Publications
886 results found
Koskeridis F, Evangelou E, Said S, et al., 2022, Pleiotropic genetic architecture and novel loci for C-reactive protein levels, Nature Communications, Vol: 13, ISSN: 2041-1723
C-reactive protein is involved in a plethora of pathophysiological conditions. Many genetic loci associated with C-reactive protein are annotated to lipid and glucose metabolism genes supporting common biological pathways between inflammation and metabolic traits. To identify novel pleiotropic loci, we perform multi-trait analysis of genome-wide association studies on C-reactive protein levels along with cardiometabolic traits, followed by a series of in silico analyses including colocalization, phenome-wide association studies and Mendelian randomization. We find 41 novel loci and 19 gene sets associated with C-reactive protein with various pleiotropic effects. Additionally, 41 variants colocalize between C-reactive protein and cardiometabolic risk factors and 12 of them display unexpected discordant effects between the shared traits which are translated into discordant associations with clinical outcomes in subsequent phenome-wide association studies. Our findings provide insights into shared mechanisms underlying inflammation and lipid metabolism, representing potential preventive and therapeutic targets.
Mustafa R, Mens MMJ, van Hilten A, et al., 2022, An atlas of genetic regulation and disease associations of microRNAs
<jats:title>Abstract</jats:title><jats:p>MicroRNAs (miRNAs) are small non-coding RNAs that post-transcriptionally regulate gene expression. Identification of genetic variants influencing the transcription of miRNAs can provide an understanding of their genetic regulation and implication in human disease. Here we present genome-wide association studies of 2,083 plasma circulating miRNAs measured by next-generation sequencing in 2,178 participants of the Rotterdam Study to identify miRNA-expression quantitative trait loci (miR-eQTLs). We report 4,310 cis- and trans-miR-eQTLs for 64 miRNAs that have been replicated across independent studies. Many of these miR-eQTLs overlap with gene expression, protein, and metabolite-QTLs and with disease-associated variants. The consequences of perturbation in miRNA transcription on a wide range of clinical conditions are systematically investigated in phenome-wide association studies, with their causality tested using Mendelian randomization. Integration of genomics and miRNAs enables interrogation of the genetic architecture of miRNAs, revealing their clinical importance, and providing valuable resources for future studies of miRNAs in human disease.</jats:p>
Ghanbari M, Mustafa R, Mens M, et al., 2022, An atlas of genetic regulation and disease associations of microRNAs
<jats:title>Abstract</jats:title> <jats:p>MicroRNAs (miRNAs) are small non<jats:italic>-</jats:italic>coding RNAs that post-transcriptionally regulate gene expression. Identification of genetic variants influencing the transcription of miRNAs can provide an understanding of their genetic regulation and implication in human disease. Here we present genome-wide association studies of 2,083 plasma circulating miRNAs measured by next-generation sequencing in 2,178 participants of the Rotterdam Study to identify miRNA-expression quantitative trait loci (miR-eQTLs). We report 4,310 cis- and trans-miR-eQTLs for 64 miRNAs that have been replicated across independent studies. Many of these miR-eQTLs overlap with gene expression, protein, and metabolite-QTLs and with disease-associated variants. The consequences of perturbation in miRNA transcription on a wide range of clinical conditions are systematically investigated in phenome-wide association studies, with their causality tested using Mendelian randomization. Integration of genomics and miRNAs enables interrogation of the genetic architecture of miRNAs, revealing their clinical importance, and providing valuable resources for future studies of miRNAs in human disease.</jats:p>
Whitaker M, Elliott J, Bodinier B, et al., 2022, Variant-specific symptoms of COVID-19 in a study of 1,542,510 adults in England, Nature Communications, Vol: 13, Pages: 1-10, ISSN: 2041-1723
Infection with SARS-CoV-2 virus is associated with a wide range of symptoms. The REal-time Assessment of Community Transmission -1 (REACT-1) study monitored the spread and clinical manifestation of SARS-CoV-2 among random samples of the population in England from 1 May 2020 to 31 March 2022. We show changing symptom profiles associated with the different variants over that period, with lower reporting of loss of sense of smell or taste for Omicron compared to previous variants, and higher reporting of cold-like and influenza-like symptoms, controlling for vaccination status. Contrary to the perception that recent variants have become successively milder, Omicron BA.2 was associated with reporting more symptoms, with greater disruption to daily activities, than BA.1. With restrictions lifted and routine testing limited in many countries, monitoring the changing symptom profiles associated with SARS-CoV-2 infection and effects on daily activities will become increasingly important.
