Participant choices for return of genomic results in the eMERGE Network

AbstractThis editorial provides context for a series of published case reports in ACI Open by summarizing activities and outputs of joint electronic health record integration and pharmacogenomics workgroups in the NIH-funded electronic Medical Records and Genomics (eMERGE) Network. A case report is a useful tool to describe the range of capabilities that an IT infrastructure or a particular technology must support. The activities we describe have informed infrastructure requirements used during eMERGE phase III, provided a venue to share experiences and ask questions among other eMERGE sites, summarized potential hazards that might be encountered for specific clinical decision support (CDS) implementation scenarios, and provided a simple framework that captured progress toward implementing CDS at eMERGE sites in a consistent format.

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Association between triglycerides, known risk SNVs and conserved rare variation in SLC25A40 in a multi-ancestry cohort

BMC Medical Genomics ◽

10.1186/s12920-020-00854-2 ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Elisabeth A. Rosenthal ◽

David R. Crosslin ◽

Adam S. Gordon ◽

David S. Carrell ◽

Ian B. Stanaway ◽

...

Keyword(s):

Gene Cluster ◽

Large Family ◽

Missense Variant ◽

Mixed Ancestry ◽

Limited Sample ◽

Health Records ◽

Pathogenic Variants ◽

Phenotype Data ◽

Emerge Network ◽

Using Data

Abstract Background Elevated triglycerides (TG) are associated with, and may be causal for, cardiovascular disease (CVD), and co-morbidities such as type II diabetes and metabolic syndrome. Pathogenic variants in APOA5 and APOC3 as well as risk SNVs in other genes [APOE (rs429358, rs7412), APOA1/C3/A4/A5 gene cluster (rs964184), INSR (rs7248104), CETP (rs7205804), GCKR (rs1260326)] have been shown to affect TG levels. Knowledge of genetic causes for elevated TG may lead to early intervention and targeted treatment for CVD. We previously identified linkage and association of a rare, highly conserved missense variant in SLC25A40, rs762174003, with hypertriglyceridemia (HTG) in a single large family, and replicated this association with rare, highly conserved missense variants in a European American and African American sample. Methods Here, we analyzed a longitudinal mixed-ancestry cohort (European, African and Asian ancestry, N = 8966) from the Electronic Medical Record and Genomics (eMERGE) Network. We tested associations between median TG and the genes of interest, using linear regression, adjusting for sex, median age, median BMI, and the first two principal components of ancestry. Results We replicated the association between TG and APOC3, APOA5, and risk variation at APOE, APOA1/C3/A4/A5 gene cluster, and GCKR. We failed to replicate the association between rare, highly conserved variation at SLC25A40 and TG, as well as for risk variation at INSR and CETP. Conclusions Analysis using data from electronic health records presents challenges that need to be overcome. Although large amounts of genotype data is becoming increasingly accessible, usable phenotype data can be challenging to obtain. We were able to replicate known, strong associations, but were unable to replicate moderate associations due to the limited sample size and missing drug information.

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Pediatric Oncologists’ Experiences Returning and Incorporating Genomic Sequencing Results into Cancer Care

Journal of Personalized Medicine ◽

10.3390/jpm11060570 ◽

2021 ◽

Vol 11 (6) ◽

pp. 570

Author(s):

Rebecca L. Hsu ◽

Amanda M. Gutierrez ◽

Sophie K. Schellhammer ◽

Jill O. Robinson ◽

Sarah Scollon ◽

...

Keyword(s):

