[Nationally standardized broad consent in practice: initial experiences, current developments, and critical assessment]. / National standardisierter Broad Consent in der Praxis: erste Erfahrungen, aktuelle Entwicklungen und kritische Betrachtungen.

BACKGROUND: The digitalization in the healthcare sector promises a secondary use of patient data in the sense of a learning healthcare system. For this, the Medical Informatics Initiative's (MII) Consent Working Group has created an ethical and legal basis with standardized consent documents. This paper describes the systematically monitored introduction of these documents at the MII sites. METHODS: The monitoring of the introduction included regular online surveys, an in-depth analysis of the introduction processes at selected sites, and an assessment of the documents in use. In addition, inquiries and feedback from a large number of stakeholders were evaluated. RESULTS: The online surveys showed that 27 of the 32 sites have gradually introduced the consent documents productively, with a current total of 173,289 consents. The analysis of the implementation procedures revealed heterogeneous organizational conditions at the sites. The requirements of various stakeholders were met by developing and providing supplementary versions of the consent documents and additional information materials. DISCUSSION: The introduction of the MII consent documents at the university hospitals creates a uniform legal basis for the secondary use of patient data. However, the comprehensive implementation within the sites remains challenging. Therefore, minimum requirements for patient information and supplementary recommendations for best practice must be developed. The further development of the national legal framework for research will not render the participation and transparency mechanisms developed here obsolete.

[Foundations for the scientific use of extensive health care data in Germany-results of the Data Sharing working group of the Medical Informatics Initiative]. / Grundlagen für die wissenschaftliche Nutzung umfangreicher Versorgungsdaten in Deutschland ­ Ergebnisse der AG Data Sharing der Medizininformatik-Initiative.

Healthcare data are an important resource in applied medical research. They are available multicentrically. However, it remains a challenge to enable standardized data exchange processes between federal states and their individual laws and regulations. The Medical Informatics Initiative (MII) was founded in 2016 to implement processes that enable cross-clinic access to healthcare data in Germany. Several working groups (WGs) have been set up to coordinate standardized data structures (WG Interoperability), patient information and declarations of consent (WG Consent), and regulations on data exchange (WG Data Sharing). Here we present the most important results of the Data Sharing working group, which include agreed terms of use, legal regulations, and data access processes. They are already being implemented by the established Data Integration Centers (DIZ) and Use and Access Committees (UACs). We describe the services that are necessary to provide researchers with standardized data access. They are implemented with the Research Data Portal for Health, among others. Since the pilot phase, the processes of 385 active researchers have been used on this basis, which, as of April 2024, has resulted in 19 registered projects and 31 submitted research applications.

Data protection-compliant broad consent for secondary use of health care data and human biosamples for (bio)medical research: Towards a new German national standard.

BACKGROUND: The secondary use of deidentified but not anonymized patient data is a promising approach for enabling precision medicine and learning health care systems. In most national jurisdictions (e.g., in Europe), this type of secondary use requires patient consent. While various ethical, legal, and technical analyses have stressed the opportunities and challenges for different types of consent over the past decade, no country has yet established a national consent standard accepted by the relevant authorities. METHODS: A working group of the national Medical Informatics Initiative in Germany conducted a requirements analysis and developed a GDPR-compliant broad consent standard. The development included consensus procedures within the Medical Informatics Initiative, a documented consultation process with all relevant stakeholder groups and authorities, and the ultimate submission for approval via the national data protection authorities. RESULTS: This paper presents the broad consent text together with a guidance document on mandatory safeguards for broad consent implementation. The mandatory safeguards comprise i) independent review of individual research projects, ii) organizational measures to protect patients from involuntary disclosure of protected information, and iii) comprehensive information for patients and public transparency. This paper further describes the key issues discussed with the relevant authorities, especially the position on additional or alternative consent approaches such as dynamic consent. DISCUSSION: Both the resulting broad consent text and the national consensus process are relevant for similar activities internationally. A key challenge of aligning consent documents with the various stakeholders was explaining and justifying the decision to use broad consent and the decision against using alternative models such as dynamic consent. Public transparency for all secondary use projects and their results emerged as a key factor in this justification. While currently largely limited to academic medicine in Germany, the first steps for extending this broad consent approach to wider areas of application, including smaller institutions and medical practices, are currently under consideration.