Salman E, Kadota A, Okami Y, et al., 2022, Investigation of the urinary sodium-to-potassium ratio target level based on the recommended dietary intake goals for the Japanese population: The INTERMAP Japan, Hypertension Research, Vol: 45, Pages: 1850-1860, ISSN: 0916-9636
Growing epidemiological evidence has shown an association of the urinary sodium (Na) to potassium (K) ratio (Na/K ratio) with blood pressure and cardiovascular diseases. However, no clear cutoff level has been defined. We investigated the cutoff level of the urinary Na/K ratio under different dietary guidelines for Japanese individuals, especially that endorsed by the 2020 revised Japanese Dietary Reference Intakes (DRIs). A population of 1145 Japanese men and women aged 40 to 59 years from the INTERMAP study was examined. Using high-quality standardized data, the averages of two 24 h urinary collections and four 24 h dietary recalls were used to calculate the 24 h urinary and dietary Na/K ratios, respectively. Associations between the urinary and dietary Na/K ratios were tested by sex- and age-adjusted partial correlation. The optimal urinary Na/K ratio cutoff level was determined by receiver operating characteristic (ROC) curves and sex-specific cross tables for recommended dietary K and salt. Overall, the average molar ratio of 24 h urinary Na/K was 4.3. We found moderate correlations (P < 0.001) of the 24 h urinary Na/K ratio with 24 h urinary Na and K excretion (r = 0.52, r = −0.49, respectively) and the dietary Na/K ratio (r = 0.53). ROC curves showed that a 24 h urinary Na/K ratio of approximately 2 predicted Na and K intake that meets the dietary goals of the Japanese DRIs. The range of urinary Na/K ratios meeting the dietary goals of the Japanese DRIs for both Na and K was 1.6‒2.2 for men and 1.7‒1.9 for women. Accomplishing a urinary Na/K ratio of 2 would be desirable to achieve the DRIs dietary goals for both Na and K simultaneously in middle-aged Japanese men and women accustomed to Japanese dietary habits. This observational study is registered at www.clinicaltrials.gov as NCT00005271.
Chan SH, Bylstra Y, Teo JX, et al., 2022, Analysis of clinically relevant variants from ancestrally diverse Asian genomes, Nature Communications, Vol: 13, ISSN: 2041-1723
Asian populations are under-represented in human genomics research. Here, we characterize clinically significant genetic variation in 9051 genomes representing East Asian, South Asian, and severely under-represented Austronesian-speaking Southeast Asian ancestries. We observe disparate genetic risk burden attributable to ancestry-specific recurrent variants and identify individuals with variants specific to ancestries discordant to their self-reported ethnicity, mostly due to cryptic admixture. About 27% of severe recessive disorder genes with appreciable carrier frequencies in Asians are missed by carrier screening panels, and we estimate 0.5% Asian couples at-risk of having an affected child. Prevalence of medically-actionable variant carriers is 3.4% and a further 1.6% harbour variants with potential for pathogenic classification upon additional clinical/experimental evidence. We profile 23 pharmacogenes with high-confidence gene-drug associations and find 22.4% of Asians at-risk of Centers for Disease Control and Prevention Tier 1 genetic conditions concurrently harbour pharmacogenetic variants with actionable phenotypes, highlighting the benefits of pre-emptive pharmacogenomics. Our findings illuminate the diversity in genetic disease epidemiology and opportunities for precision medicine for a large, diverse Asian population.
Mosscrop L, Watber P, Elliot P, et al., 2022, Evaluation of the impact of pre-analytical conditions on sample stability for the detection of SARS-CoV-2 RNA, Journal of Virological Methods, Vol: 309, Pages: 1-5, ISSN: 0166-0934
Demand for accurate SARS-CoV-2 diagnostics is high. Most samples in the UK are collected in the community and rely on the postal service for delivery to the laboratories. The current recommendation remains that swabs should be collected in Viral Transport Media (VTM) and transported with a cold chain to the laboratory for RNA extraction and RT-qPCR. This is not always possible. We aimed to test the stability of SARS-CoV-2 RNA subjected to different pre-analytical conditions. Swabs were dipped into PBS containing cultured SARS-CoV-2 and placed in either a dry tube or a tube containing either normal saline or VTM. The tubes were then stored at different temperatures (20–50 °C) for variable periods (8 h to 5 days). Samples were tested by RT-qPCR targeting SARS-CoV-2 E gene. VTM outperformed swabs in saline and dry swabs in all conditions. Samples in VTM were stable, independent of a cold chain, for 5 days, with a maximum increase in cycle threshold (Ct) of 1.34 when held at 40 °C. Using normal saline as the transport media resulted in a loss of sensitivity (increased Ct) over time and with increasing temperature (up to 7.8 cycles compared to VTM). SARS-CoV-2 was not detected in 3/9 samples in normal saline when tested after 120 h incubation. Transportation of samples in VTM provides a high level of confidence in the results despite the potential for considerable, uncontrolled variation in temperature and longer transportation periods. False negative results may be seen after 96 h in saline and viral loads will appear lower.
Dehghan A, Pinto RC, Karaman I, et al., 2022, Metabolome-wide association study on ABCA7 indicates a role of ceramide metabolism in Alzheimer's disease., Proceedings of the National Academy of Sciences of USA, Vol: 119, Pages: 1-12, ISSN: 0027-8424
Genome-wide association studies (GWASs) have identified genetic loci associated with the risk of Alzheimer's disease (AD), but the molecular mechanisms by which they confer risk are largely unknown. We conducted a metabolome-wide association study (MWAS) of AD-associated loci from GWASs using untargeted metabolic profiling (metabolomics) by ultraperformance liquid chromatography-mass spectrometry (UPLC-MS). We identified an association of lactosylceramides (LacCer) with AD-related single-nucleotide polymorphisms (SNPs) in ABCA7 (P = 5.0 × 10-5 to 1.3 × 10-44). We showed that plasma LacCer concentrations are associated with cognitive performance and genetically modified levels of LacCer are associated with AD risk. We then showed that concentrations of sphingomyelins, ceramides, and hexosylceramides were altered in brain tissue from Abca7 knockout mice, compared with wild type (WT) (P = 0.049-1.4 × 10-5), but not in a mouse model of amyloidosis. Furthermore, activation of microglia increases intracellular concentrations of hexosylceramides in part through induction in the expression of sphingosine kinase, an enzyme with a high control coefficient for sphingolipid and ceramide synthesis. Our work suggests that the risk for AD arising from functional variations in ABCA7 is mediated at least in part through ceramides. Modulation of their metabolism or downstream signaling may offer new therapeutic opportunities for AD.
