The COVID-19 Data Exchange Platform of the German University Medicine.

COVID-19 has challenged the healthcare systems worldwide. To quickly identify successful diagnostic and therapeutic approaches large data sharing approaches are inevitable. Though organizational clinical data are abundant, many of them are available only in isolated silos and largely inaccessible to external researchers. To overcome and tackle this challenge the university medicine network (comprising all 36 German university hospitals) has been founded in April 2020 to coordinate COVID-19 action plans, diagnostic and therapeutic strategies and collaborative research activities. 13 projects were initiated from which the CODEX project, aiming at the development of a Germany-wide Covid-19 Data Exchange Platform, is presented in this publication. We illustrate the conceptual design, the stepwise development and deployment, first results and the current status.

The ACGT Master Ontology and its applications--towards an ontology-driven cancer research and management system.

OBJECTIVE: This paper introduces the objectives, methods and results of ontology development in the EU co-funded project Advancing Clinico-genomic Trials on Cancer-Open Grid Services for Improving Medical Knowledge Discovery (ACGT). While the available data in the life sciences has recently grown both in amount and quality, the full exploitation of it is being hindered by the use of different underlying technologies, coding systems, category schemes and reporting methods on the part of different research groups. The goal of the ACGT project is to contribute to the resolution of these problems by developing an ontology-driven, semantic grid services infrastructure that will enable efficient execution of discovery-driven scientific workflows in the context of multi-centric, post-genomic clinical trials. The focus of the present paper is the ACGT Master Ontology (MO). METHODS: ACGT project researchers undertook a systematic review of existing domain and upper-level ontologies, as well as of existing ontology design software, implementation methods, and end-user interfaces. This included the careful study of best practices, design principles and evaluation methods for ontology design, maintenance, implementation, and versioning, as well as for use on the part of domain experts and clinicians. RESULTS: To date, the results of the ACGT project include (i) the development of a master ontology (the ACGT-MO) based on clearly defined principles of ontology development and evaluation; (ii) the development of a technical infrastructure (the ACGT Platform) that implements the ACGT-MO utilizing independent tools, components and resources that have been developed based on open architectural standards, and which includes an application updating and evolving the ontology efficiently in response to end-user needs; and (iii) the development of an Ontology-based Trial Management Application (ObTiMA) that integrates the ACGT-MO into the design process of clinical trials in order to guarantee automatic semantic integration without the need to perform a separate mapping process.

Towards an interoperable information infrastructure providing decision support for genomic medicine.

Genetic dispositions play a major role in individual disease risk and treatment response. Genomic medicine, in which medical decisions are refined by genetic information of particular patients, is becoming increasingly important. Here we describe our work and future visions around the creation of a distributed infrastructure for pharmacogenetic data and medical decision support, based on industry standards such as the Web Ontology Language (OWL) and the Arden Syntax.

ACGT: advancing clinico-genomic trials on cancer - four years of experience.

The challenges regarding seamless integration of distributed, heterogeneous and multilevel data arising in the context of contemporary, post-genomic clinical trials cannot be effectively addressed with current methodologies. An urgent need exists to access data in a uniform manner, to share information among different clinical and research centers, and to store data in secure repositories assuring the privacy of patients. Advancing Clinico-Genomic Trials (ACGT) was a European Commission funded Integrated Project that aimed at providing tools and methods to enhance the efficiency of clinical trials in the -omics era. The project, now completed after four years of work, involved the development of both a set of methodological approaches as well as tools and services and its testing in the context of real-world clinico-genomic scenarios. This paper describes the main experiences using the ACGT platform and its tools within one such scenario and highlights the very promising results obtained.

User-specific perspectives on ontologies.

Ontologies are more and more used in clinical informatics in different settings and supporting different functionalities. Most experts see the role of ontologies as operating in a black box and being invisible for the end-user. With respect to some of the systems that have recently been developed this is only partly possible. Therefore, we provide a methodology to create an end-user perspective on a clinical ontology. This will foster participation of the clinical expert in both ontology exploitation and ontology maintenance. This methodology does not only provide the basis for a better integration of the experts into the ontology-based system, but it can be used to support patient empowerment by helping the patient to understand the content that is stored and partake in its management.

The ObTiMA system - ontology-based managing of clinical trials.

Clinical Trial Management Systems promise to help researchers in managing the large amounts of data occurring in clinical trials. In such systems Case Report Forms for capturing all patient data can usually be defined freely for a given trial. But if database definitions are automatically derived from such trial-specific definitions then the collected data cannot be easily compared to or integrated into other trials. We address this interoperability issue with an approach based on ontology and semantic data mediation. This resulted in the development of the ObTiMA system which is composed of a component for setting-up clinical trials and another for handling patient data during trials. Both components offer data reusability by relying on shared concepts defined in an ontology covering the whole cancer care and research spectrum.

