Biomedical subjects

Robert C Green

Publications and source records attributed to Robert C Green.

10 recordsLinked to original sources

PubMed2026

Recommendations for return of secondary genomic findings in observational cohort studies.

The return of secondary genomic findings (ROSF) to participants in observational cohort studies has evolved from a topic of debate to an accepted standard. This Perspective synthesizes the proceedings of a 2024 National Heart, Lung and Blood Institute-sponsored workshop and the broader literature to provide updated guidance for ROSF. Building on the 2010 National Heart, Lung and Blood Institute Working Group recommendations and the 2014 Clinical Sequencing Exploratory Research/Electronic Medical Records and Genomics 'floor and ceiling' framework, we address four areas: an integrated ethical framework for observational cohort settings; the emerging challenge of returning novel result types beyond monogenic variants, including polygenic risk scores, somatic mosaicism and pharmacogenomic findings; health equity and community engagement as structural prerequisites for ethical ROSF; and scalability challenges, including technology-assisted disclosure. Drawing on implementation experience from large-scale sequencing programs, we offer recommendations that balance researcher obligations with participant autonomy and equitable access to the benefits of genomic research.

Journal Article↗

PubMed2026

Elective genomic sequencing for adults in research, clinical and commercial contexts.

PURPOSE: Elective genomic sequencing (EGS) returns monogenic disease findings in multiple genes, including potentially novel variants, and may also provide participants with carrier status, pharmacogenomic and other health-related information. The PeopleSeq Study assessed participants' motivations for and concerns about EGS and the associated clinical and psychosocial outcomes across diverse EGS providers. METHODS: We administered a shared questionnaire to participants who chose to undergo EGS via 18 academic, clinical, or commercial EGS platforms. RESULTS: We enrolled 1575 participants, of whom 1147 (72.8%) completed a questionnaire after receiving their EGS results. A majority (60.3%) of the participants who completed a post-result questionnaire self-reported receiving results they assessed as important, including negative findings, and 75.9% reported a form of health-related utility. Among a subset (19.4%) who shared their EGS reports, 16.6% (37 of n = 223) received a monogenic finding and self-reported results deemed "important" were consistent with EGS reports. Most participants (74.1%) discussed their results with their family, but fewer discussed their results with a healthcare provider other than the site team (41.7%) or had one or more medical visits as a direct result of their EGS testing (23.1%). Participants expressed diverse motivations for EGS, with 91.4% expressing interest in their personal disease risk and 54% who expressed quasi-indication-based motivations related to family medical history. Individuals motivated by family history reported important results at a significantly higher rate. CONCLUSIONS: Early adopters of EGS are motivated by general interest in their health as well as quasi-indication-based considerations such as family history. A majority of participants learned results they considered medically important, but a much smaller segment engaged healthcare providers with their results.

Genomic testing↗

PubMed2025

Operationalizing the Wilson-Jungner principles for the genomics era: Consensus recommendations from the International Consortium on Newborn Sequencing.

PURPOSE: For decades, the selection of disorders included in newborn screening (NBS) programs has been guided by principles published by Wilson and Jungner in 1968. As research explores the expansion of conditions included in NBS through genomic sequencing, there is a critical need for updated recommendations to address the opportunities and complexities of genomic data. METHODS: The International Consortium on Newborn Sequencing includes leaders from over 16 research projects investigating genomic NBS across the United Kingdom, Europe, United States, and Oceania. Consortium members were invited to participate in a modified Delphi study, aggregating opinion on the selection of conditions for genomic NBS through 3 rounds of online questionnaires, with feedback provided to participants between rounds. RESULTS: In round 1, 94 participants completed the questionnaire, and 10 of 43 statements reached consensus. In round 2, 81 participants completed the questionnaire, and 14 of 27 statements reached consensus. In round 3, 68 participants completed the questionnaire, and all 10 statements reached 72% or more consensus. CONCLUSION: The 10 consensus recommendations developed in this study can guide future research and public health programs performing genomic NBS. This process also identified key areas of participant discordance, highlighting important topics for future research.

Humans↗

PubMed2025

Data-driven consideration of genetic disorders for global genomic newborn screening programs.

PURPOSE: Over 30 international studies are exploring newborn sequencing (NBSeq) to expand the range of genetic disorders included in newborn screening. Substantial variability in gene selection across programs exists, highlighting the need for a systematic approach to prioritize genes. METHODS: We assembled a data set comprising 25 characteristics about each of the 4390 genes included in 27 NBSeq programs. We used regression analysis to identify several predictors of inclusion and developed a machine learning model to rank genes for public health consideration. RESULTS: Among 27 NBSeq programs, the number of genes analyzed ranged from 134 to 4299, with only 74 (1.7%) genes included by over 80% of programs. The most significant associations with gene inclusion across programs were presence on the US Recommended Uniform Screening Panel (inclusion increase of 74.7%, CI: 71.0%-78.4%), robust evidence on the natural history (29.5%, CI: 24.6%-34.4%), and treatment efficacy (17.0%, CI: 12.3%-21.7%) of the associated genetic disease. A boosted trees machine learning model using 13 predictors achieved high accuracy in predicting gene inclusion across programs (area under the curve = 0.915, R2 = 84%). CONCLUSION: The machine learning model developed here provides a ranked list of genes that can adapt to emerging evidence and regional needs, enabling more consistent and informed gene selection in NBSeq initiatives.

