Publications by authors named "Rory Collins"

208 Publications

Association of kidney function with NMR-quantified lipids, lipoproteins, and metabolic measures in Mexican adults.

J Clin Endocrinol Metab 2021 Jul 3. Epub 2021 Jul 3.

Faculty of Medicine, National Autonomous University of Mexico, Mexico City, Mexico.

Context: Chronic kidney disease (CKD) and diabetes are associated with dyslipidaemia, metabolic abnormalities, and atherosclerotic risk. Nuclear magnetic resonance (NMR) spectroscopy provides much more detail on lipoproteins than traditional assays.

Methods: In about 38,000 participants from the Mexico City Prospective Study, aged 35-84 years and not using lipid-lowering medication, NMR spectroscopy quantified plasma concentrations of lipoprotein particles, their lipidic compositions, and other metabolic measures. Linear regression related low eGFR (<60mL/min/1.73m2) to each NMR-measure after adjustment for confounders and for multiplicity. Analyses were done separately for those with and without diabetes.

Results: Among the 38,081 participants (mean age 52 years, 64% women), low eGFR was present for 4.8% (306/6,403) of those with diabetes and 1.2% (365/31,678) of those without diabetes. Among both those with and without diabetes, low eGFR was significantly associated with higher levels of 58 NMR-measures - including apolipoprotein B (Apo-B), the particle numbers of most Apo-B containing lipoproteins, the cholesterol and triglycerides carried in these lipoproteins, several fatty acids, total cholines and phosphatidylcholine, citrate, glutamine, phenylalanine, β-OH-butyrate, and the inflammatory measure glycoprotein-A - and significantly lower levels of 13 NMR-measures, including medium and small high-density lipoprotein particle measures, very low-density lipoprotein particle size, the ratio of saturated:total fatty acids, valine, tyrosine, and aceto-acetate.

Conclusions: In this Mexican population with high levels of adiposity and diabetes, low kidney function was associated with widespread alterations in lipidic and metabolic profiles, both in those with and without diabetes. These alterations may help explain the higher atherosclerotic risk experienced by people with CKD.
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http://dx.doi.org/10.1210/clinem/dgab497DOI Listing
July 2021

Sequencing of 640,000 exomes identifies variants associated with protection from obesity.

Science 2021 07;373(6550)

Geisinger Obesity Institute, Geisinger Health System, Danville, PA 17882, USA.

Large-scale human exome sequencing can identify rare protein-coding variants with a large impact on complex traits such as body adiposity. We sequenced the exomes of 645,626 individuals from the United Kingdom, the United States, and Mexico and estimated associations of rare coding variants with body mass index (BMI). We identified 16 genes with an exome-wide significant association with BMI, including those encoding five brain-expressed G protein-coupled receptors (, , , , and ). Protein-truncating variants in were observed in ~4/10,000 sequenced individuals and were associated with 1.8 kilograms per square meter lower BMI and 54% lower odds of obesity in the heterozygous state. Knock out of in mice resulted in resistance to weight gain and improved glycemic control in a high-fat diet model. Inhibition of GPR75 may provide a therapeutic strategy for obesity.
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http://dx.doi.org/10.1126/science.abf8683DOI Listing
July 2021

United Kingdom Biobank (UK Biobank): JACC Focus Seminar 6/8.

J Am Coll Cardiol 2021 07;78(1):56-65

Big Data Institute, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom.

An increasing number of people are now living with cardiovascular disease (CVD), with concomitant CVD-related hospitalizations, operations, and prescriptions. To ultimately deliver optimal cardiovascular care, access to population-based biobanks with data on multiomics, phenotypes, and lifestyle risk factors are crucial. UK Biobank is a cohort study that incorporated data between 2006 and 2010 from over half a million individuals (40 to 69 years of age) at recruitment from across the United Kingdom. As one of the most accessible, largest, and in-depth cohort studies in the world, UK Biobank continues to enhance the resource with the addition of data from various omics platforms (eg, genomics, metabolomics, proteomics), multimodal imaging, self-reported risk factors and health outcomes, and linkage to electronic health records. The vision of UK Biobank is to allow as many researchers as possible to apply their expertise and imagination to undertake research to prevent, diagnose, and treat a wide range of chronic conditions, including CVD.
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http://dx.doi.org/10.1016/j.jacc.2021.03.342DOI Listing
July 2021

Brain imaging before and after COVID-19 in UK Biobank.

medRxiv 2021 Jun 20. Epub 2021 Jun 20.

There is strong evidence for brain-related pathologies in COVID-19, some of which could be a consequence of viral neurotropism. The vast majority of brain imaging studies so far have focused on qualitative, gross pathology of moderate to severe cases, often carried out on hospitalised patients. It remains unknown however whether the impact of COVID-19 can be detected in milder cases, in a quantitative and automated manner, and whether this can reveal a possible mechanism for the spread of the disease. UK Biobank scanned over 40,000 participants before the start of the COVID-19 pandemic, making it possible to invite back in 2021 hundreds of previously-imaged participants for a second imaging visit. Here, we studied the effects of the disease in the brain using multimodal data from 782 participants from the UK Biobank COVID-19 re-imaging study, with 394 participants having tested positive for SARS-CoV-2 infection between their two scans. We used structural and functional brain scans from before and after infection, to compare longitudinal brain changes between these 394 COVID-19 patients and 388 controls who were matched for age, sex, ethnicity and interval between scans. We identified significant effects of COVID-19 in the brain with a loss of grey matter in the left parahippocampal gyrus, the left lateral orbitofrontal cortex and the left insula. When looking over the entire cortical surface, these results extended to the anterior cingulate cortex, supramarginal gyrus and temporal pole. We further compared COVID-19 patients who had been hospitalised (n=15) with those who had not (n=379), and while results were not significant, we found comparatively similar findings to the COVID-19 vs control group comparison, with, in addition, a greater loss of grey matter in the cingulate cortex, central nucleus of the amygdala and hippocampal cornu ammonis (all |Z|>3). Our findings thus consistently relate to loss of grey matter in limbic cortical areas directly linked to the primary olfactory and gustatory system. Unlike in disease studies, the availability of pre-infection imaging data helps avoid the danger of pre-existing risk factors or clinical conditions being mis-interpreted as disease effects. Since a possible entry point of the virus to the central nervous system might be via the olfactory mucosa and the olfactory bulb, these brain imaging results might be the hallmark of the spread of the disease (or the virus itself) via olfactory and gustatory pathways.
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http://dx.doi.org/10.1101/2021.06.11.21258690DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8240690PMC
June 2021

Challenges and Opportunities in IBD Clinical Trial Design.

Gastroenterology 2021 Aug 20;161(2):400-404. Epub 2021 Apr 20.

