The ethics of polygenic scores in psychiatry: minefield or opportunity for patient-centered psychiatry?

Recent advancements in psychiatric genetics have sparked a lively debate on the opportunities and pitfalls of incorporating polygenic scores into clinical practice. Yet, several ethical concerns have been raised, casting doubt on whether further development and implementation of polygenic scores would be compatible with providing ethically responsible care. While these ethical issues warrant thoughtful consideration, it is equally important to recognize the unresolved need for guidance on heritability among patients and their families. Increasing the availability of genetic counseling services in psychiatry should be regarded as a first step toward meeting these needs. As a next step, future integration of novel genetic tools such as polygenic scores into genetic counseling may be a promising way to improve psychiatric counseling practice. By embedding the exploration of polygenic psychiatry into the supporting environment of genetic counseling, some of the previously identified ethical pitfalls may be prevented, and opportunities to bolster patient empowerment can be seized upon. To ensure an ethically responsible approach to psychiatric genetics, active collaboration with patients and their relatives is essential, accompanied by educational efforts to facilitate informed discussions between psychiatrists and patients.

Experiences of pediatric cancer patients (age 12-18 years) with extensive germline sequencing for cancer predisposition: a qualitative study.

This study explored the experiences and needs of adolescents, ranging from 12 to 18 years old, who have recently been diagnosed with cancer and participated in a nationwide germline genetic sequencing study within the context of pediatric oncology. The 21 adolescents in this qualitative interview study viewed genetic sequencing as an integral part of their cancer journey. They often characterized germline sequencing as "good-to-know" without specifying immediate utility. While the adolescents comprehended the significance of germline genetic sequencing, they were less focused on its potential long-term implications. Adolescents expressed a strong desire to be actively engaged in decisions related to genetics. They advocated for a participatory role in genetic decision-making from a young age onwards. They recommended that re-consent should be sought before re-analysis of their genetic data is performed and believe that patients should have the opportunity to provide (re-)consent once they reach adulthood. Moreover, the adolescents emphasized the importance of developing counseling materials that are not only concise but also visually attractive. In conclusion, this study underscores the positive perception that adolescents diagnosed with cancer hold regarding germline genetic sequencing. They articulate a strong interest in being actively involved in genetic decision-making. To address these articulated needs and preferences, we recommend the development of visually engaging counseling materials. These materials should effectively convey both the immediate and long-term implications of genetic sequencing, enabling adolescents with cancer to make informed decisions about genetic sequencing.

Highly Evolvable: Investigating Interspecific and Intraspecific Venom Variation in Taipans (Oxyuranus spp.) and Brown Snakes (Pseudonaja spp.).

Snake venoms are complex mixtures of toxins that differ on interspecific (between species) and intraspecific (within species) levels. Whether venom variation within a group of closely related species is explained by the presence, absence and/or relative abundances of venom toxins remains largely unknown. Taipans (Oxyuranus spp.) and brown snakes (Pseudonaja spp.) represent medically relevant species of snakes across the Australasian region and provide an excellent model clade for studying interspecific and intraspecific venom variation. Using liquid chromatography with ultraviolet and mass spectrometry detection, we analyzed a total of 31 venoms covering all species of this monophyletic clade, including widespread localities. Our results reveal major interspecific and intraspecific venom variation in Oxyuranus and Pseudonaja species, partially corresponding with their geographical regions and phylogenetic relationships. This extensive venom variability is generated by a combination of the absence/presence and differential abundance of venom toxins. Our study highlights that venom systems can be highly dynamical on the interspecific and intraspecific levels and underscores that the rapid toxin evolvability potentially causes major impacts on neglected tropical snakebites.

Parents' experiences with large-scale sequencing for genetic predisposition in pediatric renal cancer: A qualitative study.

