA) statement guidelines the articles were screened and evaluated using full-text analysis. Eleven out of 383 articles found in systematic literature review were finally included for analysis in this literature review. Most of them use graphs to represent temporal relations, often representing the connection among laboratory data points. Only two papers report that the graph data were further processed by comparing the patient graphs using similarity measurements. Graphs representing individual patients are hardly used in research context, only eleven papers considered such kind of graphs in their investigations. The potential of graph theoretical algorithms, which are already well established, could help increasing this research field, but currently there are too few papers to estimate how this area of research will develop. Altogether, the use of such patient graphs could be a promising technique to develop decision support systems for diagnosis, medication or therapy of patients using similarity measurements or different kinds of analysis.

Methods for a similarity measure for clinical attributes based on survival data analysis.

BACKGROUND: Case-based reasoning is a proven method that relies on learned cases from the past for decision support of a new case. The accuracy of such a system depends on the applied similarity measure, which quantifies the similarity between two cases. This work proposes a collection of methods for similarity measures especially for comparison of clinical cases based on survival data, as they are available for example from clinical trials. METHODS: Our approach is intended to be used in scenarios, where it is of interest to use longitudinal data, such as survival data, for a case-based reasoning approach. This might be especially important, where uncertainty about the ideal therapy decision exists. The collection of methods consists of definitions of the local similarity of nominal as well as numeric attributes, a calculation of attribute weights, a feature selection method and finally a global similarity measure. All of them use survival time (consisting of survival status and overall survival) as a reference of similarity. As a baseline, we calculate a survival function for each value of any given clinical attribute. RESULTS: We define the similarity between values of the same attribute by putting the estimated survival functions in relation to each other. Finally, we quantify the similarity by determining the area between corresponding curves of survival functions. The proposed global similarity measure is designed especially for cases from randomized clinical trials or other collections of clinical data with survival information. Overall survival can be considered as an eligible and alternative solution for similarity calculations. It is especially useful, when similarity measures that depend on the classic solution-describing attribute "applied therapy" are not applicable. This is often the case for data from clinical trials containing randomized arms. CONCLUSIONS: In silico evaluation scenarios showed that the mean accuracy of biomarker detection in k = 10 most similar cases is higher (0.909-0.998) than for competing similarity measures, such as Heterogeneous Euclidian-Overlap Metric (0.657-0.831) and Discretized Value Difference Metric (0.535-0.671). The weight calculation method showed a more than six times (6.59-6.95) higher weight for biomarker attributes over non-biomarker attributes. These results suggest that the similarity measure described here is suitable for applications based on survival data.

A Concept for Graph-Based Temporal Similarity of Patient Data.

Computer-based decision support systems are often used for dedicated tasks such as the detection of sepsis. However, positive predictive values for sepsis detection are reported to achieve only around 46%. In this paper we describe a novel approach to use temporal data of electronic patient records based on similarity measures. We apply the concept of case-based reasoning, which is well-established in many fields of medical informatics. Temporal patient data are organized in a time-graph structure. For the quantification of similarity between cases, we exploit graph theory based approaches. For development and evaluation of our time-graph similarity frame we use the open MIMIC III dataset. In a later phase, we envision to transfer our concept from sepsis to other diseases.

Extraction from Medical Records.

Despite using electronic medical records, free narrative text is still widely used for medical records. Such text cannot be analyzed by statistical tools and be proceed by decision support systems. To make data from texts available for such tasks a supervised machine learning algorithms might be successfully applied. In this work, we develop and compare a prototype of a medical data extraction system based on different artificial neuron networks architectures to process free medical texts in Russian language. The best F-score (0.9763) achieved on a combination of CNN prediction model and large pre-trained word2vec model. The very close result (0.9741) has shown by the MLP model with the same embedding.

Optimization of Clinical Decision Support Based on Pearson Correlation of Attributes.

Clinical decision support is very important especially in such a wide-spread disease as a coronary artery disease. A large variety of prediction methods can potentially solve the classification problem to support clinical decisions. However, not all of them provide similar efficiency for the classification of patients with coronary artery disease. We have analyzed prediction the efficiency of classifiers (Ridge Classifier, XGB Classifier and Logistic Regression) depending on the number and combination of features. We have tested 24 sets of features on 4 classifiers to proof the hypothesis that using optimized features sets with a higher Pearson ratio results in more efficient classifiers than using all available data.

A Predictive Model for Patient Similarity: Classes Based on Secondary Data and Simple Measurements as Predictors.

Predictive models optimized for average cases might work not perfect for cases deviating from average because they are based on a cohort of all patients. Models could be more personalized if they were built on a sub-cohort of patients similar to a current one and to train models on data collected from those similar patients. In this paper, we consider patient similarity as a classification task. We suppose that data such as diagnoses and treatment obtained by physicians (secondary data) are more relevant for similarity than tests and measurements (primary data). We defined several classes based on diagnoses and outcomes and apply a predictive model for classification. We used five commonly used and easy to obtain measurements as predictors for the model. All measurements were collected during the first 24 hours after admission. We have shown that classes of similar patients can be defined on the basis of a previous patient's secondary data and new patients can be classified into these classes.

Implementing Systems Medicine: A Medical Informatics Perspective.

Systems medicine is a paradigm for translating in silico methods developed for modelling biological systems into the field of medicine. Such approaches rely on the integration of as many data sources as possible, both in the dimension of disease knowledge and patient data. This is a challenging task that can only be implemented in clinical routine with the help of suitable information technology from the field of Medical Informatics. For the research project "Clinically-applicable, omics-based assessment of survival, side effects, and targets in multiple myeloma" (CLIOMMICS) we developed a prototypical systems medicine application system. It is based on a three-level-architecture covering data representation, decision support, and user interface. The core decision support component is implemented as a case-based reasoning engine. However, the architecture follows a modular design that allows to replace individual components as needed.