The RD-Connect Genome-Phenome Analysis Platform: Accelerating diagnosis, research, and gene discovery for rare diseases.

Rare disease patients are more likely to receive a rapid molecular diagnosis nowadays thanks to the wide adoption of next-generation sequencing. However, many cases remain undiagnosed even after exome or genome analysis, because the methods used missed the molecular cause in a known gene, or a novel causative gene could not be identified and/or confirmed. To address these challenges, the RD-Connect Genome-Phenome Analysis Platform (GPAP) facilitates the collation, discovery, sharing, and analysis of standardized genome-phenome data within a collaborative environment. Authorized clinicians and researchers submit pseudonymised phenotypic profiles encoded using the Human Phenotype Ontology, and raw genomic data which is processed through a standardized pipeline. After an optional embargo period, the data are shared with other platform users, with the objective that similar cases in the system and queries from peers may help diagnose the case. Additionally, the platform enables bidirectional discovery of similar cases in other databases from the Matchmaker Exchange network. To facilitate genome-phenome analysis and interpretation by clinical researchers, the RD-Connect GPAP provides a powerful user-friendly interface and leverages tens of information sources. As a result, the resource has already helped diagnose hundreds of rare disease patients and discover new disease causing genes.

Does being exposed to an educational tool influence patient preferences? The influence of an educational tool on patient preferences assessed by a discrete choice experiment.

OBJECTIVES: There is an increased interest in patient preferences informing the development and authorisation of medical products. A requirement for robust and meaningful results of such studies is that patients adequately understand the risks and benefits associated with treatments for which their preferences are elicited. This study aims to determine the influence of an educational tool, compared with traditional written information on patient preferences elicited in a discrete choice experiment (DCE). METHODS: Treatment preferences of Swedish patients with rheumatoid arthritis (RA) were assessed using a DCE. Patients were recruited via clinics, a research panel, and the Swedish Rheumatism Association. Respondents received training materials either as plain written text or as an online educational tool. The educational tool was designed to enhance understanding of the written text by using graphics, pictograms, icon arrays, spoken text, and click-on functions. Data were analysed using random parameter logit models. RESULTS: 675 patients with RA were included in the analysis. The patients received either a written information (n = 358) or information via an educational tool (n = 317). Respondents receiving the educational tool placed relatively more importance on all included side effects in their decision making, compared to respondents receiving the written text, who placed greater importance on treatment effectiveness and administration methods. CONCLUSION: Compared to the respondents receiving the written text, the decisions of respondents receiving the educational tool were more influenced by medication side effects. Further research is needed to provide guidance on how and when to use educational tools to inform and elicit patients' preferences. PRACTICE IMPLICATIONS: The ways in which attributes are presented to patients significantly impacts preferences measured in a DCE.

The case for open science: rare diseases.

The premise of Open Science is that research and medical management will progress faster if data and knowledge are openly shared. The value of Open Science is nowhere more important and appreciated than in the rare disease (RD) community. Research into RDs has been limited by insufficient patient data and resources, a paucity of trained disease experts, and lack of therapeutics, leading to long delays in diagnosis and treatment. These issues can be ameliorated by following the principles and practices of sharing that are intrinsic to Open Science. Here, we describe how the RD community has adopted the core pillars of Open Science, adding new initiatives to promote care and research for RD patients and, ultimately, for all of medicine. We also present recommendations that can advance Open Science more globally.

Short-term mental distress in research participants after receiving cardiovascular risk information.