Cancer Care ◽

Cancer Genomics ◽

Emotional Responses ◽

Genetic Counselors ◽

Genomic Sequencing ◽

Uncertain Information ◽

Time Points ◽

Genomic Results

Pediatric oncologists’ perspectives around returning and incorporating tumor and germline genomic sequencing (GS) results into cancer care are not well-described. To inform optimization of cancer genomics communication, we assessed oncologists’ experiences with return of genomic results (ROR), including their preparation/readiness for ROR, collaboration with genetic counselors (GCs) during ROR, and perceived challenges. The BASIC3 study paired pediatric oncologists with GCs to return results to patients’ families. We thematically analyzed 24 interviews with 12 oncologists at two post-ROR time points. Oncologists found pre-ROR meetings with GCs and geneticists essential to interpreting patients’ reports and communicating results to families. Most oncologists took a collaborative ROR approach where they discussed tumor findings and GCs discussed germline findings. Oncologists perceived many roles for GCs during ROR, including answering families’ questions and describing information in lay language. Challenges identified included conveying uncertain information in accessible language, limits of oncologists’ genetics expertise, and navigating families’ emotional responses. Oncologists emphasized how GCs’ and geneticists’ support was essential to ROR, especially for germline findings. GS can be successfully integrated into cancer care, but to account for the GC shortage, alternative ROR models and access to genetics resources will be needed to better support families and avoid burdening oncologists.

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Implementing genomic screening in diverse populations

Genome Medicine ◽

10.1186/s13073-021-00832-y ◽

2021 ◽

Vol 13 (1) ◽

Cited By ~ 2

Author(s):

Noura S. Abul-Husn ◽

Emily R. Soper ◽

Giovanna T. Braganza ◽

Jessica E. Rodriguez ◽

Natasha Zeid ◽

...

Keyword(s):

Screening Program ◽

African Ancestry ◽

Genomic Medicine ◽

European Ancestry ◽

Transthyretin Amyloidosis ◽

Medicine Research ◽

Screening Programs ◽

Genomic Screening ◽

Genomic Results ◽

To Receive

Abstract Background Population-based genomic screening has the predicted ability to reduce morbidity and mortality associated with medically actionable conditions. However, much research is needed to develop standards for genomic screening and to understand the perspectives of people offered this new testing modality. This is particularly true for non-European ancestry populations who are vastly underrepresented in genomic medicine research. Therefore, we implemented a pilot genomic screening program in the BioMe Biobank in New York City, where the majority of participants are of non-European ancestry. Methods We initiated genomic screening for well-established genes associated with hereditary breast and ovarian cancer syndrome (HBOC), Lynch syndrome (LS), and familial hypercholesterolemia (FH). We evaluated and included an additional gene (TTR) associated with hereditary transthyretin amyloidosis (hATTR), which has a common founder variant in African ancestry populations. We evaluated the characteristics of 74 participants who received results associated with these conditions. We also assessed the preferences of 7461 newly enrolled BioMe participants to receive genomic results. Results In the pilot genomic screening program, 74 consented participants received results related to HBOC (N = 26), LS (N = 6), FH (N = 8), and hATTR (N = 34). Thirty-three of 34 (97.1%) participants who received a result related to hATTR were self-reported African American/African (AA) or Hispanic/Latinx (HL), compared to 14 of 40 (35.0%) participants who received a result related to HBOC, LS, or FH. Among the 7461 participants enrolled after the BioMe protocol modification to allow the return of genomic results, 93.4% indicated that they would want to receive results. Younger participants, women, and HL participants were more likely to opt to receive results. Conclusions The addition of TTR to a pilot genomic screening program meant that we returned results to a higher proportion of AA and HL participants, in comparison with genes traditionally included in genomic screening programs in the USA. We found that the majority of participants in a multi-ethnic biobank are interested in receiving genomic results for medically actionable conditions. These findings increase knowledge about the perspectives of diverse research participants on receiving genomic results and inform the broader implementation of genomic medicine in underrepresented patient populations.

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Genetic variation among 82 pharmacogenes: The PGRNseq data from the eMERGE network

Clinical Pharmacology & Therapeutics ◽

10.1002/cpt.350 ◽

2016 ◽

Vol 100 (2) ◽

pp. 160-169 ◽

Cited By ~ 88

Author(s):

WS Bush ◽

DR Crosslin ◽

A Owusu‐Obeng ◽

J Wallace ◽

B Almoguera ◽

...

Keyword(s):

Genetic Variation ◽

Emerge Network

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Study of symptoms and gene expression in four Pinus species after pinewood nematode infection

Plant Genetic Resources ◽

10.1017/s1479262111000062 ◽

2011 ◽

Vol 9 (2) ◽

pp. 272-275 ◽

Cited By ~ 5

Author(s):

Albina R. Franco ◽

Carla Santos ◽

Mariana Roriz ◽

Rui Rodrigues ◽

Marta R. M. Lima ◽

...

