Publications
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Riley S, Eales O, Haw D, et al., 2021, REACT-1 round 13 interim report: acceleration of SARS-CoV-2 Delta epidemic in the community in England during late June and early July 2021
BackgroundDespite high levels of vaccination in the adult population, cases of COVID-19 have risenexponentially in England since the start of May 2021 driven by the Delta variant. However,with far fewer hospitalisations and deaths per case during the recent growth in casescompared with 2020, it is intended that all remaining social distancing legislation in Englandwill be removed from 19 July 2021.MethodsWe report interim results from round 13 of the REal-time Assessment of CommunityTransmission-1 (REACT-1) study in which a cross-sectional sample of the population ofEngland was asked to provide a throat and nose swab for RT-PCR and to answer aquestionnaire. Data collection for this report (round 13 interim) was from 24 June to 5 July2021.ResultsIn round 13 interim, we found 237 positives from 47,729 swabs giving a weighted prevalenceof 0.59% (0.51%, 0.68%) which was approximately four-fold higher compared with round 12at 0.15% (0.12%, 0.18%). This resulted from continued exponential growth in prevalencewith an average doubling time of 15 (13, 17) days between round 12 and round 13.However, during the recent period of round 13 interim only, we observed a shorter doublingtime of 6.1 (4.0, 12) days with a corresponding R number of 1.87 (1.40, 2.45). There weresubstantial increases in all age groups under the age of 75 years, and especially at youngerages, with the highest prevalence in 13 to 17 year olds at 1.33% (0.97%, 1.82%) and in 18 to24 years olds at 1.40% (0.89%, 2.18%). Infections have increased in all regions with thelargest increase in London where prevalence increased more than eight-fold from 0.13%(0.08%, 0.20%) in round 12 to 1.08% (0.79%, 1.47%) in round 13 interim. Overall,prevalence was over 3 times higher in the unvaccinated compared with those reporting twodoses of vaccine in both round 12 and round 13 interim, although there was a similarproportional increase in prevalence in vaccinated and unvaccinated individuals between thetwo rounds.DiscussionWe
Shen C, Dumontheil I, Thomas M, et al., 2021, Digital technology use and BMI: evidence from a cross-sectional analysis of an adolescent cohort study, Journal of Medical Internet Research, Vol: 23, Pages: 1-16, ISSN: 1438-8871
Background:The use of digital technology such as mobile phones is ubiquitous in adolescents. However, excessive use may have adverse health effects, possibly partially mediated by disruptions to sleep.Objective:This study aims to assess the social predictors of digital technology use and their cross-sectional association with BMI z scores and being overweight in a large sample of adolescents.Methods:We used baseline data from a subset of a large adolescent cohort from 39 schools across Greater London who participated in the Study of Cognition, Adolescents and Mobile Phones (n=1473). Digital technology use included phone calls, internet use on mobile phones, and video gaming on any device. Multilevel regression was used to assess the associations between digital technology use and age-specific and sex-specific BMI z scores and being overweight (including obesity). Measurements were derived from height and weight, obtained by the Tanita BC-418 Body Composition Analyzer. We examined whether these associations were mediated by insufficient sleep.Results:Generally, participants with lower socioeconomic status reported more use of digital technology. Controlling for socioeconomic status, internet use on mobile phones for more than 3 hours per day was associated with higher BMI z scores (adjusted β=.30, 95% CI 0.11-0.48) and greater odds of being overweight (adjusted odds ratio 1.60, 95% CI 1.09-2.34), compared with low use (≤30 minutes). Similar associations were found between video gaming and BMI z scores and being overweight. The BMI z score was more strongly related to weekday digital technology use (internet use on mobile phones and video gaming) than weekend use. Insufficient sleep partly mediated the associations between digital technology use and BMI z scores (proportion of mediation from 8.6% to 17.8%) by an indirect effect.Conclusions:We found an association between digital technology use and BMI in adolescents, partly mediated by insufficient sleep, sugg
Gill D, Zuber V, Dawson J, et al., 2021, Risk factors mediating the effect of body mass index and waist-to-hip ratio on cardiovascular outcomes: Mendelian randomization analysis, International Journal of Obesity, Vol: 45, Pages: 1428-1438, ISSN: 0307-0565
BackgroundHigher body mass index (BMI) and waist-to-hip ratio (WHR) increase the risk of cardiovascular disease, but the extent to which this is mediated by blood pressure, diabetes, lipid traits, and smoking is not fully understood.MethodsUsing consortia and UK Biobank genetic association summary data from 140,595 to 898,130 participants predominantly of European ancestry, Mendelian randomization mediation analysis was performed to investigate the degree to which systolic blood pressure (SBP), diabetes, lipid traits, and smoking mediated an effect of BMI and WHR on the risk of coronary artery disease (CAD), peripheral artery disease (PAD) and stroke.ResultsThe odds ratio of CAD per 1-standard deviation increase in genetically predicted BMI was 1.49 (95% CI 1.39 to 1.60). This attenuated to 1.34 (95% CI 1.24 to 1.45) after adjusting for genetically predicted SBP (proportion mediated 27%, 95% CI 3% to 50%), to 1.27 (95% CI 1.17 to 1.37) after adjusting for genetically predicted diabetes (41% mediated, 95% CI 18% to 63%), to 1.47 (95% CI 1.36 to 1.59) after adjusting for genetically predicted lipids (3% mediated, 95% −23% to 29%), and to 1.46 (95% CI 1.34 to 1.58) after adjusting for genetically predicted smoking (6% mediated, 95% CI −20% to 32%). Adjusting for all the mediators together, the estimate attenuated to 1.14 (95% CI 1.04 to 1.26; 66% mediated, 95% CI 42% to 91%). A similar pattern was observed when considering genetically predicted WHR as the exposure, and PAD or stroke as the outcome.ConclusionsMeasures to reduce obesity will lower the risk of cardiovascular disease primarily by impacting downstream metabolic risk factors, particularly diabetes and hypertension. Reduction of obesity prevalence alongside control and management of its mediators is likely to be most effective for minimizing the burden of obesity.