Enabling ad-hoc reuse of private data repositories through schema extraction.

BACKGROUND: Sharing sensitive data across organizational boundaries is often significantly limited by legal and ethical restrictions. Regulations such as the EU General Data Protection Rules (GDPR) impose strict requirements concerning the protection of personal and privacy sensitive data. Therefore new approaches, such as the Personal Health Train initiative, are emerging to utilize data right in their original repositories, circumventing the need to transfer data. RESULTS: Circumventing limitations of previous systems, this paper proposes a configurable and automated schema extraction and publishing approach, which enables ad-hoc SPARQL query formulation against RDF triple stores without requiring direct access to the private data. The approach is compatible with existing Semantic Web-based technologies and allows for the subsequent execution of such queries in a safe setting under the data provider's control. Evaluation with four distinct datasets shows that a configurable amount of concise and task-relevant schema, closely describing the structure of the underlying data, was derived, enabling the schema introspection-assisted authoring of SPARQL queries. CONCLUSIONS: Automatically extracting and publishing data schema can enable the introspection-assisted creation of data selection and integration queries. In conjunction with the presented system architecture, this approach can enable reuse of data from private repositories and in settings where agreeing upon a shared schema and encoding a priori is infeasible. As such, it could provide an important step towards reuse of data from previously inaccessible sources and thus towards the proliferation of data-driven methods in the biomedical domain.

Reduced Rate of Inpatient Hospital Admissions in 18 German University Hospitals During the COVID-19 Lockdown.

The COVID-19 pandemic has caused strains on health systems worldwide disrupting routine hospital services for all non-COVID patients. Within this retrospective study, we analyzed inpatient hospital admissions across 18 German university hospitals during the 2020 lockdown period compared to 2018. Patients admitted to hospital between January 1 and May 31, 2020 and the corresponding periods in 2018 and 2019 were included in this study. Data derived from electronic health records were collected and analyzed using the data integration center infrastructure implemented in the university hospitals that are part of the four consortia funded by the German Medical Informatics Initiative. Admissions were grouped and counted by ICD 10 chapters and specific reasons for treatment at each site. Pooled aggregated data were centrally analyzed with descriptive statistics to compare absolute and relative differences between time periods of different years. The results illustrate how care process adoptions depended on the COVID-19 epidemiological situation and the criticality of the disease. Overall inpatient hospital admissions decreased by 35% in weeks 1 to 4 and by 30.3% in weeks 5 to 8 after the lockdown announcement compared to 2018. Even hospital admissions for critical care conditions such as malignant cancer treatments were reduced. We also noted a high reduction of emergency admissions such as myocardial infarction (38.7%), whereas the reduction in stroke admissions was smaller (19.6%). In contrast, we observed a considerable reduction in admissions for non-critical clinical situations, such as hysterectomies for benign tumors (78.8%) and hip replacements due to arthrosis (82.4%). In summary, our study shows that the university hospital admission rates in Germany were substantially reduced following the national COVID-19 lockdown. These included critical care or emergency conditions in which deferral is expected to impair clinical outcomes. Future studies are needed to delineate how appropriate medical care of critically ill patients can be maintained during a pandemic.

The ontology of biological taxa.

MOTIVATION: The classification of biological entities in terms of species and taxa is an important endeavor in biology. Although a large amount of statements encoded in current biomedical ontologies is taxon-dependent there is no obvious or standard way for introducing taxon information into an integrative ontology architecture, supposedly because of ongoing controversies about the ontological nature of species and taxa. RESULTS: In this article, we discuss different approaches on how to represent biological taxa using existing standards for biomedical ontologies such as the description logic OWL DL and the Open Biomedical Ontologies Relation Ontology. We demonstrate how hidden ambiguities of the species concept can be dealt with and existing controversies can be overcome. A novel approach is to envisage taxon information as qualities that inhere in biological organisms, organism parts and populations. AVAILABILITY: The presented methodology has been implemented in the domain top-level ontology BioTop, openly accessible at http://purl.org/biotop. BioTop may help to improve the logical and ontological rigor of biomedical ontologies and further provides a clear architectural principle to deal with biological taxa information.

Granularity issues in the alignment of upper ontologies.

