Publications by authors named "Robert C Green"

296 Publications

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

Am J Hum Genet 2021 Nov 3. Epub 2021 Nov 3.

Brigham and Women's Hospital, Boston, MA 02115, USA; Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, USA; Ariadne Labs, Boston, MA 02215, USA; Harvard Medical School, Boston, MA 02115, USA; Mass General Brigham Personalized Medicine, Cambridge, MA 02139, USA. Electronic address:

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.
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http://dx.doi.org/10.1016/j.ajhg.2021.10.005DOI Listing
November 2021

Do research participants share genomic screening results with family members?

J Genet Couns 2021 Oct 19. Epub 2021 Oct 19.

Division of Genetics and Genomics and the Manton Center for Orphan Diseases Research, Boston Children's Hospital, Boston, MA, USA.

The public health impact of genomic screening can be enhanced by cascade testing. However, cascade testing depends on communication of results to family members. While the barriers and facilitators of family communication have been researched following clinical genetic testing, the factors impacting the dissemination of genomic screening results are unknown. Using the pragmatic Electronic Medical Records and Genomics Network-3 (eMERGE-3) study, we explored the reported sharing practices of participants who underwent genomic screening across the United States. Six eMERGE-3 sites returned genomic screening results for mostly dominant medically actionable disorders and surveyed adult participants regarding communication of results with first-degree relatives. Across the sites, 279 participants completed a 1-month and/or 6-month post-results survey. By 6 months, only 34% of the 156 respondents shared their results with all first-degree relatives and 4% did not share with any. Over a third (39%) first-degree relatives were not notified of the results. Half (53%) of participants who received their results from a genetics provider shared them with all first-degree relatives compared with 11% of participants who received their results from a non-genetics provider. The most frequent reasons for sharing were a feeling of obligation (72%) and that the information could help family members make medical decisions (72%). The most common reasons indicated for not sharing were that the family members were too young (38%), or they were not in contact (25%) or not close to them (25%). These data indicate that the professional returning the results may impact sharing patterns, suggesting that there is a need to continue to educate healthcare providers regarding approaches to facilitate sharing of genetic results within families. Finally, these data suggest that interventions to increase sharing may be universally effective regardless of the origin of the genetic result.
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http://dx.doi.org/10.1002/jgc4.1511DOI Listing
October 2021

Using the Alzheimer's Disease Neuroimaging Initiative to improve early detection, diagnosis, and treatment of Alzheimer's disease.

Alzheimers Dement 2021 Sep 28. Epub 2021 Sep 28.

Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Research, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Introduction: The Alzheimer's Disease Neuroimaging Initiative (ADNI) has accumulated 15 years of clinical, neuroimaging, cognitive, biofluid biomarker and genetic data, and biofluid samples available to researchers, resulting in more than 3500 publications. This review covers studies from 2018 to 2020.

Methods: We identified 1442 publications using ADNI data by conventional search methods and selected impactful studies for inclusion.

Results: Disease progression studies supported pivotal roles for regional amyloid beta (Aβ) and tau deposition, and identified underlying genetic contributions to Alzheimer's disease (AD). Vascular disease, immune response, inflammation, resilience, and sex modulated disease course. Biologically coherent subgroups were identified at all clinical stages. Practical algorithms and methodological changes improved determination of Aβ status. Plasma Aβ, phosphorylated tau181, and neurofilament light were promising noninvasive biomarkers. Prognostic and diagnostic models were externally validated in ADNI but studies are limited by lack of ethnocultural cohort diversity.

Discussion: ADNI has had a profound impact in improving clinical trials for AD.
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http://dx.doi.org/10.1002/alz.12422DOI Listing
September 2021

Behavioral and psychological impact of genome sequencing: a pilot randomized trial of primary care and cardiology patients.

NPJ Genom Med 2021 Aug 24;6(1):72. Epub 2021 Aug 24.

Center for Medical Ethics and Health Policy at Baylor College of Medicine, Houston, TX, USA.

Many expect genome sequencing (GS) to become routine in patient care and preventive medicine, but uncertainties remain about its ability to motivate participants to improve health behaviors and the psychological impact of disclosing results. In a pilot trial with exploratory analyses, we randomized 100 apparently healthy, primary-care participants and 100 cardiology participants to receive a review of their family histories of disease, either alone or in addition to GS analyses. GS results included polygenic risk information for eight cardiometabolic conditions. Overall, no differences were observed between the percentage of participants in the GS and control arms, who reported changes to health behaviors such as diet and exercise at 6 months post disclosure (48% vs. 36%, respectively, p = 0.104). In the GS arm, however, the odds of reporting a behavior change increased by 52% per high-risk polygenic prediction (p = 0.032). Mean anxiety and depression scores for GS and control arms had confidence intervals within equivalence margins of ±1.5. Mediation analyses suggested an indirect impact of GS on health behaviors by causing positive psychological responses (p ≤ 0.001). Findings suggest that GS did not distress participants. Future research on GS in more diverse populations is needed to confirm that it does not raise risks for psychological harms and to confirm the ability of polygenic risk predictions to motivate preventive behaviors.
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http://dx.doi.org/10.1038/s41525-021-00236-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8384838PMC
August 2021

Psychosocial Effect of Newborn Genomic Sequencing on Families in the BabySeq Project: A Randomized Clinical Trial.

JAMA Pediatr 2021 Nov;175(11):1132-1141

Center for Medical Ethics and Health Policy, Baylor College of Medicine, Houston, Texas.

Importance: Newborn genomic sequencing (nGS) may provide health benefits throughout the life span, but there are concerns that it could also have an unfavorable (ie, negative) psychosocial effect on families.

