Publications by authors named "Liam Smeeth"

534 Publications

Risk of acute respiratory infection and acute cardiovascular events following acute respiratory infection among adults with increased cardiovascular risk in England between 2008 and 2018: a retrospective, population-based cohort study.

Lancet Digit Health 2021 Dec;3(12):e773-e783

Department of Non-Communicable Disease Epidemiology, London School of Hygiene & Tropical Medicine, London, UK.

Background: Although acute respiratory infections can lead to cardiovascular complications, the effect of underlying cardiovascular risk on the incidence of acute respiratory infections and cardiovascular complications following acute respiratory infection in individuals without established cardiovascular disease is unknown. We aimed to investigate whether cardiovascular risk is associated with increased risk of acute respiratory infection and acute cardiovascular events after acute respiratory infection using 10 years of linked electronic health record (EHR) data in England.

Methods: In this retrospective, population-based cohort study we used EHRs from primary care providers registered on the Clinical Practice Research Datalink (CPRD) GOLD and Aurum databases in England. Eligible individuals were aged 40-64 years, did not have established cardiovascular disease or a chronic health condition that would make them eligible for influenza vaccination, were registered at a general practice contributing to the CPRD, and had linked Hospital Episode Statistics Admitted Patient Care data in England from Sept 1, 2008, to Aug 31, 2018. We classified cardiovascular risk on the basis of diagnosed hypertension and overall predicted cardiovascular risk, estimated by use of the QRISK2 risk-prediction tool (comparing a score of ≥10% [increased risk] with a score of <10% [low risk]). Using multivariable Poisson regression models, we calculated incidence rate ratios (IRRs) for systemic acute respiratory infection. Among individuals who had an acute respiratory infection, we used multivariable Cox regression to calculate hazard ratios (HRs) for the risk of acute cardiovascular events within 1 year of infection.

Findings: We identified 6 075 321 individuals aged 40-64 years with data in the CPRD and linked data in the Hospital Episode Statistics Admitted Patient Care database between Sept 1, 2008, and Aug 31, 2018. Of these individuals, 4 212 930 (including 526 480 [12·5%] with hypertension and 607 087 [14·4%] with a QRISK2 score of ≥10%) were included in the assessment of the incidence of acute respiratory infection. After adjusting for confounders (age, sex, ethnicity, socioeconomic status, body-mass index, alcohol consumption, smoking status, and consultation frequency in the hypertension analysis; and alcohol consumption and consultation frequency in the QRISK2 analysis), the incidence of acute respiratory infection was higher in individuals with hypertension than those without (IRR 1·04 [95% CI 1·03-1·05]) and higher in those with a QRISK2 score of 10% or higher than in those with a QRISK2 score of less than 10% (1·39 [1·37-1·40]). Of the 442 408 individuals who had an acute respiratory infection, 4196 (0·9%) had an acute cardiovascular event within 1 year of infection. After adjustment (for age, sex, ethnicity, socioeconomic status, body-mass index, alcohol consumption, and smoking status in the hypertension analysis; and for alcohol consumption in the QRISK2 analysis), hypertension (HR 1·98 [95% CI 1·83-2·15]) and a QRISK2 score of 10% or higher (3·65 [3·42-3·89]) were associated with a substantially increased risk of acute cardiovascular events after acute respiratory infection.

Interpretation: People with increased cardiovascular risk but without diagnosed cardiovascular disease, measured by diagnosed hypertension or overall predicted cardiovascular risk, could benefit from influenza and pneumococcal vaccine prioritisation to reduce their risk of both acute respiratory infection and cardiovascular complications following an acute respiratory infection.

Funding: British Heart Foundation and the Wellcome Trust.
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http://dx.doi.org/10.1016/S2589-7500(21)00203-XDOI Listing
December 2021

Risk of mortality for small newborns in Brazil, 2011-2018: A national birth cohort study of 17.6 million records from routine register-based linked data.

Lancet Reg Health Am 2021 Nov;3:None

Maternal, Adolescent, Reproductive & Child Health (MARCH) Centre, London School of Hygiene & Tropical Medicine, London WC1E 7HT, UK.

Background: Preterm birth (<37 weeks), low birth weight (LBW,<2500g), and small for gestational age (SGA,<10th centile of birth weight for gestational age and sex) are markers of newborn vulnerability with a high risk of mortality. We estimated the prevalence of phenotypes combining these three markers and quantified the mortality risk associated with them.

Methods: Population-based cohort study using routine register-based linked data on all births and deaths in Brazil from January 1, 2011, to December 31, 2018. We estimated the prevalence of preterm, LBW, and SGA individually and for phenotypes combining these characteristics. The mortality risk associated with each phenotype: early neonatal, late neonatal, neonatal, post-neonatal, infant, 1-4 years, and under five years was quantified using mortality rates and hazard ratios (HRs) with 95% confidence interval (CI) were estimated using Cox proportional hazard models.

Findings: 17,646,115 live births were included. Prevalence of preterm birth, LBW and SGA were 9.4%, 9.6% and 9.2%, respectively. Neonatal mortality risk was 16-fold (HR=15.9; 95% CI:15.7-16.1) higher for preterm compared to term, 3 times higher (HR=3.4; (95% CI:3.3-3.4) for SGA compared to adequate for gestational age (AGA), and >25 times higher for LBW (HR=25.8; (95% CI:25.5-26.1) compared to normal birth weight (NBW). 18% of all live births were included in one of the small vulnerable newborn phenotypes. Of those 8.2% were term-SGA (4.7%NBW, 3.5%LBW), 0.6% were term-AGA-LBW, 8.3% preterm-AGA (3.8%NBW, 4.5%LBW) and 1.0% preterm-SGA-LBW. Compared to term-AGA-NBW, the highest mortality risk was for preterm-LBW phenotypes (HR=36.2(95%CI 35.6-36.8) preterm-AGA-LBW, HR=62.0(95%CI 60.8-63.2) preterm-SGA-LBW). The increased mortality risk associated with vulnerable newborn phenotypes was highest in the first month of life, with attenuated but continued high risk in the post-neonatal period and 1-4 years of age.

Interpretation: Our findings support the value of using more detailed phenotypes to identify those at highest risk. More granular data can inform care at the individual level, advance research, especially for prevention, and accelerate progress towards global targets such as the Sustainable Development Goals.

Funding: Wellcome Trust.
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http://dx.doi.org/10.1016/j.lana.2021.100045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8591743PMC
November 2021

OpenSAFELY: impact of national guidance on switching anticoagulant therapy during COVID-19 pandemic.

Open Heart 2021 11;8(2)

Department of Non-communicable Disease Epidemiology, London School of Hygiene & Tropical Medicine, London, UK.

Background: Early in the COVID-19 pandemic, the National Health Service (NHS) recommended that appropriate patients anticoagulated with warfarin should be switched to direct-acting oral anticoagulants (DOACs), requiring less frequent blood testing. Subsequently, a national safety alert was issued regarding patients being inappropriately coprescribed two anticoagulants following a medication change and associated monitoring.

Objective: To describe which people were switched from warfarin to DOACs; identify potentially unsafe coprescribing of anticoagulants; and assess whether abnormal clotting results have become more frequent during the pandemic.

Methods: With the approval of NHS England, we conducted a cohort study using routine clinical data from 24 million NHS patients in England.

Results: 20 000 of 164 000 warfarin patients (12.2%) switched to DOACs between March and May 2020, most commonly to edoxaban and apixaban. Factors associated with switching included: older age, recent renal function test, higher number of recent INR tests recorded, atrial fibrillation diagnosis and care home residency. There was a sharp rise in coprescribing of warfarin and DOACs from typically 50-100 per month to 246 in April 2020, 0.06% of all people receiving a DOAC or warfarin. International normalised ratio (INR) testing fell by 14% to 506.8 patients tested per 1000 warfarin patients each month. We observed a very small increase in elevated INRs (n=470) during April compared with January (n=420).

Conclusions: Increased switching of anticoagulants from warfarin to DOACs was observed at the outset of the COVID-19 pandemic in England following national guidance. There was a small but substantial number of people coprescribed warfarin and DOACs during this period. Despite a national safety alert on the issue, a widespread rise in elevated INR test results was not found. Primary care has responded rapidly to changes in patient care during the COVID-19 pandemic.
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http://dx.doi.org/10.1136/openhrt-2021-001784DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8595296PMC
November 2021

Trends and clinical characteristics of 57.9 million COVID-19 vaccine recipients: a federated analysis of patients' primary care records using OpenSAFELY.

