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1.
Circ Genom Precis Med ; 13(4): e002680, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32602732

RESUMO

BACKGROUND: We examined how expanding electrocardiographic trait genome-wide association studies to include ancestrally diverse populations, prioritize more precise phenotypic measures, and evaluate evidence for shared genetic effects enabled the detection and characterization of loci. METHODS: We decomposed 10 seconds, 12-lead electrocardiograms from 34 668 multi-ethnic participants (15% Black; 30% Hispanic/Latino) into 6 contiguous, physiologically distinct (P wave, PR segment, QRS interval, ST segment, T wave, and TP segment) and 2 composite, conventional (PR interval and QT interval) interval scale traits and conducted multivariable-adjusted, trait-specific univariate genome-wide association studies using 1000-G imputed single-nucleotide polymorphisms. Evidence of shared genetic effects was evaluated by aggregating meta-analyzed univariate results across the 6 continuous electrocardiographic traits using the combined phenotype adaptive sum of powered scores test. RESULTS: We identified 6 novels (CD36, PITX2, EMB, ZNF592, YPEL2, and BC043580) and 87 known loci (adaptive sum of powered score test P<5×10-9). Lead single-nucleotide polymorphism rs3211938 at CD36 was common in Blacks (minor allele frequency=10%), near monomorphic in European Americans, and had effects on the QT interval and TP segment that ranked among the largest reported to date for common variants. The other 5 novel loci were observed when evaluating the contiguous but not the composite electrocardiographic traits. Combined phenotype testing did not identify novel electrocardiographic loci unapparent using traditional univariate approaches, although this approach did assist with the characterization of known loci. CONCLUSIONS: Despite including one-third as many participants as published electrocardiographic trait genome-wide association studies, our study identified 6 novel loci, emphasizing the importance of ancestral diversity and phenotype resolution in this era of ever-growing genome-wide association studies.

2.
Am J Hum Genet ; 107(1): 72-82, 2020 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-32504544

RESUMO

Genetics researchers and clinical professionals rely on diversity measures such as race, ethnicity, and ancestry (REA) to stratify study participants and patients for a variety of applications in research and precision medicine. However, there are no comprehensive, widely accepted standards or guidelines for collecting and using such data in clinical genetics practice. Two NIH-funded research consortia, the Clinical Genome Resource (ClinGen) and Clinical Sequencing Evidence-generating Research (CSER), have partnered to address this issue and report how REA are currently collected, conceptualized, and used. Surveying clinical genetics professionals and researchers (n = 448), we found heterogeneity in the way REA are perceived, defined, and measured, with variation in the perceived importance of REA in both clinical and research settings. The majority of respondents (>55%) felt that REA are at least somewhat important for clinical variant interpretation, ordering genetic tests, and communicating results to patients. However, there was no consensus on the relevance of REA, including how each of these measures should be used in different scenarios and what information they can convey in the context of human genetics. A lack of common definitions and applications of REA across the precision medicine pipeline may contribute to inconsistencies in data collection, missing or inaccurate classifications, and misleading or inconclusive results. Thus, our findings support the need for standardization and harmonization of REA data collection and use in clinical genetics and precision health research.


Assuntos
Coleta de Dados/normas , Testes Genéticos/normas , Adulto , Criança , Grupos Étnicos , Feminino , Variação Genética/genética , Genômica/normas , Humanos , Masculino , Medicina de Precisão/normas , Inquéritos e Questionários
3.
PLoS Genet ; 16(3): e1008684, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32226016

RESUMO

Lipid levels are important markers for the development of cardio-metabolic diseases. Although hundreds of associated loci have been identified through genetic association studies, the contribution of genetic factors to variation in lipids is not fully understood, particularly in U.S. minority groups. We performed genome-wide association analyses for four lipid traits in over 45,000 ancestrally diverse participants from the Population Architecture using Genomics and Epidemiology (PAGE) Study, followed by a meta-analysis with several European ancestry studies. We identified nine novel lipid loci, five of which showed evidence of replication in independent studies. Furthermore, we discovered one novel gene in a PrediXcan analysis, minority-specific independent signals at eight previously reported loci, and potential functional variants at two known loci through fine-mapping. Systematic examination of known lipid loci revealed smaller effect estimates in African American and Hispanic ancestry populations than those in Europeans, and better performance of polygenic risk scores based on minority-specific effect estimates. Our findings provide new insight into the genetic architecture of lipid traits and highlight the importance of conducting genetic studies in diverse populations in the era of precision medicine.


