Genetic ancestry and diagnostic yield of exome sequencing in a diverse population.

It has been suggested that diagnostic yield (DY) from Exome Sequencing (ES) may be lower among patients with non-European ancestries than those with European ancestry. We examined the association of DY with estimated continental/subcontinental genetic ancestry in a racially/ethnically diverse pediatric and prenatal clinical cohort. Cases (N = 845) with suspected genetic disorders underwent ES for diagnosis.

Participant perceptions of changes in psychosocial domains following participation in an adaptive deep brain stimulation trial.

Background: There has been substantial controversy in the neuroethics literature regarding the extent to which deep brain stimulation (DBS) impacts dimensions of personality, mood, and behavior.

Objective/hypothesis: Despite extensive debate in the theoretical literature, there remains a paucity of empirical data available to support or refute claims related to the psychosocial changes following DBS.

Methods: A mixed-methods approach was used to examine the perspectives of patients who underwent DBS regarding changes to their personality, authenticity, autonomy, risk-taking, and overall quality of life.

The role of polygenic risk scores in breast cancer risk perception and decision-making.

Polygenic risk scores (PRS) have the potential to improve the accuracy of clinical risk assessments, yet questions about their clinical validity and readiness for clinical implementation persist. Understanding how individuals integrate and act on the information provided by PRS is critical for their effective integration into routine clinical care, yet few studies have examined how individuals respond to the receipt of polygenic risk information. We conducted an embedded Ethical, Legal, and Social Implications (ELSI) study to examine if and how unaffected participants in a US population breast cancer screening trial understood and utilized PRS, as part of a multifactorial risk score combining traditional risk factors with a genetic risk assessment, to make screening and risk-reduction decisions.

Diagnostic Yield of Exome Sequencing in a Diverse Pediatric and Prenatal Population is not Associated with Genetic Ancestry.

Purpose: It has been hypothesized that diagnostic yield (DY) from Exome Sequencing (ES) may be lower among patients with non-European ancestries than those with European ancestry. We examined the association of DY with estimated continental genetic ancestry in a racially/ethnically diverse pediatric and prenatal clinical cohort.

Methods: Cases (N=845) with suspected genetic disorders underwent ES for diagnosis.

A draft human pangenome reference.

Here the Human Pangenome Reference Consortium presents a first draft of the human pangenome reference. The pangenome contains 47 phased, diploid assemblies from a cohort of genetically diverse individuals. These assemblies cover more than 99% of the expected sequence in each genome and are more than 99% accurate at the structural and base pair levels.

"If relatives inherited the gene, they should inherit the data." Bringing the family into the room where bioethics happens.

Biological kin share up to half of their genetic material, including predisposition to disease. Thus, variants of clinical significance identified in each individual's genome can implicate an exponential number of relatives at potential risk. This has renewed the dilemma over family access to research participant's genetic results, since prevailing U.

Post-trial access in implanted neural device research: Device maintenance, abandonment, and cost.

Background: Clinical trial participants who benefit from experimental neural devices for the treatment of debilitating and otherwise treatment-resistant conditions are generally not ensured continued access to effective therapy or maintenance of devices at the conclusion of trials.

Objective/hypothesis: Post-trial obligations have been extensively examined in the context of drug trials, but there has been little empirical examination of stakeholder perspectives regarding these obligations in the rapidly growing field of neural device research.

Methods: This study examined the perspectives of 44 stakeholders (i.

A qualitative study of unaffected ATM and CHEK2 carriers: How participants make meaning of 'moderate risk' genetic results in a population breast cancer screening trial.

Relatively little is known about experiences of individuals with a pathogenic variant in a moderately penetrant breast cancer gene, particularly those without a personal history of cancer. The WISDOM trial is testing a model of risk-based breast cancer screening that integrates genomic (nine genes and polygenic risk) and other risk factors. In the context of an embedded Ethical, Legal, and Social Implications (ELSI) study of WISDOM, we conducted qualitative interviews at two timepoints post-result disclosure with 22 ATM and CHEK2 carriers.