Br J Gen Pract 2021 Sep 24. Epub 2021 Sep 24.

London School of Hygiene and Tropical Medicine, London.

Background: On 8 December 2020 NHS England administered the first COVID-19 vaccination.

Aim: To describe trends and variation in vaccine coverage in different clinical and demographic groups in the first 100 days of the vaccine rollout.

Design And Setting: With the approval of NHS England, a cohort study was conducted of 57.9 million patient records in general practice in England, and within the infrastructure of the electronic health record software vendors EMIS and TPP using OpenSAFELY.

Method: Vaccine coverage across various subgroups of Joint Committee on Vaccination and Immunisation (JCVI) priority cohorts is described.

Results: A total of 20 852 692 patients (36.0%) received a vaccine between 8 December 2020 and 17 March 2021. Of patients aged ≥80 years not in a care home (JCVI group 2) 94.7% received a vaccine, but with substantial variation by ethnicity (White 96.2%, Black 68.3%) and deprivation (least deprived 96.6%, most deprived 90.7%). Patients with pre-existing medical conditions were more likely to be vaccinated with two exceptions: severe mental illness (89.5%) and learning disability (91.4%). There were 275 205 vaccine recipients who were identified as care home residents (JCVI group 1; 91.2% coverage). By 17 March, 1 257 914 (6.0%) recipients had a second dose.

Conclusion: The NHS rapidly delivered mass vaccination. In this study a data-monitoring framework was deployed using publicly auditable methods and a secure processing model, using linked but pseudonymised patient-level NHS data for 57.9 million patients. Targeted activity may be needed to address lower vaccination coverage observed among certain key groups.
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http://dx.doi.org/10.3399/BJGP.2021.0376DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8589463PMC
September 2021

OpenSAFELY NHS Service Restoration Observatory 1: primary care clinical activity in England during the first wave of COVID-19.

Br J Gen Pract 2021 Sep 24. Epub 2021 Sep 24.

London School of Hygiene and Tropical Medicine, London.

Background: The COVID-19 pandemic has disrupted healthcare activity. The NHS stopped non-urgent work in March 2020, later recommending services be restored to near-normal levels before winter where possible.

Aim: To describe the volume and variation of coded clinical activity in general practice, taking respiratory disease and laboratory procedures as examples.

Design And Setting: Working on behalf of NHS England, a cohort study was conducted of 23.8 million patient records in general practice, using OpenSAFELY.

Method: Activity using Clinical Terms Version 3 codes and keyword searches from January 2019 to September 2020 are described.

Results: Activity recorded in general practice declined during the pandemic, but largely recovered by September. There was a large drop in coded activity for laboratory tests, with broad recovery to pre-pandemic levels by September. One exception was the international normalised ratio test, with a smaller reduction (median tests per 1000 patients in 2020: February 8.0; April 6.2; September 6.9). The pattern of recording for respiratory symptoms was less affected, following an expected seasonal pattern and classified as 'no change'. Respiratory infections exhibited a sustained drop, not returning to pre-pandemic levels by September. Asthma reviews experienced a small drop but recovered, whereas chronic obstructive pulmonary disease reviews remained below baseline.

Conclusion: An open-source software framework was delivered to describe trends and variation in clinical activity across an unprecedented scale of primary care data. The COVD-19 pandemic led to a substantial change in healthcare activity. Most laboratory tests showed substantial reduction, largely recovering to near-normal levels by September, with some important tests less affected and recording of respiratory disease codes was mixed.
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http://dx.doi.org/10.3399/BJGP.2021.0380DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8589464PMC
September 2021

Type 2 diabetes risks and determinants in second-generation migrants and mixed ethnicity people of South Asian and African Caribbean descent in the UK.

Diabetologia 2021 Oct 20. Epub 2021 Oct 20.

MRC Unit for Lifelong Health and Ageing, Institute of Cardiovascular Science, University College London, London, UK.

Aims/hypothesis: Excess risks of type 2 diabetes in UK South Asians (SA) and African Caribbeans (AC) compared with Europeans remain unexplained. We studied risks and determinants of type 2 diabetes in first- and second-generation (born in the UK) migrants, and in those of mixed ethnicity.

Methods: Data from the UK Biobank, a population-based cohort of ~500,000 participants aged 40-69 at recruitment, were used. Type 2 diabetes was assigned using self-report and HbA. Ethnicity was both self-reported and genetically assigned using admixture level scores. European, mixed European/South Asian (MixESA), mixed European/African Caribbean (MixEAC), SA and AC groups were analysed, matched for age and sex to enable comparison. In the frames of this cross-sectional study, we compared type 2 diabetes in second- vs first-generation migrants, and mixed ethnicity vs non-mixed groups. Risks and explanations were analysed using logistic regression and mediation analysis, respectively.

Results: Type 2 diabetes prevalence was markedly elevated in SA (599/3317 = 18%) and AC (534/4180 = 13%) compared with Europeans (140/3324 = 4%). Prevalence was lower in second- vs first-generation SA (124/1115 = 11% vs 155/1115 = 14%) and AC (163/2200 = 7% vs 227/2200 = 10%). Favourable adiposity (i.e. lower waist/hip ratio or BMI) contributed to lower risk in second-generation migrants. Type 2 diabetes in mixed populations (MixESA: 52/831 = 6%, MixEAC: 70/1045 = 7%) was lower than in comparator ethnic groups (SA: 18%, AC: 13%) and higher than in Europeans (4%). Greater socioeconomic deprivation accounted for 17% and 42% of the excess type 2 diabetes risk in MixESA and MixEAC compared with Europeans, respectively. Replacing self-reported with genetically assigned ethnicity corroborated the mixed ethnicity analysis.

Conclusions/interpretation: Type 2 diabetes risks in second-generation SA and AC migrants are a fifth lower than in first-generation migrants. Mixed ethnicity risks were markedly lower than SA and AC groups, though remaining higher than in Europeans. Distribution of environmental risk factors, largely obesity and socioeconomic status, appears to play a key role in accounting for ethnic differences in type 2 diabetes risk.
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http://dx.doi.org/10.1007/s00125-021-05580-7DOI Listing
October 2021

Association between warfarin and COVID-19-related outcomes compared with direct oral anticoagulants: population-based cohort study.

J Hematol Oncol 2021 10 19;14(1):172. Epub 2021 Oct 19.

The DataLab, Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK.

Background: Thromboembolism has been reported as a consequence of severe COVID-19. Although warfarin is a commonly used anticoagulant, it acts by antagonising vitamin K, which is low in patients with severe COVID-19. To date, the clinical evidence on the impact of regular use of warfarin on COVID-19-related thromboembolism is lacking.

Methods: On behalf of NHS England, we conducted a population-based cohort study investigating the association between warfarin and COVID-19 outcomes compared with direct oral anticoagulants (DOACs). We used the OpenSAFELY platform to analyse primary care data and pseudonymously linked SARS-CoV-2 antigen testing data, hospital admissions and death records from England. We used Cox regression to estimate hazard ratios (HRs) for COVID-19-related outcomes comparing warfarin with DOACs in people with non-valvular atrial fibrillation. We also conducted negative control outcome analyses (being tested for SARS-CoV-2 and non-COVID-19 death) to assess the potential impact of confounding.

Results: A total of 92,339 warfarin users and 280,407 DOAC users were included. We observed a lower risk of all outcomes associated with warfarin versus DOACs [testing positive for SARS-CoV-2, HR 0.73 (95% CI 0.68-0.79); COVID-19-related hospital admission, HR 0.75 (95% CI 0.68-0.83); COVID-19-related deaths, HR 0.74 (95% CI 0.66-0.83)]. A lower risk of negative control outcomes associated with warfarin versus DOACs was also observed [being tested for SARS-CoV-2, HR 0.80 (95% CI 0.79-0.81); non-COVID-19 deaths, HR 0.79 (95% CI 0.76-0.83)].

Conclusions: Overall, this study shows no evidence of harmful effects of warfarin on severe COVID-19 disease.
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http://dx.doi.org/10.1186/s13045-021-01185-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8525065PMC
October 2021

Anticoagulant prescribing for atrial fibrillation and risk of incident dementia.

