Do Physicians Have a Duty to Support Secondary Use of Clinical Data in Biomedical Research? An Inquiry into the Professional Ethics of Physicians.

Secondary use of clinical data in research or learning activities (SeConts) has the potential to improve patient care and biomedical knowledge. Given this potential, the ethical question arises whether physicians have a professional duty to support SeConts. To investigate this question, we analyze prominent international declarations on physicians' professional ethics to determine whether they include duties that can be considered as good reasons for a physicians' professional duty to support SeConts. Next, we examine these documents to identify professional duties that might conflict with a potential duty of physicians to support SeConts.

Physicians' attitudes towards secondary use of clinical data for biomedical research purposes in Germany. Results of a quantitative survey.

BACKGROUND: For biomedical data-driven research purposes, secondary use of clinical data carries great but largely untapped potential. Physicians' attitudes and their needs towards secondary data use are essential to inform its practical and ethically sound implementation but are currently understudied. OBJECTIVE: Therefore, the objectives of the study are to assess physicians' (i) general attitudes and concerns, (ii) willingness to adapt workflows and to make data available for secondary use, (iii) group-specific conditions toward implementation of secondary use and associated concerns of physician-scientists and purely clinical physicians. METHODS: We developed an online survey based on a literature review and an expert interview study. Physicians in private practice and at two large German university hospitals were surveyed from May 2021 until January 2022. RESULTS: In total, 446 physicians participated in the survey. 96% [380/397] of all physicians reported a positive attitude towards secondary use; 87% [31/397] are in-principle willing to support secondary use of clinical data along with a small proportion of physicians with fundamental reservations. Secondly, the most important conditions for adapting workflows were funding of additional time and effort for research-adequate documentation (71% [286/390]) and the most important condition for providing patients' clinical data was reliable protection of patients' privacy (67% [254/382]). Thirdly, physician-scientists were more likely than purely clinical physicians to request additional funding for research-adequate documentation as a precondition for support (83% vs 69%, P = .002) and the privilege to conduct research with their own patients' clinical data before other researchers are allowed to (43% vs 11%, P < .001); while purely clinical physicians more frequently require reliable protection of patient privacy (76% vs 62%, P = .007) and monetary compensation (45% vs 25%, P < .001). CONCLUSION: Since this study presents high in-principle willingness of physicians to support secondary use along with little general concerns, it seems essential to address physicians' group-specific conditions toward secondary use in order to gain their support.

Evidence for a shared genetic contribution to loneliness and borderline personality disorder.

Loneliness, influenced by genetic and environmental factors such as childhood maltreatment, is one aspect of interpersonal dysfunction in Borderline Personality Disorder (BPD). Numerous studies link loneliness and BPD and twin studies indicate a genetic contribution to this association. The aim of our study was to investigate whether genetic predisposition for loneliness and BPD risk overlap and whether genetic risk for loneliness contributes to higher loneliness reported by BPD patients, using genome-wide genotype data. We assessed the genetic correlation of genome-wide association studies (GWAS) of loneliness and BPD using linkage disequilibrium score regression and tested whether a polygenic score for loneliness (loneliness-PGS) was associated with case-control status in two independent genotyped samples of BPD patients and healthy controls (HC; Witt2017-sample: 998 BPD, 1545 HC; KFO-sample: 187 BPD, 261 HC). In the KFO-sample, we examined associations of loneliness-PGS with reported loneliness, and whether the loneliness-PGS influenced the association between childhood maltreatment and loneliness. We found a genetic correlation between the GWAS of loneliness and BPD in the Witt2017-sample (rg = 0.23, p = 0.015), a positive association of loneliness-PGS with BPD case-control status (Witt2017-sample: NkR² = 2.3%, p = 2.7*10-12; KFO-sample: NkR² = 6.6%, p = 4.4*10-6), and a positive association between loneliness-PGS and loneliness across patient and control groups in the KFO-sample (ß = 0.186, p = 0.002). The loneliness-PGS did not moderate the association between childhood maltreatment and loneliness in BPD. Our study is the first to use genome-wide genotype data to show that the genetic factors underlying variation in loneliness in the general population and the risk for BPD overlap. The loneliness-PGS was associated with reported loneliness. Further research is needed to investigate which genetic mechanisms and pathways are involved in this association and whether a genetic predisposition for loneliness contributes to BPD risk.

