Age-Based Genomic Screening during Childhood: Ethical and Practical Considerations in Public Health Genomics Implementation

Genomic sequencing offers an unprecedented opportunity to detect inherited variants that are implicated in rare Mendelian disorders, yet there are many challenges to overcome before this technology can routinely be applied in the healthy population. The age-based genomic screening (ABGS) approach is a novel alternative to genome-scale sequencing at birth that aims to provide highly actionable genetic information to parents over the course of their child’s routine health care. ABGS utilizes an established metric to identify conditions with high clinical actionability and incorporates information about the age of onset and age of intervention to determine the optimal time to screen for any given condition. Ongoing partnerships with parents and providers are instrumental to the co-creation of educational resources and strategies to address potential implementation barriers. Implementation science frameworks and informative empirical data are used to evaluate strategies to establish this unique clinical application of targeted genomic sequencing. Ultimately, a pilot project conducted in primary care pediatrics clinics will assess patient and implementation outcomes, parent and provider perspectives, and the feasibility of ABGS. A validated, stakeholder-informed, and practical ABGS program will include hundreds of conditions that are actionable during infancy and childhood, setting the stage for a longitudinal implementation that can assess clinical and health economic outcomes

Barriers and Facilitators for Population Genetic Screening in Healthy Populations: A Systematic Review

Studies suggest that 1–3% of the general population in the United States unknowingly carry a genetic risk factor for a common hereditary disease. Population genetic screening is the process of offering otherwise healthy patients in the general population testing for genomic variants that predispose them to diseases that are clinically actionable, meaning that they can be prevented or mitigated if they are detected early. Population genetic screening may significantly reduce morbidity and mortality from these diseases by informing risk-specific prevention or treatment strategies and facilitating appropriate participation in early detection. To better understand current barriers, facilitators, perceptions, and outcomes related to the implementation of population genetic screening, we conducted a systematic review and searched PubMed, Embase, and Scopus for articles published from date of database inception to May 2020. We included articles that 1) detailed the perspectives of participants in population genetic screening programs and 2) described the barriers, facilitators, perceptions, and outcomes related to population genetic screening programs among patients, healthcare providers, and the public. We excluded articles that 1) focused on direct-to-consumer or risk-based genetic testing and 2) were published before January 2000. Thirty articles met these criteria. Barriers and facilitators to population genetic screening were organized by the Social Ecological Model and further categorized by themes. We found that research in population genetic screening has focused on stakeholder attitudes with all included studies designed to elucidate individuals’ perceptions. Additionally, inadequate knowledge and perceived limited clinical utility presented a barrier for healthcare provider uptake. There were very few studies that conducted long-term follow-up and evaluation of population genetic screening. Our findings suggest that these and other factors, such as prescreen counseling and education, may play a role in the adoption and implementation of population genetic screening. Future studies to investigate macro-level determinants, strategies to increase provider buy-in and knowledge, delivery models for prescreen counseling, and long-term outcomes of population genetic screening are needed for the effective design and implementation of such programs.Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD4202019819

Parental Guidance Suggested: Engaging Parents as Partners in Research Studies of Genomic Screening for a Pediatric Population

Recent advances in genomic sequencing and genomic medicine are reshaping the landscape of clinical care. As a screening modality, genetic sequencing has the potential to dramatically expand the clinical utility of newborn screening (NBS), though significant barriers remain regarding ethical, legal, and social implications (ELSI) and technical and evidentiary challenges. Stakeholder-informed implementation research is poised to grapple with many of these barriers, and parents are crucial stakeholders in this process. We describe the formation and activities of a Community Research Board (CRB) composed of parents with diverse backgrounds assembled to participate in an ongoing research partnership with genomic and public health researchers at the University of North Carolina. The mission of the CRB is to provide insight into parental perspectives regarding the prospect of adding genomic sequencing to NBS and collaboratively develop strategies to ensure its equitable uptake. We describe how these contributions can improve the accessibility of research and recruitment methods and promote trust and inclusivity within diverse communities to maximize the societal benefit of population genomic screening in healthy children