Heart 2021 12 13;107(23):1898-1904. Epub 2021 Oct 13.

Department of Non-communicable Disease Epidemiology, London School of Hygiene & Tropical Medicine, London, UK

Objective: The aim of this study was to investigate the association between oral anticoagulant type (direct oral anticoagulants (DOACs) vs vitamin K antagonists (VKAs)) and incident dementia or mild cognitive impairment (MCI) among patients with newly diagnosed atrial fibrillation (AF).

Methods: Using linked electronic health record (EHR) data from the Clinical Practice Research Datalink in the UK, we conducted a historical cohort study among first-time oral anticoagulant users with incident non-valvular AF diagnosed from 2012 to 2018. We compared the incidence of (1) clinically coded dementia and (2) MCI between patients prescribed VKAs and DOACs using Cox proportional hazards regression models, with age as the underlying timescale, accounting for calendar time and time on treatment, sociodemographic and lifestyle factors, clinical comorbidities and medications.

Results: Of 39 200 first-time oral anticoagulant users (44.6% female, median age 76 years, IQR 68-83), 20 687 (53%) were prescribed a VKA and 18 513 (47%) a DOAC at baseline. Overall, 1258 patients (3.2%) had GP-recorded incident dementia, incidence rate 16.5 per 1000 person-years. DOAC treatment for AF was associated with a 16% reduction in dementia diagnosis compared with VKA treatment in the whole cohort (adjusted HR 0.84, 95% CI: 0.73 to 0.98) and with a 26% reduction in incident MCI (adjusted HR 0.74, 95% CI: 0.65 to 0.84). Findings were similar across various sensitivity analyses.

Conclusions: Incident EHR-recorded dementia and MCI were less common among patients prescribed DOACs for new AF compared with those prescribed VKAs.
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http://dx.doi.org/10.1136/heartjnl-2021-319672DOI Listing
December 2021

Associations between cesarean delivery and child mortality: A national record linkage longitudinal study of 17.8 million births in Brazil.

PLoS Med 2021 Oct 12;18(10):e1003791. Epub 2021 Oct 12.

Infectious Disease Department, Faculty of Epidemiology and Population Health, London School of Hygiene & Tropical Medicine, London, United Kingdom.

Background: There is an increasing use of cesarean delivery (CD) based on preference rather than on medical indication. However, the extent to which nonmedically indicated CD benefits or harms child survival remains unclear. Our hypothesis was that in groups with a low indication for CD, this procedure would be associated with higher child mortality and in groups with a clear medical indication CD would be associated with improved child survival chances.

Methods And Findings: We conducted a population-based cohort study in Brazil by linking routine data on live births between January 1, 2012 and December 31, 2018 and assessing mortality up to 5 years of age. Women with a live birth who contributed records during this period were classified into one of 10 Robson groups based on their pregnancy and delivery characteristics. We used propensity scores to match CD with vaginal deliveries (1:1) and prelabor CD with unscheduled CD (1:1) and estimated associations with child mortality using Cox regressions. A total of 17,838,115 live births were analyzed. After propensity score matching (PSM), we found that live births to women in groups with low expected frequencies of CD (Robson groups 1 to 4) had a higher death rate up to age 5 years if they were born via CD compared with vaginal deliveries (HR = 1.25, 95% CI: 1.22 to 1.28; p < 0.001). The relative rate was greatest in the neonatal period (HR = 1.39, 95% CI: 1.34 to 1.45; p < 0.001). There was no difference in mortality rate when comparing offspring born by a prelabor CD to those born by unscheduled CD. For the live births to women with a CD in a prior pregnancy (Robson group 5), the relative rates for child mortality were similar for those born by CD compared with vaginal deliveries (HR = 1.05, 95% CI: 1.00 to 1.10; p = 0.024). In contrast, for live births to women in groups with high expected rates of CD (Robson groups 6 to 10), the child mortality rate was lower for CD than for vaginal deliveries (HR = 0.90, 95% CI: 0.89 to 0.91; p < 0.001), particularly in the neonatal period (HR = 0.84, 95% CI: 0.83 to 0.85; p < 0.001). Our results should be interpreted with caution in clinical practice, since relevant clinical data on CD indication were not available.

Conclusions: In this study, we observed that in Robson groups with low expected frequencies of CD, this procedure was associated with a 25% increase in child mortality. However, in groups with high expected frequencies of CD, the findings suggest that clinically indicated CD is associated with a reduction in child mortality.
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http://dx.doi.org/10.1371/journal.pmed.1003791DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8509988PMC
October 2021

Protocol for an observational cohort study investigating personalised medicine for intensification of treatment in people with type 2 diabetes mellitus: the PERMIT study.

BMJ Open 2021 09 27;11(9):e046912. Epub 2021 Sep 27.

Department of Health Services Research and Policy, London School of Hygiene and Tropical Medicine, London, UK.

Introduction: For people with type 2 diabetes mellitus (T2DM) who require an antidiabetic drug as an add-on to metformin, there is controversy about whether newer drug classes such as dipeptidyl peptidase-4 inhibitors (DPP4i) or sodium-glucose co-transporter-2 inhibitors (SGLT2i) reduce the risk of long-term complications compared with sulfonylureas (SU). There is widespread variation across National Health Service Clinical Commissioning Groups (CCGs) in drug choice for second-line treatment in part because National Institute for Health and Care Excellence guidelines do not specify a single preferred drug class, either overall or within specific patient subgroups. This study will evaluate the relative effectiveness of the three most common second-line treatments in the UK (SU, DPP4i and SGLT2i as add-ons to metformin) and help target treatments according to individual risk profiles.

Methods And Analysis: The study includes people with T2DM prescribed one of the second-line treatments-of-interest between 2014 and 2020 within the UK Clinical Practice Research Datalink linked with Hospital Episode Statistics and Office of National Statistics. We will use an instrumental variable (IV) method to estimate short-term and long-term relative effectiveness of second-line treatments according to individuals' risk profiles. This method minimises bias from unmeasured confounders by exploiting the natural variation in second-line prescribing across CCGs as an IV for the choice of prescribed treatment. The primary outcome to assess short-term effectiveness will be change in haemoglobin A1c (%) 12 months after treatment initiation. Outcome measures to assess longer-term effectiveness (maximum ~6 years) will include microvascular and macrovascular complications, all-cause mortality and hospital admissions during follow-up.

Ethics And Dissemination: This study was approved by the Independent Scientific Advisory Committee (20-064) and the London School of Hygiene & Tropical Medicine Research Ethics Committee (21395). Results, codelists and other analysis code will be made available to patients, clinicians, policy-makers and researchers.
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http://dx.doi.org/10.1136/bmjopen-2020-046912DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8477338PMC
September 2021

Atopic Eczema-Associated Fracture Risk and Oral Corticosteroids: A Population-Based Cohort Study.

J Allergy Clin Immunol Pract 2021 Sep 24. Epub 2021 Sep 24.

Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK; Health Data Research UK, London, UK.

Background: Evidence suggests adults with atopic eczema have increased fracture risk. However, it is unclear whether oral corticosteroids explain the association.

Objective: To assess to what extent oral corticosteroids mediate the relationship between atopic eczema and fractures.

Methods: We conducted a cohort study using English primary care (Clinical Practice Research Datalink) and hospital admissions (Hospital Episode Statistics) records (1998-2016) including adults (18 years old and older) with atopic eczema matched (age, sex, and general practice) with up to 5 adults without atopic eczema. We used Cox regression to estimate hazard ratios (HRs) for specific major osteoporotic fractures (hip, spine, pelvis, or wrist) and for any-site fracture comparing individuals with atopic eczema with those without, adjusting for 6 different definitions of time-updated oral corticosteroid use (ever any prescription, ever high-dose, and recent, cumulative, current, or peak dose).

Results: We identified 526,808 individuals with atopic eczema and 2,569,030 without. We saw evidence of an association between atopic eczema and major osteoporotic fractures (eg, spine HR 1.15, 99% CI 1.08-1.22; hip HR 1.11, 99% CI 1.08-1.15) that remained after additionally adjusting for oral corticosteroids (eg, cumulative corticosteroid dose: spine HR 1.09, 99% CI 1.03-1.16; hip HR 1.09, 99% CI 1.06-1.12). Fracture rates were higher in people with severe atopic eczema than in people without even after adjusting for oral corticosteroids (eg, spine HR [99% CI]: confounder-adjusted 2.31 [1.91-2.81]; additionally adjusted for cumulative dose 1.71 [1.40-2.09]).