Patient data for commercial companies? An ethical framework for sharing patients' data with for-profit companies for research.

BACKGROUND: Research using data from medical care promises to advance medical science and improve healthcare. Academia is not the only sector that expects such research to be of great benefit. The research-based health industry is also interested in so-called 'real-world' health data to develop new drugs, medical technologies or data-based health applications. While access to medical data is handled very differently in different countries, and some empirical data suggest people are uncomfortable with the idea of companies accessing health information, this paper aims to advance the ethical debate about secondary use of medical data generated in the public healthcare sector by for-profit companies for medical research (ReuseForPro). METHODS: We first clarify some basic concepts and our ethical-normative approach, then discuss and ethically evaluate potential claims and interests of relevant stakeholders: patients as data subjects in the public healthcare system, for-profit companies, the public, and physicians and their healthcare institutions. Finally, we address the tensions between legitimate claims of different stakeholders in order to suggest conditions that might ensure ethically sound ReuseForPro. RESULTS: We conclude that there are good reasons to grant for-profit companies access to medical data if they meet certain conditions: among others they need to respect patients' informational rights and their actions need to be compatible with the public's interest in health benefit from ReuseForPro.

Patients' Willingness to Provide Their Clinical Data for Research Purposes and Acceptance of Different Consent Models: Findings From a Representative Survey of Patients With Cancer.

BACKGROUND: Secondary use of clinical data for biomedical research purposes holds great potential for various types of noninterventional, data-driven studies. Patients' willingness to support research with their clinical data is a crucial prerequisite for research progress. OBJECTIVE: The aim of the study was to learn about patients' attitudes and expectations regarding secondary use of their clinical data. In a next step, our results can inform the development of an appropriate governance framework for secondary use of clinical data for research purposes. METHODS: A questionnaire was developed to assess the willingness of patients with cancer to provide their clinical data for biomedical research purposes, considering different conditions of data sharing and consent models. The Cancer Registry of the German federal state of Baden-Württemberg recruited a proportionally stratified random sample of patients with cancer and survivors of cancer based on a full census. RESULTS: In total, 838 participants completed the survey. Approximately all participants (810/838, 96.7%) showed general willingness to make clinical data available for biomedical research purposes; however, they expected certain requirements to be met, such as comparable data protection standards for data use abroad and the possibility to renew consent at regular time intervals. Most participants (620/838, 73.9%) supported data use also by researchers in commercial companies. More than half of the participants (503/838, 60%) were willing to give up control over clinical data in favor of research benefits. Most participants expressed acceptance of the broad consent model (494/838, 58.9%), followed by data use by default (with the option to opt out at any time; 419/838, 50%); specific consent for every study showed the lowest acceptance rate (327/838, 39%). Patients expected physicians to share their data (763/838, 91.1%) and their fellow patients to support secondary use with their clinical data (679/838, 81%). CONCLUSIONS: Although patients' general willingness to make their clinical data available for biomedical research purposes is very high, the willingness of a substantial proportion of patients depends on additional requirements. Taking these perspectives into account is essential for designing trustworthy governance of clinical data reuse and sharing. The willingness to accept the loss of control over clinical data to enhance the benefits of research should be given special consideration.

Borderline personality disorder and the big five: molecular genetic analyses indicate shared genetic architecture with neuroticism and openness.