OBJECTIVES: The application of upper ontologies has been repeatedly advocated for to support the interoperability between different domain ontologies for facilitating the shared use of data within and across disciplines. BioTop is an upper domain ontology that aims at aligning more specialized biomolecular and biomedical ontologies. The integration of BioTop and the upper ontology Basic Formal Ontology (BFO) is the objective of this study. METHODS: BFO was manually integrated into BioTop, observing both its free text and formal definitions. BioTop classes were attached to BFO classes as children and BFO classes were reused in the formal definitions of BioTop classes. A description logics reasoner was used to check the logical consistency of this integration. The domain adequacy was checked manually by domain experts. RESULTS: Logical inconsistencies were found by the reasoner when applying the BFO classes for fiat and aggregated objects in some of the BioTop class definitions. We discovered that the definition of those particular classes in BFO was dependent on the notion of physical connectedness. Hence we suggest ignoring a BFO subbranch in order not to hinder cross-granularity integration. CONCLUSION: Without introducing a more sophisticated theory of granularity, the described problems cannot be properly dealt with. Whereas we argue that an upper ontology should be granularity-independent, we illustrate how granularity-dependent domain ontologies can still be embedded into the framework of BioTop in combination with BFO.

Automatic mapping of clinical documentation to SNOMED CT.

Clinical documentation needs to be fine-grained to truthfully represent the history, development, and treatment of a patient. But natural language, as the main information carrier, is characterized by many issues, like idiosyncratic terminology, spelling and grammar errors, and a lack of grammatical structure. Therefore coding systems, like ICD-10, have been introduced, but their use varies highly among physicians, and they are often used incompletely or incorrectly. The almost exponential growth of clinical data is yet another problem. We present a new methodology to process this data: Through combining several natural language processing methods we extract morphemes from clinical texts and map them onto concepts from SNOMED CT. We first performed a manual analysis of clinical texts received from a university hospital and evaluated the issues found in them. Based on this we implemented a prototypical system which incorporates both the OpenNLP and the MorphoSaurus natural language processing systems.

How granularity issues concern biomedical ontology integration.

The application of upper ontologies has been repeatedly advocated for supporting interoperability between domain ontologies in order to facilitate shared data use both within and across disciplines. We have developed BioTop as a top-domain ontology to integrate more specialized ontologies in the biomolecular and biomedical domain. In this paper, we report on concrete integration problems of this ontology with the domain-independent Basic Formal Ontology (BFO) concerning the issue of fiat and aggregated objects in the context of different granularity levels. We conclude that the third BFO level must be ignored in order not to obviate cross-granularity integration.

Ten theses on clinical ontologies.

We present ten principles for clinical ontologies that describe the authors' opinion about what should be understood by the notion of clinical ontologies and what not. In contrast to clinical terminology systems, clinical ontologies are considered to be semantic reference systems and for that--first of all--strive to account for the properties of the domain entities themselves and their proper formal definitions--rather than just linking clinical terms together.

Towards a top-domain ontology for linking biomedical ontologies.

In this paper we present the ongoing development and extension work on BioTop--a top-domain ontology for linking biomedical domain ontologies. We start by making the case for the application of a common ontology to interface independent biomedical domain ontologies by introducing a set of more general classes. Then we briefly depict the relation of BioTop to the GENIA ontology as starting point of its initial developement. Afterwards we propose our distinction of ontologies into top, top-domain and domain ones and describe our approach to the integration of the top ontology BFO into BioTop. Then we present our plans to join the OBO and OBO Foundry repository of ontologies and list its admission principles in relation to our ontology. Some actual BioTop interface classes are shown subsequently. We conclude by detailing on some planned BioTop usages in the area of BioNLP and cancer research and show some further intended improvements.

Ensuring sustainability of software tools and services by cooperation with a research infrastructure.

Sustainability of project output and especially of the maintenance and further development of software is of growing concern for the research community. In the personalized medicine project p-medicine solutions that address this sustainability problem were developed and discussed in a workshop. They involve a number of interrelated and mutually supportive measures including the creation of a service center, building modular software, using common data standards, mutual service exchange with a research infrastructure, Open Source and fee-based software provision, joint promotion and deployment of tools in a regulated, clinical trial situation. These ideas join a nascent literature seeking to understand how project output can be put into a sustainable environment and to suggest solutions that may be useful for academic projects in general.

Usability on the p-medicine infrastructure: an extended usability concept.