Conclusions: Our findings suggest that little of the association between atopic eczema and major osteoporotic fractures is explained by oral corticosteroid use.
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http://dx.doi.org/10.1016/j.jaip.2021.09.026DOI Listing
September 2021

Carbohydrate-dense snacks are a key feature of the nutrition transition among Ghanaian adults - findings from the RODAM study.

Food Nutr Res 2021 6;65. Epub 2021 May 6.

Department of Molecular Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany.

Background: African populations in sub-Saharan Africa and African migrants in Europe are facing a rapid upsurge in obesity. This trend has been related to urbanization, migration and associated shifts in lifestyle, including dietary habits. Whether changes in eating patterns contribute to the rising burden of obesity among African populations is currently unknown.

Objective: Our aims in conducting this study were to characterize eating patterns among Ghanaian adults living in their country of origin and in Europe and to explore associations of meal patterns with body mass index (BMI).

Design: Within the cross-sectional RODAM (Research on Obesity and Diabetes among African Migrants) study, data of single 24-h dietary recalls from Ghanaian adults in rural Ghana ( = 20), urban Ghana ( = 42), and Europe ( = 172) were recorded. Eating frequencies, energy intake, and macronutrient composition of eating occasions (EOs, i.e. meals or snacks) were compared between study sites based on descriptive statistics and -/Kruskal-Wallis tests.

Results: A rising gradient of EO frequencies from rural Ghana through urban Ghana to Europe was observed, mainly reflecting the differences in snacking frequencies (≥1 snack per day: 20 vs. 48 vs. 52%, = 0.008). Meal frequencies were similar across study sites (≥3 meals per day: 30 vs. 33 vs. 38%, = 0.80). Meals were rich in carbohydrates (median 54.5, interquartile range (IQR): 43.2-64.0 energy%) and total fats (median: 27.0, IQR: 19.9-34.4 energy %); their protein content was lowest in rural Ghana, followed by urban Ghana and Europe ( = 0.0005). Snacks mainly contained carbohydrates (median: 75.7, IQR: 61.0-89.2 energy%). In linear regression analyses, there was a non-significant trend for an inverse association between snacking frequencies and BMI.

Discussion And Conclusions: The observed integration of carbohydrate-dense snacks into the diet supports the growing evidence for a nutrition transition among African populations undergoing socioeconomic development. This analysis constitutes a starting point to further investigate the nutritional implications of increased snacking frequencies on obesity and metabolic health in these African populations.
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http://dx.doi.org/10.29219/fnr.v65.5435DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8388941PMC
May 2021

Severity of SARS-CoV-2 alpha variant (B.1.1.7) in England.

Clin Infect Dis 2021 Sep 6. Epub 2021 Sep 6.

TPP, TPP House, 129 Low Lane, Horsforth, Leeds, UK.

Background: The SARS-CoV-2 alpha variant (B.1.1.7) is associated with higher transmissibility than wild type virus, becoming the dominant variant in England by January 2021. We aimed to describe the severity of the alpha variant in terms of the pathway of disease from testing positive to hospital admission and death.

Methods: With the approval of NHS England, we linked individual-level data from primary care with SARS-CoV-2 community testing, hospital admission, and ONS all-cause death data. We used testing data with S-gene target failure as a proxy for distinguishing alpha and wild-type cases, and stratified Cox proportional hazards regression to compare the relative severity of alpha cases compared to wild type diagnosed from 16th November 2020 to 11th January 2021.

Results: Using data from 185,234 people who tested positive for SARS-CoV-2 in the community (alpha=93,153; wild-type=92,081), in fully adjusted analysis accounting for individual-level demographics and comorbidities as well as regional variation in infection incidence, we found alpha associated with 73% higher hazards of all-cause death (aHR: 1.73 (95% CI 1.41 - 2.13; P<.0001)) and 62% higher hazards of hospital admission (aHR: 1.62 ((95% CI 1.48 - 1.78; P<.0001), compared to wild-type virus. Among patients already admitted to ICU, the association between alpha and increased all-cause mortality was smaller and the confidence interval included the null (aHR: 1.20 (95% CI 0.74 - 1.95; P=0.45)).

Conclusions: The SARS-CoV-2 alpha variant is associated with an increased risk of both hospitalisation and mortality than wild-type virus.
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http://dx.doi.org/10.1093/cid/ciab754DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8522415PMC
September 2021

Identifying Care Home Residents in Electronic Health Records - An OpenSAFELY Short Data Report.

Wellcome Open Res 2021 27;6:90. Epub 2021 Apr 27.

1 Electronic Health Records Research Group, Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, WC1E 7HT, UK.

Care home residents have been severely affected by the COVID-19 pandemic. Electronic Health Records (EHR) hold significant potential for studying the healthcare needs of this vulnerable population; however, identifying care home residents in EHR is not straightforward. We describe and compare three different methods for identifying care home residents in the newly created OpenSAFELY-TPP data analytics platform.  Working on behalf of NHS England, we identified individuals aged 65 years or older potentially living in a care home on the 1st of February 2020 using (1) a complex address linkage, in which cleaned GP registered addresses were matched to old age care home addresses using data from the Care and Quality Commission (CQC); (2) coded events in the EHR; (3) household identifiers, age and household size to identify households with more than 3 individuals aged 65 years or older as potential care home residents. Raw addresses were not available to the investigators. Of 4,437,286 individuals aged 65 years or older, 2.27% were identified as potential care home residents using the complex address linkage, 1.96% using coded events, 3.13% using household size and age and 3.74% using either of these methods. 53,210 individuals (32.0% of all potential care home residents) were classified as care home residents using all three methods. Address linkage had the largest overlap with the other methods; 93.3% of individuals identified as care home residents using the address linkage were also identified as such using either coded events or household age and size.  We have described the partial overlap between three methods for identifying care home residents in EHR, and provide detailed instructions for how to implement these in OpenSAFELY-TPP to support research into the impact of the COVID-19 pandemic on care home residents.
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http://dx.doi.org/10.12688/wellcomeopenres.16737.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8374378PMC
April 2021

Medications for chronic obstructive pulmonary disease: a historical non-interventional cohort study with validation against RCT results.

Health Technol Assess 2021 08;25(51):1-70

Department of Non-communicable Disease Epidemiology, Faculty of Epidemiology and Population Health, London School of Hygiene & Tropical Medicine, London, UK.

Background: Chronic obstructive pulmonary disease treatment is informed by randomised controlled trial results, but it is unclear if these findings apply to people excluded from these trials. We used data from the TORCH (TOwards a Revolution in COPD Health) randomised controlled trial to validate non-interventional methods for assessing the clinical effectiveness of chronic obstructive pulmonary disease treatment in the UK Clinical Practice Research Datalink, before applying these methods to the analysis of people who would have been excluded from TORCH.

Objectives: To validate the use of non-interventional Clinical Practice Research Datalink data and methods for estimating chronic obstructive pulmonary disease treatment effects against trial results, and, using validated methods, to determine treatment effects in people who would have been excluded from the TORCH trial.

Design: A historical non-interventional cohort design, including validation against randomised controlled trial results.

Setting: The UK Clinical Practice Research Datalink.

Participants: People aged ≥ 18 years with chronic obstructive pulmonary disease registered in Clinical Practice Research Datalink GOLD between January 2000 and January 2017. For objective 1, we prepared a cohort that was analogous to the TORCH trial cohort by applying TORCH trial inclusion/exclusion criteria followed by individual matching to TORCH trial participants. For objectives 2 and 3, we prepared cohorts that were analogous to the TORCH trial that, nevertheless, would not have been eligible for the TORCH trial because of age, asthma, comorbidity or mild disease.

Interventions: The long-acting beta-2 agonist and inhaled corticosteroid combination product Seretide (GlaxoSmithKline plc) [i.e. fluticasone propionate plus salmeterol (FP-SAL)] compared with (1) no FP-SAL exposure or (2) exposure to salmeterol (i.e. the long-acting beta-2 agonist) only.