Objective: To assess the psychosocial effect of nGS on families from the BabySeq Project, a randomized clinical trial evaluating the effect of nGS on the clinical care of newborns from well-baby nurseries and intensive care units.

Design, Setting, And Participants: In this randomized clinical trial conducted from May 14, 2015, to May 21, 2019, at well-baby nurseries and intensive care units at 3 Boston, Massachusetts, area hospitals, 519 parents of 325 infants completed surveys at enrollment, immediately after disclosure of nGS results, and 3 and 10 months after results disclosure. Statistical analysis was performed on a per-protocol basis from January 16, 2019, to December 1, 2019.

Intervention: Newborns were randomized to receive either standard newborn screening and a family history report (control group) or the same plus an nGS report of childhood-onset conditions and highly actionable adult-onset conditions (nGS group).

Main Outcomes And Measures: Mean responses were compared between groups and, within the nGS group, between parents of children who received a monogenic disease risk finding and those who did not in 3 domains of psychosocial impact: parent-child relationship (Mother-to-Infant Bonding Scale), parents' relationship (Kansas Marital Satisfaction Scale), and parents' psychological distress (Edinburgh Postnatal Depression Scale anxiety subscale).

Results: A total of 519 parents (275 women [53.0%]; mean [SD] age, 35.1 [4.5] years) were included in this study. Although mean scores differed for some outcomes at singular time points, generalized estimating equations models did not show meaningful differences in parent-child relationship (between-group difference in adjusted mean [SE] Mother-to-Infant Bonding Scale scores: postdisclosure, 0.04 [0.15]; 3 months, -0.18 [0.18]; 10 months, -0.07 [0.20]; joint P = .57) or parents' psychological distress (between-group ratio of adjusted mean [SE] Edinburgh Postnatal Depression Scale anxiety subscale scores: postdisclosure, 1.04 [0.08]; 3 months, 1.07 [0.11]; joint P = .80) response patterns between study groups over time for any measures analyzed in these 2 domains. Response patterns on one parents' relationship measure differed between groups over time (between-group difference in adjusted mean [SE] Kansas Marital Satisfaction Scale scores: postdisclosure, -0.19 [0.07]; 3 months, -0.04 [0.07]; and 10 months, -0.01 [0.08]; joint P = .02), but the effect decreased over time and no difference was observed on the conflict measure responses over time. We found no evidence of persistent negative psychosocial effect in any domain.

Conclusions And Relevance: In this randomized clinical trial of nGS, there was no persistent negative psychosocial effect on families among those who received nGS nor among those who received a monogenic disease risk finding for their infant.

Trial Registration: ClinicalTrials.gov Identifier: NCT02422511.
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http://dx.doi.org/10.1001/jamapediatrics.2021.2829DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8383160PMC
November 2021

Physician-directed genetic screening to evaluate personal risk for medically actionable disorders: a large multi-center cohort study.

BMC Med 2021 08 18;19(1):199. Epub 2021 Aug 18.

Invitae, 1400 16th Street, San Francisco, CA, 94103, USA.

Background: The use of proactive genetic screening for disease prevention and early detection is not yet widespread. Professional practice guidelines from the American College of Medical Genetics and Genomics (ACMG) have encouraged reporting pathogenic variants that confer personal risk for actionable monogenic hereditary disorders, but only as secondary findings from exome or genome sequencing. The Centers for Disease Control and Prevention (CDC) recognizes the potential public health impact of three Tier 1 actionable disorders. Here, we report results of a large multi-center cohort study to determine the yield and potential value of screening healthy individuals for variants associated with a broad range of actionable monogenic disorders, outside the context of secondary findings.

Methods: Eligible adults were offered a proactive genetic screening test by health care providers in a variety of clinical settings. The screening panel based on next-generation sequencing contained up to 147 genes associated with monogenic disorders within cancer, cardiovascular, and other important clinical areas. Sequence and intragenic copy number variants classified as pathogenic, likely pathogenic, pathogenic (low penetrance), or increased risk allele were considered clinically significant and reported. Results were analyzed by clinical area and severity/burden of disease using chi-square tests without Yates' correction.

Results: Among 10,478 unrelated adults screened, 1619 (15.5%) had results indicating personal risk for an actionable monogenic disorder. In contrast, only 3.1 to 5.2% had clinically reportable variants in genes suggested by the ACMG version 2 secondary findings list to be examined during exome or genome sequencing, and 2% had reportable variants related to CDC Tier 1 conditions. Among patients, 649 (6.2%) were positive for a genotype associated with a disease of high severity/burden, including hereditary cancer syndromes, cardiovascular disorders, or malignant hyperthermia susceptibility.

Conclusions: This is one of the first real-world examples of specialists and primary care providers using genetic screening with a multi-gene panel to identify health risks in their patients. Nearly one in six individuals screened for variants associated with actionable monogenic disorders had clinically significant results. These findings provide a foundation for further studies to assess the role of genetic screening as part of regular medical care.
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http://dx.doi.org/10.1186/s12916-021-01999-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8371767PMC
August 2021

Effects of participation in a U.S. trial of newborn genomic sequencing on parents at risk for depression.

J Genet Couns 2021 Jul 26. Epub 2021 Jul 26.

Division of Genetics and Genomics, Boston Children's Hospital, Boston, Massachusetts, USA.

