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Returning actionable genomic results in a research biobank: Analytic validity, clinical implementation, and resource utilization.

ABSTRACT: Over 100 million research participants around the world have had research array-based genotyping (GT) or genome sequencing (GS), but only a small fraction of these have been offered return of actionable genomic findings (gRoR). Between 2017 and 2021, we analyzed genomic results from 36,417 participants in the Mass General Brigham Biobank and offered to confirm and return pathogenic and likely pathogenic variants (PLPVs) in 59 genes. Variant verification prior to participant recontact revealed that GT falsely identified PLPVs in 44.9% of samples, and GT failed to identify 72.0% of PLPVs detected in a subset of samples that were also sequenced. GT and GS detected verified PLPVs in 1% and 2.5% of the cohort, respectively. Of 256 participants who were alerted that they carried actionable PLPVs, 37.5% actively or passively declined further disclosure. 76.3% of those carrying PLPVs were unaware that they were carrying the variant, and over half of those met published professional criteria for genetic testing but had never been tested. This gRoR protocol cost approximately $129,000 USD per year in laboratory testing and research staff support, representing $14 per participant whose DNA was analyzed or $3,224 per participant in whom a PLPV was confirmed and disclosed. These data provide logistical details around gRoR that could help other investigators planning to return genomic results.

SUBMITTER: Blout Zawatsky CL

PROVIDER: S-EPMC8715145 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Practices and Attitudes toward Returning Genomic Research Results to Low-Resource Research Participants.

Project description:IntroductionMany research programs are challenged to accommodate low-resource research participants' (LRRP) ancillary care needs when returning genomic research results. We define LRRP as those who are low income, uninsured, underinsured, or facing barriers to act upon the results returned. This study evaluates current policies and practices surrounding return of results (RoR) to LRRP, as well as the attitudes of investigators toward providing ancillary care to LRRP.MethodsA semi-structured interview study was conducted with representatives of 35 genomic research programs nationwide. Eligible programs were returning, or planning to return, medically actionable genomic results to participants.ResultsThree content categories emerged from this study, including: (1) RoR structures, (2) barriers to RoR to LRRP, and (3) solutions to meet community and LRRP needs. Three major structures of RoR emerged: (1) RoR Embedded in Clinical Care, (2) RoR Independent of Clinical Care, and (3) Reliance on Clinical Partnerships to Facilitate RoR. Inadequacy of program resources to address the needs of LRRP was commonly considered a significant obstacle. The attitudes and views of informants regarding responsibility to provide ancillary care for LRRP receiving genomic results were highly varied. Some informants believed that genomic sequencing and testing was not a priority for LRRP because of other pressing issues in their lives, such as housing and food insecurity. Research programs differ regarding whether clinical and social support for LRRP is considered within the purview of the research team. Some programs instituted accommodations for LRRP, including social work referral and insurance enrollment assistance.ConclusionSupport to access downstream treatment is not readily available for LRRP in many genomic research programs. Development of best practices and policies for managing RoR to LRRP is needed.

| S-EPMC8592386 | biostudies-literature

A feasibility study of returning clinically actionable somatic genomic alterations identified in a research laboratory.

Project description:PurposeMolecular profiling performed in the research setting usually does not benefit the patients that donate their tissues. Through a prospective protocol, we sought to determine the feasibility and utility of performing broad genomic testing in the research laboratory for discovery, and the utility of giving treating physicians access to research data, with the option of validating actionable alterations in the CLIA environment.Experimental design1200 patients with advanced cancer underwent characterization of their tumors with high depth hybrid capture sequencing of 201 genes in the research setting. Tumors were also tested in the CLIA laboratory, with a standardized hotspot mutation analysis on an 11, 46 or 50 gene platform.Results527 patients (44%) had at least one likely somatic mutation detected in an actionable gene using hotspot testing. With the 201 gene panel, 945 patients (79%) had at least one alteration in a potentially actionable gene that was undetected with the more limited CLIA panel testing. Sixty-four genomic alterations identified on the research panel were subsequently tested using an orthogonal CLIA assay. Of 16 mutations tested in the CLIA environment, 12 (75%) were confirmed. Twenty-five (52%) of 48 copy number alterations were confirmed. Nine (26.5%) of 34 patients with confirmed results received genotype-matched therapy. Seven of these patients were enrolled onto genotype-matched targeted therapy trials.ConclusionExpanded cancer gene sequencing identifies more actionable genomic alterations. The option of CLIA validating research results can provide alternative targets for personalized cancer therapy.

| S-EPMC5522029 | biostudies-literature

Challenges in returning results in a genomic medicine implementation study: the Return of Actionable Variants Empirical (RAVE) study.