Griffin J, Albaloul AH, Kopytek A, et al., 2021, Effect of ultraprocessed food intake on cardiometabolic risk is mediated by diet quality: a cross-sectional study, BMJ Nutrition, Prevention & Health, Vol: 4, Pages: 174-180, ISSN: 2516-5542
Objective: To examine the effect of the consumption of ultraprocessed food on diet quality, and cardiometabolic risk (CMR) in an occupational cohort.Design: Cross-sectional.Setting: Occupational cohort.Participants: 53 163 British police force employees enrolled (2004–2012) into the Airwave Health Monitoring Study. A total of 28 forces across the UK agreed to participate. 9009 participants with available 7-day diet record data and complete co-variate data are reported in this study.Main outcome measures: A CMR and Dietary Approaches to Stop Hypertension score were treated as continuous variables and used to generate measures of cardiometabolic health and diet quality. Secondary outcome measures include percentage of energy from fat, saturated fat, carbohydrate, protein and non-milk extrinsic sugars (NMES) and fibre grams per 1000 kcal of energy intake.Results: In this cohort, 58.3%±11.6 of total energy intake was derived from ultraprocessed (NOVA 4) foods. Ultraprocessed food intake was negatively correlated with diet quality (r=−0.32, p<0.001), fibre (r=−0.20, p<0.001) and protein (r = −0.40, p<0.001) and positively correlated with fat (r=0.18, p<0.001), saturated fat (r=0.14, p<0.001) and nmes (r=0.10, p<0.001) intake . Multivariable analysis suggests a positive association between ultraprocessed food (NOVA 4) consumption and CMR. However, this main effect was no longer observed after adjustment for diet quality (p=0.209). Findings from mediation analysis indicate that the effect of ultraprocessed food (NOVA 4) intake on CMR is mediated by diet quality (p<0.001).Conclusions: Ultraprocessed food consumption is associated with a deterioration in diet quality and positively associated with CMR, although this association is mediated by and dependent on the quality of the diet. The negative impact of ultraprocessed food consumption on diet quality needs to be addressed and controlled studies are needed to fully compre
McCartney DL, Min JL, Richmond RC, et al., 2021, Genome-wide association studies identify 137 genetic loci for DNA methylation biomarkers of aging, Genome Biology, Vol: 22, ISSN: 1474-7596
Background:Biological aging estimators derived from DNA methylation data are heritable and correlate with morbidity and mortality. Consequently, identification of genetic and environmental contributors to the variation in these measures in populations has become a major goal in the field.Results:Leveraging DNA methylation and SNP data from more than 40,000 individuals, we identify 137 genome-wide significant loci, of which 113 are novel, from genome-wide association study (GWAS) meta-analyses of four epigenetic clocks and epigenetic surrogate markers for granulocyte proportions and plasminogen activator inhibitor 1 levels, respectively. We find evidence for shared genetic loci associated with the Horvath clock and expression of transcripts encoding genes linked to lipid metabolism and immune function. Notably, these loci are independent of those reported to regulate DNA methylation levels at constituent clock CpGs. A polygenic score for GrimAge acceleration showed strong associations with adiposity-related traits, educational attainment, parental longevity, and C-reactive protein levels.Conclusion:This study illuminates the genetic architecture underlying epigenetic aging and its shared genetic contributions with lifestyle factors and longevity.
Aikaterini I, Emmanuel M, Karaman I, et al., 2021, Metabolic phenotyping and cardiovascular disease: Overview of evidence from epidemiological settings, Heart, Vol: 107, Pages: 1123-1129, ISSN: 1355-6037
Metabolomics, the comprehensive measurement of low-molecular-weight molecules in biological fluids used for metabolic phenotyping, has emerged as a promising tool to better understand pathways underlying cardiovascular disease (CVD) and to improve cardiovascular risk stratification. Here, we present the main methodologies for metabolic phenotyping, the methodological steps to analyse these data in epidemiological settings and the associated challenges. We discuss evidence from epidemiological studies linking metabolites to coronary heart disease and stroke. These studies indicate the systemic nature of CVD and identify associated metabolic pathways such as gut microbial cometabolism, branched-chain amino acids, glycerophospholipid and cholesterol metabolism, as well as activation of inflammatory processes. Integration of metabolomic with genomic data can provide new evidence for involved biochemical pathways and potential for causality using Mendelian randomisation. The clinical utility of metabolic biomarkers for cardiovascular risk stratification in healthy individuals has not yet been established. As sample sizes with high-dimensional molecular data increase in epidemiological settings, integration of metabolomic data across studies and platforms with other molecular data will lead to new understanding of the metabolic processes underlying CVD and contribute to identification of potentially novel preventive and pharmacological targets. Metabolic phenotyping offers a powerful tool in the characterisation of the molecular signatures of CVD, paving the way to new mechanistic understanding and therapies, as well as improving risk prediction of CVD patients. However, there are still challenges to face in order to contribute to clinically important improvements in CVD.