Eales O, Haw D, Wang H, et al., 2022, Quantifying changes in the IFR and IHR over 23 months of the SARS-CoV-2 pandemic in England
<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>The relationship between prevalence of infection and severe outcomes such as hospitalisation and death changed over the course of the COVID-19 pandemic. The REal-time Assessment of Community Transmission-1 (REACT-1) study estimated swab positivity in England approximately monthly from May 2020 to 31 March 2022. This period covers widespread circulation of the original strain, the emergence of the Alpha, Delta and Omicron variants and the rollout of England’s mass vaccination campaign.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>Here, we explore this changing relationship between prevalence of swab positivity and the infection fatality rate (IFR) and infection hospitalisation rate (IHR) over 23 months of the pandemic in England, using publicly available data for the daily number of deaths and hospitalisations, REACT-1 swab positivity data, time-delay models and Bayesian P-spline models. We analyse data for all age groups together, as well as in two sub-groups: those aged 65 and over and those aged 64 and under.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>During 2020, we estimated the IFR to be 0.67% and the IHR to be 2.6%. By late-2021/early-2022 the IFR and IHR had both decreased to 0.097% and 0.76% respectively. Continuous estimates of the IFR and IHR of the virus were observed to increase during the periods of Alpha and Delta’s emergence. During periods of vaccination rollout, and the emergence of the Omicron variant, the IFR and IHR of the virus decreased. During 2020, we estimated a time-lag of 19 days between hospitalisation and swab positivity, and 26 days between deaths and swab positivity. By late-2021/early-2022 these time-lags had decreased to 7 days for hospitalisations, and 18 days for deaths.</jats:
Chadeau-Hyam M, Tang D, Eales O, et al., 2022, Omicron SARS-CoV-2 epidemic in England during February 2022: A series of cross-sectional community surveys, The Lancet Regional Health Europe, Vol: 21, Pages: 1-11, ISSN: 2666-7762
BackgroundThe Omicron wave of COVID-19 in England peaked in January 2022 resulting from the rapid transmission of the Omicron BA.1 variant. We investigate the spread and dynamics of the SARS-CoV-2 epidemic in the population of England during February 2022, by region, age and main SARS-CoV-2 sub-lineage.MethodsIn the REal-time Assessment of Community Transmission-1 (REACT-1) study we obtained data from a random sample of 94,950 participants with valid throat and nose swab results by RT-PCR during round 18 (8 February to 1 March 2022).FindingsWe estimated a weighted mean SARS-CoV-2 prevalence of 2.88% (95% credible interval [CrI] 2.76–3.00), with a within-round effective reproduction number (R) overall of 0.94 (0·91–0.96). While within-round weighted prevalence fell among children (aged 5 to 17 years) and adults aged 18 to 54 years, we observed a level or increasing weighted prevalence among those aged 55 years and older with an R of 1.04 (1.00–1.09). Among 1,616 positive samples with sublineages determined, one (0.1% [0.0–0.3]) corresponded to XE BA.1/BA.2 recombinant and the remainder were Omicron: N=1047, 64.8% (62.4–67.2) were BA.1; N=568, 35.2% (32.8–37.6) were BA.2. We estimated an R additive advantage for BA.2 (vs BA.1) of 0.38 (0.34–0.41). The highest proportion of BA.2 among positives was found in London.InterpretationIn February 2022, infection prevalence in England remained high with level or increasing rates of infection in older people and an uptick in hospitalisations. Ongoing surveillance of both survey and hospitalisations data is required.FundingDepartment of Health and Social Care, England.
