Fair and equitable AI in biomedical research and healthcare: Social science perspectives.

Artificial intelligence (AI) offers opportunities but also challenges for biomedical research and healthcare. This position paper shares the results of the international conference "Fair medicine and AI" (online 3-5 March 2021). Scholars from science and technology studies (STS), gender studies, and ethics of science and technology formulated opportunities, challenges, and research and development desiderata for AI in healthcare. AI systems and solutions, which are being rapidly developed and applied, may have undesirable and unintended consequences including the risk of perpetuating health inequalities for marginalized groups. Socially robust development and implications of AI in healthcare require urgent investigation. There is a particular dearth of studies in human-AI interaction and how this may best be configured to dependably deliver safe, effective and equitable healthcare. To address these challenges, we need to establish diverse and interdisciplinary teams equipped to develop and apply medical AI in a fair, accountable and transparent manner. We formulate the importance of including social science perspectives in the development of intersectionally beneficent and equitable AI for biomedical research and healthcare, in part by strengthening AI health evaluation.

The Marburg Museum Anatomicum and its unusual gynecological specimens: A brief history and ethical contextualisation.

INTRODUCTION: The Marburg Museum Anatomicum displays a number of unique specimens related to obstetric problems. An ethically intensely disputed example is the bisected body of a pregnant woman and her fetus. Current information stemming from previous publications relates it to a fictional young woman who, who, having got pregnant by a student, committed suicide. This narrative was derived from a novel by the author Walter Bloem (1868-1951), orally transmitted without further proof of reliability. The present study attempts to uncover the true background beyond this narrative and to clarify the acquisition of the body by the anatomical collection and its personal background. SOURCES AND METHODS: Archival material as well as contemporary publications of professors of obstetrics and of anatomy along with data derived from civil and ecclesiastic registry offices were evaluated and compared with observations on the specimen. FINDINGS: Comparison of data derived from the fictional description and observations on the specimen showed significant differences, excluding the narrative as a reliable source. Closer examination of the scientific output of former chairs of obstetrics showed that Professor Wilhelm Zangemeister (1871-1930), head of the clinics of gynecology and obstetrics between 1910 and 1925, published several studies on the clinical significance of narrow pelvis during delivery. In his textbook of obstetrics, published in 1927, he showed an illustration of a frozen section of a pregnant woman with kyphosis who had died from myocarditis. The drawing clearly represents the specimen, having been mounted in a large glass vessel in 1922 and included in the collection of the Anatomical Institute. CONCLUSIONS: The current narrative on the bisected body of a pregnant woman and her fetus preserved in the Marburg Museum Anatomicum has nothing to do with the specimen in the collection. In fact, the latter was prepared in 1922 by order of the former professor of obstetrics, Wilhelm Zangemeister, who later published the case in his textbook of obstetrics. The ethical consequences of the changing ontological status and origin of the specimen and its public display are discussed.

Process of risk assessment by research ethics committees: foundations, shortcomings and open questions.

Risks and burdens in the study participation, as well as an adequate risk-benefit balance, are key concepts for the evaluation of clinical studies by research ethics committees (RECs). An adequate assessment and continuous monitoring to ensure compliance of risks and burdens in clinical trials have long been described as a central task in research ethics. However, there is currently no uniform and solid theoretical approach to risk assessment by RECs. Regulatory standards of research ethics such as the Declaration of Helsinki provide only minimal guidance on how risk decisions are considered. Due to discrepancies in the existing literature and guidance documents, adequate risk assessment by RECs remains to be elusive. In this article, we address current definitions of risk and present our own concept of aggregate risk definition. Moreover, we highlight the concept of benefit, the standard of reasonableness with respect to ethics literature and different approaches of risk-benefit assessment. In order to present a comprehensive theoretical approach of risk assessment by RECs, further understanding of the definitions of risk may improve adequate decision-making tasks by RECs. To improve the process of risk assessment by RECs, a dynamic framework will be illustrated, showing step-by-step risk assessment functions. This approach may be a promising tool to ensure adequacy in risk assessment by RECs.

