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1.
Allergy Asthma Clin Immunol ; 17(1): 120, 2021 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-34819160

RESUMO

BACKGROUND: The hygiene hypothesis posits that microbial exposure reduces risk of asthma and other respiratory-related diseases. Helicobacter pylori and hepatitis A virus (HAV) are common fecal-oral infections. Our study aimed to examine associations of seropositivity to these agents with asthma in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). METHODS: A total of 12,471 HCHS/SOL participants with baseline data on self-reported physician-diagnosed asthma, and antibodies anti-H. pylori and anti-HAV were included in this cross-sectional analysis. Multivariable logistic regression models were used to estimate the odds ratios and 95% confidence intervals for the overall associations of seropositivity to each agent with asthma. Analyses were also stratified by Hispanic/Latino background. Effect modification by smoking status and nativity were tested. An analysis restricted to individuals with spirometry-defined chronic obstructive pulmonary disease (COPD) was also considered. RESULTS: The weighted overall prevalence of asthma was 16.6%. The weighted seroprevalence of H. pylori was 56.6% and of HAV was 76.6%, and they significantly differed by Hispanic/Latino background. After accounting for age, sex, education and other key confounders, we found no associations between H. pylori or HAV seropositivity with asthma (with and without COPD), either for all individuals combined or for any of the six specific backgrounds. There were no significant interactions by smoking and nativity. CONCLUSION: Our findings did not provide support for the role of H. pylori or HAV, as evidence of the hygiene hypothesis in asthma among the large and diverse Hispanic/Latino populations of the HCHS/SOL. Trial registration NCT02060344.

2.
Ethn Dis ; 31(4): 547-558, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34720558

RESUMO

Inclusion of historically underrepresented populations in biomedical research is critical for large precision medicine research initiatives. Among 13,721 Hispanic Community Health Study/Study of Latinos (HCHS/SOL) enrollees, we used multivariable-adjusted prevalence ratios to describe characteristics associated with participants' willingness to consent to different levels of biospecimen and genetic data analysis and sharing. At baseline (2008-2011), HCHS/SOL participants almost universally consented to the use of biospecimens and genetic data by study investigators and their collaborators (97.6%; 95%CI: 97.1, 98.0). Fewer consented to biospecimen and genetic data sharing with investigators not affiliated with the HCHS/SOL research team (81%, 95%CI: 80, 82) or any data sharing with commercial/for-profit entities (75%, 95%CI: 74, 76). Those refusing to share their data beyond the study investigators group were more often females, Spanish language-speakers and non-US born individuals. As expected, participants who were retained and reconsented at the six-year follow up visit tended to embrace broader data sharing, although this varied by group. Over time, Puerto Ricans and Dominicans were more likely to convert to broader data sharing than individuals of a Mexican background. Our analysis suggests that acculturation and immigration status of specific Hispanic/Latino communities may influence decisions about participation in genomic research projects and biobanks.

3.
Front Genet ; 12: 712602, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34745204

RESUMO

Pharmacogenomics (PGx) studies how a person's genes affect the response to medications and is quickly becoming a significant part of precision medicine. The clinical application of PGx principles has consistently been cited as a major opportunity for improving therapeutic outcomes. Several recent studies have demonstrated that most individuals (> 90%) harbor PGx variants that would be clinically actionable if prescribed a medication relevant to that gene. In multiple well-conducted studies, the results of PGx testing have been shown to guide therapy choice and dosing modifications which improve treatment efficacy and reduce the incidence of adverse drug reactions (ADRs). Although the value of PGx testing is evident, its successful implementation in a clinical setting presents a number of challenges to molecular diagnostic laboratories, healthcare systems, providers and patients. Different molecular methods can be applied to identify PGx variants and the design of the assay is therefore extremely important. Once the genotyping results are available the biggest technical challenge lies in turning this complex genetic information into phenotypes and actionable recommendations that a busy clinician can effectively utilize to provide better medical care, in a cost-effective, efficient and reliable manner. In this paper we describe a successful and highly collaborative implementation of the PGx testing program at the University of Minnesota and MHealth Fairview Molecular Diagnostic Laboratory and selected Pharmacies and Clinics. We offer detailed descriptions of the necessary components of the pharmacogenomic testing implementation, the development and technical validation of the in-house SNP based multiplex PCR based assay targeting 20 genes and 48 SNPs as well as a separate CYP2D6 copy number assay along with the process of PGx report design, results of the provider and pharmacists usability studies, and the development of the software tool for genotype-phenotype translation and gene-phenotype-drug CPIC-based recommendations. Finally, we outline the process of developing the clinical workflow that connects the providers with the PGx experts within the Molecular Diagnostic Laboratory and the Pharmacy.