ToolPool Gesundheitsforschung - A Repository for Software and Services Focused on Supporting Clinical and Epidemiological Research.

The academic research environment is characterized by self-developed, innovative, customized solutions, which are often free to use for third parties with open-source code and open licenses. On the other hand, they are maintained only to a very limited extent after the end of project funding. The ToolPool Gesundheitsforschung addresses the problem of finding ready to use solutions by building a registry of proven and supported tools, services, concepts and consulting offers. The goal is to provide an up-to-date selection of "relevant" solutions for a given domain that are immediately usable and that are actually used by third parties, rather than aiming at a complete list of all solutions which belong to that domain. Proof of relevance and usage must be provided, for example, by concrete application scenarios, experience reports by uninvolved third parties, references in publications or workshops held. Quality assurance is carried out for new entries by an agreed list of admission criteria, for existing entries at least once a year by a special task force. Currently, 79 solutions are represented, this number is to be significantly expanded by involving of new editors from current national funding initiatives in Germany.

[The way to routine data from 16 emergency departments for cross-sectoral health services research : Experiences, challenges and solution approaches from the extraction of pseudonymous data for the INDEED project]. / Der Weg zu Routinedaten aus 16 Notaufnahmen für die sektorenübergreifende Versorgungsforschung : Erfahrungen, Herausforderungen und Lösungsansätze aus der Extraktion pseudonymer Daten für das Projekt INDEED.

BACKGROUND: In Germany there is currently no health reporting on cross-sectoral care patterns in the context of an emergency department care treatment. The INDEED project (Utilization and trans-sectoral patterns of care for patients admitted to emergency departments in Germany) collects routine data from 16 emergency departments, which are later merged with outpatient billing data from 2014 to 2017 on an individual level. AIM: The methodological challenges in planning of the internal merging of routine clinical and administrative data from emergency departments in Germany up to the final data extraction are presented together with possible solution approaches. METHODS: Data were selected in an iterative process according to the research questions, medical relevance, and assumed data availability. After a preparatory phase to clarify formalities (including data protection, ethics), review test data and correct if necessary, the encrypted and pseudonymous data extraction was performed. RESULTS: Data from the 16 cooperating emergency departments came mostly from the emergency department and hospital information systems. There was considerable heterogeneity in the data. Not all variables were available in every emergency department because, for example, they were not standardized and digitally available or the extraction effort was judged to be too high. CONCLUSION: Relevant data from emergency departments are stored in different structures and in several IT systems. Thus, the creation of a harmonized data set requires considerable resources on the part of the hospital as well as the data processing unit. This needs to be generously calculated for future projects.

[Secondary Use of Electronic Medical Record Data from Primary Health Care is Feasible: Report from RADAR Project]. / Sekundäre Nutzung von hausärztlichen Routinedaten ist machbar ­ Bericht vom RADAR Projekt.

Objectives It is difficult to obtain longitudinal 'real world' data from ambulatory medical care in Germany in a systematic way. Our vision is a large German research data repository featuring representative, anonymized patient and outpatient health care data, longitudinal, continuously updated and across different providers, offering a perspective of linking secondary care data or additional data obtained from research cohorts, for example patient reported data or biodata, and will be accessible for other researchers. Here we report specific methods and results from the RADAR project.Methods Survey of legislation, design of technical processes and organisational solutions, with a feasibility study to evaluate technical and content functionality, acceptability and performance fitness for health services research questions.Results In 2016, a multi-disciplinary scientific team initiated the development of a privacy protection and IT security concept for data exported from the electronic medical records (EMR) of physicians' practices in line with the European General Data Protection Regulation. Technical and organisational requirements for lawful research infrastructure were developed and executed for use in a specific case, namely ̒oral anticoagulation'. In 7 Lower Saxonian general practices, 100 patients were selected by their physician and their data - reduced to 40 essential data fields - extracted from EMR via a mandatory software interface after informed consent. Still in the practice, the data were split into identifying or medical data. These were encrypted and transferred either to a trusted third party (TTP) or to a data repository, respectively. 75 patients who met our inclusion criteria (minimum of one year of oral anticoagulation treatment) received a quality-of-life questionnaire via the TTP. Of the 66 returns, 63 responses were then linked to the EMR data in the repository.Conclusion Results from RADAR project proved the technical and organisational feasibility of lawful, pseudonymised data acquisition and the linkage of questionnaires to EMR data. The protecting concepts privacy by design and data minimization (Art. 25 GDPR with Recital 78) were implemented. Without informed consent, secondary use of routine data from ambulatory care which are sufficiently anonymized but still meaningful is all but impossible under current German law.