Chair, IOIBD; Division of Gastroenterology and Hepatology, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida. Electronic address:

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http://dx.doi.org/10.1053/j.gastro.2021.03.065DOI Listing
August 2021

Abdominal and gluteo-femoral markers of adiposity and risk of vascular-metabolic mortality in a prospective study of 150 000 Mexican adults.

Eur J Prev Cardiol 2021 Mar 9. Epub 2021 Mar 9.

School of Medicine, National Autonomous University of Mexico, Mexico City, Mexico.

Aims: Results of previous studies of abdominal adiposity and risk of vascular-metabolic mortality in Hispanic populations have been conflicting. We report results from a large prospective study of Mexican adults with high levels of abdominal adiposity.

Methods And Results: A total of 159 755 adults aged ≥35 years from Mexico City were enrolled in a prospective study and followed for 16 years. Cox regression, adjusted for confounders, yielded mortality rate ratios (RRs) associated with three markers of abdominal adiposity (waist circumference, waist-hip ratio, and waist-height ratio) and one marker of gluteo-femoral adiposity (hip circumference) for cause-specific mortality before age 75 years. To reduce reverse causality, deaths in the first 5 years of follow-up and participants with diabetes or other prior chronic disease were excluded. Among 113 163 participants without prior disease and aged 35-74 years at recruitment, all adiposity markers were positively associated with vascular-metabolic mortality. Comparing the top versus bottom tenth of the sex-specific distributions, the vascular-metabolic mortality RRs at ages 40-74 years were 2.32 [95% confidence interval (CI) 1.84-2.94] for waist circumference, 2.22 (1.71-2.88) for the waist-hip ratio, 2.63 (2.06-3.36) for the waist-height ratio, and 1.58 (1.29-1.93) for hip circumference. The RRs corresponding to each standard deviation (SD) higher usual levels of these adiposity markers were 1.34 (95% CI 1.27-1.41), 1.31 (1.23-1.39), 1.38 (1.31-1.45), and 1.18 (1.13-1.24), respectively. For the markers of abdominal adiposity, the RRs did not change much after further adjustment for other adiposity markers, but for hip circumference the association was reversed; given body mass index and waist circumference, the RR for vascular-metabolic mortality for each one SD higher usual hip circumference was 0.80 (0.75-0.86).

Conclusions: In this study of Mexican adults, abdominal adiposity (and in particular the waist-height ratio) was strongly and positively associated with vascular-metabolic mortality. For a given amount of general and abdominal adiposity, however, higher hip circumference was associated with lower vascular-metabolic mortality.
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http://dx.doi.org/10.1093/eurjpc/zwab038DOI Listing
March 2021

Low-intensity daily smoking and cause-specific mortality in Mexico: prospective study of 150 000 adults.

Int J Epidemiol 2021 07;50(3):955-964

Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health (NDPH), University of Oxford, Oxford, UK.

Background: Research is needed to determine the relevance of low-intensity daily smoking to mortality in countries such as Mexico, where such smoking habits are common.

Methods: Prospective study of 159 755 Mexican adults recruited from 1998-2004 and followed for cause-specific mortality to 1 January 2018. Participants were categorized according to baseline self-reported smoking status. Confounder-adjusted mortality rate ratios (RRs) at ages 35-89 were estimated using Cox regression, after excluding those with previous chronic disease (to avoid reverse causality).

Results: Among 42 416 men and 86 735 women aged 35-89 and without previous disease, 18 985 men (45%) and 18 072 women (21%) reported current smoking and 8866 men (21%) and 53 912 women (62%) reported never smoking. Smoking less than daily was common: 33% of male current smokers and 39% of female current smokers. During follow-up, the all-cause mortality RRs associated with the baseline smoking categories of <10 cigarettes per day (average during follow-up 4 per day) or ≥10 cigarettes per day (average during follow-up 10 per day), compared with never smoking, were 1.17 (95% confidence interval 1.10-1.25) and 1.54 (1.42-1.67), respectively. RRs were similar irrespective of age or sex. The diseases most strongly associated with daily smoking were respiratory cancers, chronic obstructive pulmonary disease and gastrointestinal and vascular diseases. Ex-daily smokers had substantially lower mortality rates than those who were current daily smokers at recruitment.

Conclusions: In this Mexican population, low-intensity daily smoking was associated with increased mortality. Of those smoking 10 cigarettes per day on average, about one-third were killed by their habit. Quitting substantially reduced these risks.
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http://dx.doi.org/10.1093/ije/dyab013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8271211PMC
July 2021

Changes in the Diagnosis and Management of Diabetes in Mexico City Between 1998-2004 and 2015-2019.

Diabetes Care 2021 04 10;44(4):944-951. Epub 2021 Feb 10.

Faculty of Medicine, National Autonomous University of Mexico, Mexico City, Mexico.

Objective: To investigate the trends in diabetes prevalence, diagnosis, and management among Mexican adults who were participants in a long-term prospective study.

Research Design And Methods: From 1998 to 2004, 159,755 adults from Mexico City were recruited to a prospective study, and from 2015 to 2019, 10,144 survivors were resurveyed. Diabetes was defined as self-reported diagnosis, glucose-lowering medication use, or HbA ≥6.5%. Controlled diabetes was defined as HbA <7%. Prevalence estimates were uniformly standardized for age, sex, and residential district. Cox models explored the relevance of controlled and inadequately controlled diabetes to cause-specific mortality.

Results: During 1998-2004 and 2015-2019, 99,623 and 8,986 participants were aged 45-84 years. Diabetes prevalence had increased from 26% in 1998-2004 to 35% by 2015-2019. Of those with diabetes, the proportion previously diagnosed had increased from 76% to 89%, and glucose-lowering medication use among them had increased from 80% to 94%. Median HbA among those with diabetes had decreased from 8.2% to 7.3%, and the proportion of participants with controlled diabetes had increased from 16% to 37%. Use of blood pressure-lowering medication among those with previously diagnosed diabetes had increased from 35% to 51%, and their use of lipid-lowering therapy had increased from 1% to 14%. The excess mortality risk associated with diabetes accounted for 34% of deaths at ages 35-74 years, of which 5% were attributable to controlled and 29% to inadequately controlled diabetes.

Conclusions: Inadequately controlled diabetes is a leading cause of premature adult death in Mexico. Improvements in diabetes management have increased diagnosis and control, but substantial opportunities remain to improve treatment, particularly with lipid-lowering therapy.
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http://dx.doi.org/10.2337/dc20-2276DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7985415PMC
April 2021

Approaches to minimising the epidemiological impact of sources of systematic and random variation that may affect biochemistry assay data in UK Biobank.

Wellcome Open Res 2020 4;5:222. Epub 2021 Jan 4.

Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, OXFORD, Oxon, OX3 7LF, UK.

