Table 1.
Illustrative quotes related to identified themes that express ethical actions and obligations to maximize benefits, minimize risks, promote justice, and support autonomy (Beauchamp and Childress 2013). Note that many of the quotes include the abbreviation PRS for polygenic risk score (citations within quotes are omitted)
| Theme | Illustrative quote |
|---|---|
| Need for increased diversity in genetic research | “We discuss the important ethical, legal, and social implications of increasing ancestral diversity in genetic studies of cardiometabolic disease and the challenges that arise from the (1) lack of diversity in current reference populations and available analytic samples and the (2) unequal generation of health-associated genomic data and their prediction accuracies” (Fernandez-Rhodes et al. 2020) |
| “The lack of representative GWAS has been recognized as a key obstacle in the project of Precision Medicine. Initiatives like the All of Us study, the Clinical Sequencing Evidence-Generating Research Consortium (CSER), the Human Genome Reference Program (HGRP), the PRS Diversity Consortium, and others have been designed to address both the underlying science and clinical translation, as well as longstanding debates about the role of race in medicine, genetics, and genomics” (James et al. 2021) | |
| Need for responsible data safeguarding and sharing | “In addition, many of the approaches used in research (e.g., anonymization, de-identification) are not applicable to genetic information because the genome is the ultimate identifier. Thus there is a requirement for additional strategies that preserve the privacy of genomic data while not compromising the accuracy of the results” (McLaren et al. 2016) |
| “In particular, disease risk prediction based on patient characteristics, including PRSs, has the potential to be used against the patient, and thus tight regulation is needed. To balance the advantage of advancing healthcare using large-scale EHR data and potential concerns of privacy violations, more up-to-date regulatory measures are needed to match the pace of technological development” (Li et al. 2020) | |
| “Barriers to such data-sharing include non-harmonized or unclear data protection laws and data localization requirements, which can preclude the creation of large representative datasets. Legal doctrines including collection limitation and data minimization, purpose limitation, and strict interpretations of consent requirements and anonymization requirements, all common to data protection law, can impede the collection of rich datasets and the efficient sharing thereof” (Knoppers et al. 2021) | |
| Empirical demonstration of validity and utility | “For both sets of evidence, assumptions on effectiveness and cost-effectiveness based on results of modeling must be backed by evidence of scientific validity and clinical utility from systematic empirical research such as pilot studies or clinical trials” (Chowdhury et al. 2013) |
| “PRSs have strong face validity; they intuitively seem to make sense, but this apparent face validity is not enough. More comparative research is needed to investigate the construct, content, and criterion validity of PRS, to explore alternative ways of quantifying polygenic risk, and to rigorously compare new and current methods” (Janssens 2019) | |
| “There remains a gap in evidence from prospective observational studies or treatment trials regarding the appropriate placement of PRS in risk assessment and lipid treatment decisions relative to information on rare monogenic gene variants, particularly in multiethnic populations” (O'Donnell 2020) | |
| “Poorly designed and/or described studies call into question the validity of some PRS to predict their target outcome, and relatively few studies have externally benchmarked multiple scores’ performance” (Wand et al. 2021) | |
| Need for accurate communication | “This conceptual transfer from monogenic disorders to polygenic disease is quite inappropriate, because polygenic disease involves the co-inheritance of several genetic determinants that usually have to interact with environmental factors before the disease becomes manifest. The genetic determinants for a phenotype can be variable and they may interact with different ways; some of the genetic factors can even be protective for the occurrence of the disease” (Galton and Ferns 1999) |
| “We argue that particular attention should be paid to the difficulties associated with the communication and interpretation of results. This would be due, in part, to the fact that, given the etiological complexity of psychiatric disorders, a PRS in the top percentile would be an indicator of risk, not a definitive prognosis. For this reason, nuance and skill would be required in articulating and ensuring correct understanding (both of counsellors and patients) of ‘complex’ risk. While the difficulties associated with feedback of complex genetic risk are not necessarily unique to PRS, they nevertheless warrant consideration given its recency” (Palk et al. 2019) | |
| Need for guidelines, standards, and possible regulation | “Another measure to build public trust and sustainability of omics fields could be legislative initiatives to create a multidisciplinary oversight body, at arm’s length from conflicts of interests, to carry out independent, impartial, and transparent innovation analyses and prospective technology assessment” (Ozdemir et al. 2009) |
| “As GWAS sample sizes increase and PRS become more powerful, they are set to play a role in research and personalized medicine. However, despite the growing application and importance of PRS, there are limited guidelines for performing PRS analyses, which can lead to inconsistency between studies and misinterpretation of results” (Choi et al. 2020) | |
| “Although we have provided explicit recommendations on how to acknowledge study design limitations and their effects on the interpretation and generalizability of a PRS, future research should attempt to establish best practices to guide the field” (Wand et al. 2021) | |
| "Stricter controls need to be put in place to regulate companies offering direct-to-consumer genetic tests” (Manrique de Lara et al. 2019) |