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Aims Aspirin is widely used in cardiovascular disease prevention but is also associated with an increased risk of bleeding. The net effect of aspirin on dementia and cognitive impairment is uncertain. Methods and results In the ASCEND trial, 15 480 people from the UK with diabetes and no history of cardiovascular disease were randomized to aspirin 100 mg daily or matching placebo for a mean of 7.4 years. The 15 427 ASCEND participants with no recorded dementia prior to baseline were included in this cognitive study with a primary pre-specified outcome of ‘broad dementia’, comprising dementia, cognitive impairment, or confusion. This was ascertained through participant, carer, or general practitioner report or hospital admission diagnosis, by 31 March 2019 (∼2 years beyond the scheduled treatment period). The broad dementia outcome occurred in a similar percentage of participants in the aspirin group and placebo group: 548 participants (7.1%) vs. 598 (7.8%), rate ratio 0.91 [95% confidence interval (CI), 0.81–1.02]. Thus, the CI excluded proportional hazards of >2% and proportional benefits of >19%. Conclusion Aspirin does not have a large proportional effect on the risk of dementia. Trials or meta-analyses with larger total numbers of incident dementia cases to increase statistical power are needed to assess whether any modest proportional 10–15% benefits of 5–7 years of aspirin use on dementia exist. Clinical Trial Registration Current Controlled Trials number, ISRCTN60635500; ClinicalTrials.gov number: NCT00135226.

Background: Mendelian randomization studies of systolic blood pressure (SBP) can assess the shape and strength of the associations of genetically predicted differences in SBP with major disease outcomes and are less constrained by biases in observational analyses. This study aimed to compare the associations of usual and genetically predicted SBP with major cardiovascular disease (CVD) outcomes, overall and by levels of SBP, age, and sex. Methods: The China Kadoorie Biobank involved a 12-year follow-up of a prospective study of 489 495 adults aged 40 to 79 years with no prior CVD and 86 060 with genetic data. Outcomes included major vascular events (59 490/23 151 in observational/genetic analyses), and its components (ischemic stroke [n=39 513/12 043], intracerebral hemorrhage [7336/5243], and major coronary events [7871/4187]). Genetically predicted SBP used 460 variants obtained from European ancestry genome-wide studies. Cox regression estimated adjusted hazard ratios for incident CVD outcomes down to usual SBP levels of 120 mm Hg. Results: Both observational and genetic analyses demonstrated log-linear positive associations of SBP with major vascular event and other major CVD types in the range of 120 to 170 mm Hg. Consistent with the observational analyses, the hazard ratios per 10 mm Hg higher genetically predicted SBP were 2-fold greater for intracerebral hemorrhage (1.71 [95% CI, 1.58–1.87]) than for ischemic stroke (1.37 [1.30–1.45]) or major coronary event (1.29 [1.18–1.42]). Genetic analyses also demonstrated 2-fold greater hazard ratios for major vascular event in younger (1.69 [95% CI, 1.54–1.86]) than in older people (1.28 [1.18–1.38]). Conclusions: The findings provide support for initiation of blood pressure-lowering treatment at younger ages and below the conventional cut-offs for hypertension to maximize CVD prevention, albeit the absolute risks of CVD are far greater in older people.

Background Atrial fibrillation (AF) has a higher prevalence in men than in women and is associated with measures of adiposity and lean mass (LM). However, it remains uncertain whether the risks of AF associated with these measures vary by sex. Methods Among 477 904 UK Biobank participants aged 40–69 without prior AF, 23 134 incident AF cases were identified (14 400 men, 8734 women; median follow-up 11.1 years). Cox proportional hazards models were used to estimate the covariate adjusted hazard ratios (HRs) describing the association of AF with weight, measures of adiposity [fat mass (FM), waist circumference (WC)] and LM, and their independent relevance, by sex. Results Weight and WC were independently associated with risk of AF [HR: 1.25 (1.23–1.27) per 10 kg, HR: 1.11 (1.09–1.14) per 10 cm, respectively], with comparable effects in both sexes. The association with weight was principally driven by LM, which, per 5 kg, conferred double the risk of AF compared with FM when mutually adjusted [HR: 1.20 (1.19–1.21), HR: 1.10 (1.09–1.11), respectively]; however, the effect of LM was weaker in men than in women (p-interaction = 4.3 x 10−9). Comparing the relative effects of LM, FM and WC identified different patterns within each sex; LM was the strongest predictor for both, whereas WC was stronger than FM in men but not in women. Conclusions LM and FM (as constituents of weight) and WC are risk factors for AF. However, the independent relevance of general adiposity for AF was more limited in men than in women. The relevance of both WC and LM suggests a potentially important role for visceral adiposity and muscle mass in AF development.