OBJECTIVE: In pediatric oncology, large-scale genetic sequencing contributes to the identification of cancer predisposition, which can facilitate surveillance and family counseling. Our qualitative study explores families' motives, knowledge, and views regarding germline genetic sequencing to improve future counseling and support. METHODS: Semi-structured interviews were conducted with parents of children with renal tumors participating in a national center, germline sequencing study. An inductive thematic analysis approach was used. Twenty nine parents participated, 17 mothers and 12 fathers. The median age of the affected children was 4 years. RESULTS: Parents were generally positive about sequencing and reported a combination of individual and altruistic motives to participate. Some families counseled about sequencing shortly after cancer diagnosis felt overwhelmed. Many parents had difficulties distinguishing between panel and exome-wide analysis. Families in which no predisposition was identified felt reassured. Most families did not experience distress after a predisposition was disclosed, although sometimes stress following disclosure of a predisposition added to pre-existing (cancer-related) stress. CONCLUSIONS: Even though families reported positive experiences with germline genetic sequencing to detect cancer predisposition, timing of consent for sequencing as well as parents' understanding of genetic concepts can be further improved.

Convergent evolution of toxin resistance in animals.

Convergence is the phenomenon whereby similar phenotypes evolve independently in different lineages. One example is resistance to toxins in animals. Toxins have evolved many times throughout the tree of life. They disrupt molecular and physiological pathways in target species, thereby incapacitating prey or deterring a predator. In response, molecular resistance has evolved in many species exposed to toxins to counteract their harmful effects. Here, we review current knowledge on the convergence of toxin resistance using examples from a wide range of toxin families. We explore the evolutionary processes and molecular adaptations driving toxin resistance. However, resistance adaptations may carry a fitness cost if they disrupt the normal physiology of the resistant animal. Therefore, there is a trade-off between maintaining a functional molecular target and reducing toxin susceptibility. There are relatively few solutions that satisfy this trade-off. As a result, we see a small set of molecular adaptations appearing repeatedly in diverse animal lineages, a phenomenon that is consistent with models of deterministic evolution. Convergence may also explain what has been called 'autoresistance'. This is often thought to have evolved for self-protection, but we argue instead that it may be a consequence of poisonous animals feeding on toxic prey. Toxin resistance provides a unique and compelling model system for studying the interplay between trophic interactions, selection pressures and the molecular mechanisms underlying evolutionary novelties.

Towards a Responsible Transition to Learning Healthcare Systems in Precision Medicine: Ethical Points to Consider.

Learning healthcare systems have recently emerged as a strategy to continuously use experiences and outcomes of clinical care for research purposes in precision medicine. Although it is known that learning healthcare transitions in general raise important ethical challenges, the ethical ramifications of such transitions in the specific context of precision medicine have not extensively been discussed. Here, we describe three levers that institutions can pull to advance learning healthcare systems in precision medicine: (1) changing testing of individual variability (such as genes); (2) changing prescription of treatments on the basis of (genomic) test results; and/or (3) changing the handling of data that link variability and treatment to clinical outcomes. Subsequently, we evaluate how patients can be affected if one of these levers are pulled: (1) patients are tested for different or more factors than before the transformation, (2) patients receive different treatments than before the transformation and/or (3) patients' data obtained through clinical care are used, or used more extensively, for research purposes. Based on an analysis of the aforementioned mechanisms and how these potentially affect patients, we analyze why learning healthcare systems in precision medicine need a different ethical approach and discuss crucial points to consider regarding this approach.

Widespread Evolution of Molecular Resistance to Snake Venom α-Neurotoxins in Vertebrates.

Venomous snakes are important subjects of study in evolution, ecology, and biomedicine. Many venomous snakes have alpha-neurotoxins (α-neurotoxins) in their venom. These toxins bind the alpha-1 nicotinic acetylcholine receptor (nAChR) at the neuromuscular junction, causing paralysis and asphyxia. Several venomous snakes and their predators have evolved resistance to α-neurotoxins. The resistance is conferred by steric hindrance from N-glycosylated asparagines at amino acids 187 or 189, by an arginine at position 187 that has been hypothesized to either electrostatically repulse positively charged neurotoxins or sterically interfere with α-neurotoxin binding, or proline replacements at positions 194 or 197 of the nAChR ligand-binding domain to inhibit α-neurotoxin binding through structural changes in the receptor. Here, we analyzed this domain in 148 vertebrate species, and assessed its amino acid sequences for resistance-associated mutations. Of these sequences, 89 were sequenced de novo. We find widespread convergent evolution of the N-glycosylation form of resistance in several taxa including venomous snakes and their lizard prey, but not in the snake-eating birds studied. We also document new lineages with the arginine form of inhibition. Using an in vivo assay in four species, we provide further evidence that N-glycosylation mutations reduce the toxicity of cobra venom. The nAChR is of crucial importance for normal neuromuscular function and is highly conserved throughout the vertebrates as a result. Our research shows that the evolution of α-neurotoxins in snakes may well have prompted arms races and mutations to this ancient receptor across a wide range of sympatric vertebrates. These findings underscore the inter-connectedness of the biosphere and the ripple effects that one adaption can have across global ecosystems.