Main Outcome Measures: Exacerbations, mortality, pneumonia and time to treatment change.

Results: For objective 1, the exacerbation rate ratio was comparable to that in the TORCH trial for FP-SAL compared with salmeterol (0.85, 95% confidence interval 0.74 to 0.97, vs. TORCH trial 0.88, 95% confidence interval 0.81 to 0.95), but not for FP-SAL compared with no FP-SAL (1.30, 95% confidence interval 1.19 to 1.42, vs. TORCH trial 0.75, 95% confidence interval 0.69 to 0.81). Active comparator results were also consistent with the TORCH trial for mortality (hazard ratio 0.93, 95% confidence interval 0.65 to 1.32, vs. TORCH trial hazard ratio 0.93, 95% confidence interval 0.77 to 1.13) and pneumonia (risk ratio 1.39, 95% confidence interval 1.04 to 1.87, vs. TORCH trial risk ratio 1.47, 95% confidence interval 1.25 to 1.73). For objectives 2 and 3, active comparator results were consistent with the TORCH trial for exacerbations, with the exception of people with milder chronic obstructive pulmonary disease, in whom we observed a stronger protective association (risk ratio 0.56, 95% confidence interval 0.46 to 0.70, vs. TORCH trial risk ratio 0.85, 95% confidence interval 0.74 to 0.97). For the analysis of mortality, we saw a lack of association with being prescribed FP-SAL (vs. being prescribed salmeterol), with the exception of those with prior asthma, for whom we observed an increase in mortality (hazard ratio 1.49, 95% confidence interval 1.21 to 1.85, vs. TORCH trial-analogous HR 0.93, 95% confidence interval 0.64 to 1.32).

Conclusions: Routinely collected electronic health record data can be used to successfully measure chronic obstructive pulmonary disease treatment effects when comparing two treatments, but not for comparisons between active treatment and no treatment. Analyses involving patients who would have been excluded from trials mostly suggests that treatment effects for FP-SAL are similar to trial effects, although further work is needed to characterise a small increased risk of death in those with concomitant asthma.

Limitations: Some of our analyses had small numbers.

Future Work: The differences in treatment effects that we found should be investigated further in other data sets. Currently recommended chronic obstructive pulmonary disease inhaled combination therapy (other than FP-SAL) should also be investigated using these methods.

Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in ; Vol. 25, No. 51. See the NIHR Journals Library website for further project information.
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http://dx.doi.org/10.3310/hta25510DOI Listing
August 2021

Using the Robson classification to assess caesarean section rates in Brazil: an observational study of more than 24 million births from 2011 to 2017.

BMC Pregnancy Childbirth 2021 Aug 30;21(1):589. Epub 2021 Aug 30.

Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, United Kingdom.

Background: Applying the Robson classification to all births in Brazil, the objectives of our study were to estimate the rates of caesarean section delivery, assess the extent to which caesarean sections were clinically indicated, and identify variation across socioeconomic groups.

Methods: We conducted a population-based study using routine records of the Live Births Information System in Brazil from January 1, 2011, to December 31, 2017. We calculated the relative size of each Robson group; the caesarean section rate; and the contribution to the overall caesarean section rate. We categorised Brazilian municipalities using the Human Development Index to explore caesarean section rates further. We estimated the time trend in caesarean section rates.

Results: The rate of caesarean sections was higher in older and more educated women. Prelabour caesarean sections accounted for more than 54 % of all caesarean deliveries. Women with a previous caesarean section (Group 5) made up the largest group (21.7 %). Groups 6-9, for whom caesarean sections would be indicated in most cases, all had caesarean section rates above 82 %, as did Group 5. The caesarean section rates were higher in municipalities with a higher HDI. The general Brazilian caesarean section rate remained stable during the study period.

Conclusions: Brazil is a country with one of the world's highest caesarean section rates. This nationwide population-based study provides the evidence needed to inform efforts to improve the provision of clinically indicated caesarean sections. Our results showed that caesarean section rates were lower among lower socioeconomic groups even when clinically indicated, suggesting sub-optimal access to surgical care.
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http://dx.doi.org/10.1186/s12884-021-04060-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8406968PMC
August 2021

Estimating underreporting of leprosy in Brazil using a Bayesian approach.

PLoS Negl Trop Dis 2021 08 25;15(8):e0009700. Epub 2021 Aug 25.

Tropical Medicine Centre, University of Brasília, Brasília, Brazil.

Background: Leprosy remains concentrated among the poorest communities in low-and middle-income countries and it is one of the primary infectious causes of disability. Although there have been increasing advances in leprosy surveillance worldwide, leprosy underreporting is still common and can hinder decision-making regarding the distribution of financial and health resources and thereby limit the effectiveness of interventions. In this study, we estimated the proportion of unreported cases of leprosy in Brazilian microregions.

Methodology/principal Findings: Using data collected between 2007 to 2015 from each of the 557 Brazilian microregions, we applied a Bayesian hierarchical model that used the presence of grade 2 leprosy-related physical disabilities as a direct indicator of delayed diagnosis and a proxy for the effectiveness of local leprosy surveillance program. We also analyzed some relevant factors that influence spatial variability in the observed mean incidence rate in the Brazilian microregions, highlighting the importance of socioeconomic factors and how they affect the levels of underreporting. We corrected leprosy incidence rates for each Brazilian microregion and estimated that, on average, 33,252 (9.6%) new leprosy cases went unreported in the country between 2007 to 2015, with this proportion varying from 8.4% to 14.1% across the Brazilian States.

Conclusions/significance: The magnitude and distribution of leprosy underreporting were adequately explained by a model using Grade 2 disability as a marker for the ability of the system to detect new missing cases. The percentage of missed cases was significant, and efforts are warranted to improve leprosy case detection. Our estimates in Brazilian microregions can be used to guide effective interventions, efficient resource allocation, and target actions to mitigate transmission.
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http://dx.doi.org/10.1371/journal.pntd.0009700DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8423270PMC
August 2021

Risks of covid-19 hospital admission and death for people with learning disability: population based cohort study using the OpenSAFELY platform.

BMJ 2021 07 14;374:n1592. Epub 2021 Jul 14.

TPP, TPP House, Horsforth, Leeds, UK.

Objective: To assess the association between learning disability and risk of hospital admission and death from covid-19 in England among adults and children.

Design: Population based cohort study on behalf of NHS England using the OpenSAFELY platform.

Setting: Patient level data were obtained for more than 17 million people registered with a general practice in England that uses TPP software. Electronic health records were linked with death data from the Office for National Statistics and hospital admission data from NHS Secondary Uses Service.

Participants: Adults (aged 16-105 years) and children (<16 years) from two cohorts: wave 1 (registered with a TPP practice as of 1 March 2020 and followed until 31 August 2020); and wave 2 (registered 1 September 2020 and followed until 8 February 2021). The main exposure group consisted of people on a general practice learning disability register; a subgroup was defined as those having profound or severe learning disability. People with Down's syndrome and cerebral palsy were identified (whether or not they were on the learning disability register).

Main Outcome Measure: Covid-19 related hospital admission and covid-19 related death. Non-covid-19 deaths were also explored.

Results: For wave 1, 14 312 023 adults aged ≥16 years were included, and 90 307 (0.63%) were on the learning disability register. Among adults on the register, 538 (0.6%) had a covid-19 related hospital admission; there were 222 (0.25%) covid-19 related deaths and 602 (0.7%) non-covid deaths. Among adults not on the register, 29 781 (0.2%) had a covid-19 related hospital admission; there were 13 737 (0.1%) covid-19 related deaths and 69 837 (0.5%) non-covid deaths. Wave 1 hazard ratios for adults on the learning disability register (adjusted for age, sex, ethnicity, and geographical location) were 5.3 (95% confidence interval 4.9 to 5.8) for covid-19 related hospital admission and 8.2 (7.2 to 9.4) for covid-19 related death. Wave 2 produced similar estimates. Associations were stronger among those classified as having severe to profound learning disability, and among those in residential care. For both waves, Down's syndrome and cerebral palsy were associated with increased hazards for both events; Down's syndrome to a greater extent. Hazard ratios for non-covid deaths followed similar patterns with weaker associations. Similar patterns of increased relative risk were seen for children, but covid-19 related deaths and hospital admissions were rare, reflecting low event rates among children.