Background: Statin therapy is effective for the prevention of atherosclerotic cardiovascular disease and is widely prescribed, but there are persisting concerns that statin therapy might frequently cause muscle pain or weakness. We aimed to address these through an individual participant data meta-analysis of all recorded adverse muscle events in large, long-term, randomised, double-blind trials of statin therapy. Methods: Randomised trials of statin therapy were eligible if they aimed to recruit at least 1000 participants with a scheduled treatment duration of at least 2 years, and involved a double-blind comparison of statin versus placebo or of a more intensive versus a less intensive statin regimen. We analysed individual participant data from 19 double-blind trials of statin versus placebo (n=123 940) and four double-blind trials of a more intensive versus a less intensive statin regimen (n=30 724). Standard inverse-variance-weighted meta-analyses of the effects on muscle outcomes were conducted according to a prespecified protocol. Findings: Among 19 placebo-controlled trials (mean age 63 years [SD 8], with 34 533 [27·9%] women, 59 610 [48·1%] participants with previous vascular disease, and 22 925 [18·5%] participants with diabetes), during a weighted average median follow-up of 4·3 years, 16 835 (27·1%) allocated statin versus 16 446 (26·6%) allocated placebo reported muscle pain or weakness (rate ratio [RR] 1·03; 95% CI 1·01–1·06). During year 1, statin therapy produced a 7% relative increase in muscle pain or weakness (1·07; 1·04–1·10), corresponding to an absolute excess rate of 11 (6–16) events per 1000 person-years, which indicates that only one in 15 ([1·07–1·00]/1·07) of these muscle-related reports by participants allocated to statin therapy were actually due to the statin. After year 1, there was no significant excess in first reports of muscle pain or weakness (0·99; 0·96–1·02). For all years combined, more intensive statin regimens (ie, 40–80 mg atorvastatin or 20–40 mg rosuvastatin once per day) yielded a higher RR than less intensive or moderate-intensity regimens (1·08 [1·04–1·13] vs 1·03 [1·00–1·05]) compared with placebo, and a small excess was present (1·05 [0·99–1·12]) for more intensive regimens after year 1. There was no clear evidence that the RR differed for different statins, or in different clinical circumstances. Statin therapy yielded a small, clinically insignificant increase in median creatine kinase values of approximately 0·02 times the upper limit of normal. Interpretation: Statin therapy caused a small excess of mostly mild muscle pain. Most (>90%) of all reports of muscle symptoms by participants allocated statin therapy were not due to the statin. The small risks of muscle symptoms are much lower than the known cardiovascular benefits. There is a need to review the clinical management of muscle symptoms in patients taking a statin. Funding: British Heart Foundation, Medical Research Council, Australian National Health and Medical Research Council.

IntroductionAmong individuals with diabetes, high adiposity has been associated with lower cardiovascular disease (CVD) mortality (the so-called ‘obesity paradox’ phenomenon) in Western populations, for reasons that are still not fully elucidated. Moreover, little is known about such phenomena in Chinese adults with diabetes among whom very few were obese. We aimed to assess the associations of adiposity with vascular and non-vascular mortality among individuals with diabetes, and compare these with associations among individuals without diabetes.Research design and methodsIn 2004–2008, the prospective China Kadoorie Biobank recruited >512 000 adults from 10 areas in China. After ~10 years of follow-up, 3509 deaths (1431 from CVD) were recorded among 23 842 individuals with diabetes but without prior major diseases at baseline. Cox regression yielded adjusted HRs associating adiposity with mortality.ResultsAmong people with diabetes, body mass index (BMI) (mean 25.0 kg/m2) was positively log linearly associated with CVD incidence (n=9943; HR=1.19 (95% CI 1.15 to 1.22) per 5 kg/m2), but showed U-shaped associations with CVD and overall mortality, with lowest risk at 22.5–24.9 kg/m2. At lower BMI, risk of death (n=671) within 28 days of CVD onset was particularly elevated, with an HR of 3.26 (95% CI 2.29 to 4.65) at 2 relative to 22.5–24.9 kg/m2, but no higher mortality risk at BMI ≥25.0 kg/m2. These associations were similar in self-reported and screen-detected diabetes, and persisted after extensive attempts to address reverse causality and confounding. Among individuals without diabetes (mean BMI 23.6 kg/m2; n=23 305 deaths), there were less extreme excess mortality risks at low BMI.ConclusionsAmong relatively lean Chinese adults with diabetes, there were contrasting associations of adiposity with CVD incidence and with mortality. The high mortality risk at low and high BMI levels highlights, if causal, the importance of maintaining normal weight among people with diabetes.