Evaluating parents’ decisions about next-generation sequencing for their child in the NC NEXUS (North Carolina Newborn Exome Sequencing for Universal Screening) study: a randomized controlled trial protocol

Abstract Background Using next-generation sequencing (NGS) in newborn screening (NBS) could expand the number of genetic conditions detected pre-symptomatically, simultaneously challenging current precedents, raising ethical concerns, and extending the role of parental decision-making in NBS. The NC NEXUS (Newborn Exome Sequencing for Universal Screening) study seeks to assess the technical possibilities and limitations of NGS-NBS, devise and evaluate a framework to convey various types of genetic information, and develop best practices for incorporating NGS-NBS into clinical care. The study is enrolling both a healthy cohort and a cohort diagnosed with known disorders identified through recent routine NBS. It uses a novel age-based metric to categorize a priori the large amount of data generated by NGS-NBS and interactive online decision aids to guide parental decision-making. Primary outcomes include: (1) assessment of NGS-NBS sensitivity, (2) decision regret, and (3) parental decision-making about NGS-NBS, and, for parents randomized to have the option of requesting them, additional findings (diagnosed and healthy cohorts). Secondary outcomes assess parents’ reactions to the study and to decision-making. Methods/design Participants are parents and children in a well-child cohort recruited from a prenatal clinic and a diagnosed cohort recruited from pediatric clinics that treat children with disorders diagnosed through traditional NBS (goal of 200 children in each cohort). In phase 1, all parent participants use an online decision aid to decide whether to accept NGS-NBS for their child and provide consent for NGS-NBS. In phase 2, parents who consent to NGS-NBS are randomized to a decision arm or control arm (2:1 allocation) and learn their child’s NGS-NBS results, which include conditions from standard (non-NGS) NBS plus other highly actionable childhood-onset conditions. Parents in the decision arm use a second decision aid to make decisions about additional results from their child’s sequencing. In phase 3, decision arm participants learn additional results they have requested. Online questionnaires are administered at up to five time points. Discussion NC NEXUS will use a rigorous interdisciplinary approach designed to collect rich data to inform policy, practice, and future research. Trial registration clinicaltrials.gov, NCT02826694 . Registered on 11 July, 2016

Evaluating the Clinical Validity of Gene-Disease Associations: An Evidence-Based Framework Developed by the Clinical Genome Resource

Supplemental Data Supplemental Data include 65 figures and can be found with this article online at http://dx.doi.org/10.1016/j.ajhg.2017.04.015. Supplemental Data Document S1. Figures S1–S65 Download Document S2. Article plus Supplemental Data Download Web Resources ClinGen, https://www.clinicalgenome.org/ ClinGen Gene Curation, https://www.clinicalgenome.org/working-groups/gene-curation/ ClinGen Gene Curation SOP, https://www.clinicalgenome.org/working-groups/gene-curation/projects-initiatives/gene-disease-clinical-validity-sop/ ClinGen Knowledge Base, https://search.clinicalgenome.org/kb/agents/sign_up OMIM, http://www.omim.org/ Orphanet, http://www.orpha.net/consor/cgi-bin/index.php With advances in genomic sequencing technology, the number of reported gene-disease relationships has rapidly expanded. However, the evidence supporting these claims varies widely, confounding accurate evaluation of genomic variation in a clinical setting. Despite the critical need to differentiate clinically valid relationships from less well-substantiated relationships, standard guidelines for such evaluation do not currently exist. The NIH-funded Clinical Genome Resource (ClinGen) has developed a framework to define and evaluate the clinical validity of gene-disease pairs across a variety of Mendelian disorders. In this manuscript we describe a proposed framework to evaluate relevant genetic and experimental evidence supporting or contradicting a gene-disease relationship and the subsequent validation of this framework using a set of representative gene-disease pairs. The framework provides a semiquantitative measurement for the strength of evidence of a gene-disease relationship that correlates to a qualitative classification: “Definitive,” “Strong,” “Moderate,” “Limited,” “No Reported Evidence,” or “Conflicting Evidence.” Within the ClinGen structure, classifications derived with this framework are reviewed and confirmed or adjusted based on clinical expertise of appropriate disease experts. Detailed guidance for utilizing this framework and access to the curation interface is available on our website. This evidence-based, systematic method to assess the strength of gene-disease relationships will facilitate more knowledgeable utilization of genomic variants in clinical and research settings