Asaria P, Bennett J, Elliott P, et al., 2022, Contributions of event rates, pre-hospital deaths and hospital case fatality to variations in myocardial infarction mortality in 326 districts in England: spatial analysis of linked hospitalisation and mortality data, The Lancet Public Health, Vol: 7, Pages: e813-e824, ISSN: 2468-2667
Background: Myocardial infarction (MI) mortality varies substantially within high-income countries. There is limited guidance on what interventions – primary and secondary prevention and/or improving care pathways and quality – can reduce and equalise MI mortality. Our aimwas to understand the contribution of incidence (event rate), pre-hospital deaths and hospital case-fatality, to how MI mortality varies within England.Methods: We used linked data on hospitalisation and deaths from 2015-2018 with geographical identifiers to estimate MI death and event rates, pre-hospital deaths and hospital case fatality for men and women aged 45 years and older in 326 districts in England. Data were analysed in a Bayesian spatial model that accounted for similarities and differences inspatial patterns of fatal and non-fatal MI. Results: The 99th to 1st percentile ratio of age-standardised MI death rate was 2.63 (95% credible interval 2.45-2.83) in women and 2.56 (2.37-2.76) in men across districts, with death rate highest in north of England. The main contributor to this variation was MI event rate, with a 99th to 1st percentile ratio of 2.55 (2.39-2.72) (women) and 2.17 (2.08-2.27) (men) across districts. Pre-hospital mortality was greater than hospital case fatality in every district. Prehospital mortality had a 99th to 1st percentile ratio 1.60 (1.50-1.70) in women and 1.75 (1.66-1.86) in men across districts and made a greater contribution to case-fatality variation thanhospital case fatality which had a 99th to 1st percentile ratio of 1.39 (1.29-1.49) (women) and1.49 (1.39-1.60) (men). The contribution of case fatality to variation in deaths across districtswas largest in middle ages. Pre-hospital mortality was slightly higher in men than women inmost districts and age groups, whereas hospital case fatality was higher in women in virtuallyall districts at ages up to and including 65-74 years; after this age, it became similar betweenthe sexes.3Interpretation: Mos
Yin X, Rodgers A, Perkovic A, et al., 2022, Effects of salt substitutes on clinical outcomes: a systematic review and meta-analysis, Heart, Vol: 108, Pages: 1608-1615, ISSN: 1355-6037
Objectives The Salt Substitute and Stroke Study (SSaSS) recently reported blood pressure-mediated benefits of a potassium-enriched salt substitute on cardiovascular outcomes and death. This study assessed the effects of salt substitutes on a breadth of outcomes to quantify the consistency of the findings and understand the likely generalisability of the SSaSS results.Methods We searched PubMed, Embase and the Cochrane Library up to 31 August 2021. Parallel group, step-wedge or cluster randomised controlled trials reporting the effect of salt substitute on blood pressure or clinical outcomes were included. Meta-analyses and metaregressions were used to define the consistency of findings across trials, geographies and patient groups.Results There were 21 trials and 31 949 participants included, with 19 reporting effects on blood pressure and 5 reporting effects on clinical outcomes. Overall reduction of systolic blood pressure (SBP) was −4.61 mm Hg (95% CI −6.07 to −3.14) and of diastolic blood pressure (DBP) was −1.61 mm Hg (95% CI −2.42 to −0.79). Reductions in blood pressure appeared to be consistent across geographical regions and population subgroups defined by age, sex, history of hypertension, body mass index, baseline blood pressure, baseline 24-hour urinary sodium and baseline 24-hour urinary potassium (all p homogeneity >0.05). Metaregression showed that each 10% lower proportion of sodium choloride in the salt substitute was associated with a −1.53 mm Hg (95% CI −3.02 to −0.03, p=0.045) greater reduction in SBP and a −0.95 mm Hg (95% CI −1.78 to −0.12, p=0.025) greater reduction in DBP. There were clear protective effects of salt substitute on total mortality (risk ratio (RR) 0.89, 95% CI 0.85 to 0.94), cardiovascular mortality (RR 0.87, 95% CI 0. 81 to 0.94) and cardiovascular events (RR 0.89, 95% CI 0.85 to 0.94).Conclusions The beneficial effects of salt substitutes on blood press
Eales O, Ainslie KEC, Walters CE, et al., 2022, Appropriately smoothing prevalence data to inform estimates of growth rate and reproduction number, Epidemics: the journal of infectious disease dynamics, Vol: 40, ISSN: 1755-4365
The time-varying reproduction number () can change rapidly over the course of a pandemic due to changing restrictions, behaviours, and levels of population immunity. Many methods exist that allow the estimation of from case data. However, these are not easily adapted to point prevalence data nor can they infer across periods of missing data. We developed a Bayesian P-spline model suitable for fitting to a wide range of epidemic time-series, including point-prevalence data. We demonstrate the utility of the model by fitting to periodic daily SARS-CoV-2 swab-positivity data in England from the first 7 rounds (May 2020–December 2020) of the REal-time Assessment of Community Transmission-1 (REACT-1) study. Estimates of over the period of two subsequent rounds (6–8 weeks) and single rounds (2–3 weeks) inferred using the Bayesian P-spline model were broadly consistent with estimates from a simple exponential model, with overlapping credible intervals. However, there were sometimes substantial differences in point estimates. The Bayesian P-spline model was further able to infer changes in over shorter periods tracking a temporary increase above one during late-May 2020, a gradual increase in over the summer of 2020 as restrictions were eased, and a reduction in during England’s second national lockdown followed by an increase as the Alpha variant surged. The model is robust against both under-fitting and over-fitting and is able to interpolate between periods of available data; it is a particularly versatile model when growth rate can change over small timescales, as in the current SARS-CoV-2 pandemic. This work highlights the importance of pairing robust methods with representative samples to track pandemics.