Little is known about the incidence rates and importance of major modifiable risk factors for hip and major osteoporotic fractures in low- and middle-income countries. We estimated the age- and sex-specific incidence of hip, major osteoporotic, and any fractures and their associated risk factors in Chinese adults.This was a prospective study of 512,715 adults, aged 30-79 years, recruited from 10 diverse areas in China from 2004 to 2008 and followed up for 10 years. Age- and sex-specific incidence rates were estimated, and Cox regression was used to yield adjusted hazard ratios (HRs) and population attributable fractions for risk factors.The incidence rates of hip fracture in Chinese adults were 5.1 (95% confidence interval [CI] 5.0-5.3) per 10,000 person-years; they were higher in women than in men and increased by two- to threefold per 10-year older age. Among men, five risk factors for hip fracture, including low education (HR = 1.23; 95% CI 1.04-1.45), regular smoker (1.22, 1.03-1.45), lower weight (1.59, 1.34-1.88), alcohol drinker (1.18, 1.02-1.36), and prior fracture (1.62, 1.33-1.98), accounted for 44.3% of hip fractures. Among women, lower weight (1.30, 1.15-1.46), low physical activity (1.22, 1.10-1.35), diabetes (1.62, 1.41-1.86), prior fracture (1.54, 1.33-1.77), and self-rated poor health (1.29, 1.13-1.47) accounted for 24.9% of hip fractures. Associations of risk factors with major osteoporotic or any fractures were weaker than those with hip fractures.The age- and sex-specific incidence rates of hip fracture in Chinese adults were comparable with those in Western populations. Five potentially modifiable factors accounted for half of the hip fractures in men and one quarter in women.

Stroke and carotid atherosclerosis are associated with dementia. Carotid endarterectomy (CEA) reduces stroke risk, although its effect on later dementia is uncertain. Participants in the Asymptomatic Carotid Surgery Trial (ACST-1), randomly allocated to immediate vs. deferral of CEA (i.e., no intervention unless or until triggered by ipsilateral transient ischaemic attack or stroke), were followed, to study effects on dementia.From 1993 to 2003, ACST-1 included 3 120 participants with asymptomatic tight carotid stenosis. All UK and Swedish patients (n = 1 601; 796 immediate vs. 805 deferral) were followed with trial records, national electronic health record linkage, and (UK only) by post and telephone. Cumulative incidence and competing risk analyses were used to measure the effects of risk factors and CEA on dementia risk. Intention to treat analyses yielded hazard ratios (HRs; immediate vs. deferral) of dementia.The median follow up was 19.4 years (interquartile range 16.9 - 21.7). Dementia was recorded in 107 immediate CEA patients and 115 allocated delayed surgery; 1 290 patients died (1 091 [538 vs. 536] before any dementia diagnosis). Dementia incidence rose with age and with female sex (men: 8.3% aged70 years at trial entry vs. 15.1% aged ≥ 70; women: 15.1% aged70 years at trial entry vs. 22.4% aged ≥ 70 years) and was higher in those with pre-existing cerebral infarction (silent or with prior symptoms; 20.2% vs. 13.6%). Dementia risk was similar in both randomised groups: 6.7% vs. 6.6% at 10 years and 14.3% vs. 15.5% at 20 years, respectively. The dementia HR was 0.98 (95% confidence interval [CI] 0.75 - 1.28; p = .89), with no heterogeneity in the neutral effect of immediate CEA on dementia related to age, carotid stenosis, blood pressure, diabetes, country of residence, or medical treatments at trial entry (heterogeneity values p.05).CEA was not associated with significant reductions in the long term hazards of dementia, but the CI did not exclude a proportional benefit or hazard of about 25%.

Background Chronological age is the strongest risk factor for most chronic diseases. Developing a biomarker-based age and understanding its most important contributing biomarkers may shed light on the effects of age on later-life health and inform opportunities for disease prevention. Methods A subpopulation of 141 254 individuals healthy at baseline were studied, from among 480 019 UK Biobank participants aged 40–70 recruited in 2006–2010, and followed up for 6–12 years via linked death and secondary care records. Principal components of 72 biomarkers measured at baseline were characterized and used to construct sex-specific composite biomarker ages using the Klemera Doubal method, which derived a weighted sum of biomarker principal components based on their linear associations with chronological age. Biomarker importance in the biomarker ages was assessed by the proportion of the variation in the biomarker ages that each explained. The proportions of the overall biomarker and chronological age effects on mortality and age-related hospital admissions explained by the biomarker ages were compared using likelihoods in Cox proportional hazard models. Results Reduced lung function, kidney function, reaction time, insulin-like growth factor 1, hand grip strength, and higher blood pressure were key contributors to the derived biomarker age in both men and women. The biomarker ages accounted for >65% and >84% of the apparent effect of age on mortality and hospital admissions for the healthy and whole populations, respectively, and significantly improved prediction of mortality (p < .001) and hospital admissions (p < 1 × 10−10) over chronological age alone. Conclusions This study suggests that a broader, multisystem approach to research and prevention of diseases of aging warrants consideration.