Conclusions: People with learning disability have markedly increased risks of hospital admission and death from covid-19, over and above the risks observed for non-covid causes of death. Prompt access to covid-19 testing and healthcare is warranted for this vulnerable group, and prioritisation for covid-19 vaccination and other targeted preventive measures should be considered.
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http://dx.doi.org/10.1136/bmj.n1592DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8278652PMC
July 2021

Detecting behavioural changes in human movement to inform the spatial scale of interventions against COVID-19.

PLoS Comput Biol 2021 07 12;17(7):e1009162. Epub 2021 Jul 12.

Department of Infectious Disease Epidemiology, London School of Hygiene & Tropical Medicine, London, United Kingdom.

On March 23 2020, the UK enacted an intensive, nationwide lockdown to mitigate transmission of COVID-19. As restrictions began to ease, more localized interventions were used to target resurgences in transmission. Understanding the spatial scale of networks of human interaction, and how these networks change over time, is critical to targeting interventions at the most at-risk areas without unnecessarily restricting areas at low risk of resurgence. We use detailed human mobility data aggregated from Facebook users to determine how the spatially-explicit network of movements changed before and during the lockdown period, in response to the easing of restrictions, and to the introduction of locally-targeted interventions. We also apply community detection techniques to the weighted, directed network of movements to identify geographically-explicit movement communities and measure the evolution of these community structures through time. We found that the mobility network became more sparse and the number of mobility communities decreased under the national lockdown, a change that disproportionately affected long distance connections central to the mobility network. We also found that the community structure of areas in which locally-targeted interventions were implemented following epidemic resurgence did not show reorganization of community structure but did show small decreases in indicators of travel outside of local areas. We propose that communities detected using Facebook or other mobility data be used to assess the impact of spatially-targeted restrictions and may inform policymakers about the spatial extent of human movement patterns in the UK. These data are available in near real-time, allowing quantification of changes in the distribution of the population across the UK, as well as changes in travel patterns to inform our understanding of the impact of geographically-targeted interventions.
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http://dx.doi.org/10.1371/journal.pcbi.1009162DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8297940PMC
July 2021

Assessment of common infections and incident dementia using UK primary and secondary care data: a historical cohort study.

Lancet Healthy Longev 2021 Jul;2(7):e426-e435

Faculty of Epidemiology and Population Health, London School of Hygiene & Tropical Medicine, London WC1E 7HT, UK.

Background: Common infections have been associated with dementia risk; however, evidence is scarce. We aimed to investigate the association between common infections and dementia in adults (≥65 years) in a UK population-based cohort study.

Methods: We did a historical cohort study of individuals who were 65 years and older with no history of dementia or cognitive impairment using the Clinical Practice Research Datalink linked to Hospital Episode Statistics between Jan 1, 2004, and Dec 31, 2018. Multivariable Cox proportional hazard regression models were used to estimate the association between time-updated previous common infections (sepsis, pneumonia, other lower respiratory tract infections, urinary tract infections, and skin and soft tissue infections) and incident dementia diagnosis. We also tested for effect modification by diabetes since it is an independent risk factor for dementia and co-occurs with infection.

Findings: Between Jan 1, 2004, and Dec 31, 2018, our study included 989 800 individuals (median age 68·6 years [IQR 65·0-77·0]; 537 602 [54·3%] women) of whom 402 204 (40·6%) were diagnosed with at least one infection and 56 802 (5·7%) had incident dementia during a median follow-up of 5·2 years (IQR 2·3-9·0). Dementia risk increased in those with any infection (adjusted hazard ratio [HR] 1·53 [95% CI 1·50-1·55]) compared with those without infection. HRs were highest for sepsis (HR 2·08 [1·89-2·29]) and pneumonia (HR 1·88 [1·77-1·99]) and for infections leading to hospital admission (1·99 [1·94-2·04]). HRs were also higher in individuals with diabetes compared with those without diabetes.

Interpretation: Common infections, particularly those resulting in hospitalisation, were associated with an increased risk of dementia persisting over the long term. Whether reducing infections lowers the risk of subsequent dementia warrants evaluation.

Funding: Alzheimer's Society, Wellcome Trust, and the Royal Society.
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http://dx.doi.org/10.1016/S2666-7568(21)00118-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8245326PMC
July 2021

Ethnic differences in guideline-indicated statin initiation for people with type 2 diabetes in UK primary care, 2006-2019: A cohort study.

PLoS Med 2021 06 29;18(6):e1003672. Epub 2021 Jun 29.

University College London, London, United Kingdom.

Background: Type 2 diabetes is 2-3 times more prevalent in people of South Asian and African/African Caribbean ethnicity than people of European ethnicity living in the UK. The former 2 groups also experience excess atherosclerotic cardiovascular disease (ASCVD) complications of diabetes. We aimed to study ethnic differences in statin initiation, a cornerstone of ASCVD primary prevention, for people with type 2 diabetes.

Methods And Findings: Observational cohort study of UK primary care records, from 1 January 2006 to 30 June 2019. Data were studied from 27,511 (88%) people of European ethnicity, 2,386 (8%) people of South Asian ethnicity, and 1,142 (4%) people of African/African Caribbean ethnicity with incident type 2 diabetes, no previous ASCVD, and statin use indicated by guidelines. Statin initiation rates were contrasted by ethnicity, and the number of ASCVD events that could be prevented by equalising prescribing rates across ethnic groups was estimated. Median time to statin initiation was 79, 109, and 84 days for people of European, South Asian, and African/African Caribbean ethnicity, respectively. People of African/African Caribbean ethnicity were a third less likely to receive guideline-indicated statins than European people (n/N [%]: 605/1,142 [53%] and 18,803/27,511 [68%], respectively; age- and gender-adjusted HR 0.67 [95% CI 0.60 to 0.76], p < 0.001). The HR attenuated marginally in a model adjusting for total cholesterol/high-density lipoprotein cholesterol ratio (0.77 [95% CI 0.69 to 0.85], p < 0.001), with no further diminution when deprivation, ASCVD risk factors, comorbidity, polypharmacy, and healthcare usage were accounted for (fully adjusted HR 0.76 [95% CI 0.68, 0.85], p < 0.001). People of South Asian ethnicity were 10% less likely to receive a statin than European people (1,489/2,386 [62%] and 18,803/27,511 [68%], respectively; fully adjusted HR 0.91 [95% CI 0.85 to 0.98], p = 0.008, adjusting for all covariates). We estimated that up to 12,600 ASCVD events could be prevented over the lifetimes of people currently affected by type 2 diabetes in the UK by equalising statin prescribing across ethnic groups. Limitations included incompleteness of recording of routinely collected data.

Conclusions: In this study we observed that people of African/African Caribbean ethnicity with type 2 diabetes were substantially less likely, and people of South Asian ethnicity marginally less likely, to receive guideline-indicated statins than people of European ethnicity, even after accounting for sociodemographics, healthcare usage, ASCVD risk factors, and comorbidity. Underuse of statins in people of African/African Caribbean or South Asian ethnicity with type 2 diabetes is a missed opportunity to prevent cardiovascular events.
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http://dx.doi.org/10.1371/journal.pmed.1003672DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8241069PMC
June 2021

Ethnic differences in the incidence of clinically diagnosed influenza: an England population-based cohort study 2008-2018.

Wellcome Open Res 2021 10;6:49. Epub 2021 Jun 10.

Department of Non-communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK.