Benedetto U, Sinha S, Mulla A, et al., 2022, Implications of elevated troponin on time-to-surgery in non-ST elevation myocardial infarction (NIHR Health Informatics Collaborative: TROP-CABG study)., Int J Cardiol, Vol: 362, Pages: 14-19
Implications of elevated troponin on time-to-surgery in non-ST elevation myocardial infarction(NIHR Health Informatics Collaborative:TROP-CABG study). Benedetto et al. BACKGROUND: The optimal timing of coronary artery bypass grafting (CABG) in patients with non-ST elevation myocardial infarction (NSTEMI) and the utility of pre-operative troponin levels in decision-making remains unclear. We investigated (a) the association between peak pre-operative troponin and survival post-CABG in a large cohort of NSTEMI patients and (b) the interaction between troponin and time-to-surgery. METHODS AND RESULTS: Our cohort consisted of 1746 patients (1684 NSTEMI; 62 unstable angina) (mean age 69 ± 11 years,21% female) with recorded troponins that had CABG at five United Kingdom centers between 2010 and 2017. Time-segmented Cox regression was used to investigate the interaction of peak troponin and time-to-surgery on early (within 30 days) and late (beyond 30 days) survival. Average interval from peak troponin to surgery was 9 ± 15 days, with 1466 (84.0%) patients having CABG during the same admission. Sixty patients died within 30-days and another 211 died after a mean follow-up of 4 ± 2 years (30-day survival 0.97 ± 0.004 and 5-year survival 0.83 ± 0.01). Peak troponin was a strong predictor of early survival (adjusted P = 0.002) with a significant interaction with time-to-surgery (P interaction = 0.007). For peak troponin levels <100 times the upper limit of normal, there was no improvement in early survival with longer time-to-surgery. However, in patients with higher troponins, early survival increased progressively with a longer time-to-surgery, till day 10. Peak troponin did not influence survival beyond 30 days (adjusted P = 0.64). CONCLUSIONS: Peak troponin in NSTEMI patients undergoing CABG was a significant predictor of earl
Shen C, Mireku MO, Di Simplicio M, et al., 2022, Bidirectional associations between sleep problems and behavioural difficulties and health‐related quality of life in adolescents: Evidence from the SCAMP longitudinal cohort study, JCPP Advances, Vol: 2, Pages: 1-11, ISSN: 2692-9384
BackgroundSleep problems show associations with negative outcomes in both physical and mental health in adolescents, but the associations may be reciprocal. We aimed to assess bidirectional associations between sleep problems and mental health symptoms including behavioural difficulties (internalising and externalising difficulties) and low health-related quality of life (HRQoL).MethodsA total of 6616 adolescents (52.4% females) across Greater London completed baseline assessments when they were aged 11–12 years, and 3803 of them (57.2% females) completed follow-up assessments at aged 13–15 years. Weekday and weekend sleep duration were derived from self-reported bedtime, sleep onset latency and wake time. Sleep disturbance was assessed using a standardized sleep disturbance scale. Internalising and externalising difficulties were assessed using subscales of the Strength and Difficulties Questionnaire. HRQoL was assessed using the KIDSCREEN-10 questionnaire. Cross-lagged structural equation modelling was used with multiple imputation to examine bidirectional associations between sleep problems and mental health symptoms.ResultsFemales had greater internalising difficulties, worse HRQoL and more sleep disturbance than males. Persistent insufficient weekday and weekend sleep, and sleep disturbance (i.e., at both baseline and follow-up) were associated with internalising and externalising difficulties and low HRQoL at follow-up (ORs ranged from 1.53 to 3.63). Persistent externalising difficulties and low HRQoL were also associated with insufficient weekend sleep and sleep disturbance at follow-up (ORs ranged from 1.68 to 4.25). Using continuous variables, we found bidirectional associations between weekday sleep duration and HRQoL, weekend sleep duration and externalising score, sleep quality and internalising score, and sleep quality and HRQoL. The association magnitudes were mostly similar in the two directions.ConclusionsOur study showed bidirectional as
Elliott P, Eales O, Bodinier B, et al., 2022, Dynamics of a national Omicron SARS-CoV-2 epidemic during January 2022 in England, Nature Communications, Vol: 13, ISSN: 2041-1723
Rapid transmission of the SARS-CoV-2 Omicron variant has led to record-breaking case incidence rates around the world. Since May 2020, the REal-time Assessment of Community Transmission-1 (REACT-1) study tracked the spread of SARS-CoV-2 infection in England through RT-PCR of self-administered throat and nose swabs from randomly-selected participants aged 5 years and over. In January 2022, we found an overall weighted prevalence of 4.41% (n=102,174), three-fold higher than in November to December 2021; we sequenced 2,374 (99.2%) Omicron infections (19 BA.2), and only 19 (0.79%) Delta, with a growth rate advantage for BA.2 compared to BA.1 or BA.1.1. Prevalence was decreasing overall (reproduction number R=0.95, 95% credible interval [CrI], 0.93, 0.97), but increasing in children aged 5 to 17 years (R=1.13, 95% CrI, 1.09, 1.18). In England during January 2022, we observed unprecedented levels of SARS-CoV-2 infection, especially among children, driven by almost complete replacement of Delta by Omicron.
Francis C, Futschik M, Huang J, et al., 2022, Genome-wide associations of aortic distensibility suggest causality for aortic aneurysms and brain white matter hyperintensities, Nature Communications, Vol: 13, ISSN: 2041-1723
Aortic dimensions and distensibility are key risk factors for aortic aneurysms and dissections, as well as for other cardiovascular and cerebrovascular diseases. We present genome-wide associations of ascending and descending aortic distensibility and area derived from cardiac magnetic resonance imaging (MRI) data of up to 32,590 Caucasian individuals in UK Biobank. We identify 102 loci (including 27 novel associations) tagging genes related to cardiovascular development, extracellular matrix production, smooth muscle cell contraction and heritable aortic diseases. Functional analyses highlight four signalling pathways associated with aortic distensibility (TGF-, IGF, VEGF and PDGF). We identify distinct sex-specific associations with aortic traits. We develop co-expression networks associated with aortic traits and apply phenome-wide Mendelian randomization (MR-PheWAS), generating evidence for a causal role for aortic distensibility in development of aortic aneurysms. Multivariable MR suggests a causal relationship between aortic distensibility and cerebral white matter hyperintensities, mechanistically linking aortic traits and brain small vessel disease.
