Polygenic Risk Scores in Child and Adolescent PsychiatryEthical, Clinical, and Legal Implications
Recently, more than 500 genomic loci associated with various psychiatric disorders, including schizophrenia, depression, and autism spectrum disorders, have been identified. This makes it possible to generate polygenic risk scores (PRS) to stratify individuals by risk for different psychiatric disorders compared to the general population. As a prediction tool, psychiatric PRS would likely be most valuable when applied to individuals before the onset of illness. In about 75% of cases, the onset of psychiatric disorders or prodromal features occurs by early adulthood making psychiatric PRS likely most useful for children and adolescents. PRS have the potential to improve early identification, and lead to enhanced monitoring and interventions to potentially prevent or delay onset, and minimize morbidity and risk for suicide, the second leading cause of death in the U.S. in ages 10–24. Despite their promise, PRS could be especially perilous in the context of psychiatry, and our preliminary work has found that PRS are already being used in child and adolescent psychiatry. There is significant stigma around mental illness, and a history of misuse of “predictors” of “undesirable” behaviors or mental illness in the US. Thus, psychiatric PRS could be another tool used against patients with psychiatric disorders. Further, psychiatric PRS are arguably the first tool with the capacity to generate risk predictions about psychiatric disorders for any individual and there are key legal gaps in the protection of the privacy of this information and the prevention of genetic discrimination. To promote responsible use of psychiatric PRS in children and adolescents, we will use a mixed-methods approach that includes qualitative, quantitative ,and legal analysis to: 1) give voice to stakeholders (i.e., patients, parents/caregivers, clinicians) by examining their perspectives regarding whether psychiatric PRS should be used and, if so, how; and 2) examine the legal and regulatory landscape to identify what safeguards may be necessary. Although some of these gaps also apply to other genetic information, we will focus on identifying potential policy solutions for the likely uses and misuses of psychiatric PRS against individuals with or at risk of psychiatric disorders, almost 30% of the US population. The long-term goal of this research is to develop ethically-justified and empirically-informed guidelines to address the ethical challenges raised by the use of psychiatric PRS with children and adolescents.
Pediatric Deep Brain StimulationNeuroethics and Decision-Making
The BRAIN Initiative and other sponsors are investing in deep brain stimulation (DBS) and adaptive DBS (aDBS) systems, in large part, given their promise to improve the management of refractory movement and psychiatric disorders. DBS is FDA-approved for adults with refractory movement disorders such as Parkinson's disease, essential tremor, and offered under FDA-humanitarian device exemptions (HDE) for adults with refractory dystonia and obsessive compulsive disorder (OCD). The use of DBS in children (< 18 years old) has received little attention but it is quickly increasing. DBS is already offered under an FDA-HDE for children (≥ 7 years old) with refractory dystonia, making this movement disorder the most common indication for pediatric DBS (pDBS). In the same way as interest and research in DBS for psychiatric disorders is increasing in adults (e.g., OCD, anorexia, depression, Tourette syndrome (TS)), pDBS for psychiatric disorders is also on the rise. We identified 97 publications reporting pDBS for movement disorders (e.g., dystonia, essential tremor), as well as for psychiatric conditions (e.g., anorexia and TS) in pediatric patients (excluding epilepsy), 47 DBS trials on Clinicaltrials.gov in which minors are eligible, and at least 27 hospitals in the U.S. that are currently conducting pDBS. This study will allow us to examine which neuroethics issues, if any, actually pose a problem in this setting, determine how these issues manifest, what is the magnitude of the problem from the perspective of stakeholders, develop ethically-justified guidelines to help manage these issues, and study ways to improve decision making and informed consent processes.
The long-term goal of this research is to develop empirically-informed and ethically-justified management plans for pressing neuroethics issues raised by the clinical use of invasive neuromodulation in minors. This will help prevent ethical missteps and misuses of DBS in children. The objective of this proposal, which is the first step in pursuit of that goal, is to identify pressing neuroethics issues and decisional needs related to pDBS from the perspective of key stakeholders, and develop a decision aid (DA) for those considering pDBS. This study will empirically examine neuroethics challenges associated with research and translation of pDBS for treating neuropsychiatric and movement disorders. Identifying and understanding pDBS neuroethics issues can help develop management plans to promote the responsible research and translation of pDBS, and maximize its social utility. If pDBS is eventually considered safe and effective, minimizing pressing neuroethics challenges will contribute to the uptake of this neurotechnology among the thousands who could benefit from these systems.
Polygenic Embryo ScreeningTowards Informed Decision-Making
Preimplantation genetic testing (PGT) has been used for years to avoid implantation of embryos harboring rare monogenic disease-causing alleles or aneuploidies. However, recent progress in complex trait genetics, coupled with the technical ability to generate accurate genome-wide genotypes from single-cell input, have made it possible to genetically screen embryos for common polygenic traits and disease risk. There are several ethically relevant differences between conventional PGT for monogenic disease risk and screening based on polygenic risk scores (PRS). For example, unlike PGT, PES allows screening and selecting against risk for many of the most common and deadly diseases in the US (e.g., diabetes, heart disease, cancer, mental health disorders). In practice, PES may be used as a screening tool for multiple common polygenic conditions at the same time. Problematically, PES also could be used to screen against stigmatized conditions such as psychiatric disorders, and it allows selecting for "desirable" polygenic traits, including height and intelligence. Perhaps most importantly, PES is inherently probabilistic and subject to noise; results for each embryo would be reported in terms of percentage risk for a given condition(s).
While popular media has raised the specter of "designer babies", and private industry has begun to offer services of dubious merit, little empirical work has been done to quantify the utility of polygenic embryo screening (PES), assess stakeholders' perspectives, and examine its ethical implications.
The inherent ambiguity of PES requires careful consideration in order for clinicians, patients, policymakers, and the general public to make informed decisions about the potential consequences of implementing PES. Recently, we published a study examining the utility of PES (Karavani et al., Cell, 2019); we demonstrated the statistical limitations of applying polygenic scores for the purpose of selecting embryos on the basis of PRSs for quantitative traits. Given current technology, we found that the average gain due to screening would be modest, with extremely wide confidence intervals, resulting in considerable uncertainty for any clinicians and patients seeking PES. However, our preliminary data suggests that in the context of disease risk reduction, there is potential for much greater predictive power for PES. Moreover, although research momentum for PRS has grown exponentially in the last few years, there is little empirical data on the perspectives and attitudes of clinicians and patients regarding the potential clinical application of PRS, and no data at all in the context of assisted reproductive technology (ART).
In order to build a framework for the consideration of the ethical, legal, and social implications (ELSI) of PES, it is necessary to assess the attitudes and perspectives of clinicians and patients who would be most likely to use and be impacted by PES.