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  1. Article ; Online: ANNORE: genetic fine-mapping with functional annotation.

    Fisher, Virginia / Sebastiani, Paola / Cupples, L Adrienne / Liu, Ching-Ti

    Human molecular genetics

    2023  Volume 31, Issue 1, Page(s) 32–40

    Abstract: Genome-wide association studies (GWASs) have successfully identified loci of the human genome implicated in numerous complex traits. However, the limitations of this study design make it difficult to identify specific causal variants or biological ... ...

    Abstract Genome-wide association studies (GWASs) have successfully identified loci of the human genome implicated in numerous complex traits. However, the limitations of this study design make it difficult to identify specific causal variants or biological mechanisms of association. We propose a novel method, AnnoRE, which uses GWAS summary statistics, local correlation structure among genotypes and functional annotation from external databases to prioritize the most plausible causal single-nucleotide polymorphisms (SNPs) in each trait-associated locus. Our proposed method improves upon previous fine-mapping approaches by estimating the effects of functional annotation from genome-wide summary statistics, allowing for the inclusion of many annotation categories. By implementing a multiple regression model with differential shrinkage via random effects, we avoid reductive assumptions on the number of causal SNPs per locus. Application of this method to a large GWAS meta-analysis of body mass index identified six loci with significant evidence in favor of one or more variants. In an additional 24 loci, one or two variants were strongly prioritized over others in the region. The use of functional annotation in genetic fine-mapping studies helps to distinguish between variants in high LD and to identify promising targets for follow-up studies.
    MeSH term(s) Chromosome Mapping/methods ; Genome-Wide Association Study/methods ; Humans ; Multifactorial Inheritance ; Polymorphism, Single Nucleotide/genetics ; Quantitative Trait Loci
    Language English
    Publishing date 2023-03-22
    Publishing country England
    Document type Journal Article ; Meta-Analysis ; Research Support, N.I.H., Extramural
    ZDB-ID 1108742-0
    ISSN 1460-2083 ; 0964-6906
    ISSN (online) 1460-2083
    ISSN 0964-6906
    DOI 10.1093/hmg/ddab210
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  2. Article ; Online: The impact of obesity on lung function measurements and respiratory disease: A Mendelian randomization study.

    Liu, Jiayan / Xu, Hanfei / Cupples, L Adrienne / O' Connor, George T / Liu, Ching-Ti

    Annals of human genetics

    2023  Volume 87, Issue 4, Page(s) 174–183

    Abstract: Introduction: Observational studies have shown that body mass index (BMI) and waist-to-hip ratio (WHR) are both inversely associated with lung function, as assessed by forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1). However, ... ...

    Abstract Introduction: Observational studies have shown that body mass index (BMI) and waist-to-hip ratio (WHR) are both inversely associated with lung function, as assessed by forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1). However, observational data are susceptible to confounding and reverse causation.
    Methods: We selected genetic instruments based on their relevant large-scale genome-wide association studies. Summary statistics of lung function and asthma came from the UK Biobank and SpiroMeta Consortium meta-analysis (n = 400,102). After examining pleiotropy and removing outliers, we applied inverse-variance weighting to estimate the causal association of BMI and BMI-adjusted WHR (WHRadjBMI) with FVC, FEV1, FEV1/FVC, and asthma. Sensitivity analyses were performed using weighted median, MR-Egger, and MRlap methods.
    Results: We found that BMI was inversely associated with FVC (effect estimate, -0.167; 95% confidence interval (CI), -0.203 to -0.130) and FEV1 (effect estimate, -0.111; 95%CI, -0.149 to -0.074). Higher BMI was associated with higher FEV1/FVC (effect estimate, 0.079; 95%CI, 0.049 to 0.110) but was not significantly associated with asthma. WHRadjBMI was inversely associated with FVC (effect estimate, -0.132; 95%CI, -0.180 to -0.084) but has no significant association with FEV1. Higher WHR was associated with higher FEV1/FVC (effect estimate, 0.181; 95%CI, 0.130 to 0.232) and with increased risk of asthma (effect estimate, 0.027; 95%CI, 0.001 to 0.053).
    Conclusion: We found significant evidence that increased BMI is suggested to be causally related to decreased FVC and FEV1, and increased BMI-adjusted WHR could lead to lower FVC value and higher risk of asthma. Higher BMI and BMI-adjusted WHR were suggested to be causally associated with higher FEV1/FVC.
    MeSH term(s) Humans ; Asthma/genetics ; Body Mass Index ; Forced Expiratory Volume ; Genome-Wide Association Study ; Lung ; Mendelian Randomization Analysis ; Obesity/genetics
    Language English
    Publishing date 2023-04-03
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 333-5
    ISSN 1469-1809 ; 0003-4800
    ISSN (online) 1469-1809
    ISSN 0003-4800
    DOI 10.1111/ahg.12506
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  3. Article ; Online: Small Dense Low-Density Lipoprotein Cholesterol Is the Most Atherogenic Lipoprotein Parameter in the Prospective Framingham Offspring Study.