4.
Mol Genet Genomic Med ; : e1832, 2021 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-34800009

RESUMO

BACKGROUND: Circulating markers of oxidative stress have been associated with lower lung function. Our objective was to study the association of gene expression levels of oxidative stress pathway genes (ALOX12, ALOX15, ARG2, GSTT1, LPO, MPO, NDUFB3, PLA2G7, and SOD3) and lung function forced expiratory volume in one second (FEV1 ), forced vital capacity (FVC) in Coronary Artery Risk Development in Young Adults study. METHODS: Lung function was measured using spirometry and the Nanostring platform was used to estimate gene expression levels. Linear regression models were used to study association of lung function measured at year 30, 10-year decline in lung function and gene expression after adjustment for center, smoking, and BMI, measured at year 25. RESULTS: The 10-year decline of FEV1 was faster in highest NDUFB3 quartile compared to the lowest (difference = -2.09%; p = 0.001) after adjustment for multiple comparisons. The 10-year decline in FEV1 and FVC was nominally slower in highest versus lowest quartile of PLA2G7 (difference = 1.14%; p = 0.02, and difference = 1.06%; p = 0.005, respectively). The other genes in the study were not associated with FEV1 or FVC. CONCLUSION: Higher gene expression levels in oxidative stress pathway genes are associated with faster 10-year FEV1 decline.

5.
Artigo em Inglês | MEDLINE | ID: mdl-34633448

RESUMO

Though T cell immunosenescence is a major risk factor for age-related diseases, susceptibility to infections, and responses to vaccines, differences in T cells subset counts and representation by age and sex have not been determined for a large sample representative of the national population of the US. We evaluated the counts of T cell subsets including total, CD4+ and CD8+ T cells, and their naïve (Tn), effector memory (Tem) and effector subsets, in the context of age, sex and exposure to cytomegalovirus (CMV) infection among 8,848 Health and Retirement Study (HRS) participants, a nationally representative study of adults over 55 years. Total T cells (CD3+) and CD4+ cells declined markedly with age; CD8+ T cells declined somewhat less. While CD4+ T cell declines with age occurred for both CMV seropositive and CMV seronegative groups, total T cells and CD8+ cells were both substantially higher among the CMV seropositive group. Numbers of Tn CD4+ and CD8+ cells were strongly and inversely related to age, were better conserved among women, and were independent of CMV seropositivity. By contrast, accumulation of the CD8+ and CD4+ Tem and effector subsets was CMV-associated. This is the first study to provide counts of T cell subsets by age and sex in a national sample of older US adults over the age of 55 years. Understanding T cell changes with age and sex is an important first step in determining strategies to reduce its impact on age-related diseases and susceptibility to infection.

6.
Artigo em Inglês | MEDLINE | ID: mdl-34637066

RESUMO

PURPOSE: The higher prevalence of cognitive impairment/ dementia among cancer survivors is likely multifactorial. Since both exposures to cytomegalovirus (CMV) and inflammation are common among elderly cancer survivors, we evaluated their contribution towards dementia. METHODS: Data from 1387 cancer survivors and 7004 participants without cancer in the 2016 wave of the Health and Retirement Study (HRS) was used in this study. Two inflammatory biomarkers, C-reactive protein (CRP) and neutrophil-lymphocyte ratio (NLR), were used to create an inflammation score. We used survey logistic regression adjusted for survey design parameters. RESULTS: CMV seropositivity was not associated with cognitive impairment among cancer survivors (p = 0.2). In addition, inflammation was associated with elevated odds of cognitive impairment (OR = 2.2, 95% CI [1.2, 4.2]). Cancer survivors who were both CMV seropositive and had increased inflammation had the highest odds of cognitive impairment compared to those who were CMV seronegative and had low inflammation (OR = 3.8, 95% CI [1.5, 9.4]). The stratified analysis among cancer survivors showed this association was seen only among cancer survivors in whom the cancer was diagnosed within three years of measurement of inflammation score and CMV serostatus (OR = 18.5; 95% CI [6.1, 56.1]). CONCLUSION: The CMV seropositivity and high inflammation was associated with higher cognitive impairment among cancer survivors. The stronger associations seen among cancer survivors diagnosed within the last three years suggest that strategies to reduce CMV activation and inflammation during or immediately after cancer treatment may be important in reducing the prevalence of cognitive impairment/ dementia among cancer survivors.

