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Incidental findings from whole-body imaging in population-based studies potentially carry medical relevance and are, for the most part, experienced as unsolicited and unexpected. Given that these features are shared with secondary findings in genetic and genomic contexts, it is somewhat intuitive that the legal and ethical discourse on incidental findings from imaging would be highly relevant to comparable debates about the management of genomic findings that are not directly related to the primary focus of the research. In this chapter we explore issues raised by incidental findings in the context of imaging research that are also relevant to secondary findings in the context of genomics. These issues will be discussed separately, but in truth they tend to overlap with one another and are fundamentally connected. The purpose of this discussion is not only to explore how the debate on dealing with incidental findings from imaging informs the modern debate on secondary findings in genomics and genetics but also to set the stage for the rest of the book by laying out the practical and ethical challenges that need to be addressed in all types of biomedical research that generate additional findings of potential medical relevance and, therefore, of potential interest to participants.

Research and innovation in healthcare can change existing practices aiming at constant improvement of diagnosis, treatment and prevention. As a new holistic approach Systems Medicine (SM) may revolutionize the healthcare system. This paper analyzes ethical and economic obstacles of SMs development from a niche innovation to a standard solution. We adapt a model of innovation theory to structure the barriers of adopting SM to become standard in the medical system. SM has the potential to change the medical system if barriers to this innovation can be overcome. The article discusses the potential of SM in becoming the future health paradigm considering these barriers and provides an overview of the current situation.

Die Systemmedizin stellt unter den aktuellen biomedizinischen Forschungsansatzen einen der wichtigsten Treiber von E-Health dar. Das Spektrum der IT-Werkzeuge, -Technologien, -Methoden und -Strategien, die durch die Systemmedizin in spezifischer Weise gebundelt werden, reicht dabei von „Dauerposten“ der digitalen Agenda wie der elektronischen Patientenakte uber „Big Data“ bis hin zu verbesserten Risikovorhersagemodellen. Vor diesem Hintergrund prasentiert das Kapitel Ergebnisse aus Online-Fokusgruppen, die mit Experten zum Konzept und zur Translation der Systemmedizin durchgefuhrt wurden. Die Ergebnisse zeigen, dass eine Vielzahl von E-Health-Themen als relevant fur die Erfolgschancen der Systemmedizin eingestuft wird und viele Experten der Systemmedizin insbesondere einen Beitrag zur Entwicklung neuartiger Scores zutrauen. Hinsichtlich der normativ brisanten Fragen, ob a) solche neuen Scores zur echten Einzelfallpradiktion herangezogen werden konnen und sollten und ob b) in automatisch generierten Therapieempfehlungen auch Daten zur Cost-Performance-Relation eingehen durfen, besteht unter den Experten indes Dissens.

In the German National Cohort (GNC), 30,000 individuals are examined with whole-body MRI (wbMRI), of which about 3000 participants are expected to receive an incidental finding (IF) disclosure. In order to get feedback from participants and to evaluate the IF-management procedure of the wbMRI substudy, a follow-up questionnaire was developed. This single-center pilot trial was aimed to get a first impression on feasibility reproducibility and validity of such a survey in order to take necessary adjustments before initiating the survey among several thousand participants. The questionnaires were sent out in test–retest manner to 86 participants who received a wbMRI examination in January–February 2016 at the imaging center in Neubrandenburg. The ratio of participants with and without IF notification was 1:1. Descriptive statistics was performed. A first response of 94% and completion proportion of 99% were achieved. Participants were satisfied with the examination procedure. Ninety-five percent of participants considered it very important to receive notification of IFs. Participants reported minimal stress levels while waiting for a possible IF notification letter, but high stress levels when an IF letter was received. Phrasing of the IF reports was rated in 97% as well understandable and in 55% as beneficial to health status. This questionnaire will serve researchers within the GNC as a fundamental instrument not only for quality management analyses but also for the investigation of still unacknowledged scientific and ethical questions contributing to evidence-based guidelines concerning the complex approach to IFs in future population-based imaging. • Evidence-based guidelines for reporting incidental findings in population whole-body MRI are lacking. • Pilot-testing of a questionnaire for the evaluation of practical and ethical aspects of the procedure to report incidental findings in the German National Cohort shows a high level of acceptance and high return rate by participants. • Participants reported minimal stress levels while waiting for a possible incidental finding notification letter, which increased significantly, when such a letter was received.