Background Taller adult height is associated with lower risks of ischaemic heart disease in both conventional and Mendelian randomisation studies, providing support for a causal association, but the associations of height with ischaemic stroke and ischaemic stroke subtypes are uncertain. Purpose To examine the causal relevance of height for ischaemic stroke and ischaemic stroke subtypes. Methods Two-sample Mendelian randomisation analyses were used to examine the associations of height with: (i) ischaemic stroke and ischaemic stroke subtypes in MEGASTROKE (using summary data from 34 217 ischaemic stroke cases), and with (ii) established cardiovascular and other risk factors using individual data from 336 433 participants in UK Biobank and 57 785 in the China Kadoorie Biobank. Instruments for Mendelian randomisation were constructed from up to 3280 height-associated genetic variants, previously identified as having genome-wide significant effects on height. Results Genetically-determined taller height was inversely associated with ischaemic stroke (3% [95% CI: 1–6] lower risk per 1 standard deviation taller height) in MEGASTROKE but this masked much stronger opposing associations on risks of different ischaemic stroke subtypes: 15% (95% CI: 9–21) higher risk of cardioembolic stroke, 10% (4–15) lower risk of large-artery atherosclerotic stroke, and 15% (10–20) lower risk of small-vessel stroke (Figure). Genetically-determined taller height was strongly associated with atrial fibrillation and higher lean body mass and lung function but more weakly associated with lower levels of LDL cholesterol and blood pressure. Conclusions The findings support a causal association between taller adult height and risk of atrial fibrillation and cardioembolic stroke. The opposing associations of height with other ischaemic stroke subtypes provide further support for considering ischaemic stroke subtypes as distinct diseases in both research and clinical practice. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): Medical Research Council, British Heart Foundation

Background Platelet activation plays a major role in the atherothrombotic complications of diabetes. Thromboxane (TX)A2 is a pro-thrombotic prostanoid, synthesized via cyclooxygenase-1 and released by activated platelets. The metabolism of TXA2 in vivo leads to a major stable end-product, 11-dehydro-TXB2 (TXM), measurable in urine and reflecting the whole-body rate of TXA2 biosynthesis. In two large trials of high-risk, aspirin-treated (mostly, without diabetes) patients, (CHARISMA and HOPE trials), the baseline rate of urinary TXM excretion was an independent predictor of future cardiovascular events. Purpose The aim of the ASCEND (A Study of Cardiovascular Events in Diabetes) TXM sub-study was to investigate the association between baseline urinary TXM and future serious vascular events or revascularization (SVE-R), major bleeds and incident cancer independent of other risk factors and treatment, in people with diabetes and no manifest cardiovascular disease at trial entry. Methods Urinary TXM was measured by a previously GC/MS-validated, immunoassay in 6,487 participants with eligible baseline samples. Analyses excluded 539 participants using NSAIDs. TXM appeared log-normally distributed, so analyses were by quintiles and per SD (=0.622) of continuous loge TXM. The association of loge TXM with outcome was adjusted by basic factors (age, sex, sample volume and randomized treatment allocation) and by the predictors of log TXM (smoking, type 2 diabetes treated with insulin or oral hypoglycaemics, HDL cholesterol, body mass index, urinary albumin/creatinine ratio, eGFR). The association of log TXM with non-vascular, non-cancer MedDRA outcomes was investigated to determine whether TXM had a general effect on outcome. During a mean of 6.6 years follow-up there were 618 SVE-Rs, 206 bleeds and 700 cancers among these patients. Results Log TXM correlated significantly with SVE-R, hazard ratio (HR) per 1 SD of log TXM: 1.13 (1.04–1.23), p=0.003 (Figure 1, panel a), non-significantly with major bleeds [HR 1.15 (1.00–1.32), p=0.055] (Figure 1, panel b), and marginally significantly with cancer [HR 1.09 (1.01–1.17), p=0.03] (Figure 1, panel c). There was no association of log TXM with non-vascular non-cancer MedDRA outcomes (HR per 1 SD, 0.99; 99% CI, 0.94–1.05). Conclusion The rate of urinary TXM excretion, a non-invasive biomarker of TXA2-mediated platelet activation in vivo, is log-linearly associated with serious vascular events independent of other risk factors in people with diabetes. Its potential association with cancer must be viewed as hypothesis-generating and needs confirmation. Figure 1 Funding Acknowledgement Type of funding source: Public grant(s) – EU funding. Main funding source(s): IMI1: Surrogate markers for micro- and macro-vascular hard endpoints for innovative diabetes tools (SUMMIT).

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.

BackgroundTaller adult height is associated with lower risks of ischaemic heart disease in both observational and Mendelian randomisation studies, but little is known about the causal relevance of height for different subtypes of ischaemic stroke and the mechanisms involved.MethodsHeight-associated genetic variants (up to 2,931) from previous genome-wide association studies were used to construct genetic instruments in different populations. Two-sample Mendelian randomisation approaches were used to examine the associations of genetically-determined height with ischaemic stroke and its subtypes in multiple ancestries (MEGASTROKE: 60,341 ischaemic stroke cases) supported by additional cases in Europeans (UK Biobank: 4,055 cases) and in Chinese (China Kadoorie Biobank: 10,297 cases). The associations of genetically-determined height with established cardiovascular and other risk factors were also examined in Europeans (UK Biobank: 336,750 participants) and Chinese (China Kadoorie Biobank: 58,277 participants).ResultsGenetically-determined height was inversely associated with ischaemic stroke (4% [95% CI: 1–7] lower risk per 1 standard deviation taller height in MEGASTROKE). This masked much stronger opposing associations of height with different subtypes, with a 12% (95% CI: 6–17) higher risk of cardioembolic stroke, 11% (6–16) lower risk of large-artery stroke, and 14% (9–18) lower risk of small-vessel stroke. Genetically-determined height was strongly positively associated with atrial fibrillation, lean body mass and lung function, and inversely associated with levels of LDL cholesterol and blood pressure in both Europeans and Chinese.ConclusionsIn multiple ancestries, genetic associations support the causal relevance of taller adult height for higher risk of cardioembolic stroke (in addition to atrial fibrillation) and lower risk of other ischaemic strokes, highlighting the need to properly differentiate subtypes of ischaemic stroke in both clinical practice and research.