8.
ACS Meas Sci Au ; 1(1): 35-45, 2021 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-34476422

RESUMO

The thousands of features commonly observed when performing untargeted metabolomics with quadrupole time-of-flight (QTOF) and Orbitrap mass spectrometers often correspond to only a few hundred unique metabolites of biological origin, which is in the range of what can be assayed in a single targeted metabolomics experiment by using a triple quadrupole (QqQ) mass spectrometer. A major benefit of performing targeted metabolomics with QqQ mass spectrometry is the affordability of the instruments relative to high-resolution QTOF and Orbitrap platforms. Optimizing targeted methods to profile hundreds of metabolites on a QqQ mass spectrometer, however, has historically been limited by the availability of authentic standards, particularly for "unknowns" that have yet to be structurally identified. Here, we report a strategy to develop multiple reaction monitoring (MRM) methods for QqQ instruments on the basis of high-resolution spectra, thereby enabling us to use data from untargeted metabolomics to design targeted experiments without the need for authentic standards. We demonstrate that using high-resolution fragmentation data alone to design MRM methods results in the same quantitative performance as when methods are optimized by measuring authentic standards on QqQ instruments, as is conventionally done. The approach was validated by showing that Orbitrap ID-X data can be used to establish MRM methods on a Thermo TSQ Altis and two Agilent QqQs for hundreds of metabolites, including unknowns, without a dependence on standards. Finally, we highlight an application where metabolite profiling was performed on an ID-X and a QqQ by using the strategy introduced here, with both data sets yielding the same result. The described approach therefore allows us to use QqQ instruments, which are often associated with targeted metabolomics, to profile knowns and unknowns at a comprehensive scale that is typical of untargeted metabolomics.

9.
Diabetes Res Clin Pract ; 180: 109004, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34391830

RESUMO

AIM: To evaluate whether the extent of return to fasting state 2-hours after a glucose challenge among normoglycemic individuals is associated with lower risk of incident prediabetes/ type 2 diabetes in the Coronary Artery Risk Development in Young Adults (CARDIA) cohort study. METHODS: We evaluated this association among 1879 normoglycemic adults who were categorized into three groups: 'Low post load' (2hPG < FPG); 'Medium post load' (2hPG ≥ FPG and < 75th percentile of the difference); and 'High post load' (2hPG > FPG and ≥ 75th percentile of the difference). We used Cox proportional hazards regression to evaluate the association of the difference in 2hPG and FPG with incident diabetes/prediabetes after adjustment for demographic and clinical covariates. RESULTS: During 20 years of follow-up, 8% developed type 2 diabetes and 35% developed prediabetes. Compared to those with 'Low post load', the risk of type 2 diabetes was higher for participants with 'High post load' [HR: 1.56, 95% CI (1.03, 2.37)] and similar for participants with 'Medium post load' [HR: 0.99, 95% CI (0.64, 1.52)]. However, HRs for incident prediabetes among participants with 'High post load' [HR = 1.2, 95 %CI = (0.98, 1.46)] was not significantly different compared to participants with 'Low post load'. CONCLUSION: Among normoglycemic individuals, a difference between 2hPG and FPG concentration > 0.9 mmol/L can be used to stratify individuals at higher risk for developing type 2 diabetes.