Eales O, Martins LDO, Page AJ, et al., 2022, Dynamics of competing SARS-CoV-2 variants during the Omicron epidemic in England, Nature Communications, Vol: 13, ISSN: 2041-1723
The SARS-CoV-2 pandemic has been characterised by the regular emergence of genomic variants. With natural and vaccine-induced population immunity at high levels, evolutionary pressure favours variants better able to evade SARS-CoV-2 neutralising antibodies. The Omicron variant (first detected in November 2021) exhibited a high degree of immune evasion, leading to increased infection rates worldwide. However, estimates of the magnitude of this Omicron wave have often relied on routine testing data, which are prone to several biases. Using data from the REal-time Assessment of Community Transmission-1 (REACT-1) study, a series of cross-sectional surveys assessing prevalence of SARS-CoV-2 infection in England, we estimated the dynamics of England’s Omicron wave (from 9 September 2021 to 1 March 2022). We estimate an initial peak in national Omicron prevalence of 6.89% (5.34%, 10.61%) during January 2022, followed by a resurgence in SARS-CoV-2 infections as the more transmissible Omicron sub-lineage, BA.2 replaced BA.1 and BA.1.1. Assuming the emergence of further distinct variants, intermittent epidemics of similar magnitudes may become the ‘new normal’.
Atchison C, Moshe M, Brown J, et al., 2022, Validity of self-testing at home with rapid SARS-CoV-2 antibody detection by lateral flow immunoassay, Publisher: medRxiv
<h4>ABSTRACT</h4> <h4>Background</h4> Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibody lateral flow immunoassays (LFIA) can be carried out in the home and have been used as an affordable and practical approach to large-scale antibody prevalence studies. However, assay performance differs from that of high-throughput laboratory-based assays which can be highly sensitive. We explore LFIA performance under field conditions compared to laboratory-based ELISA and assess the potential of LFIAs to identify people who lack functional antibodies following infection or vaccination. <h4>Methods</h4> Field evaluation of a self-administered LFIA test (Fortress, NI) among 3758 participants from the REal-time Assessment of Community Transmission-2 (REACT-2) study in England selected based on vaccination history and previous LFIA result to ensure a range of antibody titres. In July 2021, participants performed, at home, a self-administered LFIA on finger-prick blood, reported and submitted a photograph of the result, and provided a self-collected capillary blood sample (Tasso-SST) for serological assessment of IgG antibodies to the spike protein using the Roche Elecsys® Anti-SARS-CoV-2 assay. We compared the self-administered and reported LFIA result to the quantitative Roche assay and checked the reading of the LFIA result with an automated image analysis (ALFA). In a subsample of 250 participants, we compared the results to live virus neutralisation. <h4>Results</h4> Almost all participants (3593/3758, 95.6%) had been vaccinated or reported prior infection, with most having received one (862, 22.9%) or two (2430, 64.7%) COVID-19 vaccine doses. Overall, 2777/3758 (73.9%) were positive on self-reported LFIA, 2811/3457 (81.3%) positive by LFIA when ALFA-reported, and 3622/3758 (96.4%) positive on Roche anti-S (using the manufacturer reference standard threshold for positivity of 0.8 U ml -1 ). Live virus neutra
Eales O, Wang H, Bodinier B, et al., 2022, SARS-CoV-2 lineage dynamics in England from September to November 2021: high diversity of Delta sub-lineages and increased transmissibility of AY.4.2, BMC Infectious Diseases, Vol: 22, ISSN: 1471-2334
Background: Since the emergence of SARS-CoV-2, evolutionary pressure has driven large increases in the transmissibility of the virus. However, with increasing levels of immunity through vaccination and natural infection the evolutionary pressure will switch towards immune escape. Genomic surveillance in regions of high immunity is crucial in detecting emerging variants that can more successfully navigate the immune landscape. Methods: We present phylogenetic relationships and lineage dynamics within England (a country with high levels of immunity), as inferred from a random community sample of individuals who provided a self-administered throat and nose swab for rt-PCR testing as part of the REal-time Assessment of Community Transmission-1 (REACT-1) study. During round 14 (9 September - 27 September 2021) and 15 (19 October - 5 November 2021) lineages were determined for 1322 positive individuals, with 27.1% of those which reported their symptom status reporting no symptoms in the previous month.Results: We identified 44 unique lineages, all of which were Delta or Delta sub-lineages, and found a reduction in their mutation rate over the study period. The proportion of the Delta sub-lineage AY.4.2 was increasing, with a reproduction number 15% (95% CI, 8%-23%) greater than the most prevalent lineage, AY.4. Further, AY.4.2 was less associated with the most predictive COVID-19 symptoms (p = 0.029) and had a reduced mutation rate (p = 0.050). Both AY.4.2 and AY.4 were found to be geographically clustered in September but this was no longer the case by late October/early November, with only the lineage AY.6 exhibiting clustering towards the South of England.Conclusions: As SARS-CoV-2 moves towards endemicity and new variants emerge, genomic data obtained from random community samples can augment routine surveillance data without the potential biases introduced due to higher sampling rates of symptomatic individuals.