BACKGROUND: Understanding of how cardiovascular risk information influence individuals is critical for the practice of risk assessment and the management of patients with cardiovascular disease. OBJECTIVES: The objective of this study was to investigate change in mental distress among research participants after undergoing a cardiovascular risk assessment and receiving individual test results. METHODS: In 2017, a questionnaire measuring mental distress after taking part in a risk assessment was distributed among 615 participants in the Swedish Cardiopulmonary Bio Image Study in Uppsala, Sweden, aged 50-64 years. Outcome measures were re-assessed after three months (30% were lost to follow-up). RESULTS: There were no differences in outcomes after three months for participants with normal test results or for participants who were referred to primary health care. Mental distress increased in participants who were referred to the hospital, and were further explained by the fact that these participants were diagnosed with coronary artery stenosis. CONCLUSIONS: CV risk information can be provided to individuals with lower levels of risk without concerns of inducing mental distress. However, in order to prevent unnecessary worry in contexts similar to this study, one should be prepared for different risk outcomes and plan for support for individuals with higher risk. The increased utility of powerful, yet not fully mature, imaging techniques requires careful considerations extending beyond medical risks and benefits; the clinician must also take into account the risk of mental distress and secure support when necessary.

Values and value conflicts in implementation and use of preconception expanded carrier screening - an expert interview study.

BACKGROUND: Endeavors have been made to found and incorporate ethical values in most aspects of healthcare, including health technology assessment. Health technologies and their assessment are value-laden and could trigger problems with dissemination if they contradict societal norms. Per WHO definition, preconception expanded carrier screening is a new health technology that warrants assessment. It is a genetic test offered to couples who have no known risk of recessive genetic diseases and are interested pregnancy. A test may screen for carrier status of several autosomal recessive diseases and X-linked at one go. The technique has been piloted in the Netherlands and is discussed in other countries. The aim of the study was to examine values and value conflicts that healthcare experts recounted in relation to the discussion of implementation and use of preconception ECS in Sweden. METHODS: We interviewed ten experts, who were associated with influencing health policymaking in Sweden. We employed systematizing expert interviews, which endeavor to access experts' specialist knowledge. There were four female and six male informants, of which four were physicians, three bioethicists, one a legal expert, one a theologian and one a political party representative in the parliament. The participants functioned as members of two non-governmental bodies and three governmental organizations. We employed thematic analysis to identify themes, categories and subcategories. RESULTS: Two main themes surfaced: values and value conflicts. The main categories of Respect for persons, Solidarity, Human dignity, Do no harm, Health and Love formed the first theme, while values conflicting with autonomy and integrity respectively, constituted the second theme. Concepts relating to respect for persons were the most commonly mentioned among the participants, followed by notions alluding to solidarity. Furthermore, respondents discussed values conflicting with Swedish healthcare ones such as equality and solidarity. CONCLUSIONS: The experts highlighted values and concepts that are distinctive of welfare states such as Sweden and delineated how preconception ECS could challenge such values. Moreover, the analysis revealed that certain values were deemed more substantive than others, judging by the extent and detail of inference; for example, respect for persons and solidarity were on top of the list.

Research participants' preferences for receiving genetic risk information: a discrete choice experiment.

PURPOSE: This study aims to determine research participants' preferences for receiving genetic risk information when participating in a scientific study that uses genome sequencing. METHODS: A discrete choice experiment questionnaire was sent to 650 research participants (response rate 60.5%). Four attributes were selected for the questionnaire: type of disease, disease penetrance probability, preventive opportunity, and effectiveness of the preventive measure. Panel mixed logit models were used to determine attribute level estimates and the heterogeneity in preferences. Relative importance of the attribute and the predicted uptake for different information scenarios were calculated from the estimates. In addition, this study estimates predicted uptake for receiving genetic risk information in different scenarios. RESULTS: All characteristics influenced research participants' willingness to receive genetic risk information. The most important characteristic was the effectiveness of the preventive opportunity. Predicted uptake ranged between 28% and 98% depending on what preventive opportunities and levels of effectiveness were presented. CONCLUSION: Information about an effective preventive measure was most important for participants. They valued that attribute twice as much as the other attributes. Therefore, when there is an effective preventive measure, risk communication can be less concerned with the magnitude of the probability of developing disease.

Patient Perspectives on the Value of Patient Preference Information in Regulatory Decision Making: A Qualitative Study in Swedish Patients with Rheumatoid Arthritis.