Assuntos
Diabetes Mellitus Tipo 2 , Estado Pré-Diabético , Glicemia , Estudos de Coortes , Diabetes Mellitus Tipo 2/epidemiologia , Jejum , Teste de Tolerância a Glucose , Hemoglobina A Glicada/análise , Humanos , Estado Pré-Diabético/epidemiologia , Adulto Jovem
10.
J Alzheimers Dis ; 82(1): 17-32, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34219735

RESUMO

BACKGROUND: Coupling digital technology with traditional neuropsychological test performance allows collection of high-precision metrics that can clarify and/or define underlying constructs related to brain and cognition. OBJECTIVE: To identify graphomotor and information processing trajectories using a digitally administered version of the Digit Symbol Substitution Test (DSST). METHODS: A subset of Long Life Family Study participants (n = 1,594) completed the DSST. Total time to draw each symbol was divided into 'writing' and non-writing or 'thinking' time. Bayesian clustering grouped participants by change in median time over intervals of eight consecutively drawn symbols across the 90 s test. Clusters were characterized based on sociodemographic characteristics, health and physical function data, APOE genotype, and neuropsychological test scores. RESULTS: Clustering revealed four 'thinking' time trajectories, with two clusters showing significant changes within the test. Participants in these clusters obtained lower episodic memory scores but were similar in other health and functional characteristics. Clustering of 'writing' time also revealed four performance trajectories where one cluster of participants showed progressively slower writing time. These participants had weaker grip strength, slower gait speed, and greater perceived physical fatigability, but no differences in cognitive test scores. CONCLUSION: Digital data identified previously unrecognized patterns of 'writing' and 'thinking' time that cannot be detected without digital technology. These patterns of performance were differentially associated with measures of cognitive and physical function and may constitute specific neurocognitive biomarkers signaling the presence of subtle to mild dysfunction. Such information could inform the selection and timing of in-depth neuropsychological assessments and help target interventions.


Assuntos
Tecnologia Digital , Função Executiva , Pensamento , Redação , Idoso , Teorema de Bayes , Feminino , Humanos , Masculino , Testes Neuropsicológicos/estatística & dados numéricos , Tempo de Reação
11.
Transplant Cell Ther ; 27(10): 836.e1-836.e7, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34174468

RESUMO

Graft-versus-host-disease (GVHD) is a multistep process that involves T-cell recognition and priming toward alloantigen, expansion, acquisition of effector function, and repeated tissue injury, resulting in clinical manifestations of the disease. All of these processes have considerable metabolic demands and understanding the key role of mitochondria in cellular metabolism as it relates to GVHD has increased significantly. Mitochondrial DNA (mtDNA) haplotypes have been linked to functional differences in vitro, suggesting they have functional differences at an organismal level. We previously used mtDNA typing to assess the impact of mtDNA haplotypes on outcomes of ~400 allo-HCT patients. This pilot study identified uncommon mtDNA haplotypes potentially associated with inferior outcomes. We sought to validate pilot findings of associations between donor and recipient mitochondrial haplotypes and transplant outcome. We examined a cohort of 4143 donor-recipient pairs obtained from the Center for International Blood and Marrow Transplant Research. MtDNA was extracted from whole blood or peripheral blood mononuclear cells from donors and recipients and sequenced to discern haplotype. We used multiple regression analysis to examine the independent association of mtDNA haplotype with overall survival and grade III-IV acute GVHD (aGVHD) adjusting for known risk factors for poor transplant outcome. Neither recipient nor donor mtDNA haplotype reached groupwise significance for overall survival (P =.26 and .39, respectively) or grade III-IV aGVHD (P = .68 and.57, respectively). Adjustment for genomically determined ancestry in the subset of donor-recipient pairs for which this was available did not materially change results. We conclude that our original finding was due to chance in a small sample size and that there is essentially no evidence that mtDNA haplotype or haplotype mismatch contributes to risk of serious outcomes after allogeneic transplantation.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Doadores não Relacionados , Haplótipos , Humanos , Leucócitos Mononucleares , Mitocôndrias , Projetos Piloto
12.
Am J Epidemiol ; 190(11): 2461-2473, 2021 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-34142699