: UK Biobank is a large prospective study that recruited 500,000 participants aged 40 to 69 years, between 2006-2010.The study has collected (and continues to collect) extensive phenotypic and genomic data about its participants. In order to enhance further the value of the UK Biobank resource, a wide range of biochemistry markers were measured in all participants with an available biological sample. Here, we describe the approaches UK Biobank has taken to minimise error related to sample collection, processing, retrieval and assay measurement. : During routine quality control checks, the laboratory team observed that some assay results were lower than expected for samples acquired during certain time periods. Analyses were undertaken to identify and correct for the unexpected dilution identified during sample processing, and for expected error caused by laboratory drift of assay results. : The vast majority (92%) of biochemistry serum assay results were assessed to be not materially affected by dilution, with an estimated difference in concentration of less than 1% (i.e. either lower or higher) than that expected if the sample were unaffected; 8.3% were estimated to be diluted by up to 10%; very few samples appeared to be diluted more than this. Biomarkers measured in urine (creatinine, microalbumin, sodium, potassium) and red blood cells (HbA1c) were not affected. In order to correct for laboratory variation over the assay period, all assay results were adjusted for date of assay, with the exception of those that had a high biological coefficient of variation or evident seasonal variability: vitamin D, lipoprotein (a), gamma glutamyltransferase, C-reactive protein and rheumatoid factor. : Rigorous approaches related to sample collection, processing, retrieval, assay measurement and data analysis have been taken to mitigate the impact of both systematic and random variation in epidemiological analyses that use the biochemistry assay data in UK Biobank.
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http://dx.doi.org/10.12688/wellcomeopenres.16171.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7739095.2PMC
January 2021

Impact of the COVID-19 pandemic on the detection and management of colorectal cancer in England: a population-based study.

Lancet Gastroenterol Hepatol 2021 03 15;6(3):199-208. Epub 2021 Jan 15.

Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK; Medical Research Council Population Health Research Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK; Big Data Institute, University of Oxford, Oxford, UK.

Background: There are concerns that the COVID-19 pandemic has had a negative effect on cancer care but there is little direct evidence to quantify any effect. This study aims to investigate the impact of the COVID-19 pandemic on the detection and management of colorectal cancer in England.

Methods: Data were extracted from four population-based datasets spanning NHS England (the National Cancer Cancer Waiting Time Monitoring, Monthly Diagnostic, Secondary Uses Service Admitted Patient Care and the National Radiotherapy datasets) for all referrals, colonoscopies, surgical procedures, and courses of rectal radiotherapy from Jan 1, 2019, to Oct 31, 2020, related to colorectal cancer in England. Differences in patterns of care were investigated between 2019 and 2020. Percentage reductions in monthly numbers and proportions were calculated.

Findings: As compared to the monthly average in 2019, in April, 2020, there was a 63% (95% CI 53-71) reduction (from 36 274 to 13 440) in the monthly number of 2-week referrals for suspected cancer and a 92% (95% CI 89-95) reduction in the number of colonoscopies (from 46 441 to 3484). Numbers had just recovered by October, 2020. This resulted in a 22% (95% CI 8-34) relative reduction in the number of cases referred for treatment (from a monthly average of 2781 in 2019 to 2158 referrals in April, 2020). By October, 2020, the monthly rate had returned to 2019 levels but did not exceed it, suggesting that, from April to October, 2020, over 3500 fewer people had been diagnosed and treated for colorectal cancer in England than would have been expected. There was also a 31% (95% CI 19-42) relative reduction in the numbers receiving surgery in April, 2020, and a lower proportion of laparoscopic and a greater proportion of stoma-forming procedures, relative to the monthly average in 2019. By October, 2020, laparoscopic surgery and stoma rates were similar to 2019 levels. For rectal cancer, there was a 44% (95% CI 17-76) relative increase in the use of neoadjuvant radiotherapy in April, 2020, relative to the monthly average in 2019, due to greater use of short-course regimens. Although in June, 2020, there was a drop in the use of short-course regimens, rates remained above 2019 levels until October, 2020.

Interpretation: The COVID-19 pandemic has led to a sustained reduction in the number of people referred, diagnosed, and treated for colorectal cancer. By October, 2020, achievement of care pathway targets had returned to 2019 levels, albeit with smaller volumes of patients and with modifications to usual practice. As pressure grows in the NHS due to the second wave of COVID-19, urgent action is needed to address the growing burden of undetected and untreated colorectal cancer in England.

Funding: Cancer Research UK, the Medical Research Council, Public Health England, Health Data Research UK, NHS Digital, and the National Institute for Health Research Oxford Biomedical Research Centre.
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http://dx.doi.org/10.1016/S2468-1253(21)00005-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7808901PMC
March 2021

Association of Blood Pressure With Cause-Specific Mortality in Mexican Adults.

JAMA Netw Open 2020 09 1;3(9):e2018141. Epub 2020 Sep 1.

Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom.

Importance: Elevated blood pressure is a major cause of premature death, but there is little direct evidence demonstrating this association in studies of Hispanic populations.

Objective: To assess the association between blood pressure and cause-specific mortality in a large cohort of Mexican adults with a high prevalence of uncontrolled diabetes.

Design, Setting, And Participants: A total of 159 755 adults aged 35 years or older from 2 districts in Mexico City were recruited to this cohort study between April 1998 and September 2004 and followed up until January 2018. The present analyses focused on 133 613 participants who were aged 35 to 74 years and had no history of chronic disease besides diabetes.

Exposure: Blood pressure.

Main Outcomes And Measures: Cox regression, adjusted for confounders, yielded mortality rate ratios (RRs) for deaths of participants occurring between ages 35 and 74 years.

Results: Of the 133 613 participants (43 263 [32.4%] men; mean [SD] age, 50 [11] years), 16 911 (12.7%) had self-reported previously diagnosed diabetes (including 8435 [6.3%] with uncontrolled diabetes, defined as hemoglobin A1c ≥9%) and 6548 (4.9%) had undiagnosed diabetes. Systolic blood pressure (SBP) was associated with vascular mortality between ages 35 to 74 years, with each 20 mm Hg lower usual SBP associated with 35% lower vascular mortality (RR, 0.65; 95% CI, 0.61-0.68), including 48% lower stroke mortality (RR, 0.52; 95% CI, 0.47-0.59) and 32% lower ischemic heart disease mortality (RR, 0.68; 95% CI, 0.63-0.74). These RRs were broadly similar in those with and without diabetes. Compared with those without diabetes and SBP less than 135 mm Hg at recruitment, the vascular mortality RR was 2.8 (95% CI, 2.4-3.3) for those without diabetes and SBP of 155 mm Hg or greater, 4.7 (95% CI, 4.1-5.4) for those with uncontrolled diabetes and SBP less than 135 mm Hg, and 8.9 (95% CI, 7.2-11.1) for those with uncontrolled diabetes and SBP of 155 mm Hg or greater. Lower SBP was also associated with decreased kidney-related mortality (RR per 20 mm Hg lower usual SBP, 0.69; 95% CI, 0.64-0.74), decreased mortality from infection (RR, 0.81; 95% CI, 0.71-0.91), and decreased mortality from hepatobiliary disease (RR, 0.87; 95% CI, 0.78-0.98), but not decreased neoplastic or respiratory mortality. SBP was more informative for vascular mortality than other blood pressure measures (eg, compared with SBP, diastolic blood pressure was only two-thirds as informative).