A look into the future? Patients' and health care staff's perception and evaluation of genetic information and the right not to know.

The progress of medical genetics leads to a significant increase in genetic knowledge and a vast expansion of genetic diagnostics. However, it is still unknown how these changes will be integrated into medical practice and how they will change patients' and healthy persons' perception and evaluation of genetic diagnoses and genetic knowledge. Therefore, we carried out a comprehensive questionnaire survey with more than 500 patients, clients seeking genetic counseling, health care staff, and healthy persons (N = 523). The questionnaire survey covered detailed questions on the value of genetic diagnoses for the different groups of study participants, the right to know or not to know genetic diagnoses, possible differences between genetic and other medical diagnoses, and the practical use and implications of genetic knowledge with a special focus on hereditary neuropsychiatric diseases. A huge majority of the participants (90.7%) stated to have a right to learn every aspect of her or his genetic make-up. Similarly, study participants showed high interest (81.8%) in incidental health care findings-independent of whether the diseases are treatable or not. One can derive from the data outcome that study participants did not follow the implications of a "genetic exceptionalism" and often considered genetic findings as equivalent in relation to other medical diagnoses.

Genomic information and a person's right not to know: A closer look at variations in hypothetical informational preferences in a German sample.

In clinical practice and in research, there is an ongoing debate on how to return incidental and secondary findings of genetic tests to patients and research participants. Previous investigations have found that most of the people most of the time are in favor of full disclosure of results. Yet, the option to reject disclosure, based on the so-called right not to know, can be valuable especially for some vulnerable subgroups of recipients. In the present study we investigated variations in informational preferences in the context of genetic testing in a large and diverse German sample. This survey examined health care professionals, patients, participants of genetic counseling sessions and members of the general population (N = 518). Survey participants were assessed regarding their openness to learning about findings under various hypothetical scenarios, as well as their attitudes about the doctor-patient-relationship in a disclosure situation and about informational transfer to third parties. While the majority of participants wanted to learn about their findings, the extent of support of disclosure varied with features of the hypothetical diagnostic scenarios (e.g., controllability of disease; abstract vs. concrete scenario description) and demographic characteristics of the subjects. For example, subjects with higher levels of education were more selective with regards to the kind of information they want to receive than those with lower levels of education. We discuss implications of these findings for the debate about the right not to know and for the clinical practice of informed consent procedures.

Different concepts and models of information for family-relevant genetic findings: comparison and ethical analysis.

Genetic predispositions often concern not only individual persons, but also other family members. Advances in the development of genetic tests lead to a growing number of genetic diagnoses in medical practice and to an increasing importance of genetic counseling. In the present article, a number of ethical foundations and preconditions for this issue are discussed. Four different models for the handling of genetic information are presented and analyzed including a discussion of practical implications. The different models' ranges of content reach from a strictly autonomous position over self-governed arrangements in the practice of genetic counseling up to the involvement of official bodies and committees. The different models show a number of elements which seem to be very useful for the handling of genetic data in families from an ethical perspective. In contrast, the limitations of the standard medical attempt regarding confidentiality and personal autonomy in the context of genetic information in the family are described. Finally, recommendations for further ethical research and the development of genetic counseling in families are given.

Ethical and legal framework and regulation for off-label use: European perspective.

For more than 20 years the off-label use of drugs has been an essential part of the ethical and legal considerations regarding the international regulation of drug licensing. Despite a number of regulatory initiatives in the European Union, there seems to remain a largely unsatisfactory situation following a number of critical descriptions and statements from actors in the field. The present article gives an overview of the ethical and legal framework and developments in European countries and identifies existing problems and possible pathways for solutions in this important regulatory area. In addition to the presentation of the ethical and legal foundations, some attention is given to criticisms from medical practitioners to the current handling of off-label drug use. The review also focuses on the situation confronted by patients and physicians when off-label prescriptions are necessary. Through legal descriptions from a number of countries, possible solutions for future discussion of European health care policy are selected and explained.