Keyword(s):

Virulent Strain ◽

Pine Wilt Disease ◽

Bursaphelenchus Xylophilus ◽

Wilt Disease ◽

Pinewood Nematode ◽

Pine Trees ◽

Severe Infections ◽

Genomic Results ◽

Avirulent Isolate

Pine wilt disease, caused by the pinewood nematode Bursaphelenchus xylophilus (Steiner and Buhrer) Nickle, is originating severe infections in pine trees. The disease is detected when external symptoms appear (e.g. needle chlorosis), but trees could remain asymptomatic for long periods and serve as a long-term host. The primary goal of this study was to assess the effect of inoculation with an avirulent isolate of B. xylophilus (C14-5) on different Pinus spp. seedlings (P. sylvestris, P. nigra, P. pinea and P. pinaster). At the same time, seedlings were also inoculated with a virulent strain, HF, in order to compare the phenotypic and genomic results of the two types of inoculations. The effect of inoculation was determined in terms of expression of various Pinus genes potentially involved in the response to the disease.The results suggest that P. pinea and P. nigra are more resistant to infection by the nematode than P. sylvestris and P. pinaster. The phenotypic and genetic differences were more marked among P. pinea and P. pinaster.

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Abstract 15209: LPA Variants Are Associated With Aortic Valve Stenosis, Heart Failure and Chronic Kidney Disease

Circulation ◽

10.1161/circ.142.suppl_3.15209 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Ozan Dikilitas ◽

Benjamin A Satterfield ◽

Maya Safarova ◽

Shoa L Clarke ◽

Catherine Tcheandjieu ◽

...

Keyword(s):

Heart Failure ◽

Chronic Kidney Disease ◽

Kidney Disease ◽

Aortic Valve ◽

Aortic Valve Stenosis ◽

European Ancestry ◽

Atherosclerotic Cardiovascular Disease ◽

Disease Phenotypes ◽

Emerge Network ◽

Artery Disease

Background: The pathophysiology of lipoprotein (a) [Lp(a)] remains obscure. We conducted a phenome wide analysis study (PheWAS) to identify pleiotropic effects of LPA variants. Methods: Among 51,843 European-ancestry participants (age 58±16 years, 54% female) of the electronic MEdical Records and Genomics (eMERGE) network we assessed whether LPA variants exhibited pleiotropic affects through an electronic health record-based PheWAS. We adjusted significant associations by presence of atherosclerotic cardiovascular disease (ASCVD; defined as a composite of coronary heart disease, cerebrovascular disease, and peripheral artery disease) to determine whether those associations were independent of ASCVD. Results: In PheWAS analysis, we tested 864 phecodes with 36 independent LPA variants. We identified 21 significant associations with non-ASCVD phenotypes including heart failure, aortic valve stenosis, and chronic kidney disease of which 14 were replicated across independent cohorts. The strength of associations between the LPA variant rs10455872 and both heart failure and aortic valve stenosis related phecodes were significantly attenuated after adjustment for ASCVD. However, the association with chronic kidney disease phecode remained independent following adjustment for ASCVD without any attenuation in the estimated odds ratio (Table). Conclusions: LPA genetic variants were associated with aortic valve stenosis, heart failure and chronic kidney disease. The observed association of LPA variant rs10455872 with aortic stenosis and heart failure appear to be partially mediated by ASCVD, while the association with chronic kidney disease appears to be independent of ASCVD. Additional studies are needed to elucidate potential mechanisms by which Lp(a) may contribute to the pathogenesis of non-ASCVD disease phenotypes.

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A scalable EHR-based approach for phenotype discovery and variant interpretation for hereditary cancer genes

10.1101/2021.03.18.21253763 ◽

2021 ◽

Author(s):

Chenjie Zeng ◽

Lisa A Bastarache ◽

Ran Tao ◽

Eric Venner ◽

Scott Hebbring ◽

...