Conclusions And Relevance: Blood pressure was most strongly associated with vascular and kidney-related mortality in this Mexican population, with particularly high absolute excess mortality rates among individuals with diabetes. The findings reinforce the need for more widespread use of blood pressure-lowering medication in Mexico, particularly among those with diabetes.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.18141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7519421PMC
September 2020

Randomization versus Real-World Evidence. Reply.

N Engl J Med 2020 07;383(4):e21

University of Oxford, Oxford, United Kingdom

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http://dx.doi.org/10.1056/NEJMc2020020DOI Listing
July 2020

Independent risk factors for simvastatin-related myopathy and relevance to different types of muscle symptom.

Eur Heart J 2020 09;41(35):3336-3342

Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, Big Data Institute, University of Oxford, Old Road Campus, Oxford OX3 7LF, UK.

Aims: Statins are widely used to prevent cardiovascular events, but little is known about the impact of different risk factors for statin-related myopathy or their relevance to reports of other types of muscle symptom.

Methods And Results: An observational analysis was undertaken of 171 clinically adjudicated cases of myopathy (defined as unexplained muscle pain or weakness with creatine kinase >10× upper limit of normal) and, separately, of 15 208 cases of other muscle symptoms among 58 390 individuals with vascular disease treated with simvastatin for a mean of 3.4 years. Cox proportional hazards models were used to identify independent predictors of myopathy. The rate of myopathy was low: 9 per 10 000 person-years of simvastatin therapy. Independent risk factors for myopathy included: simvastatin dose, ethnicity, sex, age, body mass index, medically treated diabetes, concomitant use of niacin-laropiprant, verapamil, beta-blockers, diltiazem and diuretics. In combination, these risk factors predicted more than a 30-fold risk difference between the top and bottom thirds of a myopathy risk score (hazard ratio : 34.35, 95% CI: 12.73-92.69, P across thirds = 9·1 × 10-48). However, despite the strong association with myopathy, this score was not associated with the other reported muscle symptoms (P across thirds = 0.93). Likewise, although SLCO1B1 genotype was associated with myopathy, it was not associated with other muscle symptoms.

Conclusions: The absolute risk of simvastatin-related myopathy is low, but individuals at higher risk can be identified to help guide patient management. The lack of association of the myopathy risk score with other muscle symptoms reinforces randomized placebo-controlled evidence that statins do not cause the vast majority of reported muscle symptoms.
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http://dx.doi.org/10.1093/eurheartj/ehaa574DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7544537PMC
September 2020

COVID-19 pandemic and admission rates for and management of acute coronary syndromes in England.

Lancet 2020 08 14;396(10248):381-389. Epub 2020 Jul 14.

Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, Oxford, UK; Medical Research Council Population Health Research Unit, Nuffield Department of Population Health, Oxford, UK. Electronic address:

Background: Several countries affected by the COVID-19 pandemic have reported a substantial drop in the number of patients attending the emergency department with acute coronary syndromes and a reduced number of cardiac procedures. We aimed to understand the scale, nature, and duration of changes to admissions for different types of acute coronary syndrome in England and to evaluate whether in-hospital management of patients has been affected as a result of the COVID-19 pandemic.

Methods: We analysed data on hospital admissions in England for types of acute coronary syndrome from Jan 1, 2019, to May 24, 2020, that were recorded in the Secondary Uses Service Admitted Patient Care database. Admissions were classified as ST-elevation myocardial infarction (STEMI), non-STEMI (NSTEMI), myocardial infarction of unknown type, or other acute coronary syndromes (including unstable angina). We identified revascularisation procedures undertaken during these admissions (ie, coronary angiography without percutaneous coronary intervention [PCI], PCI, and coronary artery bypass graft surgery). We calculated the numbers of weekly admissions and procedures undertaken; percentage reductions in weekly admissions and across subgroups were also calculated, with 95% CIs.

Findings: Hospital admissions for acute coronary syndrome declined from mid-February, 2020, falling from a 2019 baseline rate of 3017 admissions per week to 1813 per week by the end of March, 2020, a reduction of 40% (95% CI 37-43). This decline was partly reversed during April and May, 2020, such that by the last week of May, 2020, there were 2522 admissions, representing a 16% (95% CI 13-20) reduction from baseline. During the period of declining admissions, there were reductions in the numbers of admissions for all types of acute coronary syndrome, including both STEMI and NSTEMI, but relative and absolute reductions were larger for NSTEMI, with 1267 admissions per week in 2019 and 733 per week by the end of March, 2020, a percent reduction of 42% (95% CI 38-46). In parallel, reductions were recorded in the number of PCI procedures for patients with both STEMI (438 PCI procedures per week in 2019 vs 346 by the end of March, 2020; percent reduction 21%, 95% CI 12-29) and NSTEMI (383 PCI procedures per week in 2019 vs 240 by the end of March, 2020; percent reduction 37%, 29-45). The median length of stay among patients with acute coronary syndrome fell from 4 days (IQR 2-9) in 2019 to 3 days (1-5) by the end of March, 2020.

Interpretation: Compared with the weekly average in 2019, there was a substantial reduction in the weekly numbers of patients with acute coronary syndrome who were admitted to hospital in England by the end of March, 2020, which had been partly reversed by the end of May, 2020. The reduced number of admissions during this period is likely to have resulted in increases in out-of-hospital deaths and long-term complications of myocardial infarction and missed opportunities to offer secondary prevention treatment for patients with coronary heart disease. The full extent of the effect of COVID-19 on the management of patients with acute coronary syndrome will continue to be assessed by updating these analyses.

Funding: UK Medical Research Council, British Heart Foundation, Public Health England, Health Data Research UK, and the National Institute for Health Research Oxford Biomedical Research Centre.
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http://dx.doi.org/10.1016/S0140-6736(20)31356-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7429983PMC
August 2020

Questioning statin therapy for older patients - Authors' reply.

Lancet 2020 06;395(10240):1832-1833

Clinical Trial Service Unit, Nuffield Department of Population Health, Oxford, UK; Epidemiological Studies Unit, Nuffield Department of Population Health, Oxford, UK.

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http://dx.doi.org/10.1016/S0140-6736(19)33159-9DOI Listing
June 2020

The UK Biobank imaging enhancement of 100,000 participants: rationale, data collection, management and future directions.

Nat Commun 2020 05 26;11(1):2624. Epub 2020 May 26.

Nuffield Department of Population Health, University of Oxford, Oxford, UK.