Assuntos
Grupos de Populações Continentais/genética , Lipídeos/sangue , Lipídeos/genética , Bases de Dados Genéticas , Feminino , Estudo de Associação Genômica Ampla/métodos , Genótipo , Humanos , Lipídeos/análise , Masculino , Metagenômica/métodos , Grupos Minoritários , Herança Multifatorial/genética , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Estados Unidos/epidemiologia
4.
BMC Genomics ; 21(1): 228, 2020 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-32171239

RESUMO

BACKGROUND: Quantitative red blood cell (RBC) traits are highly polygenic clinically relevant traits, with approximately 500 reported GWAS loci. The majority of RBC trait GWAS have been performed in European- or East Asian-ancestry populations, despite evidence that rare or ancestry-specific variation contributes substantially to RBC trait heritability. Recently developed combined-phenotype methods which leverage genetic trait correlation to improve statistical power have not yet been applied to these traits. Here we leveraged correlation of seven quantitative RBC traits in performing a combined-phenotype analysis in a multi-ethnic study population. RESULTS: We used the adaptive sum of powered scores (aSPU) test to assess combined-phenotype associations between ~ 21 million SNPs and seven RBC traits in a multi-ethnic population (maximum n = 67,885 participants; 24% African American, 30% Hispanic/Latino, and 43% European American; 76% female). Thirty-nine loci in our multi-ethnic population contained at least one significant association signal (p < 5E-9), with lead SNPs at nine loci significantly associated with three or more RBC traits. A majority of the lead SNPs were common (MAF > 5%) across all ancestral populations. Nineteen additional independent association signals were identified at seven known loci (HFE, KIT, HBS1L/MYB, CITED2/FILNC1, ABO, HBA1/2, and PLIN4/5). For example, the HBA1/2 locus contained 14 conditionally independent association signals, 11 of which were previously unreported and are specific to African and Amerindian ancestries. One variant in this region was common in all ancestries, but exhibited a narrower LD block in African Americans than European Americans or Hispanics/Latinos. GTEx eQTL analysis of all independent lead SNPs yielded 31 significant associations in relevant tissues, over half of which were not at the gene immediately proximal to the lead SNP. CONCLUSION: This work identified seven loci containing multiple independent association signals for RBC traits using a combined-phenotype approach, which may improve discovery in genetically correlated traits. Highly complex genetic architecture at the HBA1/2 locus was only revealed by the inclusion of African Americans and Hispanics/Latinos, underscoring the continued importance of expanding large GWAS to include ancestrally diverse populations.


Assuntos
Afro-Americanos/genética , Eritrócitos/metabolismo , Grupo com Ancestrais do Continente Europeu/genética , Estudo de Associação Genômica Ampla/métodos , Hispano-Americanos/genética , Característica Quantitativa Herdável , Feminino , Genética Populacional , Humanos , Masculino , Herança Multifatorial , Fenótipo , Polimorfismo de Nucleotídeo Único , Análise de Sequência de DNA , Estados Unidos/etnologia
5.
Am J Hum Genet ; 104(6): 1088-1096, 2019 06 06.
Artigo em Inglês | MEDLINE | ID: mdl-31104772