Humans↗

PubMed2025

Nonadherence to guidelines for genetic testing in families with ovarian cancer shows racial bias.

PURPOSE: The National Comprehensive Cancer Network (NCCN) recommends germline genetic testing for individuals at risk for hereditary ovarian cancer. We sought to determine the proportion and characteristics of individuals meeting testing criteria in a multicenter biobank who were appropriately offered testing. METHODS: In this retrospective cohort study, we identified Mass General Brigham Biobank participants meeting genetic testing criteria per NCCN guidelines. Logistic regression was used to analyze sociodemographic factors associated with which participants were offered testing, completed testing, and had a family history that matched their self-report documented in the electronic medical record. RESULTS: Most eligible participants (909/1441, 63.1%) were not offered genetic testing. Participants who were Black or Hispanic had a lower likelihood of being offered testing. Compared with self-report, 988 (68.6%) participants had a family history of ovarian cancer documented in their electronic medical record. Older age, Hispanic ethnicity, and public insurance use were associated with decreased likelihoods of accurate family history documentation. Correct documentation was associated with an increased likelihood of being offered testing. CONCLUSION: The majority of participants in this study did not receive NCCN-compliant care. Germline genetic testing for hereditary ovarian cancer screening is underutilized and access to this testing is currently inequitable.

Adult↗

PubMed2024

Family genetic risk communication and reverse cascade testing in the BabySeq project.

PURPOSE: Genomic sequencing of newborns can initiate disease surveillance and therapy for children and may identify at-risk relatives through reverse cascade testing. We explored genetic risk communication and reverse cascade testing among families of newborns who underwent exome sequencing and were identified as having a risk for an autosomal dominant disease. METHODS: We conducted semistructured interviews with parents of newborns enrolled in the BabySeq Project who had a pathogenic or likely pathogenic variant associated with an autosomal dominant childhood- and/or adult-onset disease returned. We used directed content analysis to derive themes. RESULTS: From 11 families, all first-degree relatives (n = 32, 100%), 29 second-degree relatives (76%), and 26 third-degree relatives (43%) were informed of their risk. All parents (n = 22, 69% of first-degree relatives), 4 (11%) second-degree relatives, and 1 (2%) third-degree relatives underwent cascade testing. Most parents preferred to handle risk communication themselves. Parents with positive cascade testing but no associated symptoms were less inclined to share findings with relatives but highly motivated to share results if the variant's associated disease severity was high, as perceived with adult-onset conditions. One new subtheme, family member traits, was identified and defined as a relative's propensity to anxiety/concern after risk communications but did not diminish risk communication. CONCLUSION: Findings can inform more effective notification and testing practices for families of newborns at risk for hereditary genetic conditions.

Humans↗

PubMed2024

Estimating the sensitivity of genomic newborn screening for treatable inherited metabolic disorders.

PURPOSE: Over 30 research groups and companies are exploring newborn screening using genomic sequencing (NBSeq), but the sensitivity of this approach is not well understood. METHODS: We identified individuals with treatable inherited metabolic disorders (IMDs) and ascertained the proportion whose DNA analysis revealed explanatory deleterious variants (EDVs). We examined variables associated with EDV detection and estimated the sensitivity of DNA-first NBSeq. We further predicted the annual rate of true-positive and false-negative NBSeq results in the United States for several conditions on the Recommended Uniform Screening Panel. RESULTS: We identified 635 individuals with 80 unique IMDs. In univariate analyses, Black race (OR = 0.37, 95% CI: 0.16-0.89, P = .02) and public insurance (OR = 0.60, 95% CI: 0.39-0.91, P = .02) were less likely to be associated with finding EDVs. Had all individuals been screened with NBSeq, the sensitivity would have been 80.3%. We estimated that between 0 and 649.9 cases of Recommended Uniform Screening Panel IMDs would be missed annually by NBSeq in the United States. CONCLUSION: The overall sensitivity of NBSeq for treatable IMDs is estimated at 80.3%. That sensitivity will likely be lower for Black infants and those who are on public insurance.

Humans↗

PubMed2022

Patient and provider perspectives on polygenic risk scores: implications for clinical reporting and utilization.