Wong N, Meshkinfamfard S, Turbé V, et al., 2022, Machine learning to support visual auditing of home-based lateral flow immunoassay self-test results for SARS-CoV-2 antibodies, Communications Medicine, Vol: 2, ISSN: 2730-664X
Lateral flow immunoassays (LFIAs) are being used worldwide for COVID-19 mass testing and antibody prevalence studies. Relatively simple to use and low cost, these tests can be self-administered at home but rely on subjective interpretation of a test line by eye, risking false positives and negatives. Here we report the development of ALFA (Automated Lateral Flow Analysis) to improve reported sensitivity and specificity. Our computational pipeline uses machine learning, computer vision techniques and signal processing algorithms to analyse images of the Fortress LFIA SARS-CoV-2 antibody self-test, and subsequently classify results as invalid, IgG negative and IgG positive. A large image library of 595,339 participant-submitted test photographs was created as part of the REACT-2 community SARS-CoV-2 antibody prevalence study in England, UK. Automated analysis showed substantial agreement with human experts (Kappa 0.90-0.97) and performed consistently better than study participants, particularly for weak positive IgG results. Specificity (98.7-99.4%) and sensitivity (90.1-97.1%) were high compared with visual interpretation by human experts (ranges due to the varying prevalence of weak positive IgG tests in datasets). Alongside ALFA, we developed an analysis toolkit which could also detect device blood leakage issues. Given the potential for LFIAs to be used at scale in the COVID-19 response (for both antibody and antigen testing), even a small improvement in the accuracy of the algorithms could impact the lives of millions of people by reducing the risk of false positive and false negative result read-outs by members of the public. Our findings support the use of machine learning-enabled automated reading of at-home antibody lateral flow tests, to be a tool for improved accuracy for population-level community surveillance.
Said S, Pazoki R, Karhunen V, et al., 2022, Genetic analysis of over half a million people characterises C-reactive protein loci (vol 13, 2198, 2022), Nature Communications, Vol: 13, Pages: 1-1, ISSN: 2041-1723
Chan Q, Wren G, Lau CH, et al., 2022, Blood pressure interactions with the DASH dietary pattern, sodium, and potassium: The International Study of Macro-/Micronutrients and Blood Pressure (INTERMAP), The American Journal of Clinical Nutrition, Vol: 116, Pages: 216-229, ISSN: 1938-3207
BackgroundAdherence to the Dietary Approaches to Stop Hypertension (DASH) diet enhances potassium intake and reduces sodium intake and blood pressure (BP), but the underlying metabolic pathways are unclear.ObjectiveAmong free-living populations, delineate metabolic signatures associated with the DASH diet adherence, 24-hr urinary sodium and potassium excretions and the potential metabolic pathways involved.Design24-hr urinary metabolic profiling by proton nuclear magnetic resonance spectroscopy was used to characterize the metabolic signatures associated with the DASH dietary pattern score (DASH score) and 24-hr excretion of sodium and potassium among participants in the United States (n=2,164) and United Kingdom (n= 496) enrolled in the International Study of Macro- and Micronutrients and Blood Pressure (INTERMAP). Multiple linear regression and cross-tabulation analyses were used to investigate the DASH-BP relation and its modulation by sodium and potassium. Potential pathways associated with DASH adherence, sodium and potassium excretion, and BP were identified using mediation analyses and metabolic reaction networks.ResultsAdherence to DASH diet was associated with urinary potassium excretion (correlation coefficient, r = 0.42, P<0.0001). In multivariable regression analyses, a five-point higher DASH score (range 7 to 35) was associated with a lower systolic BP by 1.35 mmHg (95% confidence interval: -1.95, -0.80, P=1.2 × 10−5); control of the model for potassium but not sodium attenuated the DASH-BP relation. Two common metabolites (hippurate and citrate) mediated the potassium-BP and DASH-BP relationships, while five metabolites (succinate, alanine, S-methyl cysteine sulfoxide, 4-hydroxyhippurate, phenylacetylglutamine) were found specific to the DASH-BP relation.ConclusionsGreater adherence to DASH diet is associated with lower BP and higher potassium intake across levels of sodium intake. The DASH diet recommends greater intake of fruits, veget
Winkler TW, Rasheed H, Teumer A, et al., 2022, Differential and shared genetic effects on kidney function between diabetic and non-diabetic individuals, Communications Biology, Vol: 5, ISSN: 2399-3642
Reduced glomerular filtration rate (GFR) can progress to kidney failure. Risk factors include genetics and diabetes mellitus (DM), but little is known about their interaction. We conducted genome-wide association meta-analyses for estimated GFR based on serum creatinine (eGFR), separately for individuals with or without DM (nDM = 178,691, nnoDM = 1,296,113). Our genome-wide searches identified (i) seven eGFR loci with significant DM/noDM-difference, (ii) four additional novel loci with suggestive difference and (iii) 28 further novel loci (including CUBN) by allowing for potential difference. GWAS on eGFR among DM individuals identified 2 known and 27 potentially responsible loci for diabetic kidney disease. Gene prioritization highlighted 18 genes that may inform reno-protective drug development. We highlight the existence of DM-only and noDM-only effects, which can inform about the target group, if respective genes are advanced as drug targets. Largely shared effects suggest that most drug interventions to alter eGFR should be effective in DM and noDM.