    Ikezaki, Hiroaki / Lim, Elise / Cupples, L Adrienne / Liu, Ching-Ti / Asztalos, Bela F / Schaefer, Ernst J

    Journal of the American Heart Association

    2021  Volume 10, Issue 5, Page(s) e019140

    Abstract: Background Elevated plasma levels of direct low-density lipoprotein cholesterol (LDL-C), small dense LDL-C (sdLDL-C), low-density lipoprotein (LDL) triglycerides, triglycerides, triglyceride-rich lipoprotein cholesterol, remnant lipoprotein particle ... ...

    Abstract Background Elevated plasma levels of direct low-density lipoprotein cholesterol (LDL-C), small dense LDL-C (sdLDL-C), low-density lipoprotein (LDL) triglycerides, triglycerides, triglyceride-rich lipoprotein cholesterol, remnant lipoprotein particle cholesterol, and lipoprotein(a) have all been associated with incident atherosclerotic cardiovascular disease (ASCVD). Our goal was to assess which parameters were most strongly associated with ASCVD risk. Methods and Results Plasma total cholesterol, triglycerides, high-density lipoprotein cholesterol, direct LDL-C, sdLDL-C, LDL triglycerides, remnant lipoprotein particle cholesterol, triglyceride-rich lipoprotein cholesterol, and lipoprotein(a) were measured using standardized automated analysis (coefficients of variation, <5.0%) in samples from 3094 fasting subjects free of ASCVD. Of these subjects, 20.2% developed ASCVD over 16 years. On univariate analysis, all ASCVD risk factors were significantly associated with incident ASCVD, as well as the following specialized lipoprotein parameters: sdLDL-C, LDL triglycerides, triglycerides, triglyceride-rich lipoprotein cholesterol, remnant lipoprotein particle cholesterol, and direct LDL-C. Only sdLDL-C, direct LDL-C, and lipoprotein(a) were significant on multivariate analysis and net reclassification after adjustment for standard risk factors (age, sex, hypertension, diabetes mellitus, smoking, total cholesterol, and high-density lipoprotein cholesterol). Using the pooled cohort equation, many specialized lipoprotein parameters individually added significant information, but no parameter added significant information once sdLDL-C (hazard ratio, 1.42;
    MeSH term(s) Atherosclerosis/blood ; Atherosclerosis/epidemiology ; Biomarkers/blood ; Cholesterol, HDL/blood ; Cholesterol, LDL/blood ; Female ; Follow-Up Studies ; Forecasting ; Humans ; Male ; Middle Aged ; Prospective Studies ; Risk Factors
    Chemical Substances Biomarkers ; Cholesterol, HDL ; Cholesterol, LDL
    Language English
    Publishing date 2021-02-15
    Publishing country England
    Document type Journal Article ; Observational Study ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 2653953-6
    ISSN 2047-9980 ; 2047-9980
    ISSN (online) 2047-9980
    ISSN 2047-9980
    DOI 10.1161/JAHA.120.019140
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  4. Article ; Online: A fine-mapping study of central obesity loci incorporating functional annotation and imputation.