RESUMO

Conceptual frameworks are useful in research because they can highlight priority research domains, inform decisions about interventions, identify outcomes and factors to measure, and display how factors might relate to each other to generate and test hypotheses. Discovery, translational, and implementation research are all critical to the overall mission of genomic medicine and prevention, but they have yet to be organized into a unified conceptual framework. To fill this gap, our diverse team collaborated to develop the Genomic Medicine Integrative Research (GMIR) Framework, a simple but comprehensive tool to aid the genomics community in developing research questions, strategies, and measures and in integrating genomic medicine and prevention into clinical practice. Here we present the GMIR Framework and its development, along with examples of its use for research development, demonstrating how we applied it to select and harmonize measures for use across diverse genomic medicine implementation projects. Researchers can utilize the GMIR Framework for their own research, collaborative investigations, and clinical implementation efforts; clinicians can use it to establish and evaluate programs; and all stakeholders can use it to help allocate resources and make sure that the full complexity of etiology is included in research and program design, development, and evaluation.


Assuntos
Pesquisa Biomédica , Prestação Integrada de Cuidados de Saúde , Genética Médica , Genômica/métodos , Medicina de Precisão/métodos , Doenças Raras/genética , Projetos de Pesquisa , Humanos , Modelos Teóricos
6.
Ethn Dis ; 29(Suppl 1): 173-178, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30906166

RESUMO

The potential of genomics to improve health comes with the peril that the benefits will not be equitably available to all populations. Existing health disparities can be exacerbated if the implementation of genomic medicine does not intentionally focus on health equity. Defining what health equity means in the context of genomics and outlining how it can be achieved is important for the future of the field. Strategies to improve health equity include addressing underrepresentation of diverse populations in genomic research, investigating how genomic services can be deployed in diverse health care settings and underserved communities, increasing workforce diversity, supporting infrastructure development outside traditional research centers, and engaging communities and health care providers. By employing these strategies, the genomic research community can advance health equity in genomic medicine.


Assuntos
Serviços em Genética , Genômica , Equidade em Saúde , Previsões , Serviços em Genética/organização & administração , Serviços em Genética/tendências , Genômica/métodos , Genômica/tendências , Equidade em Saúde/normas , Equidade em Saúde/tendências , Disparidades nos Níveis de Saúde , Humanos , Melhoria de Qualidade
8.
Genet Med ; 21(5): 1100-1110, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30287922

RESUMO

PURPOSE: Clinical sequencing emerging in health care may result in secondary findings (SFs). METHODS: Seventy-four of 6240 (1.2%) participants who underwent genome or exome sequencing through the Clinical Sequencing Exploratory Research (CSER) Consortium received one or more SFs from the original American College of Medical Genetics and Genomics (ACMG) recommended 56 gene-condition pair list; we assessed clinical and psychosocial actions. RESULTS: The overall adjusted prevalence of SFs in the ACMG 56 genes across the CSER consortium was 1.7%. Initially 32% of the family histories were positive, and post disclosure, this increased to 48%. The average cost of follow-up medical actions per finding up to a 1-year period was $128 (observed, range: $0-$678) and $421 (recommended, range: $141-$1114). Case reports revealed variability in the frequency of and follow-up on medical recommendations patients received associated with each SF gene-condition pair. Participants did not report adverse psychosocial impact associated with receiving SFs; this was corroborated by 18 participant (or parent) interviews. All interviewed participants shared findings with relatives and reported that relatives did not pursue additional testing or care. CONCLUSION: Our results suggest that disclosure of SFs shows little to no adverse impact on participants and adds only modestly to near-term health-care costs; additional studies are needed to confirm these findings.