Newborn Sequencing in Genomic Medicine and Public Health

The rapid development of genomic sequencing technologies has decreased the cost of genetic analysis to the extent that it seems plausible that genome-scale sequencing could have widespread availability in pediatric care. Genomic sequencing provides a powerful diagnostic modality for patients who manifest symptoms of monogenic disease and an opportunity to detect health conditions before their development. However, many technical, clinical, ethical, and societal challenges should be addressed before such technology is widely deployed in pediatric practice. This article provides an overview of the Newborn Sequencing in Genomic Medicine and Public Health Consortium, which is investigating the application of genome-scale sequencing in newborns for both diagnosis and screening

Age-Based Genomic Screening during Childhood: Ethical and Practical Considerations in Public Health Genomics Implementation

Genomic sequencing offers an unprecedented opportunity to detect inherited variants that are implicated in rare Mendelian disorders, yet there are many challenges to overcome before this technology can routinely be applied in the healthy population. The age-based genomic screening (ABGS) approach is a novel alternative to genome-scale sequencing at birth that aims to provide highly actionable genetic information to parents over the course of their child’s routine health care. ABGS utilizes an established metric to identify conditions with high clinical actionability and incorporates information about the age of onset and age of intervention to determine the optimal time to screen for any given condition. Ongoing partnerships with parents and providers are instrumental to the co-creation of educational resources and strategies to address potential implementation barriers. Implementation science frameworks and informative empirical data are used to evaluate strategies to establish this unique clinical application of targeted genomic sequencing. Ultimately, a pilot project conducted in primary care pediatrics clinics will assess patient and implementation outcomes, parent and provider perspectives, and the feasibility of ABGS. A validated, stakeholder-informed, and practical ABGS program will include hundreds of conditions that are actionable during infancy and childhood, setting the stage for a longitudinal implementation that can assess clinical and health economic outcomes

The Rise of Population Genomic Screening: Characteristics of Current Programs and the Need for Evidence Regarding Optimal Implementation

Purpose: Advances in clinical genomic sequencing capabilities, including reduced costs and knowledge gains, have bolstered the consideration of genomic screening in healthy adult populations. Yet, little is known about the existing landscape of genomic screening programs in the United States. It can be difficult to find information on current implementation efforts and best practices, particularly in light of critical questions about equity, cost, and benefit. Methods: In 2020, we searched publicly available information on the Internet and the scientific literature to identify programs and collect information, including: setting, program funding, targeted population, test offered, and patient cost. Program representatives were contacted throughout 2020 and 2021 to clarify, update, and supplement the publicly available information. Results: Twelve programs were identified. Information was available on key program features, such as setting, genes tested, and target populations. Data on costs, outcomes, or long-term sustainability plans were not always available. Most programs offered testing at no or significantly reduced cost due to generous pilot funding, although the sustainability of these programs remains unknown. Gene testing lists were diverse, ranging from 11 genes (CDC tier 1 genes) to 59 genes (ACMG secondary findings list v.2) to broad exome and genome sequencing. This diversity presents challenges for harmonized data collection and assessment of program outcomes. Conclusions: Early programs are exploring the logistics and utility of population genomic screening in various settings. Coordinated efforts are needed to take advantage of data collected about uptake, infrastructure, and intervention outcomes to inform future research, evaluation, and program development

Increasing the diagnostic yield of exome sequencing by copy number variant analysis.