Whitaker M, Elliott J, Chadeau-Hyam M, et al., 2021, Persistent symptoms following SARS-CoV-2 infection in a random community sample of 508,707 people
IntroductionLong COVID, describing the long-term sequelae after SARS-CoV-2 infection, remains a poorlydefined syndrome. There is uncertainty about its predisposing factors and the extent of theresultant public health burden, with estimates of prevalence and duration varying widely.MethodsWithin rounds 3–5 of the REACT-2 study, 508,707 people in the community in England wereasked about a prior history of COVID-19 and the presence and duration of 29 differentsymptoms. We used uni- and multivariable models to identify predictors of persistence ofsymptoms (12 weeks or more). We estimated the prevalence of symptom persistence at 12weeks, and used unsupervised learning to cluster individuals by symptoms experienced.ResultsAmong the 508,707 participants, the weighted prevalence of self-reported COVID-19 was 19.2%(95% CI: 19.1,19.3). 37.7% of 76,155 symptomatic people post COVID-19 experienced at leastone symptom, while 14.8% experienced three or more symptoms, lasting 12 weeks or more. Thisgives a weighted population prevalence of persistent symptoms of 5.75% (5.68, 5.81) for one and2.22% (2.1, 2.26) for three or more symptoms. Almost a third of people 8,771/28,713 (30.5%)with at least one symptom lasting 12 weeks or more reported having had severe COVID-19symptoms (“significant effect on my daily life”) at the time of their illness, giving a weightedprevalence overall for this group of 1.72% (1.69,1.76). The prevalence of persistent symptomswas higher in women than men (OR: 1.51 [1.46,1.55]) and, conditional on reporting symptoms,risk of persistent symptoms increased linearly with age by 3.5 percentage points per decade oflife. Obesity, smoking or vaping, hospitalisation , and deprivation were also associated with ahigher probability of persistent symptoms, while Asian ethnicity was associated with a lowerprobability. Two stable clusters were identified based on symptoms that persisted for 12 weeks ormore: in the largest cluster, tiredness predominated
Davies B, Araghi M, Moshe M, et al., 2021, Acceptability, usability and performance of lateral flow immunoassay tests for SARSCoV-2 antibodies: REACT-2 study of self-testing in non-healthcare key workers, Publisher: Cold Spring Harbor Laboratory
BackgroundSeroprevalence studies in key worker populations are essential to understand the epidemiology of SARS-CoV-2. Various technologies, including laboratory assays and pointof-care self-tests, are available for antibody testing. The interpretation of seroprevalence studies requires comparative data on the performance of antibody tests.MethodsIn June 2020, current and former members of the UK Police forces and Fire service performed a self-test lateral flow immunoassay (LFIA) and provided a saliva sample, nasopharyngeal swab, venous blood samples for Abbott ELISA and had a nurse performed LFIA. We present the prevalence of PCR positivity and antibodies to SARS-CoV-2 in this cohort following the first wave of infection in England; the acceptability and usability of selftest LFIAs (defined as use of the LFIA kit and provision of a valid result, respectively); and determine the sensitivity and specificity of LFIAs compared to laboratory ELISAs.ResultsIn this cohort of non-healthcare key workers, 7.4% (396/5,348; 95% CI, 6.7-8.1) were antibody positive. Seroprevalence was 8.9% (6.9-11.4) in those under 40 years, 11.5% (8.8-15.0) in those of non-white British ethnicity and 7.8% (7.1-8.7) in those currently working.The self-test LFIA had an acceptability of 97.7% and a usability of 90.0%. There was substantial agreement between within-participant LFIA results (kappa 0.80; 0.77-0.83). The LFIAs (self-test and nurse-performed) had a similar performance: compared to ELISA, sensitivity was 82.1% (77.7-86.0) self-test and 76.4% (71.9-80.5) nurse-performed with specificity of 97.8% (97.3-98.2) and 98.5% (98.1-98.8) respectively.ConclusionA greater proportion of the non-healthcare key worker cohort showed evidence of previous infection with SARS-CoV-2 than the general population at 6.0% (5.8-6.1) following the first wave in England. The high acceptability and usability reported by participants and the similar performance of self-test and nurse-performed LFIAs indicate that t
Davies B, Parkes B, Bennett J, et al., 2021, Community factors and excess mortality in first wave of the COVID-19 pandemic, Nature Communications, ISSN: 2041-1723
Risk factors for increased risk of death from Coronavirus Disease 19 (COVID-19) have been identified 1,2 but less is known on characteristics that make communities resilient or vulnerable to the mortality impacts of the pandemic. We applied a two-stage Bayesian spatial model to quantify inequalities in excess mortality at the community level during the first wave of the pandemic in England. We used geocoded data on all deaths in people aged 40 years and older during March-May 2020 compared with 2015-2019 in 6,791 local communities. Here we show that communities with an increased risk of excess mortality had a high density of care homes, and/or high proportion of residents on income support, living in overcrowded homes and/or high percent of people with a non-White ethnicity (including Black, Asian and other minority ethnic groups). Conversely, after accounting for other community characteristics, we found no association between population density or air pollution and excess mortality. Overall, the social and environmental variables accounted for around 15% of the variation in mortality at community level. Effective and timely public health and healthcare measures that target the communities at greatest risk are urgently needed if England and other industrialised countries are to avoid further widening of inequalities in mortality patterns during the second wave.
Davies B, Parkes B, Bennett J, et al., 2021, Community factors and excess mortality in first wave of the COVID-19 pandemic in England, Nature Communications, ISSN: 2041-1723
Risk factors for increased risk of death from Coronavirus Disease 19 (COVID-19) have been identified but less is known on characteristics that make communities resilient or vulnerable to the mortality impacts of the pandemic. We applied a two-stage Bayesian spatial model to quantify inequalities in excess mortality at the community level during the first wave of the pandemic in England. We used geocoded data on all deaths in people aged 40 years and older during March-May 2020 compared with 2015-2019 in 6,791 local communities. Here we show that communities with an increased risk of excess mortality had a high density of care homes, and/or high proportion of residents on income support, living in overcrowded homes and/or high percent of people with a non-White ethnicity (including Black, Asian and other minority ethnic groups). Conversely, after accounting for other community characteristics, we found no association between population density or air pollution and excess mortality. Overall, the social and environmental variables accounted for around 15% of the variation in mortality at community level. Effective and timely public health and healthcare measures that target the communities at greatest risk are urgently needed if England and other industrialised countries are to avoid further widening of inequalities in mortality patterns as the pandemic progresses.