Project description:To inform the process of returning results in genome sequencing studies, we conducted a quantitative and qualitative assessment of challenges encountered during the Return of Actionable Variants Empiric (RAVE) study conducted at Mayo Clinic. Participants (n?=?2535, mean age 63?±?7, 57% female) were sequenced for 68 clinically actionable genes and 14 single nucleotide variants. Of 122 actionable results detected, 118 were returnable; results were returned by a genetic counselor-86 in-person and 12 by phone. Challenges in returning actionable results were encountered in a significant proportion (38%) of the cohort and were related to sequencing and participant contact. Sequencing related challenges (n?=?14), affecting 13 participants, included reports revised based on clinical presentation (n?=?3); reports requiring corrections (n?=?2); mosaicism requiring alternative DNA samples for confirmation (n?=?3); and variant re-interpretation due to updated informatics pipelines (n?=?6). Participant contact related challenges (n?=?44), affecting 38 participants, included nonresponders (n?=?20), decedents (n?=?1), and previously known results (n?=?23). These results should be helpful to investigators preparing for return of results in large-scale genomic sequencing projects.

| S-EPMC7198538 | biostudies-literature

Primary care providers' preferences for the communication and management of actionable genomic findings from a research biobank.

Project description:PurposeLittle is known about non-genetics health care specialists' attitudes toward the return and utilization of actionable genomic results from a research biobank. We surveyed primary care providers (PCPs) to explore their perspectives on these results and their preferences for return.MethodsWe administered a paper and web-based 27-question survey to PCPs residing locally and caring for adult patients. Recruitment was conducted in person and by email, focusing on PCPs likely to interact with results generated by our institution's biobank.ResultsOf the ~482 PCPs contacted, 77 (16%) returned surveys. Although most respondents (90%) prefer that a genetics specialist be involved in communicating biobank-generated genomic results to patients, about 40% of respondents reported that a PCP shares the responsibility to discuss these results along with other specialists. A majority of respondents (74%) felt uncomfortable communicating these results to patients. However, respondents reported significantly greater comfort with this process when offered targeted educational resources (62% with vs 10% without resources; P < 10-5).ConclusionPCPs recognize the need to engage with their patients' biobank-generated genomic results but feel uncomfortable in doing so. Relevant resources are needed to improve PCPs' confidence in the use of these types of results to affect patient care.

| S-EPMC10824104 | biostudies-literature

Proteome of Douglas-fir: a resource for genomic research

Project description:First Douglas fir proteomes by nLC-MS/MS from 12 different organs : root, stem, xylem, needle, bud, female and male flowers, immature and mature seed, immature and mature somatic embryos and callus.

2023-10-24 | PXD037815 | Pride

The UK Biobank resource with deep phenotyping and genomic data.

Project description:The UK Biobank project is a prospective cohort study with deep genetic and phenotypic data collected on approximately 500,000 individuals from across the United Kingdom, aged between 40 and 69 at recruitment. The open resource is unique in its size and scope. A rich variety of phenotypic and health-related information is available on each participant, including biological measurements, lifestyle indicators, biomarkers in blood and urine, and imaging of the body and brain. Follow-up information is provided by linking health and medical records. Genome-wide genotype data have been collected on all participants, providing many opportunities for the discovery of new genetic associations and the genetic bases of complex traits. Here we describe the centralized analysis of the genetic data, including genotype quality, properties of population structure and relatedness of the genetic data, and efficient phasing and genotype imputation that increases the number of testable variants to around 96 million. Classical allelic variation at 11 human leukocyte antigen genes was imputed, resulting in the recovery of signals with known associations between human leukocyte antigen alleles and many diseases.

| S-EPMC6786975 | biostudies-literature

EumicrobeDBLite: a lightweight genomic resource and analytic platform for draft oomycete genomes.

Project description:We have developed EumicrobeDBLite-a lightweight comprehensive genome resource and sequence analysis platform for oomycete organisms. EumicrobeDBLite is a successor of the VBI Microbial Database (VMD) that was built using the Genome Unified Schema (GUS). In this version, GUS has been greatly simplified with the removal of many obsolete modules and the redesign of others to incorporate contemporary data. Several dependences, such as perl object layers used for data loading in VMD, have been replaced with independent lightweight scripts. EumicrobeDBLite now runs on a powerful annotation engine developed at our laboratory, called 'Genome Annotator Lite'. Currently, this database has 26 publicly available genomes and 10 expressed sequence tag (EST) datasets of oomycete organisms. The browser page has dynamic tracks presenting comparative genomics analyses, coding and non-coding data, tRNA genes, repeats and EST alignments. In addition, we have defined 44 777 core conserved proteins from 12 oomycete organisms which form 2974 clusters. Synteny viewing is enabled by the incorporation of the Genome Synteny Viewer (GSV) tool. The user interface has undergone major changes for ease of browsing. Queryable comparative genomics information, conserved orthologous genes and pathways are among the new key features updated in this database. The browser has been upgraded to enable user upload of GFF files for quick view of genome annotation comparisons. The toolkit page integrates the EMBOSS package and has a gene prediction tool. Annotations for the organisms are updated once every 6 months to ensure quality. The database resource is available at www.eumicrobedb.org.

| S-EPMC6638084 | biostudies-literature

Preferences of biobank participants for receiving actionable genomic test results: results of a recontacting study.