RESUMO

Dietary guidance emphasizes healthy dietary patterns, but supporting evidence comes from self-reported dietary data, which are prone to measurement error. We explored whether nutritional biomarkers from the Women's Health Initiative Nutrition and Physical Activity Assessment Study Feeding Study (NPAAS-FS) (n = 153; 2010-2014) and the Women's Health Initiative Nutrition and Physical Activity Assessment Study Observational Study (NPAAS-OS) (n = 450; 2006-2009) could identify biomarker signatures of dietary patterns for development of corresponding regression calibration equations to help mitigate measurement error. Fasting blood samples were assayed for a specific panel of vitamins, carotenoids, and phospholipid fatty acids; 24-hour urine samples were assayed for nitrogen, sodium, and potassium levels. Intake records from the NPAAS-FS were used to calculate Healthy Eating Index 2010 (HEI-2010), Alternative Healthy Eating Index 2010 (AHEI-2010), alternative Mediterranean diet (aMED), and Dietary Approaches to Stop Hypertension (DASH) scores. Scores were regressed on blood and urine nutritional measures for discovery of dietary pattern biomarkers using a cross-validated model R2 ≥ 36% criterion (stage 1). Next, stepwise models (P ≤ 0.10 for entry/removal) using NPAAS-OS data were used to regress stage 1 dietary pattern biomarkers on NPAAS-OS self-reported dietary pattern scores using a food frequency questionnaire, a 4-day food record, and a 24-hour recall (stage 2). HEI-2010 and aMED analyses met the cross-validated R2 ≥ 36% criterion in stage 1, while AHEI-2010 and DASH analyses did not. The R2 values for HEI-2010 stage 2 calibration equations were as follows: food frequency questionnaire, 63.5%; 4-day food record, 83.1%; and 24-hour recall, 77.8%. Stage 2 aMED R2 values were 34.9%-46.8%. Dietary pattern biomarkers have potential for calibrating self-reports to enhance studies of diet-disease associations.


Assuntos
Biomarcadores/sangue , Dieta Saudável , Estado Nutricional , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/urina , Dieta Mediterrânea , Abordagens Dietéticas para Conter a Hipertensão , Feminino , Humanos , Pessoa de Meia-Idade , Pós-Menopausa/sangue , Pós-Menopausa/urina
13.
Gut ; 2021 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-34127525

RESUMO

OBJECTIVE: Tryptophan can be catabolised to various metabolites through host kynurenine and microbial indole pathways. We aimed to examine relationships of host and microbial tryptophan metabolites with incident type 2 diabetes (T2D), host genetics, diet and gut microbiota. METHOD: We analysed associations between circulating levels of 11 tryptophan metabolites and incident T2D in 9180 participants of diverse racial/ethnic backgrounds from five cohorts. We examined host genome-wide variants, dietary intake and gut microbiome associated with these metabolites. RESULTS: Tryptophan, four kynurenine-pathway metabolites (kynurenine, kynurenate, xanthurenate and quinolinate) and indolelactate were positively associated with T2D risk, while indolepropionate was inversely associated with T2D risk. We identified multiple host genetic variants, dietary factors, gut bacteria and their potential interplay associated with these T2D-relaetd metabolites. Intakes of fibre-rich foods, but not protein/tryptophan-rich foods, were the dietary factors most strongly associated with tryptophan metabolites. The fibre-indolepropionate association was partially explained by indolepropionate-associated gut bacteria, mostly fibre-using Firmicutes. We identified a novel association between a host functional LCT variant (determining lactase persistence) and serum indolepropionate, which might be related to a host gene-diet interaction on gut Bifidobacterium, a probiotic bacterium significantly associated with indolepropionate independent of other fibre-related bacteria. Higher milk intake was associated with higher levels of gut Bifidobacterium and serum indolepropionate only among genetically lactase non-persistent individuals. CONCLUSION: Higher milk intake among lactase non-persistent individuals, and higher fibre intake were associated with a favourable profile of circulating tryptophan metabolites for T2D, potentially through the host-microbial cross-talk shifting tryptophan metabolism toward gut microbial indolepropionate production.