Much emphasis has been placed on participant's psychological safety within genomic research studies; however, few studies have addressed parental psychological health effects associated with their child's participation in genomic studies, particularly when parents meet the threshold for clinical concern for depression. We aimed to determine if parents' depressive symptoms were associated with their child's participation in a randomized-controlled trial of newborn exome sequencing. Parents completed the Edinburgh Postnatal Depression Scale (EPDS) at baseline, immediately post-disclosure, and 3 months post-disclosure. Mothers and fathers scoring at or above thresholds for clinical concern on the EPDS, 12 and 10, respectively, indicating possible Major Depressive Disorder with Peripartum Onset, were contacted by study staff for mental health screening. Parental concerns identified in follow-up conversations were coded for themes. Forty-five parents had EPDS scores above the clinical threshold at baseline, which decreased by an average of 2.9 points immediately post-disclosure and another 1.1 points 3 months post-disclosure (both p ≤ .014). For 28 parents, EPDS scores were below the threshold for clinical concern at baseline, increased by an average of 4.7 points into the elevated range immediately post-disclosure, and decreased by 3.8 points at 3 months post-disclosure (both p < .001). Nine parents scored above thresholds only at 3 months post-disclosure after increasing an average of 5.7 points from immediately post-disclosure (p < .001). Of the 82 parents who scored above the threshold at any time point, 43 (52.4%) were reached and 30 (69.7%) of these 43 parents attributed their elevated scores to parenting stress, balancing work and family responsibilities, and/or child health concerns. Only three parents (7.0%) raised concerns about their participation in the trial, particularly their randomization to the control arm. Elevated scores on the EPDS were typically transient and parents attributed their symptomatology to life stressors in the postpartum period rather than participation in a trial of newborn exome sequencing.
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http://dx.doi.org/10.1002/jgc4.1475DOI Listing
July 2021

An international policy on returning genomic research results.

Genome Med 2021 07 15;13(1):115. Epub 2021 Jul 15.

Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.

The Global Alliance for Genomics and Health has approved a policy for the return of clinically actionable genomic research results, the first such policy approved by an international body. The policy acknowledges the potential medical benefits to millions of individuals who are participating in genomics research. It ties the pace of implementation to each country's clinical standards, including for the return of secondary findings, and urges funders to set aside resources to support responsible return.
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http://dx.doi.org/10.1186/s13073-021-00928-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8281644PMC
July 2021

Molecular cancer screening: in search of evidence.

Nat Med 2021 Jul;27(7):1139-1142

Harvard Medical School, Boston, MA, USA.

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http://dx.doi.org/10.1038/s41591-021-01431-5DOI Listing
July 2021

Primary care providers' responses to unsolicited Lynch syndrome secondary findings of varying clinical significance.

Genet Med 2021 10 10;23(10):1977-1983. Epub 2021 Jun 10.

PRecisiOn Medicine Translational Research (PROMoTeR) Center, Department of Population Medicine, Harvard Pilgrim Health Care Institute, Boston, MA, USA.

Purpose: How primary care providers (PCPs) respond to genomic secondary findings (SFs) of varying clinical significance (pathogenic, uncertain significance [VUS], or benign) is unknown.

Methods: We randomized 148 American Academy of Family Physicians members to review three reports with varying significance for Lynch syndrome. Participants provided open-ended responses about the follow-up they would address and organized the SF reports and five other topics in the order they would prioritize responding to them (1 = highest priority, 6 = lowest priority).

Results: PCPs suggested referrals more often for pathogenic variants or VUS than benign variants (72% vs. 16%, p < 0.001). PCPs were also more likely to address further workup, like a colonoscopy or esophagogastroduodenoscopy, in response to pathogenic variants or VUS than benign variants (43% vs. 4%, p < 0.001). The likelihoods of addressing referrals or further workup were similar when PCPs reviewed pathogenic variants and VUS (both p > 0.46). SF reports were prioritized highest for pathogenic variants (2.7 for pathogenic variants, 3.6 for VUS, 4.3 for benign variants, all p ≤ 0.014).

Conclusion: Results suggest that while PCPs appreciated the differences in clinical significance, disclosure of VUS as SFs would substantially increase downstream health-care utilization.
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http://dx.doi.org/10.1038/s41436-021-01225-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8487923PMC
October 2021

Development and Validation of a Comprehensive Genomics Knowledge Scale.

Public Health Genomics 2021 31;24(5-6):291-303. Epub 2021 May 31.

Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.

Background: Genomic testing is increasingly employed in clinical, research, educational, and commercial contexts. Genomic literacy is a prerequisite for the effective application of genomic testing, creating a corresponding need for validated tools to assess genomics knowledge. We sought to develop a reliable measure of genomics knowledge that incorporates modern genomic technologies and is informative for individuals with diverse backgrounds, including those with clinical/life sciences training.

Methods: We developed the GKnowM Genomics Knowledge Scale to assess the knowledge needed to make an informed decision for genomic testing, appropriately apply genomic technologies and participate in civic decision-making. We administered the 30-item draft measure to a calibration cohort (n = 1,234) and subsequent participants to create a combined validation cohort (n = 2,405). We performed a multistage psychometric calibration and validation using classical test theory and item response theory (IRT) and conducted a post-hoc simulation study to evaluate the suitability of a computerized adaptive testing (CAT) implementation.

Results: Based on exploratory factor analysis, we removed 4 of the 30 draft items. The resulting 26-item GKnowM measure has a single dominant factor. The scale internal consistency is α = 0.85, and the IRT 3-PL model demonstrated good overall and item fit. Validity is demonstrated with significant correlation (r = 0.61) with an existing genomics knowledge measure and significantly higher scores for individuals with adequate health literacy and healthcare providers (HCPs), including HCPs who work with genomic testing. The item bank is well suited to CAT, achieving high accuracy (r = 0.97 with the full measure) while administering a mean of 13.5 items.