Project description:PurposeWe sought to determine preferences of biobank participants whose samples were tested for clinically actionable variants but did not respond to an initial invitation to receive results.MethodsWe recontacted a subsample of participants in the Kaiser Permanente Washington/University of Washington site of the Electronic Medical Records and Genomics (eMERGE3) Network. The subsample had provided broad consent for their samples to be used for research but had not responded to one initial mailed invitation to receive their results. We sent a letter from the principal investigators with phone outreach. If no contact was made, we sent a certified letter stating our assumption that participant had actively refused. We collected reasons for declining.ResultsWe recontacted 123 participants. Response rate was 70.7% (n = 87). Of these, 62 (71.3%) declined the offer of returned results and 25 (28.7%) consented. The most common reasons provided for refusal included not wanting to know (n = 22) and concerns about insurability (n = 28).ConclusionEfforts to recontact biobank participants can yield high response. Though active refusal upon recontact was common, our data do not support assuming initial nonresponse to be refusal. Future research can work toward best practices for reconsenting, especially when clinically actionable results are possible.

| S-EPMC8194390 | biostudies-literature

Developing a Process for Returning Medically Actionable Genomic Variants to Latino Patients in a Federally Qualified Health Center.

Project description:AIM:To develop a process for returning medically actionable genomic variants to Latino patients receiving care in a Federally Qualified Health Center. METHODS:Prior to recruitment, researchers met with primary care providers to (1) orient clinicians to the project, (2) establish a process for returning actionable and nonactionable results to participants and providers through the electronic health record, and (3) develop a process for offering clinical decision support for follow-up education and care. A Community Advisory Board was engaged to provide input on recruitment strategies and materials for conveying results to participants. Participants in the Sangre Por Salud (Blood for Health) Biobank with hyperlipidemia or colon polyps represented the pool of potentially eligible participants. RESULTS:A total of 1,621 individuals were invited to participate and 710 agreed to an in- person consenting visit (194 no-showed and 16 declined). Over 12-months, 500 participants were enrolled. Participants were primarily Spanish-speaking (81.6%), female (74.2%), and enrolled because of hyperlipidemia (95.4%). All but 2 participants opted to receive primary (i.e., related to enrollment phenotypes) as well as secondary actionable results. CONCLUSION:Efforts to bring precision medicine to community-based health centers serving minority patients may require multilevel engagement activities to include individuals, providers, health systems, and the community.

| S-EPMC6363857 | biostudies-literature

Identifying Specific Combinations of Multimorbidity that Contribute to Health Care Resource Utilization: An Analytic Approach.

Project description:Multimorbidity affects the majority of elderly adults and is associated with higher health costs and utilization, but how specific patterns of morbidity influence resource use is less understood.The objective was to identify specific combinations of chronic conditions, functional limitations, and geriatric syndromes associated with direct medical costs and inpatient utilization.Retrospective cohort study using the Health and Retirement Study (2008-2010) linked to Medicare claims. Analysis used machine-learning techniques: classification and regression trees and random forest.A population-based sample of 5771 Medicare-enrolled adults aged 65 and older in the United States.Main covariates: self-reported chronic conditions (measured as none, mild, or severe), geriatric syndromes, and functional limitations. Secondary covariates: demographic, social, economic, behavioral, and health status measures.Medicare expenditures in the top quartile and inpatient utilization.Median annual expenditures were $4354, and 41% were hospitalized within 2 years. The tree model shows some notable combinations: 64% of those with self-rated poor health plus activities of daily living and instrumental activities of daily living disabilities had expenditures in the top quartile. Inpatient utilization was highest (70%) in those aged 77-83 with mild to severe heart disease plus mild to severe diabetes. Functional limitations were more important than many chronic diseases in explaining resource use.The multimorbid population is heterogeneous and there is considerable variation in how specific combinations of morbidity influence resource use. Modeling the conjoint effects of chronic conditions, functional limitations, and geriatric syndromes can advance understanding of groups at greatest risk and inform targeted tailored interventions aimed at cost containment.

| S-EPMC5309172 | biostudies-literature

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