    Zhang, Xiaoyu / Cupples, L Adrienne / Liu, Ching-Ti

    European journal of human genetics : EJHG

    2018  Volume 26, Issue 9, Page(s) 1369–1377

    Abstract: A recent genome-wide association study (GWAS) of central obesity identified 27 loci, from sex-combined analysis, associated with waist-to-hip ratio adjusted for body-mass index (WHRadjBMI) in European-ancestry individuals. Nevertheless, the identified ... ...

    Abstract A recent genome-wide association study (GWAS) of central obesity identified 27 loci, from sex-combined analysis, associated with waist-to-hip ratio adjusted for body-mass index (WHRadjBMI) in European-ancestry individuals. Nevertheless, the identified variants may not be the biological causal ones due to the presence of linkage disequilibrium (LD). To better understand the mechanisms underlying the identified loci from the GWAS meta-analysis, we first imputed summary statistics at GWAS loci to increase genetic resolution, and then we applied a Bayesian statistical fine-mapping method through PAINTOR, incorporating LD structure and functional annotations to select and prioritize the most plausible causal variants across WHRadjBMI-associated regions. Using adipose tissue- and cell-specific annotations that showed significant associations with WHRadjBMI, we identified 33 single-nucleotide polymorphisms (SNPs) from 27 sex-combined fine-mapping loci with posterior probability of causality greater than 0.9. Six of the selected 33 SNPs belong to at least one of the top five identified annotations. SNPs rs1440372 (SMAD6) and rs12608504 (JUND) are particularly important since they not only have associated functional annotations but are also GWA hits in the original study. Incorporation of functional annotations helps identify additional plausible causal variants, such as rs2213731 (DNM3-PIGC) and rs4531856 (JUND), that did not reach genome-wide significance in GWAS. Our results provide promising candidates for future functional validation experiments.
    MeSH term(s) Female ; Genetic Loci ; Genome-Wide Association Study ; Hexosyltransferases/genetics ; Humans ; Male ; Membrane Proteins/genetics ; Molecular Sequence Annotation ; Obesity/genetics ; Polymorphism, Single Nucleotide ; Proto-Oncogene Proteins c-jun/genetics ; Smad6 Protein/genetics
    Chemical Substances JunD protein, human ; Membrane Proteins ; Proto-Oncogene Proteins c-jun ; SMAD6 protein, human ; Smad6 Protein ; Hexosyltransferases (EC 2.4.1.-) ; PIGC protein, human (EC 2.4.1.198)
    Language English
    Publishing date 2018-07-02
    Publishing country England
    Document type Journal Article ; Meta-Analysis ; Research Support, N.I.H., Extramural
    ZDB-ID 1141470-4
    ISSN 1476-5438 ; 1018-4813
    ISSN (online) 1476-5438
    ISSN 1018-4813
    DOI 10.1038/s41431-018-0168-5
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    Zs.A 3589: Show issues Location:
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  5. Article: Family study designs in the age of genome-wide association studies: experience from the Framingham Heart Study.

    Cupples, L Adrienne

    Current opinion in lipidology

    2008  Volume 19, Issue 2, Page(s) 144–150

    Abstract: Purpose of review: The past year has seen the publication of many genome-wide association studies, most of which are case-control studies. These publications are at the forefront of current research into the examination of genetic effects for numerous ... ...

    Abstract Purpose of review: The past year has seen the publication of many genome-wide association studies, most of which are case-control studies. These publications are at the forefront of current research into the examination of genetic effects for numerous diseases, including diabetes, heart disease and cancer. Over the past 25 years the tour de force of genetics research has been in family studies, using segregation, linkage and association analyses. Are these approaches now passé? Here we discuss the role of family studies in modern genetics research, using results from the Framingham Heart Study as examples.
    Recent findings: Family studies permit both linkage and association analyses. Importantly, family-based association tests that consider transmission of genetic variants within a family provide important information on the genetic etiology of disease traits and avoid the potential of false-positive findings due to population substructure.
    Summary: Family-based study designs continue to contribute much to the modern era of genome-wide association studies.
    MeSH term(s) Animals ; Epidemiologic Research Design ; Family ; Genetic Predisposition to Disease/genetics ; Genome, Human/genetics ; Heart ; Humans ; United States/epidemiology
    Language English
    Publishing date 2008-04-02
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Review
    ZDB-ID 1045394-5
    ISSN 1473-6535 ; 0957-9672
    ISSN (online) 1473-6535
    ISSN 0957-9672
    DOI 10.1097/MOL.0b013e3282f73746
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  6. Article ; Online: Association of Obesity With Mortality Over 24 Years of Weight History: Findings From the Framingham Heart Study.