Conclusion: GKnowM is an updated, broadly relevant, rigorously validated 26-item measure for assessing genomics knowledge that we anticipate will be useful for assessing population genomic literacy and evaluating the effectiveness of genomics educational interventions.
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http://dx.doi.org/10.1159/000515006DOI Listing
May 2021

Purifying selection on noncoding deletions of human regulatory loci detected using their cellular pleiotropy.

Genome Res 2021 Jun 7;31(6):935-946. Epub 2021 May 7.

Department of Biomedical Informatics, Harvard Medical School, Boston, Massachusetts 02115, USA.

Genomic deletions provide a powerful loss-of-function model in noncoding regions to assess the role of purifying selection on genetic variation. Regulatory element function is characterized by nonuniform tissue and cell type activity, necessarily linking the study of fitness consequences from regulatory variants to their corresponding cellular activity. We generated a callset of deletions from genomes in the Alzheimer's Disease Neuroimaging Initiative (ADNI) and used deletions from The 1000 Genomes Project Consortium (1000GP) in order to examine whether purifying selection preserves noncoding sites of chromatin accessibility marked by DNase I hypersensitivity (DHS), histone modification (enhancer, transcribed, Polycomb-repressed, heterochromatin), and chromatin loop anchors. To examine this in a cellular activity-aware manner, we developed a statistical method, pleiotropy ratio score (PlyRS), which calculates a correlation-adjusted count of "cellular pleiotropy" for each noncoding base pair by analyzing shared regulatory annotations across tissues and cell types. By comparing real deletion PlyRS values to simulations in a length-matched framework and by using genomic covariates in analyses, we found that purifying selection acts to preserve both DHS and enhancer noncoding sites. However, we did not find evidence of purifying selection for noncoding transcribed, Polycomb-repressed, or heterochromatin sites beyond that of the noncoding background. Additionally, we found evidence that purifying selection is acting on chromatin loop integrity by preserving colocalized CTCF binding sites. At regions of DHS, enhancer, and CTCF within chromatin loop anchors, we found evidence that both sites of activity specific to a particular tissue or cell type and sites of cellularly pleiotropic activity are preserved by selection.
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http://dx.doi.org/10.1101/gr.275263.121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8168579PMC
June 2021

Precision Population Medicine in Primary Care: The Sanford Chip Experience.

Front Genet 2021 12;12:626845. Epub 2021 Mar 12.

Sanford Health Imagenetics, Sioux Falls, SD, United States.

Genetic testing has the potential to revolutionize primary care, but few health systems have developed the infrastructure to support precision population medicine applications or attempted to evaluate its impact on patient and provider outcomes. In 2018, Sanford Health, the nation's largest rural nonprofit health care system, began offering genetic testing to its primary care patients. To date, more than 11,000 patients have participated in the Sanford Chip Program, over 90% of whom have been identified with at least one informative pharmacogenomic variant, and about 1.5% of whom have been identified with a medically actionable predisposition for disease. This manuscript describes the rationale for offering the Sanford Chip, the programs and infrastructure implemented to support it, and evolving plans for research to evaluate its real-world impact.
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http://dx.doi.org/10.3389/fgene.2021.626845DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7994529PMC
March 2021

Discordant results between conventional newborn screening and genomic sequencing in the BabySeq Project.

Genet Med 2021 07 26;23(7):1372-1375. Epub 2021 Mar 26.

Division of Genetics and Genomics, The Manton Center for Orphan Disease Research, Boston Children's Hospital, and Department of Pediatrics, Harvard Medical School, Boston, MA, USA.

Purpose: Newborn screening (NBS) is performed to identify neonates at risk for actionable, severe, early-onset disorders, many of which are genetic. The BabySeq Project randomized neonates to receive conventional NBS or NBS plus exome sequencing (ES) capable of detecting sequence variants that may also diagnose monogenic disease or indicate genetic disease risk. We therefore evaluated how ES and conventional NBS results differ in this population.

Methods: We compared results of NBS (including hearing screens) and ES for 159 infants in the BabySeq Project. Infants were considered "NBS positive" if any abnormal result was found indicating disease risk and "ES positive" if ES identified a monogenic disease risk or a genetic diagnosis.

Results: Most infants (132/159, 84%) were NBS and ES negative. Only one infant was positive for the same disorder by both modalities. Nine infants were NBS positive/ES negative, though seven of these were subsequently determined to be false positives. Fifteen infants were ES positive/NBS negative, all of which represented risk of genetic conditions that are not included in NBS programs. No genetic explanation was identified for eight infants referred on the hearing screen.

Conclusion: These differences highlight the complementarity of information that may be gleaned from NBS and ES in the newborn period.
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http://dx.doi.org/10.1038/s41436-021-01146-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8263473PMC
July 2021

Universal newborn genetic screening for pediatric cancer predisposition syndromes: model-based insights.

Genet Med 2021 07 25;23(7):1366-1371. Epub 2021 Mar 25.

Harvard Medical School, Boston, MA, USA.

Purpose: Genetic testing for pediatric cancer predisposition syndromes (CPS) could augment newborn screening programs, but with uncertain benefits and costs.

Methods: We developed a simulation model to evaluate universal screening for a CPS panel. Cohorts of US newborns were simulated under universal screening versus usual care. Using data from clinical studies, ClinVar, and gnomAD, the presence of pathogenic/likely pathogenic (P/LP) variants in RET, RB1, TP53, DICER1, SUFU, PTCH1, SMARCB1, WT1, APC, ALK, and PHOX2B were assigned at birth. Newborns with identified variants underwent guideline surveillance. Survival benefit was modeled via reductions in advanced disease, cancer deaths, and treatment-related late mortality, assuming 100% adherence.