Assuntos
Testes Genéticos/economia , Achados Incidentais , Sequenciamento Completo do Genoma/ética , Adulto , Tomada de Decisões/ética , Revelação , Exoma , Feminino , Testes Genéticos/ética , Testes Genéticos/normas , Genômica/métodos , Custos de Cuidados de Saúde , Conhecimentos, Atitudes e Prática em Saúde , Pessoal de Saúde , Sequenciamento de Nucleotídeos em Larga Escala/ética , Humanos , Intenção , Masculino , Pacientes , Prevalência , Sequenciamento Completo do Genoma/economia
9.
Nucleic Acids Res ; 47(D1): D1005-D1012, 2019 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-30445434

RESUMO

The GWAS Catalog delivers a high-quality curated collection of all published genome-wide association studies enabling investigations to identify causal variants, understand disease mechanisms, and establish targets for novel therapies. The scope of the Catalog has also expanded to targeted and exome arrays with 1000 new associations added for these technologies. As of September 2018, the Catalog contains 5687 GWAS comprising 71673 variant-trait associations from 3567 publications. New content includes 284 full P-value summary statistics datasets for genome-wide and new targeted array studies, representing 6 × 109 individual variant-trait statistics. In the last 12 months, the Catalog's user interface was accessed by ∼90000 unique users who viewed >1 million pages. We have improved data access with the release of a new RESTful API to support high-throughput programmatic access, an improved web interface and a new summary statistics database. Summary statistics provision is supported by a new format proposed as a community standard for summary statistics data representation. This format was derived from our experience in standardizing heterogeneous submissions, mapping formats and in harmonizing content. Availability: https://www.ebi.ac.uk/gwas/.


Assuntos
Bases de Dados Genéticas , Estudo de Associação Genômica Ampla , Doença/genética , Variação Genética , Humanos , Análise em Microsséries , Publicações , Software , Interface Usuário-Computador
10.
PLoS One ; 14(12): e0226771, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31891604

RESUMO

We performed a hypothesis-generating phenome-wide association study (PheWAS) to identify and characterize cross-phenotype associations, where one SNP is associated with two or more phenotypes, between thousands of genetic variants assayed on the Metabochip and hundreds of phenotypes in 5,897 African Americans as part of the Population Architecture using Genomics and Epidemiology (PAGE) I study. The PAGE I study was a National Human Genome Research Institute-funded collaboration of four study sites accessing diverse epidemiologic studies genotyped on the Metabochip, a custom genotyping chip that has dense coverage of regions in the genome previously associated with cardio-metabolic traits and outcomes in mostly European-descent populations. Here we focus on identifying novel phenome-genome relationships, where SNPs are associated with more than one phenotype. To do this, we performed a PheWAS, testing each SNP on the Metabochip for an association with up to 273 phenotypes in the participating PAGE I study sites. We identified 133 putative pleiotropic variants, defined as SNPs associated at an empirically derived p-value threshold of p<0.01 in two or more PAGE study sites for two or more phenotype classes. We further annotated these PheWAS-identified variants using publicly available functional data and local genetic ancestry. Amongst our novel findings is SPARC rs4958487, associated with increased glucose levels and hypertension. SPARC has been implicated in the pathogenesis of diabetes and is also known to have a potential role in fibrosis, a common consequence of multiple conditions including hypertension. The SPARC example and others highlight the potential that PheWAS approaches have in improving our understanding of complex disease architecture by identifying novel relationships between genetic variants and an array of common human phenotypes.


Assuntos
Afro-Americanos/genética , Aterosclerose/genética , Pleiotropia Genética , Metagenômica , Fenômica , Idoso , Estudos Epidemiológicos , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único
11.
Hum Mutat ; 39(11): 1713-1720, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30311373

RESUMO

The Clinical Genome Resource (ClinGen) Ancestry and Diversity Working Group highlights the need to develop guidance on race, ethnicity, and ancestry (REA) data collection and use in clinical genomics. We present quantitative and qualitative evidence to characterize: (1) acquisition of REA data via clinical laboratory requisition forms, and (2) information disparity across populations in the Genome Aggregation Database (gnomAD) at clinically relevant sites ascertained from annotations in ClinVar. Our requisition form analysis showed substantial heterogeneity in clinical laboratory ascertainment of REA, as well as marked incongruity among terms used to define REA categories. There was also striking disparity across REA populations in the amount of information available about clinically relevant variants in gnomAD. European ancestral populations constituted the majority of observations (55.8%), allele counts (59.7%), and private alleles (56.1%) in gnomAD at 550 loci with "pathogenic" and "likely pathogenic" expert-reviewed variants in ClinVar. Our findings highlight the importance of implementing and supporting programs to increase diversity in genome sequencing and clinical genomics, as well as measuring uncertainty around population-level datasets that are used in variant interpretation. Finally, we suggest the need for a standardized REA data collection framework to be developed through partnerships and collaborations and adopted across clinical genomics.