The Human Pangenome Project: a global resource to map genomic diversity.

The human reference genome is the most widely used resource in human genetics and is due for a major update. Its current structure is a linear composite of merged haplotypes from more than 20 people, with a single individual comprising most of the sequence. It contains biases and errors within a framework that does not represent global human genomic variation.

Researcher Views on Changes in Personality, Mood, and Behavior in Next-Generation Deep Brain Stimulation.

The literature on deep brain stimulation (DBS) and adaptive DBS (aDBS) raises concerns that these technologies may affect personality, mood, and behavior. We conducted semi-structured interviews with researchers ( = 23) involved in developing next-generation DBS systems, exploring their perspectives on ethics and policy topics including whether DBS/aDBS can cause such changes. The majority of researchers reported being aware of personality, mood, or behavioral (PMB) changes in recipients of DBS/aDBS.

Perspectives and preferences regarding genomic secondary findings in underrepresented prenatal and pediatric populations: A mixed-methods approach.

Purpose: Patients undergoing clinical exome sequencing (ES) are routinely offered the option to receive secondary findings (SF). However, little is known about the views of individuals from underrepresented minority pediatric or prenatal populations regarding SF.

Methods: We explored the preferences for receiving hypothetical categories of SF (H-SF) and reasons for accepting or declining actual SF through surveying (n = 149) and/or interviewing (n = 47) 190 families undergoing pediatric or prenatal ES.

The difficulties of broad data sharing in genomic medicine: Empirical evidence from diverse participants in prenatal and pediatric clinical genomics research.

Purpose: This study aimed to understand broad data sharing decisions among predominantly underserved families participating in genomic research.

Methods: Drawing on clinic observations, semistructured interviews, and survey data from prenatal and pediatric families enrolled in a genomic medicine study focused on historically underserved and underrepresented populations, this paper expands empirical evidence regarding genomic data sharing communication and decision-making.

Results: One-third of parents declined to share family data, and pediatric participants were significantly more likely to decline than prenatal participants.

Examining access to care in clinical genomic research and medicine: Experiences from the CSER Consortium.

Introduction: Ensuring equitable access to health care is a widely agreed-upon goal in medicine, yet access to care is a multidimensional concept that is difficult to measure. Although frameworks exist to evaluate access to care generally, the concept of "access to genomic medicine" is largely unexplored and a clear framework for studying and addressing major dimensions is lacking.

Methods: Comprised of seven clinical genomic research projects, the Clinical Sequencing Evidence-Generating Research consortium (CSER) presented opportunities to examine access to genomic medicine across diverse contexts.

The limits of personalization in precision medicine: Polygenic risk scores and racial categorization in a precision breast cancer screening trial.

Population-based genomic screening is at the forefront of a new approach to disease prevention. Yet the lack of diversity in genome wide association studies and ongoing debates about the appropriate use of racial and ethnic categories in genomics raise key questions about the translation of genomic knowledge into clinical practice. This article reports on an ethnographic study of a large pragmatic clinical trial of breast cancer screening called WISDOM (Women Informed to Screen Depending On Measures of Risk).

Patient, Caregiver, and Decliner Perspectives on Whether to Enroll in Adaptive Deep Brain Stimulation Research.

This research study provides patient and caregiver perspectives as to whether or not to undergo adaptive deep brain stimulation (aDBS) research. A total of 51 interviews were conducted in a multi-site study including patients undergoing aDBS and their respective caregivers along with persons declining aDBS. Reasons highlighted for undergoing aDBS included hopes for symptom alleviation, declining quality of life, desirability of being in research, and altruism.

Ethical, Legal, and Social Implications of Fetal Gene Therapy.