Usability testing methods are nowadays integrated into the design and development of health-care software, and the need for usability in health-care information technology (IT) is widely accepted by clinicians and researchers. Usability assessment starts with the identification of specific objectives that need to be tested and continues with the definition of evaluation criteria and monitoring procedures before usability tests are performed to assess the quality of all services and tasks. Such a process is implemented in the p-medicine environment and gives feedback iteratively to all software developers in the project. GCP (good clinical practice) criteria require additional usability testing of the software. For the p-medicine project (www.p-medicine.eu), an extended usability concept (EUC) was developed. The EUC covers topics like ease of use, likeability, and usefulness, usability in trial centres characterised by a mixed care and research environment and by extreme time constraints, confidentiality, use of source documents, standard operating procedures (SOA), and quality control during data handling to ensure that all data are reliable and have been processed correctly in terms of accuracy, completeness, legibility, consistence, and timeliness. Here, we describe the p-medicine EUC, focusing on two of the many key tools: ObTiMA and the Ontology Annotator (OA).

Establishing a distributed system for the simple representation and integration of diverse scientific assertions.

BACKGROUND: Information technology has the potential to increase the pace of scientific progress by helping researchers in formulating, publishing and finding information. There are numerous projects that employ ontologies and Semantic Web technologies towards this goal. However, the number of applications that have found widespread use among biomedical researchers is still surprisingly small. In this paper we present the aTag ('associative tags') convention, which aims to drastically lower the entry barriers to the biomedical Semantic Web. aTags are short snippets of HTML+RDFa with embedded RDF/OWL based on the Semantically Interlinked Online Communities (SIOC) vocabulary and domain ontologies and taxonomies, such as the Open Biomedical Ontologies and DBpedia. The structure of aTags is very simple: a short piece of human-readable text that is 'tagged' with relevant ontological entities. This paper describes our efforts for seeding the creation of a viable ecosystem of datasets, tools and services around aTags. RESULTS: Numerous biomedical datasets in aTag format and systems for the creation of aTags have been set-up and are described in this paper. Prototypes of some of these systems are accessible at http://hcls.deri.org/atag CONCLUSIONS: The aTags convention enables the rapid development of diverse, integrated datasets and semantically interoperable applications. More work needs to be done to study the practicability of this approach in different use-case scenarios, and to encourage uptake of the convention by other groups.

The Pitfalls of Thesaurus Ontologization - the Case of the NCI Thesaurus.

Thesauri that are "ontologized" into OWL-DL semantics are highly amenable to modeling errors resulting from falsely interpreting existential restrictions. We investigated the OWL-DL representation of the NCI Thesaurus (NCIT) in order to assess the correctness of existential restrictions. A random sample of 354 axioms using the someValuesFrom operator was taken. According to a rating performed by two domain experts, roughly half of these examples, and in consequence more than 76,000 axioms in the OWL-DL version, make incorrect assertions if interpreted according to description logics semantics. These axioms therefore constitute a huge source for unintended models, rendering most logic-based reasoning unreliable. After identifying typical error patterns we discuss some possible improvements. Our recommendation is to either amend the problematic axioms in the OWL-DL formalization or to consider some less strict representational format.

Strengths and limitations of formal ontologies in the biomedical domain.

We propose a typology of representational artifacts for health care and life sciences domains and associate this typology with different kinds of formal ontology and logic, drawing conclusions as to the strengths and limitations for ontology of different kinds of logical resources, with a focus on description logics.The four types of domain representation we consider are: (i) lexico-semantic representation, (ii) representation of types of entities, (iii) representations of background knowledge, and (iv) representation of individuals.We advocate a clear distinction of the four kinds of representation in order to provide a more rational basis for using of ontologies and related artifacts to advance integration of data and interoperability of associated reasoning systems.We highlight the fact that only a minor portion of scientifically relevant facts in a domain such as biomedicine can be adequately represented by formal ontologies when the latter are conceived as representations of entity types. In particular, the attempt to encode default or probabilistic knowledge using ontologies so conceived is prone to produce unintended, erroneous models.

Detecting Underspecification in SNOMED CT concept definitions through natural language processing.

Quality assurance and audit issues play a major role in maintening large biomedical terminology, such as SNOMED CT. Several automatized techniques have been proposed to facilitate the identification of weak spots and suggest adequate improvements.In this study, we address a well-known issue within SNOMED CT: Albeit the wording of many free-text concept descriptions suggests a connection to other concepts, they are often not referred to in the logical concept definition.To detect such inconsistencies, we use a semantic indexing approach which maps free text onto a sequence of semantic identifiers. Applied to SNOMED CT concepts without attributes, our technique spots refinable concepts and suggests appropriate attributes, i.e., connections to other concepts. Based on a manual analysis of random samples, we estimate that approximately 18,000 refinable concepts can be found.