Both environmental (e.g. interpersonal traumatization during childhood and adolescence) and genetic factors may contribute to the development of Borderline Personality Disorder (BPD). Twin studies assessing borderline personality symptoms/features in the general population indicate that genetic factors underlying these symptoms/features are shared in part with the personality traits of the Five Factor Model (FFM) of personality-the "Big Five". In the present study, the genetic overlap of BPD with the Big Five -Openness to Experience, Conscientiousness, Extraversion, Agreeableness, and Neuroticism- was assessed. Linkage disequilibrium score regression was used to calculate genetic correlations between a genome-wide association study (GWAS) in central European populations on BPD (N = 2543) and GWAS on the Big Five (N = 76,551-122,886, Neuroticism N = 390,278). Polygenic scores (PGS) were calculated to test the association of the genetic disposition for the personality traits with BPD case-control status. Significant positive genetic correlations of BPD were found with Neuroticism (rg = 0.34, p = 6.3*10-5) and Openness (rg = 0.24, p = 0.036), but not with the other personality traits (all | rg | <0.14, all p > 0.30). A cluster and item-level analysis showed positive genetic correlations of BPD with the Neuroticism clusters "Depressed Affect" and "Worry", and with a broad range of Neuroticism items (N = 348,219-376,352). PGS analyses confirmed the genetic correlations, and found an independent contribution of the personality traits to BPD risk. The observed associations indicate a partially shared genetic background of BPD and the personality traits Neuroticism and Openness. Larger GWAS of BPD and the "Big Five" are needed to further explore the role of personality traits in the etiology of BPD.

Secondary Use of Clinical Data in Data-Gathering, Non-Interventional Research or Learning Activities: Definition, Types, and a Framework for Risk Assessment.

BACKGROUND: The secondary use of clinical data in data-gathering, non-interventional research or learning activities (SeConts) has great potential for scientific progress and health care improvement. At the same time, it poses relevant risks for the privacy and informational self-determination of patients whose data are used. OBJECTIVE: Since the current literature lacks a tailored framework for risk assessment in SeConts as well as a clarification of the concept and practical scope of SeConts, we aim to fill this gap. METHODS: In this study, we analyze each element of the concept of SeConts to provide a synthetic definition, investigate the practical relevance and scope of SeConts through a literature review, and operationalize the widespread definition of risk (as a harmful event of a certain magnitude that occurs with a certain probability) to conduct a tailored analysis of privacy risk factors typically implied in SeConts. RESULTS: We offer a conceptual clarification and definition of SeConts and provide a list of types of research and learning activities that can be subsumed under the definition of SeConts. We also offer a proposal for the classification of SeConts types into the categories non-interventional (observational) clinical research, quality control and improvement, or public health research. In addition, we provide a list of risk factors that determine the probability or magnitude of harm implied in SeConts. The risk factors provide a framework for assessing the privacy-related risks for patients implied in SeConts. We illustrate the use of risk assessment by applying it to a concrete example. CONCLUSIONS: In the future, research ethics committees and data use and access committees will be able to rely on and apply the framework offered here when reviewing projects of secondary use of clinical data for learning and research purposes.

A proposed severity classification of borderline symptoms using the borderline symptom list (BSL-23).

Background: The Borderline Symptom List (BSL-23) is a well-established self-rating instrument to assess the severity of borderline typical psychopathology. However, a classification of severity levels for the BSL-23 is missing. Methods: Data from 1.090 adults were used to develop a severity classification for the Borderline Symptom List (BSL-23). The severity grading was based on the distribution of the BSL-23 in 241 individuals with a diagnosis of BPD. Data from three independent samples were used to validate the previously defined severity grades.These validation samples included a group of treatment seeking patients with a diagnosis of BPD (n = 317), a sample of individuals with mental illnesses other than BPD (n = 176), and a healthy control sample (n = 356). The severity grades were validated from comparisons with established assessment instruments such as the International Personality Disorders Examination, the Structured Clinical Interview for DSM-IV, the global severity index of the Symptom Checklist (GSI, SCL-90), the Global Assessment of Functioning (GAF), and the Beck Depression Inventory (BDI-II). Results: Six grades of symptom severity were defined for the BSL-23 mean score: none or low: 0-0.3; mild: 0.3-0.7; moderate: 0.7-1.7; high: 1.7-2.7; very high: 2.7-3.5; and extremely high: 3.5-4. These grades received consistent empirical support from the independent instruments and samples. For instance, individuals with a severity grade of none or low were virtually free from diagnostic BPD-criteria, had a GSI below the normative population, and a high level of global functioning corresponding to few or no symptoms. Severity grades indicating high to extremely high levels of BPD symptoms were observed at a much higher rate in treatment-seeking patients (70.0%) than in clinical controls (17.6%) and healthy controls (0.0%). The BSL-23 score that best separated treatment-seeking BPD patients and clinical controls was 1.50, whereas the clearest discrimination of BPD patients and healthy controls was found at a score of 0.64. Conclusions: The grades of BPD-specific symptom severity derived from the distribution of the BSL-23 scores received consistent empirical validation from established assessments for psychopathology. Future studies should expand this validation by including additional instruments e.g., to assess self-esteem, loneliness, connectedness, and quality of life.

