A collaborative translational research framework for evaluating and implementing the appropriate use of human genome sequencing to improve health

Abstract

In a Policy Forum, Muin Khoury and colleagues discuss research on the clinical application of genome sequencing data.

Perspective: The Clinical Use of Polygenic Risk Scores: Race, Ethnicity, and Health Disparities

“…The added value of PRS is unclear compared with or in addition to existing prevention and management approaches based on age, family history, and environmental risk factors. 4 This is especially true among populations that are underrepresented in genomic research. Indeed, a recent perspective by Martin and colleagues warns that the clinical use of current PRS may exacerbate health disparities.…”

Direct-to-consumer genetic testing with third party interpretation: beware of spurious results

“…Over 2% of people have a (likely) disease-causing variant in one of the 59 'medically actionable' disease genes which the American College of Medical Genetics and Genomics (ACMG) recommends are opportunistically examined when people have clinical sequencing [22], but the ACMG recently stressed that this gene list was not developed with population screening in mind [23]. Whilst exome and genome sequencing may be highly useful in finding explanations for people affected by rare conditions [24], there is currently limited evidence that this technology would lead to clinical benefit if offered to the population at large [25]. Population-level genome analyses should shake our confidence in our ability to predict the consequences of even well-understood genetic variants when found outside the context of a personal or family history of the relevant disease: their penetrance will be lower than current estimates, which have generally been derived from studying the experiences of people who had targeted testing because they were considered to be at high risk of disease [26].…”

Clinical Stewardship of Genomic Information in Pediatric Critical Care: A Qualitative Interview Study

“…A needed part of a model for clinical stewardship is transparency in communication about the current state of GS implementation: that GS is being implemented before the workings of the genome are fully understood, the efficacy of therapies and clinical decisions made from GS results are still unclear, and contextualizing results is falling on families and bedside clinicians, while knowledge and decision support approaches are still being developed. 33,34 How to incorporate GS into clinical decision-making while evidence linking GS findings with outcomes is still forthcoming is unclear, but explicit and transparent acknowledgement that this is the current state of knowledge will be fundamental to clinical GS stewardship in pediatric critical care. Particularly challenging is the tension critical care clinicians must negotiate between the growing awareness that GS variant classification is dynamic with patient findings needing to be reevaluated over time, 5 and the use of GS findings to inform irrevocable decisions like critical resource allocation (organs) and withdrawal of care.…”

“…With ongoing debate about genetic exceptionalism and whether genetic information needs to be considered and protected as different or special, 40 uncertainty regarding how to translate bio-bank privacy protections to clinical care, 34 and doubt among interviewed clinicians about healthcare institutions' ability to protect patient privacy, the need to gauge the importance of genomic privacy to individual families, and approaches to GS privacy protection need to be discussed between clinicians and families. That interviewed clinicians discussed whether patients undergoing private direct-toconsumer testing and families selectively revealing pertinent GS findings to their treating clinicians is an appropriate privacy protection, makes clear the responsibility clinicians already feel towards protecting patients' GS information and that clinicians and families are already considering withholding GS information from the medical record (though not from clinical care).…”