Background: 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. Methods: 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. 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. Conclusions: 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.

Clinical trials generally need to be able to detect or to refute realistically moderate (but still worthwhile) differences between treatments in long-term disease outcome. Large-scale randomized evidence should be able to detect such effects, but medium-sized trials or medium-sized meta-analyses can, and often do, yield false-negative or exaggeratedly positive results. Hundreds of thousands of premature deaths each year could be avoided by seeking appropriately large-scale randomized evidence about various widely practicable treatments for the common causes of death, and by disseminating this evidence appropriately. This chapter takes a look at the use of large-scale randomized evidence—produced from trials and meta-analysis of trials—and how this data should be handled in order to produce accurate result.

Background: Adiposity is a major risk factor for cardiovascular diseases (CVD). However, uncertainty remains about its relevance for mortality following incident CVD, particularly among individuals with diabetes. Methods: In 2004-08 the prospective China Kadoorie Biobank recruited 512,000 adults aged 30-79 years from 10 areas in China. After ~9 years’ follow-up, 3509 deaths (1431 from CVD) and 9940 incident CVD were recorded among 23,842 individuals with diabetes but without prior major diseases. Cox regression yielded adjusted hazard ratios (HRs) associating adiposity with disease outcomes. Findings: Among people with diabetes (mean baseline BMI 25.0 kg/m2), BMI was positively associated with CVD incidence (HR=1.19 [95% CI 1.15-1.22] per 5 kg/m2), but there was a U-shaped association with CVD mortality, with the lowest risk at 22.5-24.9 kg/m2. Case fatality following CVD onset (deaths occurring within 28 days, n=671) at lower BMI was particularly marked with HR of 3.32 (2.33-4.73) at

Background Diabetes mellitus is associated with an increased risk of cardiovascular events. Aspirin use reduces the risk of occlusive vascular events but increases the risk of bleeding; the balance of benefits and hazards for the prevention of first cardiovascular events in patients with diabetes is unclear. Methods We randomly assigned adults who had diabetes but no evident cardiovascular disease to receive aspirin at a dose of 100 mg daily or matching placebo. The primary efficacy outcome was the first serious vascular event (i.e., myocardial infarction, stroke or transient ischemic attack, or death from any vascular cause, excluding any confirmed intracranial hemorrhage). The primary safety outcome was the first major bleeding event (i.e., intracranial hemorrhage, sight-threatening bleeding event in the eye, gastrointestinal bleeding, or other serious bleeding). Secondary outcomes included gastrointestinal tract cancer. Results A total of 15,480 participants underwent randomization. During a mean follow-up of 7.4 years, serious vascular events occurred in a significantly lower percentage of participants in the aspirin group than in the placebo group (658 participants [8.5%] vs. 743 [9.6%]; rate ratio, 0.88; 95% confidence interval [CI], 0.79 to 0.97; P=0.01). In contrast, major bleeding events occurred in 314 participants (4.1%) in the aspirin group, as compared with 245 (3.2%) in the placebo group (rate ratio, 1.29; 95% CI, 1.09 to 1.52; P=0.003), with most of the excess being gastrointestinal bleeding and other extracranial bleeding. There was no significant difference between the aspirin group and the placebo group in the incidence of gastrointestinal tract cancer (157 participants [2.0%] and 158 [2.0%], respectively) or all cancers (897 [11.6%] and 887 [11.5%]); long-term follow-up for these outcomes is planned. Conclusions Aspirin use prevented serious vascular events in persons who had diabetes and no evident cardiovascular disease at trial entry, but it also caused major bleeding events. The absolute benefits were largely counterbalanced by the bleeding hazard. (Funded by the British Heart Foundation and others; ASCEND Current Controlled Trials number, ISRCTN60635500 ; ClinicalTrials.gov number, NCT00135226 .).