Objectives: Based on an analysis of the potential consequences of disclosing AD suspicions from respective research and using the research ethical principle of non-maleficence, the authors of this paper argue for the thesis that the benefits of early AD detection in research outweigh the risk of potential adverse effects only in cases where studies are conducted with symptomatic people actively seeking for support, e.g. as they utilize the services of memory clinics. Conclusion: In the case of non-symptomatic volunteers, the result of the risk-benefit-assessment seems to be less distinctive. Given that disclosing results can, at least initially, cause severe distress and harm and taking into account that research examinations have a significantly increased risk of producing false-positive findings, we suggest to make use of a research-ethical “princple of caution” that supports a restrictive disclosure policy for the second group of potential study participants. This differentiated view on the benefits of disclosed findings in AD research is reflected in recommendations for the set-up of return of result processes.

Outpatient dementia healthcare is predominantly fragmented, and dementia networks (DNs) represent an integrated care concept to overcome this problem. Little is known about the patients of these networks with regard to utilisation of physicians and associated factors. We interviewed 560 caregivers of people with dementia in 13 different DNs in Germany in 2013 and assessed socio-demographics, clinical data and physician utilisation. Networks were categorised in predominantly medical DNs and community-oriented DNs. Descriptive and multivariate statistical models were used to identify associated factors between DNs and users' data. Overall, the users of networks received high rates of physician care; 93% of the sample stated at least one contact with a primary care physician within the last 6 months, and 74% had been treated by a specialist (neurology/psychiatry physician). Only 5% of the sample had no contact with a physician in the 6 months preceding the interview. Females showed a lower odds for physician specialist consultations (OR = 0.641). Users of medical DNs receive greater specialist consultations overall (OR = 8.370). Compared to the German general population and people with dementia in other settings, users of DNs receive physician care more regularly, especially with regard to the consultations of neurologist/psychiatrists. Therefore, DNs seem to perform a supportive role within the integration of physician healthcare. More research is needed on the appropriate relationship between the needs of the people with dementia and utilisation behaviour.

Der Aufsatz analysiert den Konnex zwischen Individualisierter Medizin und der Forderung nach mehr gesundheitlicher Eigenverantwortung, der oft als plausibel angenommen wird, wenn der Individualisierten Medizin das Potential zugesprochen wird, das solidarisch finanzierte Gesundheitssystem in Deutschland zu transformieren. Ausgehend von einer logischen Rekonstruktion des Verantwortungsbegriffs, die dessen Operationalisierbarkeit unter anderem an Sanktionsvollmachten der jeweiligen Verantwortungsinstanz bindet, und basierend auf einem terminologisch prazisierten Verstandnis von Individualisierter Medizin wird folgende These entwickelt: Die Annahme, im Rahmen Individualisierter Medizin sei eine verlassliche Pradiktion anlagebedingter und zugleich lebensstilabhangiger Erkrankungsrisiken moglich, verpflichtet logisch nicht zur Ubernahme der Forderung, Lebensstile mit negativem Einfluss auf personliche Erkrankungsrisiken seien zu sanktionieren. Weil die Forderung nach mehr gesundheitlicher Eigenverantwortung aus dem Programm der Individualisierten Medizin logisch nicht ohne Hinzunahme normativer Prinzipien abzuleiten ist, kann man dieses Programm selbst gut heisen, ohne sich die politische Forderung nach einem Umbau des solidarisch finanzierten Gesundheitssystems unter dem Vorzeichen gesundheitlicher Eigenverantwortung zu eigen machen zu mussen.

This article deals with ethical aspects of incidental/secondary resp. discovery findings (IFs) from imaging techniques that are generated in clinical care, medical research or the context of direct-to-consumer services. After the questions and challenges, typically raised by IFs are introduced, the second part focusses on ethical prerequisites and reflects principles that are capable of providing a normative foundation in dealing with IFs. The final part presents recommendations on the basis of these principles as a guideline to ensure responsible planning as well as to take suitable measures, to avoid (or at least mitigate) the hazards of IFs.

