Paul Elliott

Wake Forest School of Medicine, Winston-Salem, North Carolina, United States

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Publications (492)

  • Article · Dec 2016 · Environmental Health Perspectives
  • [Show abstract] [Hide abstract] ABSTRACT: Exposure to road traffic noise may increase blood pressure and heart rate. It is unclear to what extent exposure to air pollution may influence this relationship. We investigated associations between noise, blood pressure and heart rate, with harmonized data from three European cohorts, while taking into account exposure to air pollution.
    Article · Sep 2016
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    [Show abstract] [Hide abstract] ABSTRACT: Background: Methods based on spot urine samples (a single sample at one time-point) have been identified as a possible alternative approach to 24-hour urine samples for determining mean population salt intake. Objective: The aim of this study is to identify a reliable method for estimating mean population salt intake from spot urine samples. This will be done by comparing the performance of existing equations against one other and against estimates derived from 24-hour urine samples. The effects of factors such as ethnicity, sex, age, body mass index, antihypertensive drug use, health status, and timing of spot urine collection will be explored. The capacity of spot urine samples to measure change in salt intake over time will also be determined. Finally, we aim to develop a novel equation (or equations) that performs better than existing equations to estimate mean population salt intake. Methods: A systematic review and meta-analysis of individual participant data will be conducted. A search has been conducted to identify human studies that report salt (or sodium) excretion based upon 24-hour urine samples and spot urine samples. There were no restrictions on language, study sample size, or characteristics of the study population. MEDLINE via OvidSP (1946-present), Premedline via OvidSP, EMBASE, Global Health via OvidSP (1910-present), and the Cochrane Library were searched, and two reviewers identified eligible studies. The authors of these studies will be invited to contribute data according to a standard format. Individual participant records will be compiled and a series of analyses will be completed to: (1) compare existing equations for estimating 24-hour salt intake from spot urine samples with 24-hour urine samples, and assess the degree of bias according to key demographic and clinical characteristics; (2) assess the reliability of using spot urine samples to measure population changes in salt intake overtime; and (3) develop a novel equation that performs better than existing equations to estimate mean population salt intake. Results: The search strategy identified 538 records; 100 records were obtained for review in full text and 73 have been confirmed as eligible. In addition, 68 abstracts were identified, some of which may contain data eligible for inclusion. Individual participant data will be requested from the authors of eligible studies. Conclusions: Many equations for estimating salt intake from spot urine samples have been developed and validated, although most have been studied in very specific settings. This meta-analysis of individual participant data will enable a much broader understanding of the capacity for spot urine samples to estimate population salt intake.
    Full-text available · Article · Sep 2016
  • [Show abstract] [Hide abstract] ABSTRACT: Large-scale metabolomics studies involving thousands of samples present multiple challenges in data analysis, particularly when an untargeted platform is used. Studies with multiple cohorts and analysis platforms exacerbate existing problems such as peak alignment and normalization. Therefore, there is a need for robust processing pipelines which can ensure reliable data for statistical analysis. The COMBI-BIO project incorporates serum from approximately 8000 individuals, in 3 cohorts, profiled by 6 assays in 2 phases using both (1)H-NMR and UPLC-MS. Here we present the COMBI-BIO NMR analysis pipeline and demonstrate its fitness for purpose using representative quality control (QC) samples. NMR spectra were first aligned and normalized. After eliminating interfering signals, outliers identified using Hotelling's T(2) were removed and a cohort/phase adjustment was applied, resulting in two NMR datasets (CPMG and NOESY). Alignment of the NMR data was shown to increase the correlation-based alignment quality measure from 0.319 to 0.391 for CPMG and from 0.536 to 0.586 for NOESY, showing that the improvement was present across both large and small peaks. End-to-end quality assessment of the pipeline was achieved using Hotelling's T(2) distributions. For CPMG spectra, the interquartile range decreased from 1.425 in raw QC data to 0.679 in processed spectra, while the corresponding change for NOESY spectra was from 0.795 to 0.636 indicating an improvement in precision following processing. PCA indicated that gross phase and cohort differences were no longer present. These results illustrate that the pipeline produces robust and reproducible data, successfully addressing the methodological challenges of this large multi-faceted study.