As fetal gene therapies move from experimental animal models to human in utero phase I clinical trials, there is a need to consider the ethical, legal, and social implications. While fetal gene therapies are attracting more regulatory oversight than previous fetal interventions such as fetal surgery, old sociological questions should be applied to this new context. As health care pathways around fetal therapy are shaped by the ways in which a pregnant person and the fetus are constituted, and as risks and benefits are evaluated, we cannot afford to lose sight of long-term consequences, especially those pertaining to social inclusion.

Preference for secondary findings in prenatal and pediatric exome sequencing.

Objective: We aimed to determine the frequency of accepting secondary findings in families undergoing exome sequencing in prenatal and pediatric settings.

Methods: This was a secondary analysis of prospectively enrolled patients undergoing trio exome sequencing for congenital anomalies or developmental disorders in prenatal and pediatric settings, in which families were offered receiving secondary findings (initially assessed in the proband and, if identified, then in the parents). The primary outcome was frequency of accepting secondary findings.

Opportunities and challenges for the computational interpretation of rare variation in clinically important genes.

Genome sequencing is enabling precision medicine-tailoring treatment to the unique constellation of variants in an individual's genome. The impact of recurrent pathogenic variants is often understood, however there is a long tail of rare genetic variants that are uncharacterized. The problem of uncharacterized rare variation is especially acute when it occurs in genes of known clinical importance with functionally consequential variants and associated mechanisms.

Researcher Perspectives on Data Sharing in Deep Brain Stimulation.

The expansion of research on deep brain stimulation (DBS) and adaptive DBS (aDBS) raises important neuroethics and policy questions related to data sharing. However, there has been little empirical research on the perspectives of experts developing these technologies. We conducted semi-structured, open-ended interviews with aDBS researchers regarding their data sharing practices and their perspectives on ethical and policy issues related to sharing.

Toward better governance of human genomic data.

In this Commentary, we argue that in line with the dramatic increase in the collection, storage, and curation of human genomic data for biomedical research, genomic data repositories and consortia have adopted governance frameworks to address the dual objectives of enabling wide access while protecting against possible harms. However, there are ongoing debates in the scientific community about the merits and limitations of different governance frameworks in achieving these twin aims; and indeed, best practices and points for consideration are notably absent when it comes to devising a governance framework for genomic databases. Based on our collective experience of devising and assessing governance frameworks, our Commentary identifies five key functions of “good governance” (or what makes “better governance”) and three areas where trade-offs should be considered when specifying policies within those functions.

Researcher Perspectives on Ethical Considerations in Adaptive Deep Brain Stimulation Trials.

Interest and investment in closed-loop or adaptive deep brain stimulation (aDBS) systems have quickly expanded due to this neurotechnology's potential to more safely and effectively treat refractory movement and psychiatric disorders compared to conventional DBS. A large neuroethics literature outlines potential ethical concerns about conventional DBS and aDBS systems. Few studies, however, have examined stakeholder perspectives about ethical issues in aDBS research and other next-generation DBS devices.

The role of exome sequencing in newborn screening for inborn errors of metabolism.

Public health newborn screening (NBS) programs provide population-scale ascertainment of rare, treatable conditions that require urgent intervention. Tandem mass spectrometry (MS/MS) is currently used to screen newborns for a panel of rare inborn errors of metabolism (IEMs). The NBSeq project evaluated whole-exome sequencing (WES) as an innovative methodology for NBS.

Clinical Genetics Lacks Standard Definitions and Protocols for the Collection and Use of Diversity Measures.

Genetics researchers and clinical professionals rely on diversity measures such as race, ethnicity, and ancestry (REA) to stratify study participants and patients for a variety of applications in research and precision medicine. However, there are no comprehensive, widely accepted standards or guidelines for collecting and using such data in clinical genetics practice. Two NIH-funded research consortia, the Clinical Genome Resource (ClinGen) and Clinical Sequencing Evidence-generating Research (CSER), have partnered to address this issue and report how REA are currently collected, conceptualized, and used.