Results: Among 3.7 million newborns, under usual care, 1,803 developed a CPS malignancy before age 20. With universal screening, 13.3% were identified at birth as at-risk due to P/LP variant detection and underwent surveillance, resulting in a 53.5% decrease in cancer deaths in P/LP heterozygotes and a 7.8% decrease among the entire cohort before age 20. Given a test cost of $55, universal screening cost $244,860 per life-year gained; with a $20 test, the cost fell to $99,430 per life-year gained.

Conclusion: Population-based genetic testing of newborns may reduce mortality associated with pediatric cancers and could be cost-effective as sequencing costs decline.
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http://dx.doi.org/10.1038/s41436-021-01124-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8263476PMC
July 2021

Polygenic risk scores in the clinic: new perspectives needed on familiar ethical issues.

Genome Med 2021 01 28;13(1):14. Epub 2021 Jan 28.

Brigham and Women's Hospital, 75 Francis St, Boston, MA 02115, USA.

Clinical use of polygenic risk scores (PRS) will look very different to the more familiar monogenic testing. Here we argue that despite these differences, most of the ethical, legal, and social issues (ELSI) raised in the monogenic setting, such as the relevance of results to family members, the approach to secondary and incidental findings, and the role of expert mediators, continue to be relevant in the polygenic context, albeit in modified form. In addition, PRS will reanimate other old debates. Their use has been proposed both in the practice of clinical medicine and of public health, two contexts with differing norms. In each of these domains, it is unclear what endpoints clinical use of PRS should aim to maximize and under what constraints. Reducing health disparities is a key value for public health, but clinical use of PRS could exacerbate race-based health disparities owing to differences in predictive power across ancestry groups. Finally, PRS will force a reckoning with pre-existing questions concerning biomarkers, namely the relevance of self-reported race, ethnicity and ancestry, and the relationship of risk factors to disease diagnoses. In this Opinion, we argue that despite the parallels to the monogenic setting, new work is urgently needed to gather data, consider normative implications, and develop best practices around this emerging branch of genomics.
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http://dx.doi.org/10.1186/s13073-021-00829-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7844961PMC
January 2021

Clinical utility of genomic sequencing: a measurement toolkit.

NPJ Genom Med 2020 Dec 15;5(1):56. Epub 2020 Dec 15.

Stanford Medicine, Stanford, CA, USA.

Whole-genome sequencing (WGS) is positioned to become one of the most robust strategies for achieving timely diagnosis of rare genomic diseases. Despite its favorable diagnostic performance compared to conventional testing strategies, routine use and reimbursement of WGS are hampered by inconsistencies in the definition and measurement of clinical utility. For example, what constitutes clinical utility for WGS varies by stakeholder's perspective (physicians, patients, families, insurance companies, health-care organizations, and society), clinical context (prenatal, pediatric, critical care, adult medicine), and test purpose (diagnosis, screening, treatment selection). A rapidly evolving technology landscape and challenges associated with robust comparative study design in the context of rare disease further impede progress in this area of empiric research. To address this challenge, an expert working group of the Medical Genome Initiative was formed. Following a consensus-based process, we align with a broad definition of clinical utility and propose a conceptually-grounded and empirically-guided measurement toolkit focused on four domains of utility: diagnostic thinking efficacy, therapeutic efficacy, patient outcome efficacy, and societal efficacy. For each domain of utility, we offer specific indicators and measurement strategies. While we focus on diagnostic applications of WGS for rare germline diseases, this toolkit offers a flexible framework for best practices around measuring clinical utility for a range of WGS applications. While we expect this toolkit to evolve over time, it provides a resource for laboratories, clinicians, and researchers looking to characterize the value of WGS beyond the laboratory.
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http://dx.doi.org/10.1038/s41525-020-00164-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7738524PMC
December 2020

Effect of Pharmacogenetic Testing for Statin Myopathy Risk vs Usual Care on Blood Cholesterol: A Randomized Clinical Trial.

JAMA Netw Open 2020 12 1;3(12):e2027092. Epub 2020 Dec 1.

VA Boston Healthcare System, Boston, Massachusetts.

Importance: Nonadherence to statin guidelines is common. The solute carrier organic anion transporter family member 1B1 (SLCO1B1) genotype is associated with simvastatin myopathy risk and is proposed for clinical implementation. The unintended harms of using pharmacogenetic information to guide pharmacotherapy remain a concern for some stakeholders.

Objective: To determine the impact of delivering SLCO1B1 pharmacogenetic results to physicians on the effectiveness of atherosclerotic cardiovascular disease (ASCVD) prevention (measured by low-density lipoprotein cholesterol [LDL-C] levels) and concordance with prescribing guidelines for statin safety and effectiveness.

Design, Setting, And Participants: This randomized clinical trial was performed from December 2015 to July 2019 at 8 primary care practices in the Veterans Affairs Boston Healthcare System. Participants included statin-naive patients with elevated ASCVD risk. Data analysis was performed from October 2019 to September 2020.

Interventions: SLCO1B1 genotyping and results reporting to primary care physicians at baseline (intervention group) vs after 1 year (control group).

Main Outcomes And Measures: The primary outcome was the 1-year change in LDL-C level. The secondary outcomes were 1-year concordance with American College of Cardiology-American Heart Association and Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for statin therapy and statin-associated muscle symptoms (SAMS).