    Article · Sep 2016 · Journal of Proteome Research
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    [Show abstract] [Hide abstract] ABSTRACT: To dissect the genetic architecture of blood pressure and assess effects on target organ damage, we analyzed 128,272 SNPs from targeted and genome-wide arrays in 201,529 individuals of European ancestry, and genotypes from an additional 140,886 individuals were used for validation. We identified 66 blood pressure-associated loci, of which 17 were new; 15 harbored multiple distinct association signals. The 66 index SNPs were enriched for cis-regulatory elements, particularly in vascular endothelial cells, consistent with a primary role in blood pressure control through modulation of vascular tone across multiple tissues. The 66 index SNPs combined in a risk score showed comparable effects in 64,421 individuals of non-European descent. The 66-SNP blood pressure risk score was significantly associated with target organ damage in multiple tissues but with minor effects in the kidney. Our findings expand current knowledge of blood pressure-related pathways and highlight tissues beyond the classical renal system in blood pressure regulation.
    Full-text available · Article · Sep 2016 · Nature Genetics
  • [Show abstract] [Hide abstract] ABSTRACT: High blood pressure is a major risk factor for cardiovascular disease and premature death. However, there is limited knowledge on specific causal genes and pathways. To better understand the genetics of blood pressure, we genotyped 242,296 rare, low-frequency and common genetic variants in up to 192,763 individuals and used ∼155,063 samples for independent replication. We identified 30 new blood pressure- or hypertension-associated genetic regions in the general population, including 3 rare missense variants in RBM47, COL21A1 and RRAS with larger effects (>1.5 mm Hg/allele) than common variants. Multiple rare nonsense and missense variant associations were found in A2ML1, and a low-frequency nonsense variant in ENPEP was identified. Our data extend the spectrum of allelic variation underlying blood pressure traits and hypertension, provide new insights into the pathophysiology of hypertension and indicate new targets for clinical intervention.
    Article · Sep 2016 · Nature Genetics
  • [Show abstract] [Hide abstract] ABSTRACT: To better understand the molecular mechanisms underpinning physiological variation in human populations, metabolic phenotyping approaches are increasingly being applied to studies involving hundreds and thousands of biofluid samples. Hyphenated ultra-performance liquid chromatography and mass spectrometry (UPLC-MS) has become a fundamental tool for this purpose. Yet, the seemingly inevitable need to analyze large studies in multiple analytical batches for UPLC-MS analysis poses a challenge to data quality which has been recognized in the field. Herein we describe in detail a fit-for-purpose UPLC-MS platform, method set, and sample analysis workflow, capable of sustained analysis on an industrial scale and allowing batch-free operation for large studies. Using complementary reversed-phase chromatography (RPC) and hydrophilic interaction liquid chromatography (HILIC) together with high resolution orthogonal acceleration time-of-flight mass spectrometry, exceptional measurement precision is exemplified with independent epidemiological sample sets of approximately 650 and 1000 participant samples. Evaluation of molecular reference targets in repeated injections of pooled quality control (QC) samples distributed throughout each experiment demonstrates a mean retention time relative standard deviation (RSD) of <0.3% across all assays in both studies and a mean peak area RSD of <15% in the raw data. To more globally assess the quality of the profiling data, untargeted feature extraction was performed followed by data filtration according to feature intensity response to QC sample dilution. Analysis of the remaining features within the repeated QC sample measurements demonstrated median peak area RSD values of <20% for the RPC assays and <25% for the HILIC assays. These values represent the quality of the raw data, as no normalization or feature-specific intensity correction was applied. While the data in each experiment was acquired in a single continuous batch, instances of minor time-dependent intensity drift were observed, highlighting the utility of data correction techniques despite reducing the dependency on them for generating high quality data. These results demonstrate that the platform and methodology presented herein is fit-for-use in large scale metabolic phenotyping studies, challenging the assertion that such screening is inherently limited by batch effects. Details of the pipeline used to generate high quality raw data and mitigate the need for batch correction are provided.