BACKGROUND: Polygenic risk scores (PRS), which offer information about genomic risk for common diseases, have been proposed for clinical implementation. The ways in which PRS information may influence a patient's health trajectory depend on how both the patient and their primary care provider (PCP) interpret and act on PRS information. We aimed to probe patient and PCP responses to PRS clinical reporting choices METHODS: Qualitative semi-structured interviews of both patients (N=25) and PCPs (N=21) exploring responses to mock PRS clinical reports of two different designs: binary and continuous representations of PRS. RESULTS: Many patients did not understand the numbers representing risk, with high numeracy patients being the exception. However, all the patients still understood a key takeaway that they should ask their PCP about actions to lower their disease risk. PCPs described a diverse range of heuristics they would use to interpret and act on PRS information. Three separate use cases for PRS emerged: to aid in gray-area clinical decision-making, to encourage patients to do what PCPs think patients should be doing anyway (such as exercising regularly), and to identify previously unrecognized high-risk patients. PCPs indicated that receiving "below average risk" information could be both beneficial and potentially harmful, depending on the use case. For "increased risk" patients, PCPs were favorable towards integrating PRS information into their practice, though some would only act in the presence of evidence-based guidelines. PCPs describe the report as more than a way to convey information, viewing it as something to structure the whole interaction with the patient. Both patients and PCPs preferred the continuous over the binary representation of PRS (23/25 and 17/21, respectively). We offer recommendations for the developers of PRS to consider for PRS clinical report design in the light of these patient and PCP viewpoints. CONCLUSIONS: PCPs saw PRS information as a natural extension of their current practice. The most pressing gap for PRS implementation is evidence for clinical utility. Careful clinical report design can help ensure that benefits are realized and harms are minimized.

Clinical Decision-Making↗

PubMed2016

Implications of Personal Genomic Testing for Health Behaviors: The Case of Smoking.

INTRODUCTION: Direct-to-consumer personal genomic testing has the potential to influence health behaviors, including smoking. Critics of this testing highlight limited evidence to support positive behavioral benefits and caution that genomic results may provide false reassurance, leading to unhealthy behaviors. This study investigates interest in genetic risks of smoking-related diseases and changes in smoking behaviors among genomic testing consumers. METHODS: From 2012 to 2013, a longitudinal series of web surveys was conducted. A total of 1464 customers of 23andMe and Pathway Genomics completed a survey prior to viewing genomic test results, of which 1002 participants provided data on smoking behaviors 6 months after receiving results. RESULTS: At baseline, 64% of participants were never smokers, 29% were former smokers, and 7% were current smokers. Most baseline current smokers were very interested in genetic risk results for lung cancer (65%) and heart disease (72%). For lung cancer, this interest was significantly greater than former (50% very interested) and never smokers (37% very interested) (p < .0001). Even though participants were interested in smoking-related disease genetic risks, 96% reported the same smoking status at baseline and 6-month follow-up. Importantly, only 1% (n = 13/916) of former and never smokers became current smokers at 6 months and 22% (n = 14/64) of current smokers reported quitting. CONCLUSIONS: Overall, smokers show a high level of interest in genetic risks of smoking-related illnesses. The experience of receiving direct-to-consumer genomic health risks does not appear to have obvious harms related to smoking behaviors, with some potential benefits. IMPLICATIONS: In the setting of ongoing controversy surrounding direct-to-consumer genomic testing, this study provides evidence that consumers are interested in genetic risk results of smoking-related diseases. Receiving genomic testing results does not lead to smoking initiation among never smokers or reinitiation among former smokers and may be associated with a higher quit rate among current smokers at 6-month follow-up than the general population. These findings ease concerns that direct-to-consumer genomic testing could lead to false reassurance and unhealthy behaviors related to smoking.

Adolescent↗

PubMed2011

Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease.

The Alzheimer Disease Genetics Consortium (ADGC) performed a genome-wide association study of late-onset Alzheimer disease using a three-stage design consisting of a discovery stage (stage 1) and two replication stages (stages 2 and 3). Both joint analysis and meta-analysis approaches were used. We obtained genome-wide significant results at MS4A4A (rs4938933; stages 1 and 2, meta-analysis P (P(M)) = 1.7 × 10(-9), joint analysis P (P(J)) = 1.7 × 10(-9); stages 1, 2 and 3, P(M) = 8.2 × 10(-12)), CD2AP (rs9349407; stages 1, 2 and 3, P(M) = 8.6 × 10(-9)), EPHA1 (rs11767557; stages 1, 2 and 3, P(M) = 6.0 × 10(-10)) and CD33 (rs3865444; stages 1, 2 and 3, P(M) = 1.6 × 10(-9)). We also replicated previous associations at CR1 (rs6701713; P(M) = 4.6 × 10(-10), P(J) = 5.2 × 10(-11)), CLU (rs1532278; P(M) = 8.3 × 10(-8), P(J) = 1.9 × 10(-8)), BIN1 (rs7561528; P(M) = 4.0 × 10(-14), P(J) = 5.2 × 10(-14)) and PICALM (rs561655; P(M) = 7.0 × 10(-11), P(J) = 1.0 × 10(-10)), but not at EXOC3L2, to late-onset Alzheimer's disease susceptibility.

Adaptor Proteins, Signal Transducing↗