14.
J Gerontol A Biol Sci Med Sci ; 76(10): e307-e313, 2021 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-34156441

RESUMO

BACKGROUND: Gait speed is a powerful indicator of health with aging. Potential genetic contributions to gait speed and its decline with aging are not well defined. We determined the heritability of and potential genetic regions underlying change in gait speed using longitudinal data from 2379 individuals belonging to 509 families in the Long Life Family Study (mean age 64 ± 12, range 30-110 years; 45% men). METHODS: Gait speed was measured over 4 m at baseline and follow-up (7 ± 1 years). Quantitative trait linkage analyses were completed using pedigree-based maximum likelihood methods with logarithm of the odds (LOD) scores greater than 3.0, indicating genome-wide significance. We also performed linkage analysis in the top 10% of families contributing to LOD scores to allow for heterogeneity among families (HLOD). Data were adjusted for age, sex, height, and field center. RESULTS: At baseline, 26.9% of individuals had "slow" gait speed less than 1.0 m/s (mean: 1.1 ± 0.2 m/s) and gait speed declined at a rate of -0.02 ± 0.03 m/s per year (p < .0001). Baseline and change in gait speed were significantly heritable (h2 = 0.24-0.32, p < .05). We did not find significant evidence for linkage for baseline gait speed; however, we identified a significant locus for change in gait speed on chromosome 16p (LOD = 4.2). A subset of 21 families contributed to this linkage peak (HLOD = 6.83). Association analyses on chromosome 16 showed that the strongest variant resides within the ADCY9 gene. CONCLUSION: Further analysis of the chromosome 16 region, and ADCY9 gene, may yield new insight on the biology of mobility decline with aging.

15.
BMC Genomics ; 22(1): 432, 2021 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-34107879

RESUMO

BACKGROUND: Circulating white blood cell and platelet traits are clinically linked to various disease outcomes and differ across individuals and ancestry groups. Genetic factors play an important role in determining these traits and many loci have been identified. However, most of these findings were identified in populations of European ancestry (EA), with African Americans (AA), Hispanics/Latinos (HL), and other races/ethnicities being severely underrepresented. RESULTS: We performed ancestry-combined and ancestry-specific genome-wide association studies (GWAS) for white blood cell and platelet traits in the ancestrally diverse Population Architecture using Genomics and Epidemiology (PAGE) Study, including 16,201 AA, 21,347 HL, and 27,236 EA participants. We identified six novel findings at suggestive significance (P < 5E-8), which need confirmation, and independent signals at six previously established regions at genome-wide significance (P < 2E-9). We confirmed multiple previously reported genome-wide significant variants in the single variant association analysis and multiple genes using PrediXcan. Evaluation of loci reported from a Euro-centric GWAS indicated attenuation of effect estimates in AA and HL compared to EA populations. CONCLUSIONS: Our results highlighted the potential to identify ancestry-specific and ancestry-agnostic variants in participants with diverse backgrounds and advocate for continued efforts in improving inclusion of racially/ethnically diverse populations in genetic association studies for complex traits.


Assuntos
Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único , Predisposição Genética para Doença , Genômica , Humanos , Leucócitos , Fenótipo
16.
J Mol Diagn ; 23(9): 1085-1096, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34116245

RESUMO

Widespread high-throughput testing for identification of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection by RT-PCR has been a foundation in the response to the coronavirus disease 2019 (COVID-19) pandemic. Quality assurance metrics for these RT-PCR tests are still evolving as testing is widely implemented. As testing increases, it is important to understand performance characteristics and the errors associated with these tests. Herein, we investigate a high-throughput, laboratory-developed SARS-CoV-2 RT-PCR assay to determine whether modeling can generate quality control metrics that identify false-positive (FP) results due to contamination. This study reviewed repeated clinical samples focusing on positive samples that test negative on re-extraction and PCR, likely representing false positives. To identify and predict false-positive samples, we constructed machine learning-derived models based on the extraction method used. These models identified variables associated with false-positive results across all methods, with sensitivities for predicting FP results ranging between 67% and 100%. Application of the models to all results predicted a total FP rate of 0.08% across all samples, or 2.3% of positive results, similar to reports for other RT-PCR tests for RNA viruses. These models can predict quality control parameters, enabling laboratories to generate decision trees that reduce interpretation errors, allow for automated reflex testing of samples with a high FP probability, improve workflow efficiency, and increase diagnostic accuracy for patient care.