UK Biobank is a population-based cohort of half a million participants aged 40-69 years recruited between 2006 and 2010. In 2014, UK Biobank started the world's largest multi-modal imaging study, with the aim of re-inviting 100,000 participants to undergo brain, cardiac and abdominal magnetic resonance imaging, dual-energy X-ray absorptiometry and carotid ultrasound. The combination of large-scale multi-modal imaging with extensive phenotypic and genetic data offers an unprecedented resource for scientists to conduct health-related research. This article provides an in-depth overview of the imaging enhancement, including the data collected, how it is managed and processed, and future directions.
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http://dx.doi.org/10.1038/s41467-020-15948-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7250878PMC
May 2020

Mortality and recurrent vascular events after first incident stroke: a 9-year community-based study of 0·5 million Chinese adults.

Lancet Glob Health 2020 04;8(4):e580-e590

Medical Research Council Population Health Research Unit, Oxford, UK; Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK. Electronic address:

Background: Stroke is a leading cause of death and disability worldwide. Despite considerable improvements in diagnosis and treatment, little is known about the short-term and long-term prognosis after a first stroke in low-income and middle-income countries, including China. We aimed to assess the short-term and long-term risk of recurrent stroke and mortality after a first stroke for each of the major pathological stroke types.

Methods: This population-based cohort study included adults aged 35-74 years without disability who were recruited to the China Kadoorie Biobank (CKB). A baseline survey was conducted in ten geographical areas (five urban, five rural) in China, and participants had clinical measurements recorded. Participants were followed up by monitoring death registries and by electronic linkage to health registries and health insurance claims databases, with follow-up until Jan 1, 2017. Participants were excluded from analyses if they had a previous history of stroke, transient ischaemic attack, or ischaemic heart disease at baseline. All incidences of fatal and non-fatal stroke during the study period were recorded by type (ischaemic stroke, intracerebral haemorrhage, subarachnoid haemorrhage, and unspecified type). Primary outcome measures were 28-day mortality, recurrent stroke, major vascular events (recurrent stroke, myocardial infarction, or vascular death), vascular mortality, and all-cause mortality.

Findings: Of 512 715 individuals in the CKB, 489 586 participants without previous ischaemic heart disease and stroke at recruitment were included, of whom 45 732 (42 073 [92%] confirmed by brain imaging) had a stroke during the study period. The mean age was 59·3 years (SD 9·8) for participants who had a stroke (54% women) and 50·8 years (10·3) for participants with no stroke (60% women). 36 588 (80%) of the incident cases of stroke were ischaemic stroke, 7440 (16%) were intracerebral haemorrhage, 702 (2%) were subarachnoid haemorrhage, and 1002 (2%) were an unspecified stroke type. 28-day mortality was 3% (95% CI 3-4) for ischaemic stroke, 47% (46-48)for intracerebral haemorrhage, 19% (17-22; 52% for rural areas and 32% for urban areas) subarachnoid haemorrhage, and 24% (22-27) for unspecified stroke. Among participants who survived stroke at 28 days, 41% (41-42) had recurrent stroke at 5 years (ischaemic stroke 41% [41-42], intracerebral haemorrhage 44% [42-46], subarachnoid haemorrhage 22% [18-27], unspecified stroke type 40% [35-44]) and mortality at 5 years was 17% ([17-18] ischaemic stroke 16% [15-16], intracerebral haemorrhage 28% [26-29], subarachnoid haemorrhage 16% [12-20], unspecified stroke type 15% [12-19]). After a first ischaemic stroke, 91% of recurrent strokes were also ischaemic stroke; after an intracerebral haemorrhage, 56% of recurrent strokes were intracerebral haemorrhage, and 41% of recurrent strokes were ischaemic stroke.

Interpretation: After a first stroke, the risk of recurrence or death within 5 years was high among this population of Chinese adults. Urgent improvements to secondary prevention of stroke in China are needed to reduce these risks.

Funding: Wellcome Trust, Medical Research Council, British Heart Foundation, Cancer Research UK, Kadoorie Charitable Foundation, Chinese Ministry of Science and Technology, National Natural Science Foundation of China.

Copyright: © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.
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http://dx.doi.org/10.1016/S2214-109X(20)30069-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7090905PMC
April 2020

The Magic of Randomization versus the Myth of Real-World Evidence.

N Engl J Med 2020 Feb;382(7):674-678

From the Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom.

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http://dx.doi.org/10.1056/NEJMsb1901642DOI Listing
February 2020

Effects of Omega-3 Fatty Acid Supplements on Arrhythmias.

Circulation 2020 01 27;141(4):331-333. Epub 2020 Jan 27.

Medical Research Council Population Health Research Unit (S.P., R.H., L.B., J.A.), Nuffield Department of Population Health, University of Oxford, United Kingdom.

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http://dx.doi.org/10.1161/CIRCULATIONAHA.119.044165DOI Listing
January 2020

A brief history of human disease genetics.

Nature 2020 01 8;577(7789):179-189. Epub 2020 Jan 8.

Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK.

A primary goal of human genetics is to identify DNA sequence variants that influence biomedical traits, particularly those related to the onset and progression of human disease. Over the past 25 years, progress in realizing this objective has been transformed by advances in technology, foundational genomic resources and analytical tools, and by access to vast amounts of genotype and phenotype data. Genetic discoveries have substantially improved our understanding of the mechanisms responsible for many rare and common diseases and driven development of novel preventative and therapeutic strategies. Medical innovation will increasingly focus on delivering care tailored to individual patterns of genetic predisposition.
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http://dx.doi.org/10.1038/s41586-019-1879-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7405896PMC
January 2020

Strategic Need for Large Prospective Studies in Different Populations.

JAMA 2020 01;323(4):309-310

Nuffield Department of Population Health, University of Oxford, Oxford, Oxfordshire, United Kingdom.

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http://dx.doi.org/10.1001/jama.2019.19736DOI Listing
January 2020

Physical Activity, Sedentary Leisure Time, Circulating Metabolic Markers, and Risk of Major Vascular Diseases.

Circ Genom Precis Med 2019 09 28;12(9):386-396. Epub 2019 Aug 28.

Clinical Trial Service Unit and Epidemiological Studies Unit (Y.P., C.K., H.D., I.Y.M., Y.C., L.Y., R.W., F.B., R.P., R. Clarke, R. Collins, D.A.B., L.L., M.V.H., Z.C.), Nuffield Department of Population Health, University of Oxford, United Kingdom.

Background: Physical inactivity and sedentary behavior are associated with higher risk of cardiovascular disease (CVD). Little is known about the relevance of circulating metabolites for these associations.

Methods: A nested case-control study within the prospective China Kadoorie Biobank included 3195 incident CVD cases (2057 occlusive CVD and 1138 intracerebral hemorrhage) and 1465 controls aged 30 to 79 years without prior CVD or statin use at baseline. Nuclear magnetic resonance spectroscopy was used to measure 225 metabolic markers and derived traits in baseline plasma samples. Linear regression was used to relate self-reported physical activity and sedentary leisure time to biomarkers, adjusting for potential confounders. These were contrasted with associations of biomarkers with occlusive CVD risk.