    Article · Aug 2016 · Analytical Chemistry
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    Adrian P Burgess · Nathalie C Fouquet · Stefano Seri · [...] · Paul Elliott
    [Show abstract] [Hide abstract] ABSTRACT: Background Terrestrial Trunked Radio (TETRA) is a telecommunications system widely used by police and emergency services around the world. The Stewart Report on mobile telephony and health raised questions about possible health effects associated with TETRA signals. This study investigates possible effects of TETRA signals on the electroencephalogram and electrocardiogram in human volunteers. Methods Blinded randomized provocation study with a standardized TETRA signal or sham exposure. In the first of two experiments, police officers had a TETRA set placed first against the left temple and then the upper-left quadrant of the chest and the electroencephalogram was recorded during rest and active cognitive processing. In the second experiment, volunteers were subject to chest exposure of TETRA whilst their electroencephalogram and heart rate variability derived from the electrocardiogram were recorded. Results In the first experiment, we found that exposure to TETRA had consistent neurophysiological effects on the electroencephalogram, but only during chest exposure, in a pattern suggestive of vagal nerve stimulation. In the second experiment, we observed changes in heart rate variability during exposure to TETRA but the electroencephalogram effects were not replicated. Conclusions Observed effects of exposure to TETRA signals on the electroencephalogram (first experiment) and electrocardiogram are consistent with vagal nerve stimulation in the chest by TETRA. However given the small effect on heart rate variability and the lack of consistency on the electroencephalogram, it seems unlikely that this will have a significant impact on health. Long-term monitoring of the health of the police force in relation to TETRA use is on-going.
    Full-text available · Article · Jul 2016 · Environmental Research
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    Adrian P Burgess · Nathalie C Fouquet · Stefano Seri · [...] · Paul Elliott
    File available · Dataset · Jul 2016
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    [Show abstract] [Hide abstract] ABSTRACT: The genetic architecture of common traits, including the number, frequency, and effect sizes of inherited variants that contribute to individual risk, has been long debated. Genome-wide association studies have identified scores of common variants associated with type 2 diabetes, but in aggregate, these explain only a fraction of the heritability of this disease. Here, to test the hypothesis that lower-frequency variants explain much of the remainder, the GoT2D and T2D-GENES consortia performed whole-genome sequencing in 2,657 European individuals with and without diabetes, and exome sequencing in 12,940 individuals from five ancestry groups. To increase statistical power, we expanded the sample size via genotyping and imputation in a further 111,548 subjects. Variants associated with type 2 diabetes after sequencing were overwhelmingly common and most fell within regions previously identified by genome-wide association studies. Comprehensive enumeration of sequence variation is necessary to identify functional alleles that provide important clues to disease pathophysiology, but large-scale sequencing does not support the idea that lower-frequency variants have a major role in predisposition to type 2 diabetes.
    Full-text available · Article · Jul 2016 · Nature
  • [Show abstract] [Hide abstract] ABSTRACT: Background: Epidemiologic evidence suggests that relationships of red meat consumption with risk of cardiovascular diseases depends on whether or not the meat is processed, including addition of preservatives, but evidence is limited for blood pressure (BP). Objective: To examine cross-sectional associations with BP of unprocessed and processed red meat and poultry consumption, total and by type, using data from the INTERnational study on MAcro/micronutrients and blood Pressure. Design: INTERnational study on MAcro/micronutrients and blood Pressure included 4680 men and women ages 40-59 years from 17 population samples in Japan, China, the United Kingdom, and the United States. During four visits, eight BP measurements, four multipass 24-h dietary recalls, and two timed 24-h urine samples were collected. Results: Average daily total unprocessed/processed meat consumption (g/1000 kcal) was 20/5 in East Asian and 38/21 in Western participants. Unprocessed meat intakes comprised red meat for 75% in East Asian and 50% in Western participants. In Westerners, multiple linear regression analyses showed SBP/DBP differences for total unprocessed red meat consumption higher by 25 g/1000 kcal +0.74/+0.57 mmHg (P = 0.03/0.01) and for unprocessed poultry of +0.79/+0.16 mmHg (P = 0.02/0.50). Unprocessed red meat was not related to BP in East Asian participants. In Westerners, SBP/DBP differences for processed red meat higher by 12.5 g/1000 kcal were +1.20/+0.24 mmHg (P < 0.01/0.24), due to consumption of cold cuts and sausages (+1.59/+0.32 mmHg, P < 0.001/0.27). Conclusion: These findings are consistent with recommendations to limit meat intake (processed and unprocessed) to maintain and improve cardiovascular health.