Assuntos
Teste de Ácido Nucleico para COVID-19/métodos , RNA Viral/isolamento & purificação , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Automação Laboratorial , Portador Sadio/virologia , Sistemas de Apoio a Decisões Clínicas , Reações Falso-Positivas , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Aprendizado de Máquina , SARS-CoV-2/genética , Carga Viral , Fluxo de Trabalho
17.
JMIR Res Protoc ; 10(5): e28997, 2021 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-33955843

RESUMO

BACKGROUND: Hispanic/Latino sexual and gender minorities (SGM) are the fastest growing ethnic group of SGM in the United States. Cardiovascular disease (CVD) is a leading cause of morbidity and mortality among Hispanics/Latinos. SGM inequities in CVD risk have been identified as early as young adulthood, and minority stress has been identified as a potential mediator. Yet, the small number of ethnic or racial minority participants in SGM studies have precluded the examination of the intersections of sexual orientation, gender identity, and race and ethnicity. OBJECTIVE: Minority stress models conceptualize relationships between stressors in minority groups and health outcomes. In this study, we will (1) examine the influence of sexual orientation and gender identity on CVD risk among all Hispanic Community Health Study/Study of Latinos (HCHS/SOL) participants at visit 3 (2021-2024; N~9300); (2) model pathways from sexual orientation and gender identity to CVD risk through stigma, discrimination, and stress in a 1:2 matched subcohort of SGM and non-SGM participants at visit 3 (n~1680); and (3) examine the influence of resilience factors on sexual orientation or gender identity and CVD risk relationships among subcohort participants at visit 3 (n~1680). METHODS: This study will leverage existing data from the parent HCHS/SOL study (collected since 2008) while collecting new data on sexual orientation, gender identity, stigma, discrimination, stress, coping, social support, and CVD risk. Data analysis will follow the SGM minority stress model, which states that excess stigma against SGM populations leads to minority stress that increases CVD risk. In this model, coping and social support serve as resilience factors that can mitigate the impact of minority stress on CVD risk. Cross-sectional and longitudinal regression models as well as structural equation models will be used to test these relationships. RESULTS: This study was funded by the National Heart, Lung, and Blood Institute in March 2020. Recruitment is scheduled to begin in the first quarter of 2021 and continue through 2024. CONCLUSIONS: Understanding the influence of stigma-induced stress on CVD risk among Hispanic/Latino SGM has significant implications for the development of culturally specific CVD risk reduction strategies. Study findings will be used to build on identified Hispanic/Latino cultural strengths to inform adaptation and testing of family and community acceptance interventions. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/28997.

18.
Circ Genom Precis Med ; 14(3): e003201, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33844929

RESUMO

BACKGROUND: Polygenic risk scores (PRS) for coronary heart disease (CHD) may contribute to assess the overall risk of CHD. We evaluated how PRS may influence CHD risk when the distribution of age-at-onset, sex, and family health history differ significantly. METHODS: Our study included 3 family-based ascertainments: LLFS (Long Life Family Study, NIndividuals=4572), which represents a low CHD risk, and Family Heart Study, which consists of randomly selected families (FamHS-random, NIndividuals=1806), and high CHD risk families (FamHS-high risk, NIndividuals=2301). We examined the effects of PRS, sex, family ascertainment, PRS interaction with sex (PRS*sex) and with family ascertainment (PRS*LLFS and PRS*FamHS-high risk) on CHD, corrected for traditional cardiovascular risk factors using Cox proportional hazard regression models. RESULTS: Healthy-aging LLFS presented ≈17 years delayed for CHD age-at-onset compared with FamHS-high risk (P<1.0×10-4). Sex-specific association (P<1.0×10-17) and PRS*sex (P=2.7×10-3) predicted prevalent CHD. CHD age-at-onset was associated with PRS (hazard ratio [HR], 1.57; P=1.3×10-5), LLFS (HR, 0.54; P=2.6×10-5), and FamHS-high risk (HR, 2.86; P=6.70x10-15) in men, and with PRS (HR, 1.76; P=7.70×10-3), FamHS-high risk (HR, 4.88; P=8.70×10-10), and PRS×FamHS-high risk (HR, 0.61; P=3.60×10-2) in women. In the PRS extreme quartile distributions, CHD age-at-onset was associated (P<0.05) with PRS, FamHS-high risk, and PRS interactions with both low and high CHD risk families for women. For men, the PRS quartile results remained similar to the whole distribution. CONCLUSIONS: Differences in CHD family-based ascertainments show evidence of PRS interacting with sex to predict CHD risk. In women, CHD age-at-onset was associated with PRS, CHD family history, and interactions of PRS with family history. In men, PRS and CHD family history were the major effects on the CHD age-at-onset. Understanding the heterogeneity of risks associated with CHD end points at both the personal and familial levels may shed light on the underlying genetic effects influencing CHD and lead to more personalized risk prediction.