Little is known about the psychosocial impact and subjective interpretation of communicated incide ntal findings from whole-body magnetic resonance imaging (wb-MRI). This was addressed with this general population study. Data was based on the Study of Health in Pomerania (SHIP), Germany. SHIP comprised a 1.5-T wb-MRI examination. A postal survey was conducted among the first 471 participants, aged 23–84 years, who received a notification about incidental findings (response 86.0 %, n = 405). The severity of incidental findings was assessed from the participants’ and radiologists’ perspective. In total, 394 participants (97.3 %) wanted to learn about their health by undergoing wb-MRI. Strong distress while waiting for a potential notification of an incidental finding was reported by 40 participants (9.9 %), whereas 116 (28.6 %) reported moderate to severe psychological distress thereafter. Strong disagreement was noted between the subjective and radiological evaluation of the findings’ severity (kappa = 0.02). Almost all participants (n = 389, 96.0 %) were very satisfied with their examination. Despite the high satisfaction of most participants, there were numerous adverse consequences concerning the communication of incidental findings and false expectations about the likely potential benefits of whole-body-MRI. • Disclosed incidental findings from MRI may lead to substantial psychosocial distress. • Subjective and radiological evaluations of incidental findings’ severity differ strongly. • Disclosing incidental findings is strongly endorsed by study volunteers. • Study volunteers tend to have false expectations about potential benefits from MRI. • Minimizing stress in study volunteers should be a key aim in MRI research.

Research activities dealing with economic aspects of Individualized Medicine (IM) are part of many multidisciplinary IM-related projects in Germany. One important example is the Greifswald Approach to Individualized Medicine (GANI_MED). This paper presents basic principles of data protection and research ethics which are indispensable in order to guarantee that IM-related economic research which uses encoded, but reidentifiable data is in accordance with the regulatory framework and well established ethical standards in Germany. With respect to the patient-related economic research activities in GANI_MED the article also provides an example of a complete integration of an economic sub-project into the Informed Consent and Data Management Concept of a complex IM project. Last but not least the article provides initial data on the response of the GANI_MED patients to those modules of the GANI_MED consent form which enable the economic research group to receive patient-related data from health insurance companies and the “Kassenarztliche Vereinigung”. The response pattern confirms the hypothesis that patients who take part in an IM study do not automatically agree with the scientific usage of data dealing with the costs of their treatment.

In this article, two different scientific approaches to personalized medicine are compared. Biorepository at Vanderbilt University (BioVU) is a genomic biorepository at Vanderbilt University Medical Center in Nashville, TN, USA. Genetic biosamples are collected from leftover clinical blood samples; medical information is derived from an electronic medical records. Greifswald Approach to Individualized Medicine is a research resource at the University of Greifswald, Germany, comprised of clinical records combined with biosamples collected for research. We demonstrate that although both approaches are based on the collection of clinical data and biosamples, different legal milieus present in the USA and Germany as well as slight differences in scientific goals have led to different ‘ethical designs’. While BioVU can successfully operate with an ‘opt-out’ mechanism, an informed consent-based ‘opt-in’ model is indispensable to allow GANI_MED to reach its scientific goals.

Clinical epidemiological research is an important approach within Individualized Medicine. This research allows for the identification of possible biomarkers for specific diseases through the use of data from clinical treatments. From a research ethical point of view it needs to be noted that respective studies are mostly very complex. Therefore a variety of different normative requirements of both ethical and legal natures need to be met. On the one hand those studies aim for the scientific use of clinical records. On the other hand samples of biomaterial are to be collected, stored and analyzed using -omics methods. Sometimes there are also study examinations included in these studies which may produce incidental findings.

This chapter gives a summary of an empirical-ethical study which was carried out as a sub-project of GANI_MED-Greifswald. The aim of this sub-project was to investigate the reaction of participants, caused by incidental findings from a whole-body MRI in the context of SHIP, an epidemiological study conducted in Western Pomerania, Germany. As well as studying the potentially negative reactions of the participants after being informed of incidental findings, it was examined whether the participant’s subjective perception of health is influenced and whether this leads to a changed risk-benefit evaluation concerning the participation in a MRI within the medical research context. In order to investigate this, an analysis of the currently most important codices and relevant literature were taken into consideration to define the subject of discussion and regulation and thus, to define the subject of research in detail. Afterwards the study was carried out according to a mixed-methods design which showed firstly which kind of stress is indeed a result of participating in the MRI examination and which factors cause this. Furthermore, it was shown that the risk-benefit evaluation and thus, the willingness to participate, had not changed significantly after the whole-body MRI examination. However, this might be due to the fact that the research subjects often misjudged the conditions for participation by overestimating the benefits and underestimating the risks. The chapter ends with a short summary of the deductions which were drawn from this study in order to be implemented into the procedures of GANI_MED.