Results: Among 408 patients (mean [SD] age, 64.1 [7.8] years; 25 women [6.1%]), 193 were randomized to the intervention group and 215 were randomized to the control group. Overall, 120 participants (29%) had a SLCO1B1 genotype indicating increased simvastatin myopathy risk. Physicians offered statin therapy to 65 participants (33.7%) in the intervention group and 69 participants (32.1%) in the control group. Compared with patients whose physicians did not know their SLCO1B1 results at baseline, patients whose physicians received the results had noninferior reductions in LDL-C at 12 months (mean [SE] change in LDL-C, -1.1 [1.2] mg/dL in the intervention group and -2.2 [1.3] mg/dL in the control group; difference, -1.1 mg/dL; 90% CI, -4.1 to 1.8 mg/dL; P < .001 for noninferiority margin of 10 mg/dL). The proportion of patients with American College of Cardiology-American Heart Association guideline-concordant statin prescriptions in the intervention group was noninferior to that in the control group (12 patients [6.2%] vs 14 patients [6.5%]; difference, -0.003; 90% CI, -0.038 to 0.032; P < .001 for noninferiority margin of 15%). All patients in both groups were concordant with CPIC guidelines for safe statin prescribing. Physicians documented 2 and 3 cases of SAMS in the intervention and control groups, respectively, none of which was associated with a CPIC guideline-discordant prescription. Among patients with a decreased or poor SLCO1B1 transporter function genotype, simvastatin was prescribed to 1 patient in the control group but none in the intervention group.

Conclusions And Relevance: Clinical testing and reporting of SLCO1B1 results for statin myopathy risk did not result in poorer ASCVD prevention in a routine primary care setting and may have been associated with physicians avoiding simvastatin prescriptions for patients at genetic risk for SAMS. Such an absence of harm should reassure stakeholders contemplating the clinical use of available pharmacogenetic results.

Trial Registration: ClinicalTrials.gov Identifier: NCT02871934.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.27092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7716196PMC
December 2020

Low Hydrophobic Mismatch Scores Calculated for HLA-A/B/DR/DQ Loci Improve Kidney Allograft Survival.

Front Immunol 2020 29;11:580752. Epub 2020 Oct 29.

Department of Medical Microbiology and Immunology, University of Toledo, Toledo, OH, United States.

We evaluated the impact of human leukocyte antigen (HLA) disparity (immunogenicity; IM) on long-term kidney allograft survival. The IM was quantified based on physicochemical properties of the polymorphic linear donor/recipient HLA amino acids (the Cambridge algorithm) as a hydrophobic, electrostatic, amino acid mismatch scores (HMS\AMS\EMS) or eplet mismatch (EpMM) load. High-resolution HLA-A/B/DRB1/DQB1 types were imputed to calculate HMS for primary/re-transplant recipients of deceased donor transplants. The multiple Cox regression showed the association of HMS with graft survival and other confounders. The HMS integer 0-10 scale showed the most survival benefit between HMS 0 and 3. The Kaplan-Meier analysis showed that: the HMS=0 group had 18.1-year median graft survival, a 5-year benefit over HMS>0 group; HMS ≤ 3.0 had 16.7-year graft survival, a 3.8-year better than HMS>3.0 group; and, HMS ≤ 7.8 had 14.3-year grafts survival, a 1.8-year improvement over HMS>7.8 group. Stratification based on EMS, AMS or EpMM produced similar results. Additionally, the importance of HLA-DR with/without -DQ IM for graft survival was shown. In our simulation of 1,000 random donor/recipient pairs, 75% with HMS>3.0 were re-matched into HMS ≤ 3.0 and the remaining 25% into HMS≥7.8: after re-matching, the 13.5 years graft survival would increase to 16.3 years. This approach matches donors to recipients with low/medium IM donors thus preventing transplants with high IM donors.
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http://dx.doi.org/10.3389/fimmu.2020.580752DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7659444PMC
June 2021

Airmen and health-care providers' attitudes toward the use of genomic sequencing in the US Air Force: findings from the MilSeq Project.

Genet Med 2020 12 18;22(12):2003-2010. Epub 2020 Aug 18.

Center for Medical Ethics and Health Policy, Baylor College of Medicine, Houston, TX, USA.

Purpose: The use of genomic sequencing (GS) in military settings poses unique considerations, including the potential for GS to impact service members' careers. The MilSeq Project investigated the use of GS in clinical care of active duty Airmen in the United States Air Force (USAF).

Methods: We assessed perceived risks, benefits, and attitudes toward use of GS in the USAF among patient participants (n = 93) and health-care provider participants (HCPs) (n = 12) prior to receiving or disclosing GS results.

Results: Participants agreed that there are health benefits associated with GS (90% patients, 75% HCPs), though more HCPs (75%) than patients (40%) agreed that there are risks (p = 0.048). The majority of both groups (67% HCPs, 77% patients) agreed that they trust the USAF with genetic information, but far fewer agreed that genetic information should be used to make decisions about deployment (5% patients, 17% HCPs) or duty assignments (3% patients, 17% HCPs). Despite their hesitancy, patients were supportive of the USAF testing for nondisease traits that could impact their duty performance. Eighty-seven percent of patients did not think their GS results would influence their career.

Conclusion: Results suggest favorable attitudes toward the use of GS in the USAF when not used for deployment or assignment decisions.
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http://dx.doi.org/10.1038/s41436-020-0928-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7710566PMC
December 2020

Genetic counseling following direct-to consumer genetic testing: Consumer perspectives.

J Genet Couns 2021 02 9;30(1):329-334. Epub 2020 Jul 9.

Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA.

As the use and scope of direct-to-consumer genetic testing (DTC GT), also becoming known as consumer-driven genetic testing, increases, consumers may seek genetic counseling to understand their results and determine healthcare implications. In this study, we interviewed individuals who sought genetic counseling after receiving DTC GT results to explore their motivations, expectations, and experiences. Participants were recruited from the Impact of Personal Genomics (PGen) Study, a longitudinal cohort study of DTC GT customers. We interviewed 15 participants (9 females, mean age = 38 years) by telephone and analyzed the double-coded transcripts using qualitative methods. Motivations for genetic counseling included family and personal health histories, concern and confusion about results, and information-seeking; of note, one-third of our interview participants had Ehlers-Danlos syndrome Type III (hypermobility type). Expectations of genetic counseling sessions were high. Participants generally saw DTC GT results as valid and potentially impactful for their healthcare, wanted more thorough explanations in "layman's terms," a pooling of their results with their family and personal health history and a "game plan." Several participants had already accessed online resources, including resources typically used by genetics clinicians. Our results point to several elements of a successful DTC GT genetic counseling session: 1) effective contracting when starting the clinic visit, especially determining motivations for genetic counseling, results that are concerning/confusing and resources already accessed; 2) ascertainment and management of expectations and clearly communicating if and why all results may not be reviewed; 3) explaining how DTC GT differs from clinical genetic testing and why additional testing may not be indicated and 4) listening to (not dismissing) patient concerns about their results. For those patients who seek genetic counseling about DTC GT results, the findings from our study can help inform case preparation and provision of genetic counseling.
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http://dx.doi.org/10.1002/jgc4.1309DOI Listing
February 2021

Educating military primary health-care providers in genomic medicine: lessons learned from the MilSeq Project.

Genet Med 2020 10 10;22(10):1710-1717. Epub 2020 Jul 10.

Air Force Medical Genetics Center, Keesler Air Force Base, Biloxi, MS, USA.

Purpose: With few trained genetics professionals, the Military Health System is ill-equipped to manage the rapid expansion of genomic medicine. The MilSeq Project introduces an alternative service delivery model (ASDM) in which primary health-care providers (HCPs) provide post-test counseling (PTC) to healthy Airmen who have undergone exome sequencing. We describe HCP performance after a prerequisite educational intervention (EI).

Methods: After a brief EI and pre-/posteducation surveys, HCPs were eligible to provide PTC with a genetic counselor available for consult. PTC was recorded, transcribed, and reviewed. Opportunities for improvement were organized into four error adjustment categories: (1) knowledge limitation, (2) minor, (3) moderate, and (4) critical. Thematic analysis was also performed.

Results: Pre-/posteducation survey responses revealed statistically significant improvements in all domains. Minor error adjustments were most represented (n = 93), followed by knowledge limitation (n = 39) and moderate (n = 19). No critical errors were identified, and 17 transcripts required no adjustment. Thematic analysis revealed four themes that would benefit from more focused education: (1) family-centered care, (2) conveying risk, (3) disease knowledge, and (4) assay knowledge.

Conclusion: HCPs demonstrated competence in basic PTC after a brief EI. This ASDM may be a viable interim response to the shortage of genetics professionals in some systems.
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http://dx.doi.org/10.1038/s41436-020-0865-7DOI Listing
October 2020

Genome-wide association study of rate of cognitive decline in Alzheimer's disease patients identifies novel genes and pathways.

Alzheimers Dement 2020 08 23;16(8):1134-1145. Epub 2020 Jun 23.

Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.

Introduction: Variability exists in the disease trajectories of Alzheimer's disease (AD) patients. We performed a genome-wide association study to examine rate of cognitive decline (ROD) in patients with AD.

Methods: We tested for interactions between genetic variants and time since diagnosis to predict the ROD of a composite cognitive score in 3946 AD cases and performed pathway analysis on the top genes.

Results: Suggestive associations (P < 1.0 × 10 ) were observed on chromosome 15 in DNA polymerase-γ (rs3176205, P = 1.11 × 10 ), chromosome 7 (rs60465337,P = 4.06 × 10 ) in contactin-associated protein-2, in RP11-384F7.1 on chromosome 3 (rs28853947, P = 5.93 × 10 ), family with sequence similarity 214 member-A on chromosome 15 (rs2899492, P = 5.94 × 10 ), and intergenic regions on chromosomes 16 (rs4949142, P = 4.02 × 10 ) and 4 (rs1304013, P = 7.73 × 10 ). Significant pathways involving neuronal development and function, apoptosis, memory, and inflammation were identified.

Discussion: Pathways related to AD, intelligence, and neurological function determine AD progression, while previously identified AD risk variants, including the apolipoprotein (APOE) ε4 and ε2 variants, do not have a major impact.
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http://dx.doi.org/10.1002/alz.12106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7924136PMC
August 2020

The Project Baseline Health Study: a step towards a broader mission to map human health.

NPJ Digit Med 2020 5;3:84. Epub 2020 Jun 5.

Duke University, School of Medicine, Durham, NC USA.

The Project Baseline Health Study (PBHS) was launched to map human health through a comprehensive understanding of both the health of an individual and how it relates to the broader population. The study will contribute to the creation of a biomedical information system that accounts for the highly complex interplay of biological, behavioral, environmental, and social systems. The PBHS is a prospective, multicenter, longitudinal cohort study that aims to enroll thousands of participants with diverse backgrounds who are representative of the entire health spectrum. Enrolled participants will be evaluated serially using clinical, molecular, imaging, sensor, self-reported, behavioral, psychological, environmental, and other health-related measurements. An initial deeply phenotyped cohort will inform the development of a large, expanded virtual cohort. The PBHS will contribute to precision health and medicine by integrating state of the art testing, longitudinal monitoring and participant engagement, and by contributing to the development of an improved platform for data sharing and analysis.
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http://dx.doi.org/10.1038/s41746-020-0290-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7275087PMC
June 2020

Biobanks could identify medically actionable findings relevant for COVID-19 clinical care.