Neuroenhancement - perspectives of Swiss psychiatrists and general practitioners.

QUESTIONS UNDER STUDY: Although the ethical and health implications of neuroenhancement have been intensely discussed over the past years, little is known about the experiences and attitudes of physicians confronted with requests for neuroenhancing substances. The aim of this study was to explore general practitioners' and psychiatrists' familiarity with such requests and their willingness to prescribe these products. METHOD: A nation-wide cross-sectional survey among general practitioners and psychiatrists in Switzerland was conducted. A questionnaire was developed, pre-tested and sent out to a pre-defined sample of 1,600 Swiss practising physicians in the fields of psychiatry and general practice/internal medicine in the German-speaking and French-speaking part of Switzerland. RESULTS: A total of 393 questionnaires were returned (response rate: 24.7%). 80.2% of study participants were encountered requests for neuroenhancing products in their own practice, mostly not exceeding 1-2 times a year. A total of 41.1% were undecided when asked if they categorically against neuroenhancement, 49% would decide on a case-by-case basis, and 9.6% would decide according to patients' wishes. CONCLUSIONS: Swiss psychiatrists and general practitioners are confronted with requests for neuroenhancement, albeit not very frequently. Most participants embrace a pragmatic position towards neuroenhancement, although there is also a considerable degree of uncertainty about the appropriateness of a categorical refusal. A minority would follow a consumer model that leaves the decision about the use of neuroenhancers to the client, even though this conflicts with legal requirements regarding drug prescriptions.

Off-label drug use in paediatrics: a world-wide problem.

Since more than 35 years, the international medical scientific community tries to solve the problem of the off-label use of paediatric drugs. The aim is simple, but ambitious: to supply children and adolescents with effective drugs, as safe as possible, with known and well-documented side effects, and with accurate and up-to-date information on dosage and administration form. However, despite the significant efforts of paediatricians, researchers and international health politics, a number of severe obstacles for the optimal supply of children and adolescents with safe drugs remain. The detailed analysis of the problem shows not only a still remaining lack of medical knowledge, but also persistent weaknesses in the ethical, legal, medical, pharmacological, and political practices that surround the phenomenon of off-label use in paediatrics. The article gives an overview about the remaining difficulties in the field of paediatric off-label medication with special consideration to ethical and regulatory questions.

Is the commercialisation of human tissue and body material forbidden in the countries of the European Union?

The human body and its parts are widely perceived as matters beyond commercial usage. This belief is codified in several national and European documents. This so-called 'no-property rule' is held to be the default position across the countries of the European Union. However, a closer look at the most pertinent national and European documents, and also current practices in the field, reveals a gradual model of commercialisation of human tissue. In particular, we will argue that the ban on commercialisation of body material is not as strict as it may appear at first sight, leaving room for the commercial practice of tissue procurement and transfer. We argue for more transparent information for patients and tissue donors, an intensified ethical debate on commercialisation practices, and a critical review of current normative principles.

Legal and ethical consequences of international biobanking from a national perspective: the German BMB-EUCoop project.

The international transfer of human biomaterial and data has become a prerequisite for collaborative biomedical research to be successful. However, although a national legal framework for 'biobanking' has already been formulated in many countries, little is known about how an international exchange of data and samples might affect the legal position of national biobanks and their donors. The German Telematics Platform and the Competence Network 'Congenital Heart Defects' jointly instigated a project (BMB-EUCoop) to (i) identify and assess the legal risks ensuing for biobanks and their donors in the context of Europe-wide research collaborations, (ii) devise practical recommendations to minimize or avoid these risks, and (iii) provide generic informational text, contracts and agreements to facilitate their practical implementation. Four different countries were included in the study; namely, the UK, Netherlands, Austria and Switzerland. The results of the study indicate that the degree of similarity between legal systems in different countries varies according to the respective field of jurisdiction. Although personality and property rights have long been enshrined in virtually identical pieces of law, the applicable medical professional regulations were found to be somewhat heterogeneous. Furthermore, clear-cut differences were often found to be lacking between regulations that reflect either 'soft law' or the nationally binding 'hard law' that has emerged from it. In view of the potential ambiguities, the experts uniformly concluded that the rights and interests of national (in this case, German) biobanks and their donors would be best protected by explicitly addressing any uncertainties in formal contractual agreements.