The Process of Modeling Information System Architectures with IHE.

IHE has defined more than 200 integration profiles in order to improve the interoperability of application systems in healthcare. These profiles describe how standards should be used in particular use cases. These profiles are very helpful but their correct use is challenging, if the user is not familiar to the specifications. Therefore, inexperienced modelers of information systems quickly lose track of existing IHE profiles. In addition, the users of these profiles are often not aware of rules that are defined within these profiles and of dependencies that exist between the profiles. There are also modelers that do not notice the differences between the implemented actors, because they do not know the optional capabilities of some actors. The aim of this paper is therefore to describe a concept how modelers of information systems can be supported in the selection and use of IHE profiles and how this concept was prototypically implemented in the "Three-layer Graph-based meta model" modeling tool (3LGM2 Tool). The described modeling process consists of the following steps that can be looped: defining the use case, choosing suitable integration profiles, choosing actors and their options and assigning them to application systems, checking for required actor groupings and modeling transactions. Most of these steps were implemented in the 3LGM2 Tool. Further implementation effort and evaluation of our approach by inexperienced users is needed. But after that our tool should be a valuable tool for modelers planning healthcare information system architectures, in particular those based on IHE.

Designing and piloting a generic research architecture and workflows to unlock German primary care data for secondary use.

BACKGROUND: Medical data from family doctors are of great importance to health care researchers but seem to be locked in German practices and, thus, are underused in research. The RADAR project (Routine Anonymized Data for Advanced Health Services Research) aims at designing, implementing and piloting a generic research architecture, technical software solutions as well as procedures and workflows to unlock data from family doctor's practices. A long-term medical data repository for research taking legal requirements into account is established. Thereby, RADAR helps closing the gap between the European countries and to contribute data from primary care in Germany. METHODS: The RADAR project comprises three phases: (1) analysis phase, (2) design phase, and (3) pilot. First, interdisciplinary workshops were held to list prerequisites and requirements. Second, an architecture diagram with building blocks and functions, and an ordered list of process steps (workflow) for data capture and storage were designed. Third, technical components and workflows were piloted. The pilot was extended by a data integration workflow using patient-reported outcomes (paper-based questionnaires). RESULTS: The analysis phase resulted in listing 17 essential prerequisites and guiding requirements for data management compliant with the General Data Protection Regulation (GDPR). Based on this list existing approaches to fulfil the RADAR tasks were evaluated-for example, re-using BDT interface for data exchange and Trusted Third Party-approach for consent management and record linkage. Consented data sets of 100 patients were successfully exported, separated into person-identifying and medical data, pseudonymised and saved. Record linkage and data integration workflows for patient-reported outcomes in the RADAR research database were successfully piloted for 63 responders. CONCLUSION: The RADAR project successfully developed a generic architecture together with a technical framework of tools, interfaces, and workflows for a complete infrastructure for practicable and secure processing of patient data from family doctors. All technical components and workflows can be reused for further research projects. Additionally, a Trusted Third Party-approach can be used as core element to implement data privacy protection in such heterogeneous family doctor's settings. Optimisations identified comprise a fully-electronic consent recording using tablet computers, which is part of the project's extension phase.

Good Practice Data Linkage (GPD): A Translation of the German Version.