Eales O, Wang H, Haw D, et al., 2022, Trends in SARS-CoV-2 infection prevalence during England’s roadmap out of lockdown, January to July 2021
<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Following rapidly rising COVID-19 case numbers, England entered a national lockdown on 6 January 2021, with staged relaxations of restrictions from 8 March 2021 onwards.</jats:p></jats:sec><jats:sec><jats:title>Aim</jats:title><jats:p>We characterise how the lockdown and subsequent easing of restrictions affected trends in SARS-CoV-2 infection prevalence.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>On average, risk of infection is proportional to infection prevalence. The REal-time Assessment of Community Transmission-1 (REACT-1) study is a repeat cross-sectional study of over 98,000 people every round (rounds approximately monthly) that estimates infection prevalence in England. We used Bayesian P-splines to estimate prevalence and the time-varying reproduction number (<jats:italic>R</jats:italic><jats:sub><jats:italic>t</jats:italic></jats:sub>) nationally, regionally and by age group from round 8 (beginning 6 January 2021) to round 13 (ending 12 July 2021) of REACT-1. As a comparator, a separate segmented-exponential model was used to quantify the impact on <jats:italic>R</jats:italic><jats:sub><jats:italic>t</jats:italic></jats:sub> of each relaxation of restrictions.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Following an initial plateau of 1.54% until mid-January, infection prevalence decreased until 13 May when it reached a minimum of 0.09%, before increasing until the end of the study to 0.76%. Following the first easing of restrictions, which included schools reopening, the reproduction number <jats:italic>R</jats:italic><jats:sub><jats:italic>t</jats:italic></jats:sub> incre
Chadeau M, Eales O, Bodinier B, et al., 2022, Breakthrough SARS-CoV-2 infections in double and triple vaccinated adults and single dose vaccine effectiveness among children in Autumn 2021 in England: REACT-1 study, EClinicalMedicine, Vol: 48, Pages: 1-14, ISSN: 2589-5370
Background: Prevalence of SARS-CoV-2 infection with Delta variant was increasing in England in late summer 2021 among children aged 5 to 17 years, and adults who had received two vaccine doses. In September 2021, a third (booster) dose was offered to vaccinated adults aged 50 years and over, vulnerable adults and healthcare/care-home workers, and a single vaccine dose already offered to 16 and 17 year-olds was extended to children aged 12 to 15 years. Methods: SARS-CoV-2 community prevalence in England was available from self-administered throat and nose swabs using reverse transcriptase polymerase chain reaction (RT-PCR) in round 13 (24 June to 12 July 2021, N= 98,233), round 14 (9 to 27 September 2021, N = 100,527) and round 15 (19 October to 5 November 2021, N = 100,112) from the REACT-1 study randomised community surveys. Linking to National Health Service (NHS) vaccination data for consenting participants, we estimated vaccine effectiveness in children aged 12 to 17 years and compared swab-positivity rates in adults who received a third dose with those who received two doses. Findings: Weighted SARS-CoV-2 prevalence was 1.57% (1.48%, 1.66%) in round 15 compared with 0.83% (0.76%, 0.89%) in round 14, and the previously observed link between infections and hospitalisations and deaths had weakened. Vaccine effectiveness against infection in children aged 12 to 17 years was estimated (round 15) at 64.0% (50.9%, 70.6%) and 67.7% (53.8%, 77.5%) for symptomatic infections. Adults who received a third vaccine dose were less likely to test positive compared to those who received two doses, with adjusted odds ratio of 0.36 (0.25, 0.53). Interpretation: Vaccination of children aged 12 to 17 years and third (booster) doses in adults were effective at reducing infection risk. High rates of vaccination, including booster doses, are a key part of the strategy to reduce infection rates in the community.
Kaura A, Samuel NA, Roddick A, et al., 2022, PROGNOSTIC SIGNIFICANCE OF TROPONIN IN PATIENTS WITH MALIGNANCY (NIHR HEALTH INFORMATICS COLLABORATIVE TROP-MALIGNANCY STUDY), Annual Conference of the British-Cardiovascular-Society - 100 Years of Cardiology, Publisher: BMJ PUBLISHING GROUP, Pages: A135-A135, ISSN: 1355-6037
Kaura A, Roddick A, Samuel NA, et al., 2022, ASSOCIATION BETWEEN TROPONIN AND MORTALITY IN ACUTE STROKE (NIHR HEALTH INFORMATICS COLLABORATIVE TROP-STROKE STUDY), Annual Conference of the British-Cardiovascular-Society - 100 Years of Cardiology, Publisher: BMJ PUBLISHING GROUP, Pages: A129-A130, ISSN: 1355-6037
Kaura A, Sterne JAC, Trickey A, et al., 2022, DEVELOPING INFORMATICS INFRASTRUCTURE TO CURATE DATASETS USING ELECTRONIC HEALTH RECORD DATA FROM FIVE NHS HOSPITALS FOR TRANSLATIONAL CARDIOVASCULAR RESEARCH, Publisher: BMJ PUBLISHING GROUP, Pages: A27-A28, ISSN: 1355-6037
Kaura A, Goswami S, Benedetto U, et al., 2022, ASSOCIATION BETWEEN AGE, TROPONIN LEVEL AND MORTALITY IN PATIENTS PRESENTING TO HOSPITAL WITH ACUTE PULMONARY EMBOLISM (NIHR HEALTH INFORMATICS COLLABORATIVE TROP-PE STUDY), Annual Conference of the British-Cardiovascular-Society - 100 Years of Cardiology, Publisher: BMJ PUBLISHING GROUP, Pages: A129-A129, ISSN: 1355-6037
This data is extracted from the Web of Science and reproduced under a licence from Thomson Reuters. You may not copy or re-distribute this data in whole or in part without the written consent of the Science business of Thomson Reuters.