Off-label, off-limits? Parental awareness and attitudes towards off-label use in paediatrics.

Off-label drug use in paediatrics is associated with an increased risk of adverse drug reactions. Any risk-benefit analysis has to be based on value judgments that should include parents' views. However, nothing is known so far about the parents' perspective on this critical issue. Therefore, a quantitative survey with parents of healthy and chronically ill children was carried out (n = 94). Knowledge about the practise of off-label use is generally poor in both groups. Surprisingly, this is also true for the parents of children with chronic disease. Nine percent of the parents of chronically ill children and 20% of the parents of healthy children would refuse treatment with an off-label drug. Parents who have poor knowledge about the practise of off-label use tend to refuse to volunteer their child for study participation. Therefore, the information of parents on the off-label use of drugs is important to meet ethical standards and to increase the parents' acceptance of medical studies with children.

Comparative study of portal vein embolization versus portal vein ligation for induction of hypertrophy of the future liver remnant using a mini-pig model.

SUMMARY BACKGROUND DATA: The extent of hepatectomies is limited by the functional reserve of the remnant liver. The introduction of preoperative portal vein occlusion techniques to induce a preoperative hyperplasia of the future liver remnant has reduced the risk of postoperative liver failure. However, it has remained a matter of debate whether partial portal vein embolization (PVE) or suture ligation of the portal branches during exploration is the preferred technique. We compared both techniques under standardized experimental conditions in a large animal model by means of effectiveness and pathophysiologic differences. METHODS: Thirteen mini-pigs underwent portal vein ligation (PVL), 11 mini-pigs underwent PVE of 75% of the liver volume, and 6 underwent a sham operation. The animals were killed after 28 days. Laboratory liver function and damage parameters, lobar liver-to-body weight indices, portal and arterial flow alterations, and histologic changes were assessed. Ex situ arteriograms and portograms were performed to examine adaptive changes in the macroarchitecture of both vascular systems. RESULTS: The liver-to-body weight index of the nonoccluded lobe was highest after PVE (0.85) versus 0.6 (P < 0.05) after PVL. There was no significant reduction in global serum parameters reflecting total liver function. After 4 weeks, the PVL group consistently exhibited hepatopetal portal flow in the ligated lobes, which was present but significantly decreased after PVE. The ex situ angiography after PVE and PVL revealed the development of portal neocollaterals in the portal-occluded liver parts. CONCLUSIONS: Both PVL and PVE are able to induce hypertrophy of the future liver remnant. In comparison, PVE is the more effective technique to increase the future liver remnant. This is due to a more effective, durable occlusion of the portal branches. Formation of collaterals between occluded and nonoccluded liver parts seems to be the cause of inferior regeneration in the ligation group.

Nanomedicine-emerging or re-emerging ethical issues? A discussion of four ethical themes.

Nanomedicine plays a prominent role among emerging technologies. The spectrum of potential applications is as broad as it is promising. It includes the use of nanoparticles and nanodevices for diagnostics, targeted drug delivery in the human body, the production of new therapeutic materials as well as nanorobots or nanoprotheses. Funding agencies are investing large sums in the development of this area, among them the European Commission, which has launched a large network for life-sciences related nanotechnology. At the same time government agencies as well as the private sector are putting forward reports of working groups that have looked into the promises and risks of these developments. This paper will begin with an introduction to the central ethical themes as identified by selected reports from Europe and beyond. In a next step, it will analyse the most frequently invoked ethical concerns-risk assessment and management, the issues of human identity and enhancement, possible implications for civil liberties (e.g. nanodevices that might be used for covert surveillance), and concerns about equity and fair access. Although it seems that the main ethical issues are not unique to nanotechnologies, the conclusion will argue against shrugging them off as non-specific items that have been considered before in the context of other biomedical technologies, such as gene therapy or xenotransplantation. Rather, the paper will call on ethicists to help foster a rational, fair and participatory discourse on the different potential applications of nanotechnologies in medicine, which can form the basis for informed and responsible societal and political decisions.