BACKGROUND: There is increasing interest in involving patient preferences for benefits and risks in regulatory decision making. Therefore, it is essential to identify patient perspectives regarding the value of patient preference information (PPI). OBJECTIVES: The aim of this study was to explore how patients with rheumatoid arthritis (RA) value the use of PPI in regulatory decision making regarding medical products. METHODS: Regulators and patients with RA were interviewed to gather initial insights into opinions on the use of PPI in regulatory decisions regarding medical products. The interviews were used to draft and validate the interview guide for focus groups with patients with RA. Participants were purposively sampled in collaboration with the Swedish Rheumatism Association in Stockholm and Uppsala. Each focus group consisted of three to six patients (18 in total). All interviews were audio-recorded, transcribed verbatim, and analysed using content analysis. RESULTS: According to the participants, PPI could lead to regulators considering patients' needs, lifestyles and well-being when making decisions. PPI was important in all stages of the medical product lifecycle. Participants reported that, when participating in a preference study, it is important to be well-informed about the use of the study and the development, components, administration, and risks related to the medical products. CONCLUSIONS: Patients thought PPI could be valuable to consider in regulatory decisions. It is essential for patients to be well-informed when asked for their preferences. Research on information materials to inform patients in preference studies is needed to increase the value of PPI in regulatory decision making.

"A perfect society"- Swedish policymakers' ethical and social views on preconception expanded carrier screening.

To improve healthcare policymaking, commentators have recommended the use of evidence, health technology assessment, priority setting, and public engagement in the process of policymaking. Preconception expanded carrier screening, according to the World Health Organization's definition, is a novel health technology and therefore warrants assessment, part of which involves evaluating ethical and social implications. We examined ten Swedish policymakers' perspectives on ethical and social aspects of preconception expanded screening through in-depth expert interviewing, using a semi-structured questionnaire. Respondents were affiliated to governmental and non-governmental institutions that directly influence healthcare policymaking in Sweden. The interviews were recorded, transcribed verbatim, and analyzed via inductive thematic analysis method, which generated seven themes and several subthemes. Policymakers harbored concerns regarding the economics, Swedish and international political respects, implementation procedures, and societal effects, which included long-term ones. Moreover, participants detailed the role of public engagement, research, and responsibility in regard to preconception expanded carrier screening implementation. Since this is a qualitative study, with a small non-random sample, the results may not be generalizable to all policymakers in Sweden. However, the results give a profound insight into the process and interpretative knowledge of experts, in the Swedish milieu and the extent of readiness of Sweden to implement a preconception expanded carrier screening program.

From Epigenetic Associations to Biological and Psychosocial Explanations in Mental Health.

The development of mental disorders constitutes a complex phenomenon driven by unique social, psychological and biological factors such as genetics and epigenetics, throughout an individual's life course. Both environmental and genetic factors have an impact on mental health phenotypes and act simultaneously to induce changes in brain and behavior. Here, we describe and critically evaluate the current literature on gene-environment interactions and epigenetics on mental health by highlighting recent human and animal studies. We furthermore review some of the main ethical and social implications concerning gene-environment interactions and epigenetics and provide explanations and suggestions on how to move from statistical and epigenetic associations to biological and psychological explanations within a multi-disciplinary and integrative approach of understanding mental health.

Making sense of genetic risk: A qualitative focus-group study of healthy participants in genomic research.

OBJECTIVE: It is well known that research participants want to receive genetic risk information that is about high risks, serious diseases and potential preventive measures. The aim of this study was to explore, by qualitative means, something less well known: how do healthy research participants themselves make sense of genetic risk information? METHOD: A phenomenographic approach was chosen to explore research participants' understanding and assessment of genetic risk. We conducted four focus-group (N=16) interviews with participants in a research programme designed to identify biomarkers for cardiopulmonary disease. RESULTS: Among the research participants, we found four ways of understanding genetic risk: as a binary concept, as an explanation, as revealing who I am (knowledge of oneself) and as affecting life ahead. CONCLUSION: Research participants tend to understand genetic risk as a binary concept. This does not necessarily imply a misunderstanding of, or an irrational approach to, genetic risk. Rather, it may have a heuristic function in decision-making. PRACTICAL IMPLICATIONS: Risk communication may be enhanced by tailoring the communication to the participants' own lay conceptions. For example, researchers and counselors should address risk in binary terms, maybe looking out for how individual participants search for threshold figures.