Riley S, Wang H, Eales O, et al., 2021, REACT-1 round 12 report: resurgence of SARS-CoV-2 infections in England associated with increased frequency of the Delta variant
BackgroundEngland entered a third national lockdown from 6 January 2021 due to the COVID-19pandemic. Despite a successful vaccine rollout during the first half of 2021, cases andhospitalisations have started to increase since the end of May as the SARS-CoV-2 Delta(B.1.617.2) variant increases in frequency. The final step of relaxation of COVID-19restrictions in England has been delayed from 21 June to 19 July 2021.MethodsThe REal-time Assessment of Community Transmision-1 (REACT-1) study measures theprevalence of swab-positivity among random samples of the population of England. Round12 of REACT-1 obtained self-administered swab collections from participants from 20 May2021 to 7 June 2021; results are compared with those for round 11, in which swabs werecollected from 15 April to 3 May 2021.ResultsBetween rounds 11 and 12, national prevalence increased from 0.10% (0.08%, 0.13%) to0.15% (0.12%, 0.18%). During round 12, we detected exponential growth with a doublingtime of 11 (7.1, 23) days and an R number of 1.44 (1.20, 1.73). The highest prevalence wasfound in the North West at 0.26% (0.16%, 0.41%) compared to 0.05% (0.02%, 0.12%) in theSouth West. In the North West, the locations of positive samples suggested a cluster inGreater Manchester and the east Lancashire area. Prevalence in those aged 5-49 was 2.5times higher at 0.20% (0.16%, 0.26%) compared with those aged 50 years and above at0.08% (0.06%, 0.11%). At the beginning of February 2021, the link between infection ratesand hospitalisations and deaths started to weaken, although in late April 2021, infectionrates and hospital admissions started to reconverge. When split by age, the weakened linkbetween infection rates and hospitalisations at ages 65 years and above was maintained,while the trends converged below the age of 65 years. The majority of the infections in theyounger group occurred in the unvaccinated population or those without a stated vaccinehistory. We observed the rapid replacement of the Alpha (
Posma JM, Garcia-Perez I, Frost G, et al., 2021, Nutriome-metabolome relationships provide insights into dietary intake and metabolism (vol 1, pg 426, 2020), NATURE FOOD, Vol: 2, Pages: 541-542
Jain S, Jónasson JO, Pauphilet J, et al., 2021, A new combination testing methodology to identify accurate and economical point-of-care testing strategies
<jats:title>ABSTRACT</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Quick, cheap and accurate point-of-care testing is urgently needed to enable frequent, large-scale testing to contain COVID-19. Lateral flow tests for antigen and antibody detection are an obvious candidate for use in community-wide testing, because they are quick and cheap relative to lab-processed tests. However, their low accuracy has limited their adoption. We develop a new methodology to increase the diagnostic accuracy of a combination of cheap, quick and inaccurate index tests with correlated or discordant outcomes, and illustrate its performance on commercially available lateral flow immunoassays (LFIAs) for Sars-CoV-2 antibody detection.</jats:p></jats:sec><jats:sec><jats:title>Methods and Findings</jats:title><jats:p>We analyze laboratory test outcomes of 300 serum samples from health care workers detected with PCR-confirmed SARS-Cov-2 infection at least 21 days prior to sample collection, and 500 pre-pandemic serum samples, from a national seroprevalence survey, tested using eight LFIAs (Abbott, Biosure/Mologic, Orientgene-Menarini, Fortress, Biopanda I, Biopanda II, SureScreen and Wondfo) and Hybrid DABA as reference test. For each of 14 two-test combinations (e.g., Abbott, Fortress) and 16 three-test combinations (e.g., Abbott, Fortress, Biosure/Mologic) used on at least 100 positive and 100 negative samples, we classify an outcome sequence – e.g., (+,–) for (Abbott, Fortress) – as positive if its combination positive predictive value (CPPV) exceeds a given threshold, set between 0 and 1. Our main outcome measures are the sensitivity and specificity of different classification rules for classifying the outcomes of a combination test. We define testing possibility frontiers which represent sensitivity and false positive rates for different thresholds. The envelope of frontiers furt
Evangelou E, Suzuki H, Bai W, et al., 2021, Alcohol consumption in the general population is associated with structural changes in multiple organ systems., eLife, Vol: 10, Pages: 1-15, ISSN: 2050-084X
Background:Excessive alcohol consumption is associated with damage to various organs, but its multi-organ effects have not been characterised across the usual range of alcohol drinking in a large general population sample.Methods:We assessed global effect sizes of alcohol consumption on quantitative magnetic resonance imaging phenotypic measures of the brain, heart, aorta, and liver of UK Biobank participants who reported drinking alcohol.Results:We found a monotonic association of higher alcohol consumption with lower normalised brain volume across the range of alcohol intakes (–1.7 × 10−3 ± 0.76 × 10−3 per doubling of alcohol consumption, p=3.0 × 10−14). Alcohol consumption was also associated directly with measures of left ventricular mass index and left ventricular and atrial volume indices. Liver fat increased by a mean of 0.15% per doubling of alcohol consumption.Conclusions:Our results imply that there is not a ‘safe threshold’ below which there are no toxic effects of alcohol. Current public health guidelines concerning alcohol consumption may need to be revisited.