Long-term outcome of split liver transplantation using right extended grafts in adulthood: A matched pair analysis.

OBJECTIVE: Shortage of suitable organs led to the development of alternative techniques in liver transplantation. Split liver transplantation (SLT) is well established in pediatric patients. SLT is not completely accepted in adult recipients due to potential increased risk of complications. Despite satisfying results of short-term outcome, there is a leak on information of the long-term outcome. Therefore, we compared the outcome after transplantation of the right extended liver lobe with whole liver transplantation (WLT) using a matched pair's analysis. PATIENTS AND METHODS: From the period of January 1993 to February 2005, 70 SLT recipients were matched with 70 WLT recipients of whole livers. Matching criteria were: 1) indication for transplantation, 2) United Network for Organ Sharing (UNOS) status, 3) recipient age, 4) donor age, 5) cold ischemic time, and 6) year of transplantation. The outcome was analyzed retrospectively. RESULTS: Mean follow-up was 36 months. The 2- and 5-year patient survival rates after SLT and WLT were 86.3% and 82.6%, and 78.4% and 75.6%, respectively (log rank, P = 0.2127). Two- and 5-year graft survival rates were 77.3% and 77.3% after SLT and 71.9% and 65.8% after WLT, respectively (log rank, P = 0.3822). The total biliary complication rate was 11.4% in the SLT group versus 10.0% in the WLT group in the short-term course, while it was 8.5% after SLT and 10.0% after WLT in the long-term course. We did not observe significant differences between the groups in term of short- and long-term morbidity. CONCLUSION: Transplantation of the right extended lobe deriving from left lateral splitting of deceased donor livers is followed by the same long-term patient and graft survival, which is known from WLT. There were no differences in the complication rates even in long-term outcome implementing that SLT does not put the adult recipient to an increased early and late risk. Transplantation of the extended right liver lobe provides a safe and efficient procedure in adult patients to expand the number of available grafts.

Technical refinements and results in full-right full-left splitting of the deceased donor liver.

OBJECTIVE: Splitting of the liver at the line of Cantlie of otherwise healthy people is accepted worldwide as a reasonable procedure for the donors in adult living donor liver transplantation. A similar operation is still considered as experimental if performed in the deceased donor liver. The aim of this study is to evaluate the technical evolution and the results of this variant splitting technique. PATIENTS AND METHODS: From January 1999 to August 2004, a total of 35 transplants of hemilivers from deceased donors (segments V-VIII: n = 16 and segments (I)II-IV: n = 19) were performed in our center. Seven splits were performed in situ and 12 ex situ. Splitting of the vena cava was applied in 18 splits and splitting of the middle hepatic vein in 8. Seven adults and 12 adolescents received the left hemiliver with a mean age of 12 years (range, 3-64 years), of whom 21% were UNOS status 1. Recipients of right hemilivers were exclusively adults with a mean age of 48 years (range, 31-65 years), none of them were high urgent. The outcome of these 35 recipients of hemilivers was prospectively evaluated. RESULTS: Mean deceased donor age was 27 years (range, 12-57 years), the donor's body weight ranged between 55 kg and 100 kg. The mean weight of the right and left hemilivers was 1135 g (range, 745-1432 g) and 602 g (range, 289-1100 g), respectively. The mean graft recipient weight ratio in left and right hemiliver group was 1.46% (range, 0.88%-3.54%) and 1.58% (range, 1.15%-1.99%), respectively. Median follow-up was 27.4 months (range, 1-68.3 months). Four patients died (actual patient survival FR group: 87.5% versus FL group: 89.5%), 3 due to septic MOF and 1 due to graft versus host disease. In each of the 2 groups, 2 recipients had to undergo retransplantation, which resulted in an actual right and left hemiliver survival rate of 75% and 84%, respectively. The causes for retransplantation were primary nonfunction in 2 left hemilivers, chronic graft dysfunction in 1 right hemiliver, and recurrence of the primary disease in 1 recipient of a right hemiliver. Primary poor function was observed in 1 recipient of a right hemiliver. Early and late biliary complications occurred in both right and left hemiliver groups at the rate of 37.5% (n = 6) and 21% (n = 4), respectively. Arterial, portal, and venous complications were not observed in either group. CONCLUSION: The technical development of splitting along Cantlie's line is almost complete with the last challenge being the reduction of biliary complications. The key to success is the choice of adequate deceased donors and recipients. Full-right full-left splitting is safely possible and should be considered as a reasonable instrument to alleviate mortality on the adult waiting list and to reduce the need for adult and adolescent living donation.