Assuntos
Variação Genética/genética , Alelos , Grupos Étnicos , Testes Genéticos/métodos , Genômica/métodos , Humanos , Mutação
12.
Per Med ; 15(5): 403-412, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30209973

RESUMO

Advances in genomic medicine are arising from efforts to build a national learning healthcare system (LHS) and large-scale precision medicine studies. However, the underlying evidence base lacks sufficient data from populations historically underrepresented in biomedical research. Although the literature on health and healthcare disparities is extensive, disparities in the availability and quality of health information about diverse and underrepresented populations are less well characterized. This Perspective describes scientific and ethical benefits to incorporating health information from diverse and underrepresented populations in the LHS, resulting in a more robust and generalizable LHS. Near-term recommendations for incorporating diversity into the evidence base for genomic medicine are proposed, even as the groundwork for national and international efforts is underway.


Assuntos
Disparidades em Assistência à Saúde/etnologia , Disparidades em Assistência à Saúde/tendências , Diversidade Cultural , Grupos Étnicos/educação , Grupos Étnicos/genética , Genômica , Humanos , Grupos Minoritários/educação , Educação de Pacientes como Assunto/métodos , Medicina de Precisão/métodos
13.
Am J Hum Genet ; 103(3): 319-327, 2018 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-30193136

RESUMO

The Clinical Sequencing Evidence-Generating Research (CSER) consortium, now in its second funding cycle, is investigating the effectiveness of integrating genomic (exome or genome) sequencing into the clinical care of diverse and medically underserved individuals in a variety of healthcare settings and disease states. The consortium comprises a coordinating center, six funded extramural clinical projects, and an ongoing National Human Genome Research Institute (NHGRI) intramural project. Collectively, these projects aim to enroll and sequence over 6,100 participants in four years. At least 60% of participants will be of non-European ancestry or from underserved settings, with the goal of diversifying the populations that are providing an evidence base for genomic medicine. Five of the six clinical projects are enrolling pediatric patients with various phenotypes. One of these five projects is also enrolling couples whose fetus has a structural anomaly, and the sixth project is enrolling adults at risk for hereditary cancer. The ongoing NHGRI intramural project has enrolled primarily healthy adults. Goals of the consortium include assessing the clinical utility of genomic sequencing, exploring medical follow up and cascade testing of relatives, and evaluating patient-provider-laboratory level interactions that influence the use of this technology. The findings from the CSER consortium will offer patients, healthcare systems, and policymakers a clearer understanding of the opportunities and challenges of providing genomic medicine in diverse populations and settings, and contribute evidence toward developing best practices for the delivery of clinically useful and cost-effective genomic sequencing in diverse healthcare settings.


Assuntos
Genoma Humano/genética , Adulto , Análise Custo-Benefício/métodos , Assistência à Saúde/métodos , Europa (Continente) , Exoma/genética , Genômica/métodos , Humanos , National Human Genome Research Institute (U.S.) , Fenótipo , Estados Unidos , Sequenciamento Completo do Genoma/métodos
14.
Am J Hematol ; 2018 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-29905378