    Xu, Hanfei / Cupples, L Adrienne / Stokes, Andrew / Liu, Ching-Ti

    JAMA network open

    2018  Volume 1, Issue 7, Page(s) e184587

    Abstract: Importance: Many studies of the association between obesity and mortality rely on weight status at a single point in time, making it difficult to adequately address bias associated with reverse causality.: Objective: To investigate the association ... ...

    Abstract Importance: Many studies of the association between obesity and mortality rely on weight status at a single point in time, making it difficult to adequately address bias associated with reverse causality.
    Objective: To investigate the association between maximum body mass index (BMI) and all-cause mortality without the consequences of reverse causality.
    Design, setting, and participants: Prospective cohort studies for the original and offspring cohorts of the Framingham Heart Study. The follow-up period started from baseline examination 13 for the original cohort and from baseline examination 6 for the offspring cohort and ended December 31, 2014. The analyses were conducted in 2017. Participants were 6197 individuals with 3478 deaths during a mean of 17 years of follow-up.
    Main outcomes and measures: Maximum BMI over 24 years of weight history before the beginning of follow-up for all-cause mortality and cause-specific mortality. All-cause mortality and cause-specific mortality (deaths due to cardiovascular disease, cancer, or other causes).
    Results: Among 6197 participants (mean [SD] age at baseline, 62.79 [8.98] years; 55.5% female), 3478 (56.1%) died during the follow-up. A monotonic association was observed between maximum BMI and mortality, with increasing risks observed across obese I (BMI of 30 to <35; hazard ratio [HR], 1.27; 95% CI, 1.14-1.41) and obese II (BMI of 35 to <40; HR, 1.93; 95% CI, 1.68-2.20) categories. A significant association was not observed for the overweight category (BMI of 25 to <30; HR, 1.08; 95% CI, 0.99-1.18). Among never smokers, the risks increased, with a significant association emerging for individuals with maximum BMI in the overweight range (HR, 1.31; 95% CI, 1.13-1.51). The mortality rates of normal-weight individuals who were formerly overweight or obese were 47.48 and 66.67 per 1000 person-years, respectively, while individuals who never exceeded normal weight had a mortality rate of 27.93 per 1000 person-years.
    Conclusions and relevance: A monotonic association was found between maximum BMI over 24 years of weight history and subsequent all-cause mortality. Maximum BMI in the normal-weight range was associated with the lowest risk of mortality in this cohort, highlighting the importance of obesity prevention.
    MeSH term(s) Aged ; Body Mass Index ; Body Weight/physiology ; Cardiovascular Diseases/mortality ; Female ; Humans ; Longitudinal Studies ; Male ; Middle Aged ; Neoplasms/mortality ; Obesity/epidemiology ; Obesity/mortality ; Prospective Studies
    Language English
    Publishing date 2018-11-02
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ISSN 2574-3805
    ISSN (online) 2574-3805
    DOI 10.1001/jamanetworkopen.2018.4587
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  7. Article ; Online: Revisiting methods for modeling longitudinal and survival data: Framingham Heart Study.

    Ngwa, Julius S / Cabral, Howard J / Cheng, Debbie M / Gagnon, David R / LaValley, Michael P / Cupples, L Adrienne

    BMC medical research methodology

    2021  Volume 21, Issue 1, Page(s) 29

    Abstract: Background: Statistical methods for modeling longitudinal and time-to-event data has received much attention in medical research and is becoming increasingly useful. In clinical studies, such as cancer and AIDS, longitudinal biomarkers are used to ... ...