Background Individualized Medicine aims at providing optimal treatment for an individual patient at a given time based on his specific genetic and molecular characteristics. This requires excellent clinical stratification of patients as well as the availability of genomic data and biomarkers as prerequisites for the development of novel diagnostic tools and therapeutic strategies. The University Medicine Greifswald, Germany, has launched the “Greifswald Approach to Individualized Medicine” (GANI_MED) project to address major challenges of Individualized Medicine. Herein, we describe the implementation of the scientific and clinical infrastructure that allows future translation of findings relevant to Individualized Medicine into clinical practice. Methods/design Clinical patient cohorts (N > 5,000) with an emphasis on metabolic and cardiovascular diseases are being established following a standardized protocol for the assessment of medical history, laboratory biomarkers, and the collection of various biosamples for bio-banking purposes. A multi-omics based biomarker assessment including genome-wide genotyping, transcriptome, metabolome, and proteome analyses complements the multi-level approach of GANI_MED. Comparisons with the general background population as characterized by our Study of Health in Pomerania (SHIP) are performed. A central data management structure has been implemented to capture and integrate all relevant clinical data for research purposes. Ethical research projects on informed consent procedures, reporting of incidental findings, and economic evaluations were launched in parallel. peerReviewed

Incidental findings have long posed challenges for healthcare providers, but the scope and scale of these challenges have increased with the introduction of new technologies. This article assesses the impact of incidental findings on the introduction of prospective pharmacogenomic testing into clinical use. Focusing on the challenges of the incidentalome, the large set of incidental findings potentially generated through genotyping, the paper argues that provisional approaches to managing incidental findings may be implemented if necessary to allow benefits of pharmacogenomic testing to be realized in the clinical setting. In the longer term, approaches to returning incidental findings may need to focus on limiting the number of incidental findings to a number that can be addressed by patients and providers.

Background Systems medicine is the name for an assemblage of scientific strategies and practices that include bioinformatics approaches to human biology (especially systems biology); “big data” statistical analysis; and medical informatics tools. Whereas personalized and precision medicine involve similar analytical methods applied to genomic and medical record data, systems medicine draws on these as well as other sources of data. Given this distinction, the clinical translation of systems medicine poses a number of important ethical and epistemological challenges for researchers working to generate systems medicine knowledge and clinicians working to apply it. Discussion This article focuses on three key challenges: First, we will discuss the conflicts in decision-making that can arise when healthcare providers committed to principles of experimental medicine or evidence-based medicine encounter individualized recommendations derived from computer algorithms. We will explore in particular whether controlled experiments, such as comparative effectiveness trials, should mediate the translation of systems medicine, or if instead individualized findings generated through “big data” approaches can be applied directly in clinical decision-making. Second, we will examine the case of the Riyadh Intensive Care Program Mortality Prediction Algorithm, pejoratively referred to as the “death computer,” to demonstrate the ethical challenges that can arise when big-data-driven scoring systems are applied in clinical contexts. We argue that the uncritical use of predictive clinical algorithms, including those envisioned for systems medicine, challenge basic understandings of the doctor-patient relationship. Third, we will build on the recent discourse on secondary findings in genomics and imaging to draw attention to the important implications of secondary findings derived from the joint analysis of data from diverse sources, including data recorded by patients in an attempt to realize their “quantified self.” Summary This paper examines possible ethical challenges that are likely to be raised as systems medicine to be translated into clinical medicine. These include the epistemological challenges for clinical decision-making, the use of scoring systems optimized by big data techniques and the risk that incidental and secondary findings will significantly increase. While some ethical implications remain still hypothetical we should use the opportunity to prospectively identify challenges to avoid making foreseeable mistakes when systems medicine inevitably arrives in routine care.