RESUMO

Red blood cell (RBC) traits provide insight into a wide range of physiological states and exhibit moderate to high heritability, making them excellent candidates for genetic studies to inform underlying biologic mechanisms. Previous RBC trait genome-wide association studies were performed primarily in European- or Asian-ancestry populations, missing opportunities to inform understanding of RBC genetic architecture in diverse populations and reduce intervals surrounding putative functional SNPs through fine-mapping. Here, we report the first fine-mapping of six correlated (Pearson's r range: |0.04 - 0.92|) RBC traits in up to 19,036 African Americans and 19,562 Hispanic/Latinos participants of the Population Architecture using Genomics and Epidemiology (PAGE) consortium. Trans-ethnic meta-analysis of race/ethnic- and study-specific estimates for approximately 11,000 SNPs flanking 13 previously identified association signals as well as 150,000 additional array-wide SNPs was performed using inverse-variance meta-analysis after adjusting for study and clinical covariates. Approximately half of previously reported index SNP-RBC trait associations generalized to the trans-ethnic study population (p<1.7x10-4 ); previously unreported independent association signals within the ABO region reinforce the potential for multiple functional variants affecting the same locus. Trans-ethnic fine-mapping did not reveal additional signals at the HFE locus independent of the known functional variants. Finally, we identified a potential novel association in the Hispanic/Latino study population at the HECTD4/RPL6 locus for RBC count (p=1.9x10-7 ). The identification of a previously unknown association, generalization of a large proportion of known association signals, and refinement of known association signals all exemplify the benefits of genetic studies in diverse populations. This article is protected by copyright. All rights reserved.

15.
Hum Mol Genet ; 27(16): 2940-2953, 2018 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-29878111

RESUMO

C-reactive protein (CRP) is a circulating biomarker indicative of systemic inflammation. We aimed to evaluate genetic associations with CRP levels among non-European-ancestry populations through discovery, fine-mapping and conditional analyses. A total of 30 503 non-European-ancestry participants from 6 studies participating in the Population Architecture using Genomics and Epidemiology study had serum high-sensitivity CRP measurements and ∼200 000 single nucleotide polymorphisms (SNPs) genotyped on the Metabochip. We evaluated the association between each SNP and log-transformed CRP levels using multivariate linear regression, with additive genetic models adjusted for age, sex, the first four principal components of genetic ancestry, and study-specific factors. Differential linkage disequilibrium patterns between race/ethnicity groups were used to fine-map regions associated with CRP levels. Conditional analyses evaluated for multiple independent signals within genetic regions. One hundred and sixty-three unique variants in 12 loci in overall or race/ethnicity-stratified Metabochip-wide scans reached a Bonferroni-corrected P-value <2.5E-7. Three loci have no (HACL1, OLFML2B) or only limited (PLA2G6) previous associations with CRP levels. Six loci had different top hits in race/ethnicity-specific versus overall analyses. Fine-mapping refined the signal in six loci, particularly in HNF1A. Conditional analyses provided evidence for secondary signals in LEPR, IL1RN and HNF1A, and for multiple independent signals in CRP and APOE. We identified novel variants and loci associated with CRP levels, generalized known CRP associations to a multiethnic study population, refined association signals at several loci and found evidence for multiple independent signals at several well-known loci. This study demonstrates the benefit of conducting inclusive genetic association studies in large multiethnic populations.


Assuntos
Proteína C-Reativa/genética , Estudo de Associação Genômica Ampla , Metagenômica , Epidemiologia Molecular/métodos , Carbono-Carbono Liases , Enoil-CoA Hidratase/genética , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Glicoproteínas/genética , Fosfolipases A2 do Grupo VI/genética , Humanos , Desequilíbrio de Ligação , Masculino , Polimorfismo de Nucleotídeo Único
16.
Genome Biol ; 19(1): 21, 2018 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-29448949

RESUMO

The accurate description of ancestry is essential to interpret, access, and integrate human genomics data, and to ensure that these benefit individuals from all ancestral backgrounds. However, there are no established guidelines for the representation of ancestry information. Here we describe a framework for the accurate and standardized description of sample ancestry, and validate it by application to the NHGRI-EBI GWAS Catalog. We confirm known biases and gaps in diversity, and find that African and Hispanic or Latin American ancestry populations contribute a disproportionately high number of associations. It is our hope that widespread adoption of this framework will lead to improved analysis, interpretation, and integration of human genomics data.