Learning health care systems: Highly needed but challenging.

BACKGROUND: Learning health care systems (LHSs) have the potential to transform health care. However, this transformation process faces significant challenges. MATERIALS AND METHODS: Based on proposals and early examples of LHSs in the literature and conceptual analysis of the LHS mission, we provide four models with distinct organizational and ethical implications that may facilitate the transformation. RESULTS: An LHS could be developed in the following ways: by taking away practical impediments that prevent patients and professionals from engaging in scientific research (model 1: optimization LHS); by routinely analyzing observational data from electronic health records and other sources (model 2: comprehensive data LHS); by making clinical decisions based on the outcomes of the aforementioned data analyses and directly evaluating the outcomes in order to continuously improve decision-making (model 3: real-time LHS); or by embedding clinical trials into routine care delivery (model 4: full LHS). CONCLUSIONS: Each model has different ethical implications for consent and oversight. Also, the four-model approach shows that reorganizing a health care center into an LHS is not an all-or-nothing decision. Rather, it is a choice from a menu of possibilities. Instead of discussing the advantages and disadvantages of the LHS menu in its entirety, the medical community should focus on the designs and ethical aspects of each of the separate options.

Preferences to receive unsolicited findings of germline genome sequencing in a large population of patients with cancer.

BACKGROUND: In precision medicine, somatic and germline DNA sequencing are essential to make genome-guided treatment decisions in patients with cancer. However, it can also uncover unsolicited findings (UFs) in germline DNA that could have a substantial impact on the lives of patients and their relatives. It is therefore critical to understand the preferences of patients with cancer concerning UFs derived from whole-exome (WES) or whole-genome sequencing (WGS). METHODS: In a quantitative multicentre study, adult patients with cancer (any stage and origin of disease) were surveyed through a digital questionnaire based on previous semi-structured interviews. Background knowledge was provided by showing two videos, introducing basic concepts of genetics and general information about different categories of UFs (actionable, non-actionable, reproductive significance, unknown significance). RESULTS: In total 1072 patients were included of whom 701 participants completed the whole questionnaire. Overall, 686 (85.1%) participants wanted to be informed about UFs in general. After introduction of four UFs categories, 113 participants (14.8%) changed their answer: 718 (94.2%) participants opted for actionable variants, 537 (72.4%) for non-actionable variants, 635 (87.0%) participants for UFs of reproductive significance and 521 (71.8%) for UFs of unknown significance. Men were more interested in receiving certain UFs than women: non-actionable: OR 3.32; 95% CI 2.05 to 5.37, reproductive significance: OR 1.97; 95% CI 1.05 to 3.67 and unknown significance: OR 2.00; 95% CI 1.25 to 3.21. In total, 244 (33%) participants conceded family members to have access to their UFs while still alive. 603 (82%) participants agreed to information being shared with relatives, after they would pass away. CONCLUSION: Our study showed that the vast majority of patients with cancer desires to receive all UFs of genome testing, although a substantial minority does not wish to receive non-actionable findings. Incorporation of categories in informed consent procedures supports patients in making informed decisions on UFs.

Unsolicited genomic findings in daily clinical practice / Genoombreed onderzoek in de spreekkamer.

Whole genome sequencing (WGS) is increasingly being used in clinical practice. As a result, various healthcare professionals now encounter ethical dilemmas that were formerly confined within the genetics clinic. In addition to autonomy and well-being of both patients and their family members, which need to be balanced carefully, a societal perspective is also vital to ensure the ethically sound introduction of whole genome sequencing into daily practice. Important choices to be made are: who is eligible for whole genome sequencing; how can informed consent be sensibly obtained, when dealing with such vast quantities of genomic information; which type of information should be offered to patients; should professionals actively search for pathogenic mutations. The rise of WGS has an impact on the moral responsibilities incumbent on healthcare professionals and necessitates a comprehensive societal debate on the advent of personalized medicine.