The data linkage of different data sources for research purposes is being increasingly used in recent years. However, generally accepted methodological guidance is missing. The aim of this article is to provide methodological guidelines and recommendations for research projects that have been consented to across different German research societies. Another aim is to endow readers with a checklist for the critical appraisal of research proposals and articles. This Good Practice Data Linkage (GPD) was already published in German in 2019, but the aspects mentioned can easily be transferred to an international context, especially for other European Union (EU) member states. Therefore, it is now also published in English. Since 2016, an expert panel of members of different German scientific societies have worked together and developed seven guidelines with a total of 27 practical recommendations. These recommendations include (1) the research objectives, research questions, data sources, and resources; (2) the data infrastructure and data flow; (3) data protection; (4) ethics; (5) the key variables and linkage methods; (6) data validation/quality assurance; and (7) the long-term use of data for questions still to be determined. The authors provide a rationale for each recommendation. Future revisions will include new developments in science and updates of data privacy regulations.

Process Coverage and Use Case Support of Health Registry Software in Germany.

Registries usually operate an IT-infrastructure supporting at least data management as one of the business processes. Several activities in Germany between 2007 and 2018 surveyed the market of respective software products. Combining a survey with representatives of software products with a workshop protocol of software demonstrations, a detailed insight into the market of IT-components arose. A comparison between 2015 and 2018 revealed little progress. The focus is still electronic data capture functionality. With the presented activities, rich material is available to assist registry developers in the planning of their IT-infrastructure and the selection of software products.

[Good Practice Data Linkage]. / Gute Praxis Datenlinkage (GPD).

Individual data linkage of different data sources for research purposes is being increasingly used in Germany in recent years. However, generally accepted methodological guidance is missing. The aim of this article is to define such methodological standards for research projects. Another aim is to provide readers with a checklist for critical appraisal of research proposals and articles. Since 2016, an expert panel of members of different German scientific societies have worked together and developed 7 guidelines with a total of 27 practical recommendations. These recommendations include (1) research aims, questions, data sources and resources, (2) infrastructure and data flow, (3) data privacy, (4) ethics, (5) key variables and type of linkage, (6) data validation/quality assurance and (7) long-term use for future research questions. The authors provide a rationale for each recommendation. Future revisions will include any new developments in science and data privacy.

[Health and primary care surveillance among asylum seekers in reception centres in Germany: concept, development, and implementation]. / Surveillance der Gesundheit und primärmedizinischen Versorgung von Asylsuchenden in Aufnahmeeinrichtungen: Konzept, Entwicklung und Implementierung.

BACKGROUND: Reliable data on health and primary care among asylum seekers in reception centres are not routinely available, but required to plan needs-based healthcare services. OBJECTIVES: To present the concept, development, and implementation of a routine surveillance system in reception centres for asylum seekers. METHODS: In the scope of the project PRICARE, medical records in reception centres were standardized and digitized, and continuous surveillance was enabled by means of suitable IT infrastructure. The core elements of the surveillance system were developed in three project phases using an iterative and participative design. FUNDING: Federal Ministry of Health (Grant no. 2516FSB415). RESULTS: Forming the basis for the surveillance, the electronic health record Refugee Care Manager® (RefCare®) was developed and gradually implemented in 13 reception centres in three federal states. For implementing the tool in daily care routines, IT infrastructure was implemented in all sites and a legally required data protection concept was established. An indicator set was developed and agreed upon for the surveillance, comprising a total of 64 indicators in four domains: morbidity, processes of care, quality of care, and syndromic alerts. CONCLUSIONS: For the first time in Germany, a harmonized infrastructure spanning federal states was implemented in healthcare settings ensuring medical documentation and surveillance of health and healthcare of asylum seekers in conformity with data protection requirements. The surveillance is feasible; the long-term benefits of routine surveillance and research within the network will be assessed in the future.

Towards a Software Tool for Planning IHE-Compliant Information Systems.

As hospital information systems are complex and the requirements for interoperability grow with the increasing networking in healthcare, careful planning becomes more and more necessary. The use of standards as described in IHE profiles, for example, are an important prerequisite for enabling interoperability. Enterprise Architecture Planning (EAP) methods should support this, but none of the currently available EAP methods offers the option of using IHE profiles. The 3LGM2IHE project wants to close this gap and implement the support of IHE profiles in the 3LGM2 tool. This paper describes how requirements for this tool were determined and presents the results.