Intact Classical Fear Conditioning to Interpersonally Threatening Stimuli in Borderline Personality Disorder.

Threat hypersensitivity is regarded as a central mechanism of deficient emotion regulation, a core feature of patients with borderline personality disorder (BPD). Here, we employed a classical fear-conditioning protocol in which interpersonally threatening, interpersonally non-threatening, and non-social (neutral) visual stimuli were predictive of an aversive auditory stimulus in a sample of 23 medication-free adult female patients with BPD and 21 age- and IQ-matched healthy women. The results did not confirm the hypothesized enhanced and prolonged conditioned skin conductance responses (SCR) and subjective stress and expectancy ratings to interpersonally threatening stimuli in patients with BPD compared to healthy women. Patients with BPD generally expected the aversive stimulus more often irrespective of stimulus category and conditioning. Furthermore, patients with BPD showed larger conditioned SCR to interpersonally non-threatening and neutral than interpersonally threatening stimuli, while interpersonally threatening stimuli elicited higher SCR compared to non-threatening or neutral stimuli in healthy controls. Together with previous studies, the results suggest no alterations in fear conditioning to generally aversive stimuli in BPD. Further studies using stimuli with BPD-specific topics, such as abandonment or rejection, and/or to investigate more interpersonal forms of learning, such as observational or instructed conditioning, are urgently needed to further elucidate the mechanisms involved in the etiology and maintenance of threat hypersensitivity in BPD.

Psychometric Properties of the Chinese Version of the Brief Borderline Symptom List in Undergraduate Students and Clinical Patients.

The brief version of the Borderline Symptom List (BSL-23) is a self-rated scale developed from the initial 95-item version of Borderline Symptom List (BSL-95). The current study aimed to evaluate the psychometric properties of the Chinese version of the BSL-23. A total of 570 undergraduate students and 323 clinical patients completed the BSL-23, the borderline subscale of the Personality Diagnostic Questionnaire (PDQ-4+), the Center for Epidemiologic Studies Depression Scale (CES-D), the Barratt Impulsiveness Scale, 11th version (BIS-11), the Childhood Trauma Questionnaire (CTQ) and the Attachment Style Questionnaire (ASQ). A Confirmatory Factor Analysis (CFA) was conducted to test the one-factor structure of the BSL-23. Cronbach's alpha, Omega coefficient, Split-Half coefficient, Mean Inter-Item Correlation (MIC) and test-retest reliability were also measured. The correlations between the BSL-23 and other psychological variables were used to assess criterion-related validity and convergent validity. Participants who scored ≥ 5 on the borderline subscale of the PDQ-4+ were placed into the borderline personality disorder (BPD) screening-positive group, while the others were placed into the screening-negative group. Independent sample t-tests were performed to examine the differences in BSL-23 scores between the BPD screening-positive group and the BPD screening-negative group. The CFA results supported the one-factor structure of the BSL-23 in both samples. The internal consistency was high both in the undergraduate sample (Cronbach's α = 0.93, Omega = 0.95, Split-Half coefficient = 0.89, MIC = 0.38) and the clinical sample (Cronbach's α = 0.97, Omega = 0.97, Split-Half coefficient = 0.96, MIC = 0.56). The test-retest reliability within 2 weeks was 0.62. The BSL-23 displayed moderate to high correlations with the PDQ-4+-Borderline subscale, the CES-D, the BIS-11, the CTQ and the ASQ (r = 0.35 - 0.70). In addition, the BSL-23 discriminated between the BPD screening-positive and the BPD screening-negative participants, and also between the patient sample and undergraduate sample. In conclusion, the Chinese version of the BSL-23 has satisfactory psychometric properties to assess BPD symptoms.