Markers of inflammation, including plasma C-reactive protein (CRP), are associated with an increased risk of cardiovascular disease, and it has been suggested that this association is causal. However, the relationship between inflammation and cardiovascular disease has not been extensively studied in patients with chronic kidney disease. To evaluate this, we used data from the Study of Heart and Renal Protection (SHARP) to assess associations between circulating CRP and LDL cholesterol levels and the risk of vascular and non-vascular outcomes. Major vascular events were defined as nonfatal myocardial infarction, cardiac death, stroke or arterial revascularization, with an expanded outcome of vascular events of any type. Higher baseline CRP was associated with an increased risk of major vascular events (hazard ratio per 3x increase 1.28; 95% confidence interval 1.19-1.38). Higher baseline LDL cholesterol was also associated with an increased risk of major vascular events (hazard ratio per 0.6 mmol/L higher LDL cholesterol; 1.14, 1.06-1.22). Higher baseline CRP was associated with an increased risk of a range of non-vascular events (1.16, 1.12-1.21), but there was a weak inverse association between baseline LDL cholesterol and non-vascular events (0.96, 0.92-0.99). The efficacy of lowering LDL cholesterol with simvastatin/ezetimibe on major vascular events, in the randomized comparison, was similar irrespective of CRP concentration at baseline. Thus, decisions to offer statin-based therapy to patients with chronic kidney disease should continue to be guided by their absolute risk of atherosclerotic events. Estimation of such risk may include plasma biomarkers of inflammation, but there is no evidence that the relative beneficial effects of reducing LDL cholesterol depends on plasma CRP concentration.

ObjectiveTo help determine whether midlife obesity is a cause of dementia and whether low body mass index (BMI), low caloric intake, and physical inactivity are causes or merely consequences of the gradual onset of dementia by recording these factors early in a large 20-year prospective study and relating them to dementia detection rates separately during follow-up periods of MethodsA total of 1,136,846 UK women, mean age 56 (SD 5) years, were recruited in 1996 to 2001 and asked about height, weight, caloric intake, and inactivity. They were followed up until 2017 by electronic linkage to National Health Service records, detecting hospital admissions with mention of dementia. Cox regression yielded adjusted rate ratios (RRs) for first dementia detection during particular follow-up periods.ResultsFifteen years after the baseline survey, only 1% were lost to follow-up, and 89% remained alive with no detected dementia, of whom 18,695 had dementia detected later, at a mean age of 77 (SD 4) years. Dementia detection during years 15+ was associated with baseline obesity (BMI 30+ vs 20–24 kg/m2: RR 1.21, 95% confidence interval 1.16–1.26,p< 0.0001) but not clearly with low BMI, low caloric intake, or inactivity at baseline. The latter 3 factors were associated with increased dementia rates during the first decade, but these associations weakened substantially over time, approaching null after 15 years.ConclusionsMidlife obesity may well be a cause of dementia. In contrast, behavioral changes due to preclinical disease could largely or wholly account for associations of low BMI, low caloric intake, and inactivity with dementia detection during the first decade of follow-up.

BackgroundAge is the strongest risk factor for most chronic diseases, and yet individuals may age at different rates biologically. A biological age formed from biomarkers may be a stronger risk factor than chronological age and understanding what factors contribute to it could provide insight into new opportunities for disease prevention.Methods and findingsAmong 480,019 UK Biobank participants aged 40-70 recruited in 2006-2010 and followed up for 6-12 years via linked death registry and secondary care records, a subpopulation of 141,254 (29.4%) non-smoking adults in good health and with no medication use or disease history at baseline were identified. Independent components of 72 biomarkers measured at baseline were characterised by principal component analysis. The Klemera Doubal method (KDM), which derived a weighted sum of biomarker principal components based on the strengths of their linear associations with chronological age, was used to derive sex-specific biological ages in this healthy subpopulation. The proportions of the overall biological and chronological age effects on mortality, coronary heart disease and age-related non-fatal hospital admissions (based on a hospital frailty index) that were explained by biological age were assessed using log-likelihoods of proportional hazards models.Reduced lung function, reduced kidney function, slower reaction time, lower insulin-like-growth factor 1, lower hand grip strength and higher blood pressure were key contributors to biological age (explaining the highest percentages of its variance) in both men and women, while lower albumin, higher sex hormone-binding globulin and lower muscle mass in men, and higher liver enzymes, blood lipids and HbA1c in women were also important. Across both sexes, a 51-principal component biological age explained 66%, 80% and 63% of the age effects on mortality, coronary heart disease and hospital admissions, respectively. Restricting the biological age to the 12-13 key biomarkers corresponding to the 10 most importantly contributing principal components resulted in little change in these proportions for women, but a reduction to 53%, 63% and 50%, respectively, for men.ConclusionsThis study identified that markers of impaired function in a range of organs account for a substantial proportion of the apparent effect of age on disease and hospital admissions. It supports a broader, multi-system approach to research and prevention of diseases of ageing.