    Abstract Background: Statistical methods for modeling longitudinal and time-to-event data has received much attention in medical research and is becoming increasingly useful. In clinical studies, such as cancer and AIDS, longitudinal biomarkers are used to monitor disease progression and to predict survival. These longitudinal measures are often missing at failure times and may be prone to measurement errors. More importantly, time-dependent survival models that include the raw longitudinal measurements may lead to biased results. In previous studies these two types of data are frequently analyzed separately where a mixed effects model is used for the longitudinal data and a survival model is applied to the event outcome.
    Methods: In this paper we compare joint maximum likelihood methods, a two-step approach and a time dependent covariate method that link longitudinal data to survival data with emphasis on using longitudinal measures to predict survival. We apply a Bayesian semi-parametric joint method and maximum likelihood joint method that maximizes the joint likelihood of the time-to-event and longitudinal measures. We also implement the Two-Step approach, which estimates random effects separately, and a classic Time Dependent Covariate Model. We use simulation studies to assess bias, accuracy, and coverage probabilities for the estimates of the link parameter that connects the longitudinal measures to survival times.
    Results: Simulation results demonstrate that the Two-Step approach performed best at estimating the link parameter when variability in the longitudinal measure is low but is somewhat biased downwards when the variability is high. Bayesian semi-parametric and maximum likelihood joint methods yield higher link parameter estimates with low and high variability in the longitudinal measure. The Time Dependent Covariate method resulted in consistent underestimation of the link parameter. We illustrate these methods using data from the Framingham Heart Study in which lipid measurements and Myocardial Infarction data were collected over a period of 26 years.
    Conclusions: Traditional methods for modeling longitudinal and survival data, such as the time dependent covariate method, that use the observed longitudinal data, tend to provide downwardly biased estimates. The two-step approach and joint models provide better estimates, although a comparison of these methods may depend on the underlying residual variance.
    MeSH term(s) Bayes Theorem ; Bias ; Computer Simulation ; Humans ; Longitudinal Studies ; Models, Statistical ; Survival Analysis
    Language English
    Publishing date 2021-02-10
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ISSN 1471-2288
    ISSN (online) 1471-2288
    DOI 10.1186/s12874-021-01207-y
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  8. Article ; Online: Exome sequence association study of levels and longitudinal change of cardiovascular risk factor phenotypes in European Americans and African Americans from the Atherosclerosis Risk in Communities Study.

    Feofanova, Elena V / Lim, Elise / Chen, Han / Lee, MinJae / Liu, Ching-Ti / Cupples, L Adrienne / Boerwinkle, Eric

    Genetic epidemiology

    2021  Volume 45, Issue 6, Page(s) 651–663

    Abstract: Cardiovascular disease (CVD) is responsible for 31% of all deaths worldwide. Among CVD risk factors are age, race, increased systolic blood pressure (BP), and dyslipidemia. Both BP and blood lipids levels change with age, with a dose-dependent ... ...