Stress reactivity and pain-mediated stress regulation in remitted patients with borderline personality disorder.

Objective: Patients with borderline personality disorder (BPD) use nonsuicidal self-injury (NSSI) to cope with states of elevated inner tension. It is unclear to what extent remitted BPD patients experience these states and whether the experience of pain still regulates emotion. The purpose of this study was the investigation of baseline stress levels, stress reactivity, and pain-mediated stress regulation in remitted BPD patients. Method: Subjective and objective stress parameters were assessed in 30 remitted BPD patients, 30 current BPD patients, and 30 healthy controls. After stress induction, a non-nociceptive tactile stimulus, a tissue-injuring, or a noninvasive pain stimulus was applied to the right volar forearm. Results: Baseline stress levels of remitted BPD patients lie in between the stress levels of current BPD patients and healthy controls. Urge for NSSI increased significantly more in current than remitted BPD patients. The experience of pain led to a greater decrease of arousal in current compared to remitted BPD patients and healthy controls. Conclusions: States of increased tension still seem to appear in remitted BPD patients. The role of pain-mediated stress regulation appears to be reduced in remitted patients.

fMRI neurofeedback of amygdala response to aversive stimuli enhances prefrontal-limbic brain connectivity.

Down-regulation of the amygdala with real-time fMRI neurofeedback (rtfMRI NF) potentially allows targeting brain circuits of emotion processing and may involve prefrontal-limbic networks underlying effective emotion regulation. Little research has been dedicated to the effect of rtfMRI NF on the functional connectivity of the amygdala and connectivity patterns in amygdala down-regulation with neurofeedback have not been addressed yet. Using psychophysiological interaction analysis of fMRI data, we present evidence that voluntary amygdala down-regulation by rtfMRI NF while viewing aversive pictures was associated with increased connectivity of the right amygdala with the ventromedial prefrontal cortex (vmPFC) in healthy subjects (N=16). In contrast, a control group (N=16) receiving sham feedback did not alter amygdala connectivity (Group×Condition t-contrast: p<.05 at cluster-level). Task-dependent increases in amygdala-vmPFC connectivity were predicted by picture arousal (ß=.59, p<.05). A dynamic causal modeling analysis with Bayesian model selection aimed at further characterizing the underlying causal structure and favored a bottom-up model assuming predominant information flow from the amygdala to the vmPFC (xp=.90). The results were complemented by the observation of task-dependent alterations in functional connectivity of the vmPFC with the visual cortex and the ventrolateral PFC in the experimental group (Condition t-contrast: p<.05 at cluster-level). Taken together, the results underscore the potential of amygdala fMRI neurofeedback to influence functional connectivity in key networks of emotion processing and regulation. This may be beneficial for patients suffering from severe emotion dysregulation by improving neural self-regulation.

Analysis of genome-wide significant bipolar disorder genes in borderline personality disorder.

The objective of this study was to investigate the hypothesis that borderline personality disorder (BPD) and bipolar disorder (BD) share genetic variation through analysis of known genetic risk factors for BD in a well-characterized BPD case-control cohort. Genotyping of five genome-wide significant variants identified for BD (in CACNA1C, ANK3, and ODZ4) was performed in 673 BPD cases and 748 controls. A nominally significant association with BPD was found for rs1006737 in CACNA1C (P=0.0498). Sex-specific analysis showed that this signal was present only in women. This is the first report of an association between a BD risk gene and BPD where selection was not based on a priori hypotheses about its function, but on an unbiased hypothesis-free screening of the genome. Genome-wide association data of large samples of BPD are warranted and will eventually identify new risk genes and the overlap between BPD and BD if it exists.

Association between dopa decarboxylase gene variants and borderline personality disorder.

Despite heritability estimates of 37-69%, research has identified few genetic risk variants for borderline personality disorder (BPD). The present collaborative candidate gene study of 987 BPD cases and 1110 healthy controls found an association between BPD and single nucleotide polymorphism rs12718541 in the dopa decarboxylase gene.