[The risk of re-identification when analyzing electronic health records: a critical appraisal and possible solutions]. / Das Risiko von Re-Identifizierung bei der Auswertung medizinischer Routinedaten ­ Kritische Bewertung und Lösungsansätze.

BACKGROUND AND OBJECTIVES: The use of primary care data gathered from electronic health records in local practices could be an important building block for the future of health services research. However, the risks and reservations associated with using this data for research purposes should not be underestimated. We show the data protection and privacy problems that may arise through secondary analysis of routine primary care data and describe the technical solutions that are available to address these concerns - as a trust-building measure. METHODS: We screened 40 variables that are deemed important for documentation in the electronic health records of primary care physicians and rated the risk of patient re-identification when using these records from routine medical data for research purposes. The criteria used to rate the risk of re-identification were "expert perception" (inferences of a professional observer of phenotypical characteristics which are documented in the 40 variables), "researchable additional knowledge" (knowledge of characteristics of a person through publicly available information and social media networks), and "statistic frequency" according to diagnosis and medication statistics. RESULTS: Diagnoses and reasons for contacting a general practitioner can contain particularly identifiable characteristics such as "obesity" (ICD-10 E66) and "nicotine dependence" (F17). About half of all ICD codes documented in primary care fall below a critical threshold value in their absolute frequency; this is all the more problematic if diagnoses allow for re-identification due to phenotypical characteristics. Medication information holds little potential risk of re-identification of a person. However, the application of medications could be a source of re-identification, e. g., self-injections of insulin or use of inhalators. Information about times and dates are especially sensitive for the re-identification of a person. Sex and age of a patient generally pose no problems, except in the case of very young or very old individuals when these age groups are seldom represented in the practice. DISCUSSION: Routine health data are, in principle, sensitive data. Knowledge about the variables in primary care data gathered from electronic health records in local practices and the evaluation of this data allow us to more accurately estimate the risk of re-identification for the persons concerned. In particular, chronic diagnoses and/or diagnoses in long text, calendar dates for patient contacts and therapies bear a high risk of re-identification. Technical measures such as removing data, masking values and coding should make re-identification considerably more difficult. There will always be a remaining risk of re-identification which should be openly discussed to counteract concerns about a lack of data protection or a sweeping critique of digitization in healthcare.

Foundations of a metadata repository for databases of registers and trials.

The planning of case report forms (CRFs) in clinical trials or databases in registers is mostly an informal process starting from scratch involving domain experts, biometricians, and documentation specialists. The Telematikplattform für Medizinische Forschungsnetze, an umbrella organization for medical research in Germany, aims at supporting and improving this process with a metadata repository, covering the variables and value lists used in databases of registers and trials. The use cases for the metadata repository range from a specification of case report forms to the harmonization of variable collections, variables, and value lists through a formal review. The warehouse used for the storage of the metadata should at least fulfill the definition of part 3 "Registry metamodel and basic attributes" of ISO/IEC 11179 Information technology - Metadata registries. An implementation of the metadata repository should offer an import and export of metadata in the Operational Data Model standard of the Clinical Data Interchange Standards Consortium. It will facilitate the creation of CRFs and data models, improve the quality of CRFs and data models, support the harmonization of variables and value lists, and support the mapping of metadata and data.

The role of the human cerebellum in short- and long-term habituation of postural responses.

The aim of the present study was to investigate the role of the human cerebellum in short-term (STH) and long-term habituation (LTH) of postural responses to repeated platform perturbations. Ten cerebellar patients and ten age- and sex-matched healthy controls participated. Twenty backward platform translations were applied on each of 5 consecutive days. Changes of postural response size within each day were assessed to determine STH and changes across days to determine LTH. Both controls and cerebellar patients showed a significant reduction of postural response size within each day (i.e. STH). No significant reduction of postural response size was observed across days (i.e. no LTH). Both controls and cerebellar patients, however, showed a tendency of response size to increase across days suggesting long-term sensitization. The amount of changes within and across days did not significantly differ between groups. The present findings suggest that changes of postural response size to repeated perturbations do not depend upon the integrity of the cerebellum.

Cerebellar representation of the eyeblink response as revealed by PET.