Background Low-dose aspirin is of established benefit for secondary prevention of cardiovascular events but in primary prevention the benefit is finely balanced with the hazard of major bleeds, and in particular gastrointestinal (GI) bleeds. Purpose To investigate non-vascular, non-genetic risk factors for major GI bleeds and derive a score for GI bleed risk which may help identify who will receive most net benefit from aspirin. Methods In the UK Biobank prospective study of 0.5M participants aged 40–69 at recruitment, prior history of cardiovascular disease, bleeds and other medical conditions was ascertained from self-reported diagnoses and electronic heath records (EHR) prior to recruitment. Major GI bleed during 6 years of follow-up was defined based on coded diagnoses and duration of hospital stay. Non-vascular risk factors for bleed were identified from amongst 100 baseline and prior disease factors using a stepwise regression with adjustment for established vascular risk factors, aspirin and warfarin use. 10-way cross-validation was used when making risk scores. Results Among the primary prevention population without prior intracranial bleed, serious extracranial bleed or gastrointestinal ulcer in the 6 months prior to recruitment, 1682 (0.06%/y) participants had a major GI bleed (1006 upper GI, 676 lower GI) with a mean stay in hospital of 3.2 days. Antiplatelet use (in 11%) and anticoagulant use (in 1%), were associated with 1.5 and 4 fold risks of GI bleed, respectively. Stepwise regression identified a non-vascular risk score for major bleed with a 4-fold risk ratio across fifths (Figure). But the score was also associated with a 2-fold risk ratio for major vascular events. Conclusions Major GI bleeds cause substantial morbidity. A 4-fold difference in bleed risk across quintiles was distinguishable by a score based largely on EHR prior disease information and frailty measures. This score is applicable in other contexts and will be applied in the ASCEND randomised trial of daily aspirin to provide randomized evidence of the net benefit of aspirin in different risk categories. However, vascular risk factors predicted risk of GI bleeds, and non-vascular risk factors for GI bleed predicted risk of major vascular events; so the net benefit from aspirin may vary only modestly across categories by vascular and bleed risks.

Background Mendelian randomisation (MR) studies have been widely used to assess the causal relevance of risk factors for disease and to elucidate the likely effects of novel drug targets. MR studies have confirmed the causal relevance of lipoprotein(a) [Lp(a)] for risk of coronary heart disease (CHD), but the impact of prior vascular disease on these associations remains unclear, and is potentially important when testing the effects of Lp(a) lowering therapies. Purpose To examine the associations of LPA variants, as a proxy for Lp(a) levels, with risk of CHD, ischaemic stroke and peripheral vascular disease (PVD), by history of vascular disease in UK Biobank (UKB). Methods An LPA genotype score was constructed in 283,658 unrelated white British UKB participants, using 2 SNPs (rs3798220 and rs10455872) previously shown to be independently associated with, and explain ∼40% of the variance in, Lp(a) levels. The LPA score was tested for association with hospitalisation for CHD (n=23,165), presumed ischaemic stroke (n=2,579) and PVD (n=3,780) using Cox PH models. Estimated hazard ratios (per LPA variant) for cardiovascular outcomes are reported both overall and by history of vascular disease (CHD, ischaemic stroke or PVD) at baseline. Results As observed in previous studies, LPA was associated with a higher risk of CHD (Hazard ratio [HR] 1.27 per LPA variant; 95% CI: 1.24–1.31). However, the effect was substantially attenuated in participants with versus without prior vascular disease (p-interaction = 3x10–5; Figure). The effect of the LPA score on PVD was comparable to that for CHD (p-heterogeneity = 0.25), whilst the effect on ischaemic stroke was significantly weaker than that for CHD (p-heterogeneity = 6x10–3). As for CHD, the effects of the LPA score on both ischaemic stroke and PVD were weaker in those with versus those without prior vascular disease. Furthermore, the heterogeneity between the effects on cardiovascular outcomes was more extreme when stratified by history of CHD. Conclusions This MR study shows that the effects of LPA on risk of CHD, ischaemic stroke and PVD are weaker in individuals with a history of vascular disease, perhaps reflecting the effects of medications used in this setting. Therefore, MR studies in the general population may overestimate the anticipated effects of Lp(a)-lowering therapies in randomised trials, which are typically conducted in individuals with prior vascular disease. Acknowledgement/Funding British Heart Foundation

Key Points Question What is the role of carotid atherosclerosis in the association between major cardiovascular risk factors and different ischemic stroke subtypes? Findings In this population-based cohort study of Chinese adults with subtyping of incident ischemic strokes, carotid artery ultrasonographic measurements were recorded in 23 973 participants after 8 years’ follow-up. Blood pressure was associated with all ischemic stroke subtypes independently of carotid plaque burden, but after adjustment for blood pressure, carotid plaque burden was associated with probable large artery and lacunar stroke but not with probable cardioembolic stroke. Meaning Drug treatments targeting atherosclerosis may affect the risk of ischemic stroke subtypes to different extents., 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., This population-based cohort study examines the role of carotid atherosclerosis in the association between major cardiovascular risk factors and ischemic stroke.

The agricultural and agri-food industry has a prevalent, long-standing history as a successful cornerstone industry in Ontario. This historical prevalence stands true for the central rural township of Brock, Ontario as agriculture and livestock are a driving force in the township’s economy. However, throughout the last three decades, agricultural production in Ontario’s rural townships have been negatively impacted by vertical integration, globalization, and the intensification of land-based activities (Wicks & Merrett, 2003). Therefore, the aim of this research study is to determine if agritourism is a viable solution to aid in revitalizing the rural township of Brock, Ontario. This research is imperative for farm operators in rural Ontario because small family farms are seeking ways to remain economically competitive against the pressures of urbanization and changing global markets. The objectives of this research study necessitate in-depth information-gathering which will be gained from conducting semi-structured interviews with individuals whom are members of the Beaverton Agricultural Society, the Sunderland Agricultural Society, or the Ontario Federation of Agriculture (OFA). This research will provide information about why farmers decided to diversify their farms through agritourism, how agritourism has helped farming businesses (if at all), and what strategies farmers used to implement agritourism into their traditional farming practices. The findings of this research study will be utilized by for farm operators that have integrated agritourism practices into their traditional farming practices and for government programs and policies to support farm operators.