Results: Physical activity and sedentary leisure time were associated with >100 metabolic markers, with patterns of associations generally mirroring each other. Physical activity was inversely associated with very low and low-density and positively with large and very large HDL (high-density lipoprotein) particle concentrations. Physical activity was also inversely associated with alanine, glucose, lactate, acetoacetate, and the inflammatory marker glycoprotein acetyls. In general, associations of physical activity and sedentary leisure time with specific metabolic markers were directionally consistent with the associations of these metabolic markers with occlusive CVD risk. Overall, metabolic markers potentially explained ≈70% of the protective associations of physical activity and ≈50% of the positive associations of sedentary leisure time with occlusive CVD.

Conclusions: Among Chinese adults, physical activity and sedentary behavior have opposing associations with a diverse range of circulating metabolites, which may partially explain their associations with CVD risk.
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http://dx.doi.org/10.1161/CIRCGEN.118.002527DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6752700PMC
September 2019

General and Abdominal Adiposity and Mortality in Mexico City: A Prospective Study of 150 000 Adults.

Ann Intern Med 2019 09 13;171(6):397-405. Epub 2019 Aug 13.

National Autonomous University of Mexico, Mexico City, Mexico (J.A., R.R., R.T., A.G., C.G., M.S., P.K.).

Background: Some reports suggest that body mass index (BMI) is not strongly associated with mortality in Hispanic populations.

Objective: To assess the causal relevance of adiposity to mortality in Mexican adults, avoiding reverse causality biases.

Design: Prospective study.

Setting: 2 Mexico City districts.

Participants: 159 755 adults aged 35 years and older at recruitment, followed for up to 14 years. Participants with a hemoglobin A1c level of 7% or greater, diabetes, or other chronic diseases were excluded.

Measurements: BMI, waist-to-hip ratio, waist circumference, and cause-specific mortality. Cox regression, adjusted for confounders, yielded mortality hazard ratios (HRs) after at least 5 years of follow-up and before age 75 years.

Results: Among 115 400 participants aged 35 to <75 years at recruitment, mean BMI was 28.0 kg/m2 (SD, 4.1 kg/m2) in men and 29.6 kg/m2 (SD, 5.1 kg/m2) in women. The association of BMI at recruitment with all-cause mortality was J-shaped, with the minimum at 25 to <27.5 kg/m2. Above 25 kg/m2, each 5-kg/m2 increase in BMI was associated with a 30% increase in all-cause mortality (HR, 1.30 [95% CI, 1.24 to 1.36]). This association was stronger at ages 40 to <60 years (HR, 1.40 [CI, 1.30 to 1.49]) than at ages 60 to <75 years (HR, 1.24 [CI, 1.17 to 1.31]) but was not materially affected by sex, smoking, or other confounders. The associations of mortality with BMI and waist-to-hip ratio were similarly strong, and each was weakened only slightly by adjustment for the other. Waist circumference was strongly related to mortality and remained so even after adjustment for BMI and hip circumference.

Limitation: Analyses were limited to mortality.

Conclusion: General, and particularly abdominal, adiposity were strongly associated with mortality in this Mexican population.

Primary Funding Source: Mexican Health Ministry, Mexican National Council of Science and Technology, Wellcome Trust, Medical Research Council, and Kidney Research UK.
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http://dx.doi.org/10.7326/M18-3502DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6949137PMC
September 2019

Carotid Intima-Media Thickness but Not Carotid Artery Plaque in Healthy Individuals Is Linked to Lean Body Mass.

J Am Heart Assoc 2019 08 31;8(15):e011919. Epub 2019 Jul 31.

Clinical Trial Service Unit and Epidemiological Studies Unit Nuffield Department of Population Health University of Oxford Oxford United Kingdom.

Background Lean body mass has been identified as a key determinant of left ventricular mass and wall thickness. However, the importance of lean body mass or other body-size measures as normative determinants of carotid intima-media thickness (cIMT), a widely used early indicator of atherosclerosis, has not been well established. Methods and Results Carotid artery ultrasound measurements of cIMT and carotid artery plaque burden (derived from plaque number and maximum size) and measurements of body size, including height, body mass index, weight, body fat proportion, and lean body mass ([1-body fat proportion]×weight), were recorded in 25 020 participants from 10 regions of China. Analyses were restricted to a healthy younger subset (n=6617) defined as never or long-term ex-regular smokers aged <60 years (mean age, 50) without previous ischemic heart disease, stroke, diabetes mellitus, or hypertension and with plasma non-high-density lipoprotein cholesterol <4 mmol/L. Among these 6617 participants, 86% were women (because most men smoked) and 9% had carotid artery plaque. In both women and men separately, lean body mass was strongly positively associated with cIMT, but was not associated with plaque burden: overall, each 10 kg higher lean body mass was associated with a 0.03 (95% CI, 0.03-0.04) mm higher cIMT (P=5×10). Fat mass, height, and other body-size measures were more weakly associated with cIMT. Conclusions The strong association of lean body mass with cIMT, but not with plaque burden, in healthy adults suggests a normative relationship rather than reflecting atherosclerotic pathology. Common mechanisms may underlie the associations of lean body mass with cIMT and with nonatherosclerotic vascular traits.
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http://dx.doi.org/10.1161/JAHA.118.011919DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6761650PMC
August 2019

Impact of ADCY9 Genotype on Response to Anacetrapib.

Circulation 2019 Jul 23. Epub 2019 Jul 23.

Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK.

Background: Exploratory analyses of previous randomized trials generated a hypothesis that the clinical response to CETP inhibitor therapy differs by ADCY9 genotype, prompting the ongoing dal-GenE trial in individuals with a particular genetic profile. The randomized placebo-controlled REVEAL trial demonstrated the clinical efficacy of the CETP inhibitor anacetrapib among patients with pre-existing atherosclerotic vascular disease. In the present study, we have examined the impact of ADCY9 genotype on response to anacetrapib within the REVEAL trial.

Methods: Individuals with stable atherosclerotic vascular disease, who were treated with intensive atorvastatin therapy, received either anacetrapib 100 mg daily or matching placebo. Cox proportional hazards models, adjusted for the first 5 principal components of ancestry, were used to estimate the effects of allocation to anacetrapib on major vascular events (a composite of coronary death, myocardial infarction, coronary revascularization or presumed ischaemic stroke) and the interaction with ADCY9 rs1967309 genotype.