19.
ERJ Open Res ; 7(1)2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33748259

RESUMO

Background: Airflow obstruction is associated with cognitive dysfunction but studies have not assessed how emphysema, a structural phenotype of lung disease, might be associated with cognitive function independent from pulmonary function measured by spirometry. We aimed to determine the relationship between the presence of visually detectable emphysema on chest computed tomography (CT) imaging and cognitive function. Methods: We examined 2491 participants, mean age of 50 years, from the Coronary Artery Risk Development in Young Adults study who were assessed for the presence of emphysema on chest CT imaging and had cognitive function measured 5 years later with a battery of six cognitive tests. Results: Of those assessed, 172 (7%) had emphysema. After adjusting for age, sex, height, study centre, race, body mass index, education and smoking, visual emphysema was significantly associated with worse performance on most cognitive tests. Compared to those without emphysema, participants with emphysema performed worse on cognitive testing: 0.39 sd units lower (95% CI -0.53- -0.25) on the Montreal Cognitive Assessment, 0.27 sd units lower (95% CI -0.42- -0.12) on the Rey Auditory Verbal Learning Test, 0.29 sd units lower (95% CI -0.43- -0.14) on the Digit Symbol Substitution Test and 0.25 sd units lower (95% CI -0.42- -0.09) on letter fluency. Further adjustment for forced expiratory volume in 1 s (FEV1), peak FEV1 and annualised FEV1 decline did not attenuate these associations. Conclusions: The presence of emphysema on chest CT is associated with worse cognitive function, independent of airflow obstruction. These data suggest that emphysema may be a novel risk factor for cognitive impairment.

20.
Arch Pathol Lab Med ; 2021 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-33769465

RESUMO

CONTEXT.­: Quantification and detection of the t(9;22) (BCR-ABL1) translocation in chronic myelogenous leukemia and B-lymphoblastic leukemia are important for directing treatment protocols and monitoring disease relapse. However, quantification using traditional reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) is dependent on a calibration curve and is prone to laboratory-to-laboratory variation. Droplet digital polymerase chain reaction (ddPCR) is a novel method that allows for highly sensitive absolute quantification of transcript copy number. As such, ddPCR is a good candidate for disease monitoring, an assay requiring reproducible measurements with high specificity and sensitivity. OBJECTIVE.­: To compare results of ddPCR and RT-qPCR BCR-ABL1 fusion transcript measurements of patient samples and determine if either method is superior. DESIGN.­: We optimized and standardized a 1-step multiplexed ddPCR assay to detect BCR-ABL1 p190 and ABL1 e10 transcripts. The ddPCR optimization included varying cycle number and primer concentration with standardization of droplet generation and droplet number and analyses to improve data sensitivity. Following optimization, ddPCR measurements were performed on clinical samples and compared with traditional RT-qPCR results. RESULTS.­: Droplet digital polymerase chain reaction was able to detect the BCR-ABL1 p190 transcript to 0.001% (1:10-5) with a calculated limit of detection and limit of quantitation of 4.1 and 5.3 transcripts, respectively. When tested on patient samples, ddPCR was able to identify 20% more positives than a laboratory-developed 2-step RT-qPCR assay. CONCLUSIONS.­: Droplet digital polymerase chain reaction demonstrated increased detection of BCR-ABL1 compared with RT-qPCR. Improved detection of BCR-ABL1 p190 and the potential for improved standardization across multiple laboratories makes ddPCR a suitable method for the disease monitoring in patients with acute B-lymphoblastic leukemia.

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