    Article · Jul 2016 · Journal of Hypertension
  • [Show abstract] [Hide abstract] ABSTRACT: Background: Environmental tobacco smoke has an adverse association with preterm birth and birth weight. England introduced a new law to make virtually all enclosed public places and workplaces smoke free on July 1 2007. We investigated the effect of smoke-free legislation on birth outcomes in England using Hospital Episode Statistics (HES) maternity data. Methods: We used regression discontinuity, a quasi-experimental study design, which can facilitate valid causal inference, to analyze short-term effects of smoke-free legislation on birth weight, low birth weight, gestational age, preterm birth, and small for gestational age. Results: We analyzed 1,800,906 pregnancies resulting in singleton live-births in England between 1 January 2005 and 31 December 2009. In the 1 to 5 months following the introduction of the smoke-free legislation, for those entering their third trimester, the risk of low birth weight decreased by between 8% (95% CI: 4%, 12%) and 14% (95% CI: 5%, 23%), very low birth weight between 28% (95% CI: 19%, 36%) and 32% (95% CI: 21%, 41%), preterm birth between 4% (95% CI: 1%, 8%) and 9% (95% CI: 2%, 16%), and small for gestational age between 5% (95% CI: 2%, 8%) and 9% (95% CI: 2%, 15%). The estimated impact of the smoke-free legislation varied by maternal age, deprivation, ethnicity, and region. Conclusions: The introduction of smoke-free legislation in England had an immediate estimated beneficial impact on birth outcomes overall, although we did not observe improvements across all age, ethnic, or deprivation groups.
    Article · Jul 2016 · Epidemiology
  • Anne-Claire Vergnaud · Maria Aresu · Dennis McRobie · [...] · Paul Elliott
    [Show abstract] [Hide abstract] ABSTRACT: Background: Terrestrial Trunked Radio (TETRA) is a digital communication system progressively adopted by Police Forces in Great Britain since 2001. In 2000, the UK Independent Expert Group on Mobile Phones suggested that exposure to TETRA-like signal modulation might have adverse effects on health. The Airwave Health Monitoring Study was established to investigate possible long-term effects of TETRA use on health. This requires estimation of TETRA use among Police Force employees participating in the study. Methods: We investigated TETRA usage among 42,112 Police officers and staff. An algorithm was created to link each personal radio user to his/her objective radio usage records for the 26,035 participants with available data. We linked 16,577 personal radio users to their objective radio usage records and compared self-reported usage with data from the TETRA operator for those individuals. Results: For weekly usage, the correlation between self-reported and operator-derived personal radio usage was r=0.69 for number and r=0.59 for the duration of calls. Compared with objective data, participants under-reported the number of calls and over-reported the duration of calls by a factor of around 4 and 1.6 respectively. Correlations were lower and bias higher when looking at daily usage. Conclusion: Where both objective and self-reported information were available, our study showed substantial misreporting in self-reported TETRA usage. Successful linkage of large numbers of TETRA users to objective data on their personal radios will allow objective assessment of TETRA radio usage for these participants and development of algorithms to correct bias in self-reported data for the remainder.