Malik R, Georgakis MK, Vujkovic M, et al., 2021, Relationship between blood pressure and incident cardiovascular disease. Linear and non-linear Mendelian randomization analyses, Hypertension, Vol: 77, Pages: 2004-2013, ISSN: 0194-911X
Observational studies exploring whether there is a nonlinear effect of blood pressure on cardiovascular disease (CVD) risk are hindered by confounding. This limitation can be overcome by leveraging randomly allocated genetic variants in nonlinear Mendelian randomization analyses. Based on their association with blood pressure traits in a genome-wide association study of 299 024 European ancestry individuals, we selected 253 genetic variants to proxy the effect of modifying systolic and diastolic blood pressure. Considering the outcomes of incident coronary artery disease, stroke and the combined outcome of CVD, linear and nonlinear Mendelian randomization analyses were performed on 255 714 European ancestry participants without a history of CVD or antihypertensive medication use. There was no evidence favoring nonlinear relationships of genetically proxied systolic and diastolic blood pressure with the cardiovascular outcomes over linear relationships. For every 10-mm Hg increase in genetically proxied systolic blood pressure, risk of incident CVD increased by 49% (hazard ratio, 1.49 [95% CI, 1.38–1.61]), with similar estimates obtained for coronary artery disease (hazard ratio, 1.50 [95% CI, 1.38–1.63]) and stroke (hazard ratio, 1.44 [95% CI, 1.22–1.70]). Genetically proxied blood pressure had a similar relationship with CVD in men and women. These findings provide evidence to support that even for individuals who do not have elevated blood pressure, public health interventions achieving persistent blood pressure reduction will be of considerable benefit in the primary prevention of CVD.
Malik R, Georgakis MK, Vujkovic M, et al., 2021, Relationship Between Blood Pressure and Incident Cardiovascular Disease: Linear and Nonlinear Mendelian Randomization Analyses, Hypertension, Vol: 77, Pages: 2004-2013, ISSN: 0194-911X
<jats:p>Observational studies exploring whether there is a nonlinear effect of blood pressure on cardiovascular disease (CVD) risk are hindered by confounding. This limitation can be overcome by leveraging randomly allocated genetic variants in nonlinear Mendelian randomization analyses. Based on their association with blood pressure traits in a genome-wide association study of 299 024 European ancestry individuals, we selected 253 genetic variants to proxy the effect of modifying systolic and diastolic blood pressure. Considering the outcomes of incident coronary artery disease, stroke and the combined outcome of CVD, linear and nonlinear Mendelian randomization analyses were performed on 255 714 European ancestry participants without a history of CVD or antihypertensive medication use. There was no evidence favoring nonlinear relationships of genetically proxied systolic and diastolic blood pressure with the cardiovascular outcomes over linear relationships. For every 10-mm Hg increase in genetically proxied systolic blood pressure, risk of incident CVD increased by 49% (hazard ratio, 1.49 [95% CI, 1.38–1.61]), with similar estimates obtained for coronary artery disease (hazard ratio, 1.50 [95% CI, 1.38–1.63]) and stroke (hazard ratio, 1.44 [95% CI, 1.22–1.70]). Genetically proxied blood pressure had a similar relationship with CVD in men and women. These findings provide evidence to support that even for individuals who do not have elevated blood pressure, public health interventions achieving persistent blood pressure reduction will be of considerable benefit in the primary prevention of CVD.</jats:p>
Riley S, Ainslie KEC, Eales O, et al., 2021, Resurgence of SARS-CoV-2: detection by community viral surveillance, Science, Vol: 372, Pages: 990-995, ISSN: 0036-8075
Surveillance of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has mainly relied on case reporting, which is biased by health service performance, test availability, and test-seeking behaviors. We report a community-wide national representative surveillance program in England based on self-administered swab results from ~594,000 individuals tested for SARS-CoV-2, regardless of symptoms, between May and the beginning of September 2020. The epidemic declined between May and July 2020 but then increased gradually from mid-August, accelerating into early September 2020 at the start of the second wave. When compared with cases detected through routine surveillance, we report here a longer period of decline and a younger age distribution. Representative community sampling for SARS-CoV-2 can substantially improve situational awareness and feed into the public health response even at low prevalence.
Elliott J, Bodinier B, Whitaker M, et al., 2021, Cardiovascular Disease, Hypertension, Diabetes And Cystatin C Jointly Predict Covid-19 Mortality Alongside Age, Male Sex And Black Ethnicity, Scientific Sessions of the American-Heart-Association on Epidemiological and Prevention (EPI)/Lifestyle and Cardiometabolic Health, Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0009-7322
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Wood AC, Saylor G, Tzoulaki I, et al., 2021, Untargeted <SUP>1</SUP>H Nmr Metabolomics Metabolomic Analysis Reveals Pathways Of Protection Between Mediterranean-style Diet And Incident Cardiovascular Disease In The Multi-ethnic Study Of Atherosclerosis, Scientific Sessions of the American-Heart-Association on Epidemiological and Prevention (EPI)/Lifestyle and Cardiometabolic Health, Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0009-7322
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Elliott J, Whitaker M, Bodinier B, et al., 2021, Complementary Variable Selection Methods Highlight Joint Contribution Of Cystatin C And Apolipoprotein B For Cardiovascular Risk Prediction, Scientific Sessions of the American-Heart-Association on Epidemiological and Prevention (EPI)/Lifestyle and Cardiometabolic Health, Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0009-7322
Garcia-Segura ME, Durainayagam BR, Liggi S, et al., 2021, Pathway-based integration of multi-omics data reveals lipidomics alterations validated in an Alzheimer’s Disease mouse model and risk loci carriers