Let the Individuals Directly Concerned Decide: A Solution to Tragic Choices in Genetic Risk Information.

Health-care systems as well as legislators and society seem largely unprepared to face and manage the massive production of genetic risk information. Ethics committees and professional bodies usually do not involve the individuals directly concerned in defining guidelines for genetic risk communication. Therefore, they do not always reflect people's needs and preferences. We argue in this article that we currently experience a cultural shift in medicine where individuals' concerns and preferences regarding genetic risk information are playing a more significant role than before, and that this should have some normative implications. We are going toward a situation where individual citizens are approached as consumers by personal genomics companies [Prainsack: Account Res 2011;18:132-147]. In clinical and research contexts, individuals are also increasingly informed about their own responsibilities for counterbalancing their genetic risk by making individual health care and lifestyle choices. In this situation, communication of genetic risk information may rather be regulated like traffic and markets in which consumers' decision-making power has a fundamental role in the management and regulation of how a service should be provided, as well as in the creation of policy and legislation. We acknowledge that markets may be different depending on different genetic conditions. For example, genetic risk communication for rare diseases, where a close relationship with clinicians is of paramount significance, should be differently regulated than personal genetic profiles of complex diseases, where contributing risk factors related to lifestyle are modifiable by the individual.

The risk of re-identification versus the need to identify individuals in rare disease research.

There is a growing concern in the ethics literature and among policy makers that de-identification or coding of personal data and biospecimens is not sufficient for protecting research subjects from privacy invasions and possible breaches of confidentiality due to the possibility of unauthorized re-identification. At the same time, there is a need in medical science to be able to identify individual patients. In particular for rare disease research there is a special and well-documented need for research collaboration so that data and biosamples from multiple independent studies can be shared across borders. In this article, we identify the needs and arguments related to de-identification and re-identification of patients and research subjects and suggest how the different needs may be balanced within a framework of using unique encrypted identifiers.

Ethics rounds: An appreciated form of ethics support.

BACKGROUND: Ethics rounds are one way to support healthcare personnel in handling ethically difficult situations. A previous study in the present project showed that ethics rounds did not result in significant changes in perceptions of how ethical issues were handled, that is, in the ethical climate. However, there was anecdotal evidence that the ethics rounds were viewed as a positive experience and that they stimulated ethical reflection. AIM: The aim of this study was to gain a deeper understanding of how the ethics rounds were experienced and why the intervention in the form of ethics rounds did not succeed in improving the ethical climate for the staff. RESEARCH DESIGN: An exploratory and descriptive design with a qualitative approach was adopted, using individual interviews. PARTICIPANTS AND RESEARCH CONTEXT: A total of 11 healthcare personnel, working in two different psychiatry outpatient clinics and with experience of participating in ethics rounds, were interviewed. ETHICAL CONSIDERATIONS: The study was based on informed consent and was approved by one of the Swedish Regional Ethical Review Boards. FINDINGS: The participants were generally positive about the ethics rounds. They had experienced changes by participating in the ethics rounds in the form of being able to see things from different perspectives as well as by gaining insight into ethical issues. However, these changes had not affected daily work. DISCUSSION: A crucial question is whether or not increased reflection ability among the participants is a good enough outcome of ethics rounds and whether this result could have been measured in patient-related outcomes. Ethics rounds might foster cooperation among the staff and this, in turn, could influence patient care. CONCLUSION: By listening to others during ethics rounds, a person can learn to see things from a new angle. Participation in ethics rounds can also lead to better insight concerning ethical issues.

Freedom of Choice About Incidental Findings Can Frustrate Participants' True Preferences.