    Article · Jul 2016 · Environmental Research
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    [Show abstract] [Hide abstract] ABSTRACT: Coastal areas in Southeast Asia are experiencing high sodium concentrations in drinking water sources that are commonly consumed by local populations. Salinity problems caused by episodic cyclones and subsequent seawater inundations are likely (partly) related to climate change and further exacerbated by changes in upstream river flow and local land-use activities. Dietary (food) sodium plays an important role in the global burden of hypertensive disease. It remains unknown, however, if sodium in drinking water-rather than food-has similar effects on blood pressure and disease risk. In this study, we examined the effect of drinking water sodium on blood pressure of pregnant women: increases in blood pressure in this group could severely affect maternal and fetal health. Data on blood pressure, drinking water source, and personal, lifestyle, and environmental confounders was obtained from 701 normotensive pregnant women residing in coastal Bangladesh. Generalized linear mixed regression models were used to investigate association of systolic and diastolic blood pressure of these-otherwise healthy-women with their water source. After adjustment for confounders, drinkers of tube well and pond water (high saline sources) were found to have significantly higher average systolic (+4.85 and +3.62 mm Hg) and diastolic (+2.30 and +1.72 mm Hg) blood pressures than rainwater drinkers. Drinking water salinity problems are expected to exacerbate in the future, putting millions of coastal people-including pregnant women-at increased risk of hypertension and associated diseases. There is an urgent need to further explore the health risks associated to this understudied environmental health problem and feasibility of possible adaptation strategies.
    Full-text available · Article · Jun 2016 · Hypertension
  • [Show abstract] [Hide abstract] ABSTRACT: Information on exposure to, and health effects of, cardiovascular disease (CVD) risk factors is needed to develop effective strategies to prevent CVD events and deaths. Here, we provide an overview of the data and evidence on worldwide exposures to CVD risk factors and the associated health effects. Global comparative risk assessment studies have estimated that hundreds of thousands or millions of CVD deaths are attributable to established CVD risk factors (high blood pressure and serum cholesterol, smoking, and high blood glucose), high body mass index, harmful alcohol use, some dietary and environmental exposures, and physical inactivity. The established risk factors plus body mass index are collectively responsible for ≈9.7 million annual CVD deaths, with high blood pressure accounting for more CVD deaths than any other risk factor. Age-standardized CVD death rates attributable to established risk factors plus high body mass index are lowest in high-income countries, followed by Latin America and the Caribbean; they are highest in the region of central and eastern Europe and central Asia. However, estimates of the health effects of CVD risk factors are highly uncertain because there are insufficient population-based data on exposure to most CVD risk factors and because the magnitudes of their effects on CVDs in observational studies are likely to be biased. We identify directions for research and surveillance to better estimate the effects of CVD risk factors and policy options for reducing CVD burden by modifying preventable risk factors.
    Article · Jun 2016 · Circulation
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    [Show abstract] [Hide abstract] ABSTRACT: Red blood cell (RBC) traits are important heritable clinical biomarkers and modifiers of disease severity. To identify coding genetic variants associated with these traits, we conducted meta-analyses of seven RBC phenotypes in 130,273 multi-ethnic individuals from studies genotyped on an exome array. After conditional analyses and replication in 27,480 independent individuals, we identified 16 new RBC variants. We found low-frequency missense variants in MAP1A (rs55707100, minor allele frequency [MAF] = 3.3%, p = 2 × 10(-10) for hemoglobin [HGB]) and HNF4A (rs1800961, MAF = 2.4%, p < 3 × 10(-8) for hematocrit [HCT] and HGB). In African Americans, we identified a nonsense variant in CD36 associated with higher RBC distribution width (rs3211938, MAF = 8.7%, p = 7 × 10(-11)) and showed that it is associated with lower CD36 expression and strong allelic imbalance in ex vivo differentiated human erythroblasts. We also identified a rare missense variant in ALAS2 (rs201062903, MAF = 0.2%) associated with lower mean corpuscular volume and mean corpuscular hemoglobin (p < 8 × 10(-9)). Mendelian mutations in ALAS2 are a cause of sideroblastic anemia and erythropoietic protoporphyria. Gene-based testing highlighted three rare missense variants in PKLR, a gene mutated in Mendelian non-spherocytic hemolytic anemia, associated with HGB and HCT (SKAT p < 8 × 10(-7)). These rare, low-frequency, and common RBC variants showed pleiotropy, being also associated with platelet, white blood cell, and lipid traits. Our association results and functional annotation suggest the involvement of new genes in human erythropoiesis. We also confirm that rare and low-frequency variants play a role in the architecture of complex human traits, although their phenotypic effect is generally smaller than originally anticipated.