<jats:title>Abstract</jats:title><jats:p>Alzheimer’s Disease (AD) is a highly prevalent neurodegenerative disorder. Despite increasing evidence of important metabolic dysregulation in AD, the underlying metabolic changes that may impact amyloid plaque formation are not understood, particularly for late onset AD. This study analyzed genome-wide association studies (GWAS), transcriptomics and proteomics data obtained from several data repositories to obtain differentially expressed (DE) multi-omics elements in mouse models of AD. We characterized the metabolic modulation in these datasets using gene ontology, and transcription factor, pathway and cell-type enrichment analysis. A predicted lipid signature was extracted from genome-scale metabolic networks (GSMN) and subsequently validated in a lipidomic dataset derived from cortical tissue of ABCA7-null mice, a mouse model of one of the genes associated with late onset AD. Moreover, a metabolome-wide association study (MWAS) was performed to further characterize the association between dysregulated lipid metabolism in human blood serum and AD.</jats:p><jats:p>We found 203 DE transcripts, 164 DE proteins and 58 DE GWAS-derived mouse orthologs associated with significantly enriched metabolic biological processes. Lipid and bioenergetics metabolic pathways were significantly over-represented across the AD multi-omics datasets. Microglia and astrocytes were significantly enriched in the lipid-predominant AD-metabolic transcriptome. We also extracted a predicted lipid signature that was validated and robustly modelled class separation in the ABCA7 mice cortical lipidome, with 11 of these lipid species exhibiting statistically significant modulations. MWAS revealed 298 AD single nucleotide polymorphisms (SNP)-metabolite associations, of which 70% corresponded to lipid classes.</jats:p><jats:p>These results support the importance of lipid metabolism dysregulation in AD and highl
Karabegović I, Dehghan A, Elliott P, et al., 2021, Epigenome-wide association meta-analysis of DNA methylation with coffee and tea consumption, Nature Communications, Vol: 12, ISSN: 2041-1723
Coffee and tea are extensively consumed beverages worldwide which have received considerable attention regarding health. Intake of these beverages is consistently linked to, among others, reduced risk of diabetes and liver diseases; however, the mechanisms of action remain elusive. Epigenetics is suggested as a mechanism mediating the effects of dietary and lifestyle factors on disease onset. Here we report the results from epigenome-wide association studies (EWAS) on coffee and tea consumption in 15,789 participants of European and African-American ancestries from 15 cohorts. EWAS meta-analysis of coffee consumption reveals 11 CpGs surpassing the epigenome-wide significance threshold (P-value <1.1×10−7), which annotated to the AHRR, F2RL3, FLJ43663, HDAC4, GFI1 and PHGDH genes. Among them, cg14476101 is significantly associated with expression of the PHGDH and risk of fatty liver disease. Knockdown of PHGDH expression in liver cells shows a correlation with expression levels of genes associated with circulating lipids, suggesting a role of PHGDH in hepatic-lipid metabolism. EWAS meta-analysis on tea consumption reveals no significant association, only two CpGs annotated to CACNA1A and PRDM16 genes show suggestive association (P-value <5.0×10−6). These findings indicate that coffee-associated changes in DNA methylation levels may explain the mechanism of action of coffee consumption in conferring risk of diseases.
Riley S, Haw D, Walters C, et al., 2021, REACT-1 round 11 report: low prevalence of SARS-CoV-2 infection in the community prior to the third step of the English roadmap out of lockdown
BackgroundNational epidemic dynamics of SARS-CoV-2 infections are being driven by: the degree of recent indoor mixing (both social and workplace), vaccine coverage, intrinsic properties of the circulating lineages, and prior history of infection (via natural immunity). In England, infections, hospitalisations and deaths fell during the first two steps of the “roadmap” for exiting the third national lockdown. The third step of the roadmap in England takes place on 17 May 2021.MethodsWe report the most recent findings on community infections from the REal-time Assessment of Community Transmission-1 (REACT-1) study in which a swab is obtained from a representative cross-sectional sample of the population in England and tested using PCR. Round 11 of REACT-1 commenced self-administered swab-collection on 15 April 2021 and completed collections on 3 May 2021. We compare the results of REACT-1 round 11 to round 10, in which swabs were collected from 11 to 30 March 2021.ResultsBetween rounds 10 and 11, prevalence of swab-positivity dropped by 50% in England from 0.20% (0.17%, 0.23%) to 0.10% (0.08%, 0.13%), with a corresponding R estimate of 0.90 (0.87, 0.94). Rates of swab-positivity fell in the 55 to 64 year old group from 0.17% (0.12%, 0.25%) in round 10 to 0.06% (0.04%, 0.11%) in round 11. Prevalence in round 11 was higher in the 25 to 34 year old group at 0.21% (0.12%, 0.38%) than in the 55 to 64 year olds and also higher in participants of Asian ethnicity at 0.31% (0.16%, 0.60%) compared with white participants at 0.09% (0.07%, 0.11%). Based on sequence data for positive samples for which a lineage could be identified, we estimate that 92.3% (75.9%, 97.9%, n=24) of infections were from the B.1.1.7 lineage compared to 7.7% (2.1%, 24.1%, n=2) from the B.1.617.2 lineage. Both samples from the B.1.617.2 lineage were detected in London from participants not reporting travel in the previous two weeks. Also, allowing for suitable lag periods, the prior close alig
Pazoki R, Elliott J, Evangelou E, et al., 2021, Genetic analysis in European ancestry individuals identifies 517 loci associated with liver enzymes, Nature Communications, Vol: 12, ISSN: 2041-1723
Serum concentration of hepatic enzymes are linked to liver dysfunction, metabolic and cardiovascular diseases. We perform genetic analysis on serum levels of alanine transaminase (ALT), alkaline phosphatase (ALP) and gamma-glutamyl transferase (GGT) using data on 437,438 UK Biobank participants. Replication in 315,572 individuals from European descent from the Million Veteran Program, Rotterdam Study and Lifeline study confirms 517 liver enzyme SNPs. Genetic risk score analysis using the identified SNPs is strongly associated with serum activity of liver enzymes in two independent European descent studies (The Airwave Health Monitoring study and the Northern Finland Birth Cohort 1966). Gene-set enrichment analysis using the identified SNPs highlights involvement in liver development and function, lipid metabolism, insulin resistance, and vascular formation. Mendelian randomization analysis shows association of liver enzyme variants with coronary heart disease and ischemic stroke. Genetic risk score for elevated serum activity of liver enzymes is associated with higher fat percentage of body, trunk, and liver and body mass index. Our study highlights the role of molecular pathways regulated by the liver in metabolic disorders and cardiovascular disease.