Evolution of donor morbidity in living related liver transplantation: a single-center analysis of 165 cases.

OBJECTIVE: During the last 14 years, living donor liver transplantation (LDLT) has evolved to an indispensable surgical strategy to minimize mortality of adult and pediatric patients awaiting transplantation. The crucial prerequisite to performing this procedure is a minimal morbidity and mortality risk to the healthy living donor. Little is known about the learning curve involved with this type of surgery. PATIENTS AND METHODS: From January 1991 to August 2003, a total of 165 LDLTs were performed in our center. Of these, 135 were donations of the left-lateral lobe (LL, segments II and III), 3 were of the left lobe (L, segments II-IV), 3 were full-left lobes (FL, segments I-IV), and 24 were of the full-right lobe (FR, segments V-VIII). We divided the procedures into 3 periods: period 1 included the years 1991 to 1995 (LL, n = 49; L, n = 2; FR, n = 1), period 2 covered 1996 to 2000 (LL, n = 47), and period 3 covered 2001 to August 2003 (LL, n = 39; FR, n = 23; FL, n = 3; L, n = 1). Perioperative mortality and morbidity were assessed using a standardized classification. Length of stay in intensive care unit, postoperative hospital stay, laboratory results (bilirubin, INR, and LFTs), morbidity, and the different types of grafts in the 3 different periods were compared. RESULTS: One early donor death was observed in period 1 (03/07/93, case 30; total mortality, 0.61.%). Since 1991, the perioperative morbidity has continually declined (53.8% vs. 23.4% vs. 9.2%). In period 1, 28 patients had 40 complications. In period 2, 11 patients had 12 complications, and in period 3, 6 patients had 9 complications. Within the first period, 1 donor underwent relaparotomy because of bile leakage. Postoperative hospital stay was 10 days, 7 days, and 6 days, respectively. Donation of the full right lobe, in comparison with that of the left lateral lobe, resulted in a significantly diminished liver function (bilirubin and INR) during the first 5 days after donation but did not increase morbidity. One donor from period 1 experienced late death caused by amyotrophic lateral sclerosis. CONCLUSIONS: In a single center, morbidity after living liver donation strongly correlates to center experience. Despite the additional risks associated with temporary reduction of liver function, this experience enabled the team to bypass part of the learning curve when starting right lobe donation. Specific training of the surgical team and coaching by an experienced center should be implemented for centers offering this procedure to avoid the learning curve.

[Ethical aspects of evidence-based clinical medicine]. / Ethische Aspekte der Evidenz-basierten klinischen Medizin.

The application of Evidence-based Medicine (EbM) in clinical practice is characterised by different expectations shaped by the interests of the various players of the health care system. Ethical analysis of the medical ethicist anticipates such expectations, especially by giving consideration to potential negative outcomes for particular patient groups in order to identify systematic distortions and to avoid discrimination of patients concerning access to medical care. In this context, the adequacy of the basic evaluation criteria of EbM for different health conditions needs to be investigated, too. In addition possible conflicts of interest in practising EbM will have to be discussed openly with patients being involved in this process as well as in the development of evidence-based guidelines.