Keyword(s):

Hereditary Cancer ◽

Meta Analysis ◽

Genetic Disorders ◽

Genomic Medicine ◽

Risk Scores ◽

Cancer Genes ◽

Pathogenic Variants ◽

Emerge Network ◽

Uncertain Significance ◽

Potential Pathogenicity

Knowledge of the clinical spectrum of rare genetic disorders helps in disease management and variant pathogenicity interpretation. Leveraging electronic health record (EHR)-linked genetic testing data from the eMERGE network, we determined the associations between a set of 23 hereditary cancer genes and 3017 phenotypes in 23544 individuals. This phenome-wide association study replicated 45% (184/406) of known gene-phenotype associations (P = 5.1 ×10-125). Meta-analysis with an independent EHR-derived cohort of 3242 patients confirmed 14 novel associations with phenotypes in the neoplastic, genitourinary, digestive, congenital, metabolic, mental and neurologic categories. Phenotype risk scores (PheRS) based on weighted aggregations of EHR phenotypes accurately predicted variant pathogenicity for at least 50% of pathogenic variants for 8/23 genes. We generated a catalog of PheRS for 7800 variants, including 5217 variants of uncertain significance, to provide empirical evidence of potential pathogenicity. This study highlights the potential of EHR data in genomic medicine.

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Imaging of Cellular Oxidoreductase Activity Suggests Mixotrophic Metabolisms in Thiomargarita spp

mBio ◽

10.1128/mbio.01263-17 ◽

2017 ◽

Vol 8 (6) ◽

Cited By ~ 1

Author(s):

Jake V. Bailey ◽

Beverly E. Flood ◽

Elizabeth Ricci ◽

Nathalie Delherbe

Keyword(s):

Organic Carbon ◽

Time Course ◽

Genomic Data ◽

Metabolic Potential ◽

Oxidoreductase Activity ◽

Metabolic Plasticity ◽

Hypoxic Conditions ◽

Genomic Studies ◽

Genomic Results ◽

Carbon Degradation

ABSTRACT The largest known bacteria, Thiomargarita spp., have yet to be isolated in pure culture, but their large size allows for individual cells to be monitored in time course experiments or to be individually sorted for omics-based investigations. Here we investigated the metabolism of individual cells of Thiomargarita spp. by using a novel application of a tetrazolium-based dye that measures oxidoreductase activity. When coupled with microscopy, staining of the cells with a tetrazolium-formazan dye allows metabolic responses in Thiomargarita spp. to be to be tracked in the absence of observable cell division. Additionally, the metabolic activity of Thiomargarita sp. cells can be differentiated from the metabolism of other microbes in specimens that contain adherent bacteria. The results of our redox dye-based assay suggest that Thiomargarita is the most metabolically versatile under anoxic conditions, where it appears to express cellular oxidoreductase activity in response to the electron donors succinate, acetate, citrate, formate, thiosulfate, H2, and H2S. Under hypoxic conditions, formazan staining results suggest the metabolism of succinate and likely acetate, citrate, and H2S. Cells incubated under oxic conditions showed the weakest formazan staining response, and then only to H2S, citrate, and perhaps succinate. These results provide experimental validation of recent genomic studies of Candidatus Thiomargarita nelsonii that suggest metabolic plasticity and mixotrophic metabolism. The cellular oxidoreductase response of bacteria attached to the exterior of Thiomargarita also supports the possibility of trophic interactions between these largest of known bacteria and attached epibionts. IMPORTANCE The metabolic potential of many microorganisms that cannot be grown in the laboratory is known only from genomic data. Genomes of Thiomargarita spp. suggest that these largest of known bacteria are mixotrophs, combining lithotrophic metabolism with organic carbon degradation. Our use of a redox-sensitive tetrazolium dye to query the metabolism of these bacteria provides an independent line of evidence that corroborates the apparent metabolic plasticity of Thiomargarita observed in recently produced genomes. Finding new cultivation-independent means of testing genomic results is critical to testing genome-derived hypotheses on the metabolic potentials of uncultivated microorganisms. IMPORTANCE The metabolic potential of many microorganisms that cannot be grown in the laboratory is known only from genomic data. Genomes of Thiomargarita spp. suggest that these largest of known bacteria are mixotrophs, combining lithotrophic metabolism with organic carbon degradation. Our use of a redox-sensitive tetrazolium dye to query the metabolism of these bacteria provides an independent line of evidence that corroborates the apparent metabolic plasticity of Thiomargarita observed in recently produced genomes. Finding new cultivation-independent means of testing genomic results is critical to testing genome-derived hypotheses on the metabolic potentials of uncultivated microorganisms.

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