Results: Among 19,210 genotyped individuals of European ancestry, 2,504 (13.0%) had a first major vascular event during 4 years median follow-up: 1,216 (12.6%) among anacetrapib-allocated participants and 1,288 (13.4%) among placebo-allocated participants. Proportional reductions in the risk of major vascular events with anacetrapib did not differ significantly by ADCY9 genotype: HR = 0.92 (95% CI, 0.81-1.05) for GG; HR = 0.94 (95% CI, 0.84-1.06) for AG; and HR = 0.93 (95% CI, 0.76-1.13) for AA genotype carriers respectively; genotypic p for interaction = 0.96. Furthermore, there were no associations between ADCY9 genotype and the proportional reductions in the separate components of major vascular events, or meaningful differences in lipid response to anacetrapib.

Conclusions: The REVEAL trial is the single largest study to date evaluating the ADCY9 pharmacogenetic interaction. It provides no support for the hypothesis that ADCY9 genotype is materially relevant to the clinical effects of the CETP inhibitor anacetrapib. The ongoing dal-GenE study will provide direct evidence as to whether there is any specific pharmacogenetic interaction with dalcetrapib.

Clinical Trial Registration: URL: https://www.clinicaltrials.gov Unique Identifier: NCT01252953; URL: http://www.isrctn.com Unique Identifier: ISRCTN48678192; URL: https://www.clinicaltrialsregister.eu Unique Identifier: 2010-023467-18.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.119.041546DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6749971PMC
July 2019

Assessment of the Role of Carotid Atherosclerosis in the Association Between Major Cardiovascular Risk Factors and Ischemic Stroke Subtypes.

JAMA Netw Open 2019 05 3;2(5):e194873. Epub 2019 May 3.

Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom.

Importance: A better understanding of the role of atherosclerosis in the development of ischemic stroke subtypes could help to improve strategies for prevention of stroke worldwide.

Objective: To assess the role of carotid atherosclerosis in the association between major cardiovascular risk factors and ischemic stroke subtypes.

Design, Setting, And Participants: The prospective China Kadoorie Biobank cohort study was conducted in the general population of 5 urban and 5 rural areas in China, with a baseline survey obtained between June 2004 and July 2008. A random sample of 23 973 participants with no history of cardiovascular disease at enrollment who had carotid artery ultrasonographic measurements recorded at a resurvey from September 2013 to June 2014 were included. Data analysis was performed from July 1, 2016, to April 10, 2019.

Exposures: Major cardiovascular risk factors (ie, blood pressure [BP], blood lipid levels, smoking, and diabetes).

Main Outcomes And Measures: Carotid ultrasonographic measures of plaque burden (derived from number and maximum size of carotid artery plaques at resurvey) and first ischemic stroke during follow-up (n = 952), with subtyping (data release, August 2018) as lacunar (n = 263), probable large artery (n = 193), probable cardioembolic (n = 66), or unconfirmed (n = 430). Associations between cardiovascular risk factors, carotid plaque burden, and ischemic stroke subtypes were adjusted for age, sex, and geographic area.

Results: The 23 973 participants in the study had a mean (SD) age of 50.6 (10.0) years, and 14 833 (61.9%) were women. Systolic BP had a stronger association (odds ratio [OR] per SD, 1.51; 95% CI, 1.42-1.61) than plaque burden (OR per SD, 1.34; 95% CI, 1.26-1.44) with ischemic stroke, and the associations of systolic BP with each subtype of ischemic stroke were modestly attenuated by adjustment for plaque burden. After adjustment for BP, plaque burden had a stronger association with probable large artery stroke (OR, 1.43; 95% CI, 1.24-1.63) than with lacunar stroke (OR, 1.25; 95% CI, 1.10-1.43) but was not associated with probable cardioembolic stroke (OR, 1.06; 95% CI, 0.83-1.36).

Conclusions And Relevance: Although BP was an important risk factor for all ischemic stroke subtypes, carotid atherosclerosis was an important risk factor only for large artery and lacunar strokes, suggesting that drug treatments targeting atherosclerosis may reduce the risk of stroke subtypes to different extents.
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http://dx.doi.org/10.1001/jamanetworkopen.2019.4873DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6547114PMC
May 2019

Cost-effectiveness of lipid lowering with statins and ezetimibe in chronic kidney disease.

Kidney Int 2019 07 12;96(1):170-179. Epub 2019 Mar 12.

Health Economics Research Centre, Nuffield Department of Population Health, University of Oxford, UK; Centre for Primary Care and Public Health, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, UK. Electronic address:

Statin-based treatments reduce cardiovascular disease (CVD) risk in patients with non-dialysis chronic kidney disease (CKD), but it is unclear which regimen is the most cost-effective. We used the Study of Heart and Renal Protection (SHARP) CKD-CVD policy model to evaluate the effect of statins and ezetimibe on quality-adjusted life years (QALYs) and health care costs in the United States (US) and the United Kingdom (UK). Net costs below $100,000/QALY (US) or £20,000/QALY (UK) were considered cost-effective. We investigated statin regimens with or without ezetimibe 10 mg. Treatment effects on cardiovascular risk were estimated per 1-mmol/L reduction in low-density lipoprotein (LDL) cholesterol as reported in the Cholesterol Treatment Trialists' Collaboration meta-analysis, and reductions in LDL cholesterol were estimated for each statin/ezetimibe regimen. In the US, atorvastatin 40 mg ($0.103/day as of January 2019) increased life expectancy by 0.23 to 0.31 QALYs in non-dialysis patients with stages 3B to 5 CKD, at a net cost of $20,300 to $78,200/QALY. Adding ezetimibe 10 mg ($0.203/day) increased life expectancy by an additional 0.05 to 0.07 QALYs, at a net cost of $43,600 to $91,500/QALY. The cost-effectiveness findings and policy implications in the UK were similar. In summary, in patients with non-dialysis-dependent CKD, the evidence suggests that statin/ezetimibe combination therapy is a cost-effective treatment to reduce the risk of CVD.
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http://dx.doi.org/10.1016/j.kint.2019.01.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6595178PMC
July 2019

Conventional and genetic evidence on alcohol and vascular disease aetiology: a prospective study of 500 000 men and women in China.

Lancet 2019 05 4;393(10183):1831-1842. Epub 2019 Apr 4.

Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK. Electronic address:

Background: Moderate alcohol intake has been associated with reduced cardiovascular risk in many studies, in comparison with abstinence or with heavier drinking. Studies in east Asia can help determine whether these associations are causal, since two common genetic variants greatly affect alcohol drinking patterns. We used these two variants to assess the relationships between cardiovascular risk and genotype-predicted mean alcohol intake in men, contrasting the findings in men with those in women (few of whom drink).

Methods: The prospective China Kadoorie Biobank enrolled 512 715 adults between June 25, 2004, and July 15, 2008, from ten areas of China, recording alcohol use and other characteristics. It followed them for about 10 years (until Jan 1, 2017), monitoring cardiovascular disease (including ischaemic stroke, intracerebral haemorrhage, and myocardial infarction) by linkage with morbidity and mortality registries and electronic hospital records. 161 498 participants were genotyped for two variants that alter alcohol metabolism, ALDH2-rs671 and ADH1B-rs1229984. Adjusted Cox regression was used to obtain the relative risks associating disease incidence with self-reported drinking patterns (conventional epidemiology) or with genotype-predicted mean male alcohol intake (genetic epidemiology-ie, Mendelian randomisation), with stratification by study area to control for variation between areas in disease rates and in genotype-predicted intake.