Nat Med 2020 07;26(7):991

Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.

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http://dx.doi.org/10.1038/s41591-020-0953-xDOI Listing
July 2020

Multiple GYPB gene deletions associated with the U- phenotype in those of African ancestry.

Transfusion 2020 06 30;60(6):1294-1307. Epub 2020 May 30.

New York Blood Center, New York, New York.

Background: The MNS blood group system is defined by three homologous genes: GYPA, GYPB, and GYPE. GYPB encodes for glycophorin B (GPB) carrying S/s and the "universal" antigen U. RBCs of approximately 1% of individuals of African ancestry are U- due to absence of GPB. The U- phenotype has long been attributed to a deletion encompassing GYPB exons 2 to 5 and GYPE exon 1 (GYPB*01N).

Study Design And Methods: Samples from two U-individuals underwent Illumina short read whole genome sequencing (WGS) and Nanopore long read WGS. In addition, two existing WGS datasets, MedSeq (n = 110) and 1000 Genomes (1000G, n = 2535), were analyzed for GYPB deletions. Deletions were confirmed by Sanger sequencing. Twenty known U- donor samples were tested by a PCR assay to determine the specific deletion alleles present in African Americans.

Results: Two large GYPB deletions in U- samples of African ancestry were identified: a 110 kb deletion extending left of GYPB (DEL_B_LEFT) and a 103 kb deletion extending right (DEL_B_RIGHT). DEL_B_LEFT and DEL_B_RIGHT were the most common GYPB deletions in the 1000 Genomes Project 669 African genomes (allele frequencies 0.04 and 0.02). Seven additional deletions involving GYPB were seen in African, Admixed American, and South Asian samples. No samples analyzed had GYPB*01N.

Conclusions: The U- phenotype in those of African ancestry is primarily associated with two different complete deletions of GYPB (with intact GYPE). Seven additional less common GYPB deletion backgrounds were found. GYPB*01N, long assumed to be the allele commonly encoding U- phenotypes, appears to be rare.
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http://dx.doi.org/10.1111/trf.15839DOI Listing
June 2020

Quantifying Downstream Healthcare Utilization in Studies of Genomic Testing.

Value Health 2020 05 20;23(5):559-565. Epub 2020 Mar 20.

Harvard Medical School, Boston, MA, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA; Broad Institute of the Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA; Precision Medicine Translational Research Center, Department of Population Medicine, Harvard Pilgrim Health Care Institute, Boston, MA, USA. Electronic address:

Objectives: The challenges of understanding how interventions influence follow-up medical care are magnified during genomic testing because few patients have received it to date and because the scope of information it provides is complex and often unexpected. We tested a novel strategy for quantifying downstream healthcare utilization after genomic testing to more comprehensively and efficiently identify related services. We also evaluated the effectiveness of different methods for collecting these data.

Methods: We developed a risk-based approach for a trial of newborn genomic sequencing in which we defined primary conditions based on existing diagnoses and family histories of disease and defined secondary conditions based on unexpected findings. We then created patient-specific lists of services associated with managing primary and secondary conditions. Services were quantified based on medical record reviews, surveys, and telephone check-ins with parents.

Results: By focusing on services that genomic testing would most likely influence in the short-term, we reduced the number of services in our analyses by more than 90% compared with analyses of all observed services. We also identified the same services that were ordered in response to unexpected findings as were identified during expert review and by confirming whether recommendations were completed. Data also showed that quantifying healthcare utilization with surveys and telephone check-ins alone would have missed the majority of attributable services.

Conclusions: Our risk-based strategy provides an improved approach for assessing the short-term impact of genomic testing and other interventions on healthcare utilization while conforming as much as possible to existing best-practice recommendations.
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http://dx.doi.org/10.1016/j.jval.2020.01.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7293136PMC
May 2020

Returning Results in the Genomic Era: Initial Experiences of the eMERGE Network.

J Pers Med 2020 Apr 27;10(2). Epub 2020 Apr 27.

Genomic Medicine Institute, Geisinger, Danville, PA 17822, USA.

A goal of the 3rd phase of the Electronic Medical Records and Genomics (eMERGE3) Network was to examine the return of results (RoR) of actionable variants in more than 100 genes to consenting participants and their healthcare providers. Each of the 10 eMERGE sites developed plans for three essential elements of the RoR process: Disclosure to the participant, notification of the health care provider, and integration of results into the electronic health record (EHR). Procedures and protocols around these three elements were adapted as appropriate to individual site requirements and limitations. Detailed information about the RoR procedures at each site was obtained through structured telephone interviews and follow-up surveys with the clinical investigator leading or participating in the RoR process at each eMERGE3 institution. Because RoR processes at each of the 10 sites allowed for taking into account differences in population, disease focus and institutional requirements, significant heterogeneity of process was identified, including variability in the order in which patients and clinicians were notified and results were placed in the EHR. This heterogeneity in the process flow for eMERGE3 RoR reflects the "real world" of genomic medicine in which RoR procedures must be shaped by the needs of the patients and institutional environments.
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http://dx.doi.org/10.3390/jpm10020030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7354592PMC
April 2020
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