Assuntos
Estudo de Associação Genômica Ampla/normas , Genômica/normas , Grupos de Populações Continentais , Variação Genética , Humanos
17.
Genet Med ; 20(10): 1186-1195, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29388940

RESUMO

PURPOSE: Secondary findings from genomic sequencing are becoming more common. We compared how health-care providers with and without specialized genetics training anticipated responding to different types of secondary findings. METHODS: Providers with genomic sequencing experience reviewed five secondary-findings reports and reported attitudes and potential clinical follow-up. Analyses compared genetic specialists and physicians without specialized genetics training, and examined how responses varied by secondary finding. RESULTS: Genetic specialists scored higher than other providers on four-point scales assessing understandings of reports (3.89 vs. 3.42, p = 0.0002), and lower on scales assessing reporting obligations (2.60 vs. 3.51, p < 0.0001) and burdens of responding (1.73 vs. 2.70, p < 0.0001). Nearly all attitudes differed between findings, although genetic specialists were more likely to assert that laboratories had no obligations when findings had less-established actionability (p < 0.0001 in interaction tests). The importance of reviewing personal and family histories, documenting findings, learning more about the variant, and recommending familial discussions also varied according to finding (all p < 0.0001). CONCLUSION: Genetic specialists felt better prepared to respond to secondary findings than providers without specialized genetics training, but perceived fewer obligations for laboratories to report them, and the two groups anticipated similar clinical responses. Findings may inform development of targeted education and support.


Assuntos
Testes Genéticos , Genômica , Conhecimentos, Atitudes e Prática em Saúde , Análise de Sequência de DNA , Atitude do Pessoal de Saúde , Revelação , Educação Médica , Pessoal de Saúde , Humanos , Achados Incidentais , Médicos , Especialização , Inquéritos e Questionários
18.
Genet Med ; 20(8): 855-866, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29144510

RESUMO

PURPOSE: As massively parallel sequencing is increasingly being used for clinical decision making, it has become critical to understand parameters that affect sequencing quality and to establish methods for measuring and reporting clinical sequencing standards. In this report, we propose a definition for reduced coverage regions and describe a set of standards for variant calling in clinical sequencing applications. METHODS: To enable sequencing centers to assess the regions of poor sequencing quality in their own data, we optimized and used a tool (ExCID) to identify reduced coverage loci within genes or regions of particular interest. We used this framework to examine sequencing data from 500 patients generated in 10 projects at sequencing centers in the National Human Genome Research Institute/National Cancer Institute Clinical Sequencing Exploratory Research Consortium. RESULTS: This approach identified reduced coverage regions in clinically relevant genes, including known clinically relevant loci that were uniquely missed at individual centers, in multiple centers, and in all centers. CONCLUSION: This report provides a process road map for clinical sequencing centers looking to perform similar analyses on their data.


Assuntos
Análise de Sequência de DNA/métodos , Sequenciamento Completo do Exoma/métodos , Sequenciamento Completo do Genoma/métodos , Sequência de Bases , Mapeamento Cromossômico , Exoma , Genoma Humano , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Análise de Sequência de DNA/normas , Software
19.
Nat Rev Genet ; 19(3): 175-185, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29151588

RESUMO

Recent studies have highlighted the imperatives of including diverse and under-represented individuals in human genomics research and the striking gaps in attaining that inclusion. With its multidecade experience in supporting research and policy efforts in human genomics, the National Human Genome Research Institute is committed to establishing foundational approaches to study the role of genomic variation in health and disease that include diverse populations. Large-scale efforts to understand biology and health have yielded key scientific findings, lessons and recommendations on how to increase diversity in genomic research studies and the genomic research workforce. Increased attention to diversity will increase the accuracy, utility and acceptability of using genomic information for clinical care.


Assuntos
Variação Genética , Genoma Humano , Genômica/métodos , Genética Humana/métodos , Medicina de Precisão/métodos , Humanos
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