    Full-text available · Article · Jun 2016 · The American Journal of Human Genetics
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    [Show abstract] [Hide abstract] ABSTRACT: White blood cells play diverse roles in innate and adaptive immunity. Genetic association analyses of phenotypic variation in circulating white blood cell (WBC) counts from large samples of otherwise healthy individuals can provide insights into genes and biologic pathways involved in production, differentiation, or clearance of particular WBC lineages (myeloid, lymphoid) and also potentially inform the genetic basis of autoimmune, allergic, and blood diseases. We performed an exome array-based meta-analysis of total WBC and subtype counts (neutrophils, monocytes, lymphocytes, basophils, and eosinophils) in a multi-ancestry discovery and replication sample of ∼157,622 individuals from 25 studies. We identified 16 common variants (8 of which were coding variants) associated with one or more WBC traits, the majority of which are pleiotropically associated with autoimmune diseases. Based on functional annotation, these loci included genes encoding surface markers of myeloid, lymphoid, or hematopoietic stem cell differentiation (CD69, CD33, CD87), transcription factors regulating lineage specification during hematopoiesis (ASXL1, IRF8, IKZF1, JMJD1C, ETS2-PSMG1), and molecules involved in neutrophil clearance/apoptosis (C10orf54, LTA), adhesion (TNXB), or centrosome and microtubule structure/function (KIF9, TUBD1). Together with recent reports of somatic ASXL1 mutations among individuals with idiopathic cytopenias or clonal hematopoiesis of undetermined significance, the identification of a common regulatory 3' UTR variant of ASXL1 suggests that both germline and somatic ASXL1 mutations contribute to lower blood counts in otherwise asymptomatic individuals. These association results shed light on genetic mechanisms that regulate circulating WBC counts and suggest a prominent shared genetic architecture with inflammatory and autoimmune diseases.
    Full-text available · Article · Jun 2016 · The American Journal of Human Genetics
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    Dataset: S1 Appendix
    [Show abstract] [Hide abstract] ABSTRACT: South Asian replication cohort description. (DOCX)
    File available · Dataset · May 2016
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    Dataset: S3 Fig
    [Show abstract] [Hide abstract] ABSTRACT: South-Asian GWAS targeted analysis of population-specific SNPs. Relationship of observed association statistics with those expected under the null distribution (MAF>2%, Lambda = 1.022). (TIF)
    File available · Dataset · May 2016
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    Dataset: S1 Fig
    [Show abstract] [Hide abstract] ABSTRACT: South Asian GWAS–Association of SNPs with WHR by chromosome position. (A) Additive inheritance model. (B) Dominant inheritance model. (C) Recessive inheritance model. (TIF)
    File available · Dataset · May 2016

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  • 2012
    • Wake Forest School of Medicine
      Winston-Salem, North Carolina, United States
    • McGill University
      • Department of Epidemiology, Biostatistics and Occupational Health
      Montréal, Quebec, Canada
  • 2010
    • University of Oulu
      • Institute of Health Sciences
      Oulu, Oulu, Finland
  • 2006-2007
    • Fu Wai Hospital
      Peping, Beijing, China
    • Johns Hopkins University
      Baltimore, Maryland, United States
  • 2005
    • King's College London
      • Department of Nutrition and Dietetics
      London, ENG, United Kingdom
  • 2001
    • The University of Edinburgh
      • School of Clinical Sciences and Community Health
      Edinburgh, Scotland, United Kingdom
  • 1997-2001
    • Imperial College London
      Londinium, England, United Kingdom
  • 1995
    • Northwestern University
      • Department of Preventive Medicine
      Evanston, Illinois, United States