Ethicists, regulators and researchers have struggled with the question of whether incidental findings in genomics studies should be disclosed to participants. In the ethical debate, a general consensus is that disclosed information should benefit participants. However, there is no agreement that genetic information will benefit participants, rather it may cause problems such as anxiety. One could get past this disagreement about disclosure of incidental findings by letting participants express their preferences in the consent form. We argue that this freedom of choice is problematic. In transferring the decision to participants, it is assumed that participants will understand what they decide about and that they will express what they truly want. However, psychological findings about people's reaction to probabilities and risk have been shown to involve both cognitive and emotional challenges. People change their attitude to risk depending on what is at stake. Their mood affects judgments and choices, and they over- and underestimate probabilities depending on whether they are low or high. Moreover, different framing of the options can steer people to a specific choice. Although it seems attractive to let participants express their preferences to incidental findings in the consent form, it is uncertain if this choice enables people to express what they truly prefer. In order to better understand the participants' preferences, we argue that future empirical work needs to confront the participant with the complexity of the uncertainty and the trade-offs that are connected with the uncertain predictive value of genetic risk information.

Broad Consent for Research With Biological Samples: Workshop Conclusions.

Different types of consent are used to obtain human biospecimens for future research. This variation has resulted in confusion regarding what research is permitted, inadvertent constraints on future research, and research proceeding without consent. The National Institutes of Health (NIH) Clinical Center's Department of Bioethics held a workshop to consider the ethical acceptability of addressing these concerns by using broad consent for future research on stored biospecimens. Multiple bioethics scholars, who have written on these issues, discussed the reasons for consent, the range of consent strategies, and gaps in our understanding, and concluded with a proposal for broad initial consent coupled with oversight and, when feasible, ongoing provision of information to donors. This article describes areas of agreement and areas that need more research and dialogue. Given recent proposed changes to the Common Rule, and new guidance regarding storing and sharing data and samples, this is an important and timely topic.

Ethics rounds do not improve the handling of ethical issues by psychiatric staff.

BACKGROUND: One way to support healthcare staff in handling ethically difficult situations is through ethics rounds that consist of discussions based on clinical cases and are moderated by an ethicist. Previous research indicates that the handling of ethically difficult situations in the workplace might have changed after ethics rounds. This, in turn, would mean that the "ethical climate", i.e. perceptions of how ethical issues are handled, would have changed. AIM: To investigate whether ethics rounds could improve the ethical climate perceived by staff working in psychiatry outpatient clinics. METHODS: In this quasi-experimental study, six inter-professional ethics rounds led by a philosopher/ethicist were conducted at two psychiatry outpatient clinics. Changes in ethical climate were measured at these clinics as well as at two control clinics at baseline and after the intervention period using the instrument Hospital Ethical Climate Survey. RESULTS: Within-groups comparisons of median sum scores of ethical climate showed that no statistically significant differences were found in the intervention group before or after the intervention period. The median sum scores for ethical climate were significantly higher, both at baseline and after the intervention period (P ≤ 0.001; P = 0.046), in the intervention group. CONCLUSIONS: Ethics rounds in psychiatric outpatient clinics did not result in significant changes in ethical climate. Outcomes of ethics rounds might, to a higher degree, be directed towards patient-related outcomes rather than towards the staff's working environment, as the questions brought up for discussion during the ethics rounds concerned patient-related issues.

RD-Connect: an integrated platform connecting databases, registries, biobanks and clinical bioinformatics for rare disease research.

Research into rare diseases is typically fragmented by data type and disease. Individual efforts often have poor interoperability and do not systematically connect data across clinical phenotype, genomic data, biomaterial availability, and research/trial data sets. Such data must be linked at both an individual-patient and whole-cohort level to enable researchers to gain a complete view of their disease and patient population of interest. Data access and authorization procedures are required to allow researchers in multiple institutions to securely compare results and gain new insights. Funded by the European Union's Seventh Framework Programme under the International Rare Diseases Research Consortium (IRDiRC), RD-Connect is a global infrastructure project initiated in November 2012 that links genomic data with registries, biobanks, and clinical bioinformatics tools to produce a central research resource for rare diseases.