Findings: 33% (69 897/210 205) of men reported drinking alcohol in most weeks, mainly as spirits, compared with only 2% (6245/302 510) of women. Among men, conventional epidemiology showed that self-reported alcohol intake had U-shaped associations with the incidence of ischaemic stroke (n=14 930), intracerebral haemorrhage (n=3496), and acute myocardial infarction (n=2958); men who reported drinking about 100 g of alcohol per week (one to two drinks per day) had lower risks of all three diseases than non-drinkers or heavier drinkers. In contrast, although genotype-predicted mean male alcohol intake varied widely (from 4 to 256 g per week-ie, near zero to about four drinks per day), it did not have any U-shaped associations with risk. For stroke, genotype-predicted mean alcohol intake had a continuously positive log-linear association with risk, which was stronger for intracerebral haemorrhage (relative risk [RR] per 280 g per week 1·58, 95% CI 1·36-1·84, p<0·0001) than for ischaemic stroke (1·27, 1·13-1·43, p=0·0001). For myocardial infarction, however, genotype-predicted mean alcohol intake was not significantly associated with risk (RR per 280 g per week 0·96, 95% CI 0·78-1·18, p=0·69). Usual alcohol intake in current drinkers and genotype-predicted alcohol intake in all men had similarly strong positive associations with systolic blood pressure (each p<0·0001). Among women, few drank and the studied genotypes did not predict high mean alcohol intake and were not positively associated with blood pressure, stroke, or myocardial infarction.

Interpretation: Genetic epidemiology shows that the apparently protective effects of moderate alcohol intake against stroke are largely non-causal. Alcohol consumption uniformly increases blood pressure and stroke risk, and appears in this one study to have little net effect on the risk of myocardial infarction.

Funding: Chinese Ministry of Science and Technology, Kadoorie Charitable Foundation, National Natural Science Foundation of China, British Heart Foundation, Cancer Research UK, GlaxoSmithKline, Medical Research Council, and Wellcome Trust.
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http://dx.doi.org/10.1016/S0140-6736(18)31772-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6497989PMC
May 2019

Causal associations of blood lipids with risk of ischemic stroke and intracerebral hemorrhage in Chinese adults.

Nat Med 2019 04 11;25(4):569-574. Epub 2019 Mar 11.

Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK.

Stroke is the second leading cause of death worldwide and accounts for >2 million deaths annually in China. Ischemic stroke (IS) and intracerebral hemorrhage (ICH) account for an equal number of deaths in China, despite a fourfold greater incidence of IS. Stroke incidence and ICH proportion are higher in China than in Western populations, despite having a lower mean low-density lipoprotein cholesterol (LDL-C) concentration. Observational studies reported weaker positive associations of LDL-C with IS than with coronary heart disease (CHD), but LDL-C-lowering trials demonstrated similar risk reductions for IS and CHD. Mendelian randomization studies of LDL-C and IS have reported conflicting results, and concerns about the excess risks of ICH associated with lowering LDL-C may have prevented the more widespread use of statins in China. We examined the associations of biochemically measured lipids with stroke in a nested case-control study in the China Kadoorie Biobank (CKB) and compared the risks for both stroke types associated with equivalent differences in LDL-C in Mendelian randomization analyses. The results demonstrated positive associations of LDL-C with IS and equally strong inverse associations with ICH, which were confirmed by genetic analyses and LDL-C-lowering trials. Lowering LDL-C is still likely to have net benefit for the prevention of overall stroke and cardiovascular disease in China.
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http://dx.doi.org/10.1038/s41591-019-0366-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6795549PMC
April 2019

Assessment of Vascular Event Prevention and Cognitive Function Among Older Adults With Preexisting Vascular Disease or Diabetes: A Secondary Analysis of 3 Randomized Clinical Trials.

JAMA Netw Open 2019 03 1;2(3):e190223. Epub 2019 Mar 1.

Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom.

Importance: Acquisition of reliable randomized clinical trial evidence of the effects of cardiovascular interventions on cognitive decline is a priority.

Objectives: To estimate the association of cognitive aging with the avoidance of vascular events in cardiovascular intervention trials and understand whether reports of nonsignificant results exclude worthwhile benefit.

Design, Setting, And Participants: This secondary analysis of 3 randomized clinical trials in participants with preexisting occlusive vascular disease or diabetes included survivors to final in-trial follow-up in the Heart Protection Study (HPS), Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH), and Treatment of HDL (High-Density Lipoprotein) to Reduce the Incidence of Vascular Events (HPS2-THRIVE) trials of lipid modification for prevention of cardiovascular events. Data were collected from February 1994 through January 2013 and analyzed from January 2015 through December 2018.

Exposures: Incident vascular events and diabetes and statin therapy.

Main Outcomes And Measures: Cognitive function was assessed at the end of a mean (SD) of 4.9 (1.5) years of follow-up using a 14-item verbal test. Associations of the incidence of vascular events and new-onset diabetes during the trials, with cognitive function at final in-trial follow-up were estimated and expressed as years of cognitive aging (using the association of the score with age >60 years). The benefit on cognitive aging mediated through the effects of lowering low-density lipoprotein cholesterol levels on events was estimated by applying these findings to nonfatal event differences observed with statin therapy in the HPS trial.

Results: Among 45 029 participants undergoing cognitive assessment, mean (SD) age was 67.9 (8.0) years; 80.7% were men. Incident stroke (n = 1197) was associated with 7.1 (95% CI, 5.7-8.5) years of cognitive aging; incident transient ischemic attack, myocardial infarction, heart failure, and new-onset diabetes were associated with 1 to 2 years of cognitive aging. In HPS, randomization to statin therapy for 5 years resulted in 2.0% of survivors avoiding a nonfatal stroke or transient ischemic attack and 2.4% avoiding a nonfatal cardiac event, which yielded an expected reduction in cognitive aging of 0.15 (95% CI, 0.11-0.19) years. With 15 926 participants undergoing cognitive assessment, HPS had 80% power to detect a 1-year (ie, 20% during the 5 years) difference in cognitive aging.

Conclusions And Relevance: The expected cognitive benefits of the effects of preventive therapies on cardiovascular events during even the largest randomized clinical trials may have been too small to be detectable. Hence, nonsignificant findings may not provide good evidence of a lack of worthwhile benefit on cognitive function with prolonged use of such therapies.

Trial Registration: isrctn.com and ClinicalTrials.gov Identifiers: ISRCTN48489393, ISRCTN74348595, and NCT00461630.
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http://dx.doi.org/10.1001/jamanetworkopen.2019.0223DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6484650PMC
March 2019
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