Eales O, Page AJ, Tang S, et al., 2021, SARS-CoV-2 lineage dynamics in England from January to March 2021 inferred from representative community samples
Genomic surveillance for SARS-CoV-2 lineages informs our understanding of possible future changes in transmissibility and vaccine efficacy. However, small changes in the frequency of one lineage over another are often difficult to interpret because surveillance samples are obtained from a variety of sources. Here, we describe lineage dynamics and phylogenetic relationships using sequences obtained from a random community sample who provided a throat and nose swab for rt-PCR during the first three months of 2021 as part of the REal-time Assessment of Community Transmission-1 (REACT-1) study. Overall, diversity decreased during the first quarter of 2021, with the B.1.1.7 lineage (first identified in Kent) predominant, driven by a 0.3 unit higher reproduction number over the prior wild type. During January, positive samples were more likely B.1.1.7 in younger and middle-aged adults (aged 18 to 54) than in other age groups. Although individuals infected with the B.1.1.7 lineage were no more likely to report one or more classic COVID-19 symptoms compared to those infected with wild type, they were more likely to be antibody positive 6 weeks after infection. Viral load was higher in B.1.1.7 infection as measured by cycle threshold (Ct) values, but did not account for the increased rate of testing positive for antibodies. The presence of infections with non-imported B.1.351 lineage (first identified in South Africa) during January, but not during February or March, suggests initial establishment in the community followed by fade-out. However, this occurred during a period of stringent social distancing and targeted public health interventions and does not immediately imply similar lineages could not become established in the future. Sequence data from representative community surveys such as REACT-1 can augment routine genomic surveillance.
Ward H, Cooke GS, Atchison C, et al., 2021, Prevalence of antibody positivity to SARS-CoV-2 following the first peak of infection in England: Serial cross-sectional studies of 365,000 adults, The Lancet Regional Health - Europe, Vol: 4, Pages: 1-7, ISSN: 2666-7762
BackgroundThe time-concentrated nature of the first wave of the COVID-19 epidemic in England in March and April 2020 provides a natural experiment to measure changes in antibody positivity at the population level before onset of the second wave and initiation of the vaccination programme.MethodsThree cross-sectional national surveys with non-overlapping random samples of the population in England undertaken between late June and September 2020 (REACT-2 study). 365,104 adults completed questionnaires and self-administered lateral flow immunoassay (LFIA) tests for IgG against SARS-CoV-2.FindingsOverall, 17,576 people had detectable antibodies, a prevalence of 4.9% (95% confidence intervals 4.9, 5.0) when adjusted for test characteristics and weighted to the adult population of England. The prevalence declined from 6.0% (5.8, 6.1), to 4.8% (4.7, 5.0) and 4.4% (4.3, 4.5), over the three rounds of the study a difference of -26.5% (-29.0, -23.8). The highest prevalence and smallest overall decline in positivity was in the youngest age group (18-24 years) at -14.9% (-21.6, -8.1), and lowest prevalence and largest decline in the oldest group (>74 years) at -39.0% (-50.8, -27.2). The decline from June to September 2020 was largest in those who did not report a history of COVID-19 at -64.0% (-75.6, -52.3), compared to -22.3% (-27.0, -17.7) in those with SARS-CoV-2 infection confirmed on PCR.InterpretationA large proportion of the population remained susceptible to SARS-CoV-2 infection in England based on naturally acquired immunity from the first wave. Widespread vaccination is needed to confer immunity and control the epidemic at population level.FundingThis work was funded by the Department of Health and Social Care in England.
Dehghan A, Pinto R, Karaman I, et al., 2021, Metabolome-wide association study on <i>ABCA7</i> demonstrates a role for ceramide metabolism in impaired cognitive performance and Alzheimer’s disease
<jats:title>Abstract</jats:title><jats:p>Genome-wide association studies (GWAS) have identified genetic loci associated with risk of Alzheimer’s disease (AD), but underlying mechanisms are largely unknown. We conducted a metabolome-wide association study (MWAS) of AD-associated loci from GWAS using untargeted metabolic profiling (metabolomics) by ultra-performance liquid chromatography-mass spectrometry (UPLC-MS). We identified an association of lactosylceramides (LacCer) with AD-related single nucleotide polymorphisms (SNPs) in <jats:italic>ABCA7</jats:italic> (<jats:italic>P</jats:italic> = 5.0x 10<jats:sup>−5</jats:sup> to 1.3 x 10<jats:sup>−44</jats:sup>). We show that plasma LacCer concentrations are associated with cognitive performance in humans and concentrations of sphingomyelins, ceramides, and hexose-ceramides were altered in brain tissue from <jats:italic>ABCA7</jats:italic> knock out mice, compared to wild type (WT) (<jats:italic>P</jats:italic> =0.049 to 1.4 x10<jats:sup>−5</jats:sup>). We then used Mendelian randomisation to show that the association of LacCer with AD risk is potentially causal. Our work suggests that risk for AD arising from functional variations in <jats:italic>ABCA7</jats:italic> are mediated at least in part through ceramides. Modulation of their metabolism or downstream signalling may offer new therapeutic opportunities for AD.</jats:p>
Riley S, Eales O, Haw D, et al., 2021, REACT-1 round 10 report: Level prevalence of SARS-CoV-2 swab-positivity in England during third national lockdown in March 2021