People of non-White ethnicity have a higher risk of severe outcomes following influenza infection. It is unclear whether this is driven by an increased risk of infection or complications. We therefore aimed to investigate the incidence of clinically diagnosed influenza/influenza-like illness (ILI) by ethnicity in England from 2008-2018. We used linked primary and secondary healthcare data (from the Clinical Practice Research Datalink [CPRD] GOLD and Aurum databases and Hospital Episodes Statistics Admitted Patient Care [HES APC]). We included patients with recorded ethnicity who were aged 40-64 years and did not have a chronic health condition that would render them eligible for influenza vaccination. ILI infection was identified from diagnostic codes in CPRD and HES APC. We calculated crude annual infection incidence rates by ethnic group. Multivariable Poisson regression models with random effects were used to estimate any ethnic disparities in infection risk. Our main analysis adjusted for age, sex, and influenza year. A total of 3,735,308 adults aged 40-64 years were included in the study; 87.6% White, 5.2% South Asian, 4.2% Black, 1.9% Other, and 1.1% Mixed. We identified 102,316 ILI episodes recorded among 94,623 patients. The rate of ILI was highest in the South Asian (9.6 per 1,000 person-years), Black (8.4 per 1,000 person-years) and Mixed (6.9 per 1,000 person-years) ethnic groups. The ILI rate in the White ethnic group was 5.7 per 1,000 person-years. After adjustment for age sex and influenza year, higher incidence rate ratios (IRR) for ILI were seen for South Asian (1.70, 95% CI 1.66-1.75), Black (1.48, 1.44-1.53) and Mixed (1.22, 1.15-1.30) groups compared to White ethnicity. Our results suggest that influenza infection risk differs between White and non-White groups who are not eligible for routine influenza vaccination.
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http://dx.doi.org/10.12688/wellcomeopenres.16620.3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8136253.3PMC
June 2021

Realising the full potential of data-enabled trials in the UK: a call for action.

BMJ Open 2021 06 16;11(6):e043906. Epub 2021 Jun 16.

Clinical Practice Research Datalink, Medicines and Healthcare Products Regulatory Agency, London, UK.

Rationale: Clinical trials are the gold standard for testing interventions. COVID-19 has further raised their public profile and emphasised the need to deliver better, faster, more efficient trials for patient benefit. Considerable overlap exists between data required for trials and data already collected routinely in electronic healthcare records (EHRs). Opportunities exist to use these in innovative ways to decrease duplication of effort and speed trial recruitment, conduct and follow-up.

Approach: The National Institute of Health Research (NIHR), Health Data Research UK and Clinical Practice Research Datalink co-organised a national workshop to accelerate the agenda for 'data-enabled clinical trials'. Showcasing successful examples and imagining future possibilities, the plenary talks, panel discussions, group discussions and case studies covered: design/feasibility; recruitment; conduct/follow-up; collecting benefits/harms; and analysis/interpretation.

Reflection: Some notable studies have successfully accessed and used EHR to identify potential recruits, support randomised trials, deliver interventions and supplement/replace trial-specific follow-up. Some outcome measures are already reliably collected; others, like safety, need detailed work to meet regulatory reporting requirements. There is a clear need for system interoperability and a 'route map' to identify and access the necessary datasets. Researchers running regulatory-facing trials must carefully consider how data quality and integrity would be assessed. An experience-sharing forum could stimulate wider adoption of EHR-based methods in trial design and execution.

Discussion: EHR offer opportunities to better plan clinical trials, assess patients and capture data more efficiently, reducing research waste and increasing focus on each trial's specific challenges. The short-term emphasis should be on facilitating patient recruitment and for postmarketing authorisation trials where research-relevant outcome measures are readily collectable. Sharing of case studies is encouraged. The workshop directly informed NIHR's funding call for ambitious data-enabled trials at scale. There is the opportunity for the UK to build upon existing data science capabilities to identify, recruit and monitor patients in trials at scale.
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http://dx.doi.org/10.1136/bmjopen-2020-043906DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8211043PMC
June 2021

Genome-wide DNA methylation analysis on C-reactive protein among Ghanaians suggests molecular links to the emerging risk of cardiovascular diseases.

NPJ Genom Med 2021 Jun 11;6(1):46. Epub 2021 Jun 11.

Department of Public Health, Amsterdam Public Health Research Institute, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands.

Molecular mechanisms at the intersection of inflammation and cardiovascular diseases (CVD) among Africans are still unknown. We performed an epigenome-wide association study to identify loci associated with serum C-reactive protein (marker of inflammation) among Ghanaians and further assessed whether differentially methylated positions (DMPs) were linked to CVD in previous reports, or to estimated CVD risk in the same population. We used the Illumina Infinium® HumanMethylation450 BeadChip to obtain DNAm profiles of blood samples in 589 Ghanaians from the RODAM study (without acute infections, not taking anti-inflammatory medications, CRP levels < 40 mg/L). We then used linear models to identify DMPs associated with CRP concentrations. Post-hoc, we evaluated associations of identified DMPs with elevated CVD risk estimated via ASCVD risk score. We also performed subset analyses at CRP levels ≤10 mg/L and replication analyses on candidate probes. Finally, we assessed for biological relevance of our findings in public databases. We subsequently identified 14 novel DMPs associated with CRP. In post-hoc evaluations, we found that DMPs in PC, BTG4 and PADI1 showed trends of associations with estimated CVD risk, we identified a separate DMP in MORC2 that was associated with CRP levels ≤10 mg/L, and we successfully replicated 65 (24%) of previously reported DMPs. All DMPs with gene annotations (13) were biologically linked to inflammation or CVD traits. We have identified epigenetic loci that may play a role in the intersection between inflammation and CVD among Ghanaians. Further studies among other Africans are needed to confirm our findings.
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http://dx.doi.org/10.1038/s41525-021-00213-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8196035PMC
June 2021

Factors associated with deaths due to COVID-19 versus other causes: population-based cohort analysis of UK primary care data and linked national death registrations within the OpenSAFELY platform.

Lancet Reg Health Eur 2021 Jul 8;6:100109. Epub 2021 May 8.

The DataLab, Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK.

Background: Mortality from COVID-19 shows a strong relationship with age and pre-existing medical conditions, as does mortality from other causes. We aimed to investigate how specific factors are differentially associated with COVID-19 mortality as compared to mortality from causes other than COVID-19.

Methods: Working on behalf of NHS England, we carried out a cohort study within the OpenSAFELY platform. Primary care data from England were linked to national death registrations. We included all adults (aged ≥18 years) in the database on 1 February 2020 and with >1 year of continuous prior registration; the cut-off date for deaths was 9 November 2020. Associations between individual-level characteristics and COVID-19 and non-COVID deaths, classified according to the presence of a COVID-19 code as the underlying cause of death on the death certificate, were estimated by fitting age- and sex-adjusted logistic models for these two outcomes.

Findings: 17,456,515 individuals were included. 17,063 died from COVID-19 and 134,316 from other causes. Most factors associated with COVID-19 death were similarly associated with non-COVID death, but the magnitudes of association differed. Older age was more strongly associated with COVID-19 death than non-COVID death (e.g. ORs 40.7 [95% CI 37.7-43.8] and 29.6 [28.9-30.3] respectively for ≥80 vs 50-59 years), as was male sex, deprivation, obesity, and some comorbidities. Smoking, history of cancer and chronic liver disease had stronger associations with non-COVID than COVID-19 death. All non-white ethnic groups had higher odds than white of COVID-19 death (OR for Black: 2.20 [1.96-2.47], South Asian: 2.33 [2.16-2.52]), but lower odds than white of non-COVID death (Black: 0.88 [0.83-0.94], South Asian: 0.78 [0.75-0.81]).

Interpretation: Similar associations of most individual-level factors with COVID-19 and non-COVID death suggest that COVID-19 largely multiplies existing risks faced by patients, with some notable exceptions. Identifying the unique factors contributing to the excess COVID-19 mortality risk among non-white groups is a priority to inform efforts to reduce deaths from COVID-19.

Funding: Wellcome, Royal Society, National Institute for Health Research, National Institute for Health Research Oxford Biomedical Research Centre, UK Medical Research Council, Health Data Research UK.
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http://dx.doi.org/10.1016/j.lanepe.2021.100109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8106239PMC
July 2021

Ethnic differences in SARS-CoV-2 infection and COVID-19-related hospitalisation, intensive care unit admission, and death in 17 million adults in England: an observational cohort study using the OpenSAFELY platform.

Lancet 2021 05 30;397(10286):1711-1724. Epub 2021 Apr 30.

Department of Medical Statistics, London School of Hygiene & Tropical Medicine, London, UK.

Background: COVID-19 has disproportionately affected minority ethnic populations in the UK. Our aim was to quantify ethnic differences in SARS-CoV-2 infection and COVID-19 outcomes during the first and second waves of the COVID-19 pandemic in England.