Cancer patients' intentions towards receiving unsolicited genetic information obtained using next-generation sequencing.

Next-generation sequencing (NGS) can be used to generate information about a patient's tumour and personal genome. This powerful diagnostic tool provides solicited and unsolicited hereditary genetic (risk) information that could have consequences for cancer patients and their quality of life. A well-defined approach for returning appropriate genetic risk information is needed in personalized cancer care. A qualitative design with semi-structured interviews was used. We conducted interviews with 24 Dutch patients with different types of cancer, both NGS-experienced and NGS-inexperienced, to learn their intentions, needs and preferences towards receiving unsolicited genetic information obtained using NGS. Almost all participants had a positive attitude towards receiving unsolicited findings. After receiving comprehensive background information on NGS, including a binning model of four categories of unsolicited findings, most participants preferred to receive only subsets of genetic information. Their main concern was their own and others' (including family members) ability to cope with (the increased risk of having) a genetic disorder. Providing background information gave cancer patients the opportunity to select subsets of findings and increased their ability to make an informed choice. Special attention is needed for social and emotional factors to support the patients themselves and when communicating test results with their family members.

Is It Our Duty To Hunt for Pathogenic Mutations?

Should professionals systematically screen whole-genome sequencing (WGS) data to check for life-threatening mutations? Alternatively, should genome analysis focus on the primary reason for testing - that is, aiming to achieve precision medicine? We present an ethical review of the arguments and compare the act of searching for mutations with disclosing mutations that are discovered incidentally.

[Ethical dilemmas in a general practitioner's clinic due to incidental findings resulting from whole genome sequencing]. / Genoombreed onderzoek in de spreekkamer.

Whole genome sequencing (WGS) is increasingly being used in clinical practice. As a result, various healthcare professionals now encounter ethical dilemmas that were formerly confined within the genetics clinic. In addition to autonomy and well-being of both patients and their family members, which need to be balanced carefully, a societal perspective is also vital to ensure the ethically sound introduction of whole genome sequencing into daily practice. Important choices to be made are: who is eligible for whole genome sequencing; how can informed consent be sensibly obtained, when dealing with such vast quantities of genomic information; which type of information should be offered to patients; should professionals actively search for pathogenic mutations. The rise of WGS has an impact on the moral responsibilities incumbent on healthcare professionals and necessitates a comprehensive societal debate on the advent of personalized medicine.

Scanning the body, sequencing the genome: Dealing with unsolicited findings.

The introduction of novel diagnostic techniques in clinical domains such as genomics and radiology has led to a rich ethical debate on how to handle unsolicited findings that result from these innovations. Yet while unsolicited findings arise in both genomics and radiology, most of the relevant literature to date has tended to focus on only one of these domains. In this article, we synthesize and critically assess similarities and differences between "scanning the body" and "sequencing the genome" from an ethical perspective. After briefly describing the novel diagnostic contexts leading to unsolicited findings, we synthesize and reflect on six core ethical issues that relate to both specialties: terminology; benefits and risks; autonomy; disclosure of unsolicited findings to children; uncertainty; and filters and routine screening. We identify ethical rationales that pertain to both fields and may contribute to more ethically sound policies. Considerations of preserving public trust and ensuring that people perceive healthcare policies as fair also support the need for a combined debate.

Am I My Family's Keeper? Disclosure Dilemmas in Next-Generation Sequencing.

Ever since genetic testing is possible for specific mutations, ethical debate has sparked on the question of whether professionals have a duty to warn not only patients but also their relatives that might be at risk for hereditary diseases. As next-generation sequencing (NGS) swiftly finds its way into clinical practice, the question who is responsible for conveying unsolicited findings to family members becomes increasingly urgent. Traditionally, there is a strong emphasis on the duties of the professional in this debate. But what is the role of the patient and her family? In this article, we discuss the question of whose duty it is to convey relevant genetic risk information concerning hereditary diseases that can be cured or prevented to the relatives of patients undergoing NGS. We argue in favor of a shared responsibility for professionals and patients and present a strategy that reconciles these roles: a moral accountability nudge. Incorporated into informed consent and counseling services such as letters and online tools, this nudge aims to create awareness on specific patient responsibilities. Commitment of all parties is needed to ensure adequate dissemination of results in the NGS era.