BackgroundIn England, hospitalisations and deaths due to SARS-CoV-2 have been falling consistentlysince January 2021 during the third national lockdown of the COVID-19 pandemic. The firstsignificant relaxation of that lockdown occurred on 8 March when schools reopened.MethodsThe REal-time Assessment of Community Transmission-1 (REACT-1) study augmentsroutine surveillance data for England by measuring swab-positivity for SARS-CoV-2 in thecommunity. The current round, round 10, collected swabs from 11 to 30 March 2021 and iscompared here to round 9, in which swabs were collected from 4 to 23 February 2021.ResultsDuring round 10, we estimated an R number of 1.00 (95% confidence interval 0.81, 1.21).Between rounds 9 and 10 we estimated national prevalence has dropped by ~60% from0.49% (0.44%, 0.55%) in February to 0.20% (0.17%, 0.23%) in March. There weresubstantial falls in weighted regional prevalence: in South East from 0.36% (0.29%, 0.44%)in round 9 to 0.07% (0.04%, 0.12%) in round 10; London from 0.60% (0.48%, 0.76%) to0.16% (0.10%, 0.26%); East of England from 0.47% (0.36%, 0.60%) to 0.15% (0.10%,0.24%); East Midlands from 0.59% (0.45%, 0.77%) to 0.19% (0.13%, 0.28%); and NorthWest from 0.69% (0.54%, 0.88%) to 0.31% (0.21%, 0.45%). Areas of apparent higherprevalence remain in parts of the North West, and Yorkshire and The Humber. The highestprevalence in March was found among school-aged children 5 to 12 years at 0.41% (0.27%,0.62%), compared with the lowest in those aged 65 to 74 and 75 and over at 0.09% (0.05%,0.16%). The close approximation between prevalence of infections and deaths (suitablylagged) is diverging, suggesting that infections may have resulted in fewer hospitalisationsand deaths since the start of widespread vaccination.ConclusionWe report a sharp decline in prevalence of infections between February and March 2021.We did not observe an increase in the prevalence of SARS-CoV-2 following the reopening ofschools in England, although the decline of p
Yang JJ, Tzoulaki I, Karaman I, et al., 2021, Circulating trimethylamine N-oxide (TMAO) in association with diet and cardiometabolic biomarkers: an international pooled analysis, American Journal of Clinical Nutrition, Vol: 113, Pages: 1145-1156, ISSN: 0002-9165
Background: Trimethylamine N-oxide (TMAO), a diet-derived, gut microbial-host co-metabolite, has been linked to cardiometabolic diseases. However, the relationships remain unclear between diet, TMAO, and cardiometabolic health in general populations from different regions and ethnicities. Objective: To examine associations of circulating TMAO with dietary and cardiometabolic factors in a pooled analysis of 16 population-based studies from the US, Europe, and Asia.Design: Included were 32,166 adults (16,269 White, 13,293 Asian, 1,247 Hispanic/Latino, and 1,236 Black) without cardiovascular disease, cancer, chronic kidney disease, or inflammatory bowel disease. Linear regression coefficients (β) were computed for standardized TMAO with harmonized variables. Study-specific results were combined by random-effects meta-analysis. False discovery rate<0.10 was considered significant. Results: After adjustment for potential confounders, circulating TMAO was associated with intakes of animal protein and saturated fat (β=0.124 and 0.058, respectively, for 5%-energy increase) and with shellfish, total fish, eggs, and red meat (β=0.370, 0.151, 0.081, and 0.056, respectively, for 1-serving/day increase). Plant protein and nuts showed inverse associations (β=-0.126 for 5%-energy increase from plant protein and -0.123 for 1-serving/day of nuts). Although the animal protein-TMAO association was consistent across populations, fish and shellfish associations were stronger among Asians (β=0.285 and 0.578), and egg and red meat associations were more prominent among Americans (β=0.153 and 0.093). Besides, circulating TMAO was positively associated with creatinine (β=0.131 per standard deviation increase in log-TMAO), homocysteine (β=0.065), insulin (β=0.048), HbA1c (β=0.048), and glucose (β=0.023), while inversely associated with HDL-cholesterol (β=-0.047) and blood pressure (β=-0.030). Each TMAO-biomarker association
Posma JM, Stamler J, Garcia-Perez I, et al., 2021, Urinary metabolic phenotype of blood pressure, 19TH INTERNATIONAL SHR SYMPOSIUM SHR, Publisher: Lippincott, Williams & Wilkins, Pages: E70-E70, ISSN: 0263-6352
Objective: Metabolic phenotyping (metabolomics) captures systems-level information on metabolic processes by simultaneously measuring hundreds of metabolites using spectroscopic techniques. Concentrations of these metabolites are affected by genetic (host, microbiome), environmental and dietary factors and may provide insights into biochemical pathways underlying raised blood pressure (BP) in populations.Design and method: Two separate, timed 24hr urine specimens were obtained from 2,031 women and men, aged 40–59, from 8 USA population samples in the INTERMAP Study. Proton Nuclear Magnetic Resonance (1H NMR) was used to characterize a urinary metabolic signature; this was unaffected by diurnal variability and sampling time as it captures end-products of metabolism over a 24hr period. Demographic, population, medical, lifestyle and anthropometric factors were accounted for in regression models to define a urinary metabolic phenotype associated with BP.Results: 29 structurally identified urinary metabolites covaried with systolic BP (SBP), after adjustment for demographic variables, and 18 metabolites with diastolic BP (DBP), with 16 metabolites overlapping between SBP and DBP. These included metabolites related to energy metabolism, renal function, diet and gut microbiota. After adjustment for medical and lifestyle covariates, 22/14 metabolites remained associated with SBP/DBP. Joint covariate-metabolite penalized regression models identified Body Mass Index, age and family history as most important contributors, with 14 metabolites, including gut microbial co-metabolites, also included in the model. Metabolites were mapped in a symbiotic metabolic reaction network, that includes reactions mediated by 3,344 commensal gut microbial species, to highlight affected pathways (Figure). Significant single nucleotide polymorphisms (SNPs) from genome-wide association studies on cardiometabolic risk factors were mapped to genes in this network. This revealed multiple sub
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