Methods: We conducted an observational cohort study of adults (aged ≥18 years) registered with primary care practices in England for whom electronic health records were available through the OpenSAFELY platform, and who had at least 1 year of continuous registration at the start of each study period (Feb 1 to Aug 3, 2020 [wave 1], and Sept 1 to Dec 31, 2020 [wave 2]). Individual-level primary care data were linked to data from other sources on the outcomes of interest: SARS-CoV-2 testing and positive test results and COVID-19-related hospital admissions, intensive care unit (ICU) admissions, and death. The exposure was self-reported ethnicity as captured on the primary care record, grouped into five high-level census categories (White, South Asian, Black, other, and mixed) and 16 subcategories across these five categories, as well as an unknown ethnicity category. We used multivariable Cox regression to examine ethnic differences in the outcomes of interest. Models were adjusted for age, sex, deprivation, clinical factors and comorbidities, and household size, with stratification by geographical region.

Findings: Of 17 288 532 adults included in the study (excluding care home residents), 10 877 978 (62·9%) were White, 1 025 319 (5·9%) were South Asian, 340 912 (2·0%) were Black, 170 484 (1·0%) were of mixed ethnicity, 320 788 (1·9%) were of other ethnicity, and 4 553 051 (26·3%) were of unknown ethnicity. In wave 1, the likelihood of being tested for SARS-CoV-2 infection was slightly higher in the South Asian group (adjusted hazard ratio 1·08 [95% CI 1·07-1·09]), Black group (1·08 [1·06-1·09]), and mixed ethnicity group (1·04 [1·02-1·05]) and was decreased in the other ethnicity group (0·77 [0·76-0·78]) relative to the White group. The risk of testing positive for SARS-CoV-2 infection was higher in the South Asian group (1·99 [1·94-2·04]), Black group (1·69 [1·62-1·77]), mixed ethnicity group (1·49 [1·39-1·59]), and other ethnicity group (1·20 [1·14-1·28]). Compared with the White group, the four remaining high-level ethnic groups had an increased risk of COVID-19-related hospitalisation (South Asian group 1·48 [1·41-1·55], Black group 1·78 [1·67-1·90], mixed ethnicity group 1·63 [1·45-1·83], other ethnicity group 1·54 [1·41-1·69]), COVID-19-related ICU admission (2·18 [1·92-2·48], 3·12 [2·65-3·67], 2·96 [2·26-3·87], 3·18 [2·58-3·93]), and death (1·26 [1·15-1·37], 1·51 [1·31-1·71], 1·41 [1·11-1·81], 1·22 [1·00-1·48]). In wave 2, the risks of hospitalisation, ICU admission, and death relative to the White group were increased in the South Asian group but attenuated for the Black group compared with these risks in wave 1. Disaggregation into 16 ethnicity groups showed important heterogeneity within the five broader categories.

Interpretation: Some minority ethnic populations in England have excess risks of testing positive for SARS-CoV-2 and of adverse COVID-19 outcomes compared with the White population, even after accounting for differences in sociodemographic, clinical, and household characteristics. Causes are likely to be multifactorial, and delineating the exact mechanisms is crucial. Tackling ethnic inequalities will require action across many fronts, including reducing structural inequalities, addressing barriers to equitable care, and improving uptake of testing and vaccination.

Funding: Medical Research Council.
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http://dx.doi.org/10.1016/S0140-6736(21)00634-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8087292PMC
May 2021

DNA methylation as the link between migration and the major noncommunicable diseases: the RODAM study.

Epigenomics 2021 May 23;13(9):653-666. Epub 2021 Apr 23.

Department of Public Health, Amsterdam Public Health Research Institute, Amsterdam University Medical Centers, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.

We assessed epigenome-wide DNA methylation (DNAm) differences between migrant and non-migrant Ghanaians. We used the Illumina Infinium HumanMethylation450 BeadChip to profile DNAm of 712 Ghanaians in whole blood. We used linear models to detect differentially methylated positions (DMPs) associated with migration. We performed multiple post hoc analyses to validate our findings. We identified 13 DMPs associated with migration (delta-beta values: 0.2-4.5%). Seven DMPs in , , , , , and were independent of extrinsic genomic influences in public databases. Two DMPs in were associated with duration of stay in Europe among migrants. All DMPs were biologically linked to migration-related factors. Our findings provide the first insights into DNAm differences between migrants and non-migrants.
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http://dx.doi.org/10.2217/epi-2020-0329DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8173498PMC
May 2021

Real-world effects of medications for stroke prevention in atrial fibrillation: protocol for a UK population-based non-interventional cohort study with validation against randomised trial results.

BMJ Open 2021 04 15;11(4):e042947. Epub 2021 Apr 15.

Department of Non-communicable Disease Epidemiology, Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, UK.

Introduction: Patients with atrial fibrillation experience an irregular heart rate and have an increased risk of stroke; prophylactic treatment with anticoagulation medication reduces this risk. Direct-acting oral anticoagulants (DOACs) have been approved providing an alternative to vitamin K antagonists such as warfarin. There is interest from regulatory bodies on the effectiveness of medications in routine clinical practice; however, uncertainty remains regarding the suitability of non-interventional data for answering questions on drug effectiveness and on the most suitable methods to be used. In this study, we will use data from Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE)-the pivotal trial for the DOAC apixaban-to validate non-interventional methods for assessing treatment effectiveness of anticoagulants. These methods could then be applied to analyse treatment effectiveness in people excluded from or under-represented in ARISTOTLE.

Methods And Analysis: Patient characteristics from ARISTOTLE will be used to select a cohort of patients with similar baseline characteristics from two UK electronic health record (EHR) databases, Clinical Practice Research Datalink Gold and Aurum (between 1 January 2013 and 31 July 2019). Methods such as propensity score matching and coarsened exact matching will be explored in matching between EHR treatment groups to determine the optimal method of obtaining a balanced cohort.Absolute and relative risk of outcomes in the EHR trial-analogous cohort will be calculated and compared with the ARISTOTLE results; if results are deemed compatible the methods used for matching EHR treatment groups can then be used to examine drug effectiveness over a longer duration of exposure and in special patient groups of interest not studied in the trial.

Ethics And Dissemination: The study has been approved by the Independent Scientific Advisory Committee of the UK Medicines and Healthcare Products Regulatory Agency. Results will be disseminated in scientific publications and at relevant conferences.
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http://dx.doi.org/10.1136/bmjopen-2020-042947DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8055153PMC
April 2021

Discovery and fine-mapping of kidney function loci in first genome-wide association study in Africans.

Hum Mol Genet 2021 Jul;30(16):1559-1568

Non-Communicable Disease Theme, MRC/UVRI and LSHTM, Entebbe, Uganda.

Genome-wide association studies (GWAS) of kidney function have uncovered hundreds of loci, primarily in populations of European ancestry. We have undertaken the first continental African GWAS of estimated glomerular filtration rate (eGFR), a measure of kidney function used to define chronic kidney disease (CKD). We conducted GWAS of eGFR in 3288 East Africans from the Uganda General Population Cohort (GPC) and replicated in 8224 African Americans from the Women's Health Initiative. Loci attaining genome-wide significant evidence for association (P < 5 × 10-8) were followed up with Bayesian fine-mapping to localize potential causal variants. The predictive power of a genetic risk score (GRS) constructed from previously reported trans-ancestry eGFR lead single nucleotide polymorphism (SNPs) was evaluated in the Uganda GPC. We identified and validated two eGFR loci. At the glycine amidinotransferase (GATM) locus, the association signal (lead SNP rs2433603, P = 1.0 × 10-8) in the Uganda GPC GWAS was distinct from previously reported signals at this locus. At the haemoglobin beta (HBB) locus, the association signal (lead SNP rs141845179, P = 3.0 × 10-8) has been previously reported. The lead SNP at the HBB locus accounted for 88% of the posterior probability of causality after fine-mapping, but did not colocalise with kidney expression quantitative trait loci. The trans-ancestry GRS of eGFR was not significantly predictive into the Ugandan population. In the first GWAS of eGFR in continental Africa, we validated two previously reported loci at GATM and HBB. At the GATM locus, the association signal was distinct from that previously reported. These results demonstrate the value of performing GWAS in continental Africans, providing a rich genomic resource to larger consortia for further discovery and fine-mapping. The study emphasizes that additional large-scale efforts in Africa are warranted to gain further insight into the genetic architecture of CKD.
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http://dx.doi.org/10.1093/hmg/ddab088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8330895PMC
July 2021
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