Blink reflex-related areas in the human cerebellum were studied using [15O]H2O PET in eight healthy subjects. Eyeblinks were evoked by airpuff stimulation and recorded via surface electrodes. PET analysis revealed a cerebellar increase of regional cerebral blood flow in vermal lobule VI and a small ipsilateral paravermal extension in the eyeblink condition compared to rest. This activation partly overlapped with areas found in recent fMRI and animal studies investigating the cerebellar involvement in control of the unconditioned and acquisition of the conditioned eyeblink response. In conclusion, vermal lobule VI extending to ipsilateral paravermal areas appears to be involved in control of the unconditioned eyeblink response.

Limb flexion reflex-related areas in human cerebellum.

Numerous studies have shown that the cerebellum is involved in classical conditioning of specific aversive reactions. Only few studies, however, have examined the exact localization of cerebellar areas involved in the control of unconditioned reflex responses. The present study investigated cerebellar areas, which are activated during eliciting of the limb flexion reflex in healthy controls using [15O]H2O PET. Limb flexion reflex related areas were found in vermal lobules III-VI with the local maximum in vermal lobule V. Areas of activation were more widespread compared to a voluntary foot movement and a sensory foot stimulation condition. Limb flexion reflex areas probably reflect efferent reflex modulation as well as sensory inputs from the stimulus itself and/or the reflex response.

Differences in trace and delay visuomotor associative learning in cerebellar patients.

Recent studies revealed an impairment of patients with cerebellar lesions in cognitive associative learning paradigms, which could not be explained by motor deficits or increased attentional demands during performance of the motor part of the particular task. To further test the role of the cerebellum in cognitive associative learning a visuomotor associative learning paradigm was conducted, which showed some similarities to reflex conditioning. Subjects had to learn the association between a visual stimulus (i.e., a colored square) and a correct motor response (i.e., pressing a left or right target button on a specialized keyboard) in a stimulus-response paradigm. The correct side of the response was always indicated by a growing circle. The stimuli were presented in two forms: (1) the colored square ("conditioned stimulus", "CS") preceded the growing circle ("unconditioned stimulus", "US") and coterminated with the "US" (delay-condition) or (2) the offset of the colored square was separated from the onset of the circle by a short time interval (trace-condition). Eight patients with degenerative cerebellar disorders and eight age-, sex-, IQ-, and education level-matched controls participated. Both control subjects and cerebellar patients showed significant effects of learning based on reduction of decision times during performance of the task. The explicit knowledge of the correct motor response associated with each of the presented colors, however, was significantly better in control subjects. Furthermore, within-group comparisons revealed that control subjects performed significantly better in the trace-condition compared to the delay-condition, whereas no significant difference was obtained in the cerebellar group. Part of the findings in controls was explained by an age-related decline in the delay-condition. In addition, elderly control subjects appeared to benefit from cue-effects and timing-effects (i.e., fixed trace interval) in the trace-condition resulting in reduced decision times. Neither cue- nor timing-related effects fully accounted for differences between cerebellar patients and controls. The lack of a better performance in the trace-condition compared to the delay-condition in cerebellar patients suggests deficits in learning the stimulus-response association.

Effect of functional NMDA-antagonist flupirtine on automatic postural responses in Parkinson's disease.

Animal studies have demonstrated potent antiparkinsonian and other motor effects of the functional NMDA-antagonist flupirtine and suggest a therapeutic use in Parkinson's disease (PD). In healthy subjects flupirtine decreases the functionally destabilizing medium latency (ML) response following toe-up rotations of a moving platform. Because ML responses are known to be increased in PD, this study examined s the effects of flupirtine on postural responses in patients with PD. During 22 days 21 patients with PD took 50 mg, 100 mg flupirtine or placebo following a randomized, double-blind design. Clinical impairment was assessed by means of the Unified Parkinson's Disease Rating Scale (UPDRS). No significant difference between the effect of flupirtine and placebo on ML responses was observed. There was an unspecific improvement of overall UPDRS scores in placebo and flupirtine conditions compared with baseline measures which was more marked in the placebo condition. No improvement in the UPDRS motor subscale was observed. As no beneficial effect on the clinical presentation and no effect on postural responses could be demonstrated, flupirtine does not seem to be a therapeutic option in PD.