    Abstract Cardiovascular disease (CVD) is responsible for 31% of all deaths worldwide. Among CVD risk factors are age, race, increased systolic blood pressure (BP), and dyslipidemia. Both BP and blood lipids levels change with age, with a dose-dependent relationship between the cumulative exposure to hyperlipidemia and the risk of CVD. We performed an exome sequence association study using longitudinal data with up to 7805 European Americans (EAs) and 3171 African Americans (AAs) from the Atherosclerosis Risk in Communities (ARIC) study. We assessed associations of common (minor allele frequency > 5%) nonsynonymous and splice-site variants and gene-based sets of rare variants with levels and with longitudinal change of seven CVD risk factor phenotypes (BP traits: systolic BP, diastolic BP, pulse pressure; lipids traits: triglycerides, total cholesterol, high-density lipoprotein cholesterol [HDL-C], low-density lipoprotein cholesterol [LDL-C]). Furthermore, we investigated the relationship of the identified variants and genes with select CVD endpoints. We identified two novel genes: DCLK3 associated with the change of HDL-C levels in AAs and RAB7L1 associated with the change of LDL-C levels in EAs. RAB7L1 is further associated with an increased risk of heart failure in ARIC EAs. Investigation of the contribution of genetic factors to the longitudinal change of CVD risk factor phenotypes promotes our understanding of the etiology of CVD outcomes, stressing the importance of incorporating the longitudinal structure of the cohort data in future analyses.
    MeSH term(s) Black or African American/genetics ; Atherosclerosis/genetics ; Cardiovascular Diseases/epidemiology ; Cardiovascular Diseases/genetics ; Exome ; Heart Disease Risk Factors ; Humans ; Phenotype ; Risk Factors
    Language English
    Publishing date 2021-06-24
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 605785-8
    ISSN 1098-2272 ; 0741-0395
    ISSN (online) 1098-2272
    ISSN 0741-0395
    DOI 10.1002/gepi.22390
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  9. Book: Survival following initial cardiovascular events

    Cupples, L. Adrienne / D'Agostino, Ralph B.

    30 year follow-up

    (Framingham study ; 35 ; PB / National Technical Information Service ; 88-204029 ; NIH publication ; 88-2959)

    1988  

    Author's details L. Adrienne Cupples and Ralph B. D'Agostino
    Series title Framingham study ; 35
    PB / National Technical Information Service ; 88-204029
    NIH publication ; 88-2959
    The Framingham study
    Collection The Framingham study
    Keywords Cardiovascular Diseases / epidemiology ; Survival Analysis ; Follow-Up Studies
    Language English
    Size III, 454 S. : graph. Darst.
    Publisher NTIS
    Publishing place Springfield, Va
    Publishing country United States
    Document type Book
    Note Kopie
    HBZ-ID HT006192881
    Database Catalogue ZB MED Medicine, Health

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    Shelf markLoan statusLocation
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  10. Article ; Online: Sociodemographic Patterns of Exposure to Civil Aircraft Noise in the United States.

    Simon, Matthew C / Hart, Jaime E / Levy, Jonathan I / VoPham, Trang / Malwitz, Andrew / Nguyen, Daniel / Bozigar, Matthew / Cupples, L Adrienne / James, Peter / Laden, Francine / Peters, Junenette L

    Environmental health perspectives

    2022  Volume 130, Issue 2, Page(s) 27009

    Abstract: Background: Communities with lower socioeconomic status and higher prevalence of racial/ethnic minority populations are often more exposed to environmental pollutants. Although studies have shown associations between aircraft noise and property values ... ...

    Abstract Background: Communities with lower socioeconomic status and higher prevalence of racial/ethnic minority populations are often more exposed to environmental pollutants. Although studies have shown associations between aircraft noise and property values and various health outcomes, little is known about how aircraft noise exposures are sociodemographically patterned.
    Objective: Our aim was to describe characteristics of populations exposed to aviation noise by race/ethnicity, education, and income in the United States.
    Methods: Aircraft noise contours characterized as day-night average sound level (DNL) were developed for 90 U.S. airports in 2010 for DNL
    Results: Aggregated across multiple airports, block groups with a higher Hispanic population had higher odds of being exposed to aircraft noise. For example, the multinomial analysis showed that a 10-percentage point increase in a block group's Hispanic population was associated with an increased odds ratio of 39% (95% CI: 25%, 54%) of being exposed to
    Discussion: These results suggest that across U.S. airports, there is indication of sociodemographic disparities in noise exposures. https://doi.org/10.1289/EHP9307.
    MeSH term(s) Aircraft ; Airports ; Environmental Exposure ; Ethnicity ; Humans ; Minority Groups ; Noise, Transportation/adverse effects ; United States
    Language English
    Publishing date 2022-02-15
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 195189-0
    ISSN 1552-9924 ; 0091-6765 ; 1078-0475
    ISSN (online) 1552-9924
    ISSN 0091-6765 ; 1078-0475
    DOI 10.1289/EHP9307
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