As whole exome sequencing (WES) becomes more widely used in the clinical realm, a wealth of unanalyzed information will be routinely generated. Using WES read depth data to predict copy number variation (CNV) could extend the diagnostic utility of this previously underutilized data by providing clinically important information such as previously unsuspected deletions or duplications. We evaluated ExomeDepth, a free R package, in addition to an aneuploidy prediction method, to detect CNVs in WES data. First, in a blinded pilot study, five out of five genomic alterations were correctly identified from clinical samples with previously defined chromosomal gains or losses, including submicroscopic deletions, duplications, and chromosomal trisomy. We then examined CNV calls among 53 patients participating in the NCGENES research study and undergoing WES, who had existing clinical chromosomal microarray (CMA) data that could be used for validation. For unique CNVs that overlap well with WES coverage regions, sensitivity was 89% for deletions and 65% for duplications. While specificity of the algorithm calls remains a concern, this is less of an issue at high threshold filtering levels. When applied to all 672 patients from the exome sequencing study, ExomeDepth identified eleven diagnostically relevant CNVs ranging in size from a two exon deletion to whole chromosome duplications, as well as numerous other CNVs with varying clinical significance. This opportunistic analysis of WES data yields an additional 1.6% of patients in this study with pathogenic or likely pathogenic CNVs that are clinically relevant to their phenotype as well as clinically relevant secondary findings. Finally, we demonstrate the potential value of copy number analysis in cases where a single heterozygous likely or known pathogenic single nucleotide alteration is identified in a gene associated with an autosomal recessive condition

Evaluating parents’ decisions about next-generation sequencing for their child in the NC NEXUS (North Carolina Newborn Exome Sequencing for Universal Screening) study: a randomized controlled trial protocol

Abstract Background Using next-generation sequencing (NGS) in newborn screening (NBS) could expand the number of genetic conditions detected pre-symptomatically, simultaneously challenging current precedents, raising ethical concerns, and extending the role of parental decision-making in NBS. The NC NEXUS (Newborn Exome Sequencing for Universal Screening) study seeks to assess the technical possibilities and limitations of NGS-NBS, devise and evaluate a framework to convey various types of genetic information, and develop best practices for incorporating NGS-NBS into clinical care. The study is enrolling both a healthy cohort and a cohort diagnosed with known disorders identified through recent routine NBS. It uses a novel age-based metric to categorize a priori the large amount of data generated by NGS-NBS and interactive online decision aids to guide parental decision-making. Primary outcomes include: (1) assessment of NGS-NBS sensitivity, (2) decision regret, and (3) parental decision-making about NGS-NBS, and, for parents randomized to have the option of requesting them, additional findings (diagnosed and healthy cohorts). Secondary outcomes assess parents’ reactions to the study and to decision-making. Methods/design Participants are parents and children in a well-child cohort recruited from a prenatal clinic and a diagnosed cohort recruited from pediatric clinics that treat children with disorders diagnosed through traditional NBS (goal of 200 children in each cohort). In phase 1, all parent participants use an online decision aid to decide whether to accept NGS-NBS for their child and provide consent for NGS-NBS. In phase 2, parents who consent to NGS-NBS are randomized to a decision arm or control arm (2:1 allocation) and learn their child’s NGS-NBS results, which include conditions from standard (non-NGS) NBS plus other highly actionable childhood-onset conditions. Parents in the decision arm use a second decision aid to make decisions about additional results from their child’s sequencing. In phase 3, decision arm participants learn additional results they have requested. Online questionnaires are administered at up to five time points. Discussion NC NEXUS will use a rigorous interdisciplinary approach designed to collect rich data to inform policy, practice, and future research. Trial registration clinicaltrials.gov, NCT02826694. Registered on 11 July, 2016