Purpose The Heart Protection Study 2–Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE) trial of patients at high risk of vascular disease found that adding extended-release niacin-laropiprant to intensive statin-based LDL-lowering therapy had no benefit on cardiovascular outcomes. However, the trial also identified previously unrecognized serious adverse effects (including new-onset diabetes, bleeding, and infection). Our objective was to explore the safety profile of niacin-laropiprant and examine whether any patients were at lower (or higher) risk of its adverse effects. Methods HPS2-THRIVE was a randomized, double-blind trial of niacin-laropiprant (2000/40 mg/d) versus placebo among 25,673 patients at high risk of vascular disease. Information on all serious adverse events was collected during a median of 3.9 years of study treatment. Effects of niacin-laropiprant on new-onset diabetes, disturbances of diabetes control, bleeding, infection, and gastrointestinal upset were estimated by (1) time after randomization, (2) severity, (3) baseline characteristics, (4) baseline risk of the adverse event of interest, and (5) risk of major vascular event. Findings The hazard ratio (HR) for new-onset diabetes with niacin/laropiprant was 1.32 (95% CI, 1.16–1.51; P < .001), which corresponded to an absolute excess of 4 people (95% CI, 2–6) developing diabetes per 1000 person-years in the study population as a whole. Among the 8299 participants with diabetes at baseline, the HR for serious disturbances in diabetes control was 1.56 (95% CI, 1.35–1.80), corresponding to an absolute excess of 12 (95% CI, 8–16) per 1000 person-years. The HR was 1.38 (95% CI, 1.17–1.63; P < .001) for serious bleeding, corresponding to an absolute excess of 2 (95% CI, 1–3) per 1000 person-years and 1.22 (95% CI, 1.11–1.34; P < .001) for serious infection, corresponding to an absolute excess of 4 (95% CI, 2–6) per 1000 person-years. The excess risks of these serious adverse events were larger in the first year after starting niacin-laropiprant therapy than in later years (except for the excess of infection, which did not appear to attenuate with time), and the risks of nonfatal and fatal events were similarly increased. The absolute excesses of each of these adverse effects were similar regardless of the baseline risk of the outcome. Implications Practitioners or patients considering the use of niacin (in addition to, or instead of, a statin) despite the lack of evidence of cardiovascular benefits (at least when added to effective statin therapy) should take account of the significant risks of these serious adverse effects when making such decisions. ClinicalTrials.gov identifier: NCT00461630.

Stroke is the second leading cause of death worldwide and accounts for 2 million deaths annually in China

Summary Background China has high stroke rates despite the population being relatively lean. Uncertainty persists about the relevance of adiposity to risk of stroke types. We aimed to assess the associations of adiposity with incidence of stroke types and effect mediation by blood pressure in Chinese men and women. Methods The China Kadoorie Biobank enrolled 512 891 adults aged 30–79 years from ten areas (five urban and five rural) during 2004–08. During a median 9 years (IQR 8–10) of follow-up, 32 448 strokes (about 90% confirmed by neuroimaging) were recorded among 489 301 participants without previous cardiovascular disease. Cox regression analysis was used to produce adjusted hazard ratios (HRs) for ischaemic stroke (n=25 210) and intracerebral haemorrhage (n=5380) associated with adiposity. Findings Mean baseline body-mass index (BMI) was 23·6 kg/m2 (SD 3·2), and 331 723 (67·8%) participants had a BMI of less than 25 kg/m2. Throughout the range examined (mean 17·1 kg/m2 [SD 0·9] to 31·7 kg/m2 [2·0]), each 5 kg/m2 higher BMI was associated with 8·3 mm Hg (SE 0·04) higher systolic blood pressure. BMI was positively associated with ischaemic stroke, with an HR of 1·30 (95% CI 1·28–1·33 per 5 kg/m2 higher BMI), which was generally consistent with that predicted by equivalent differences in systolic blood pressure (1·25 [1·24–1·26]). The HR for intracerebral haemorrhage (1·11 [1·07–1·16] per 5 kg/m2 higher BMI) was less extreme, and much weaker than that predicted by the corresponding difference in systolic blood pressure (1·48 [1·46–1·50]). Other adiposity measures showed similar associations with stroke types. After adjustment for usual systolic blood pressure, the positive associations with ischaemic stroke were attenuated (1·05 [1·03–1·07] per 5 kg/m2 higher BMI); for intracerebral haemorrhage, they were reversed (0·73 [0·70–0·77]). High adiposity (BMI >23 kg/m2) accounted for 14·7% of total stroke (16·5% of ischaemic stroke and 6·7% of intracerebral haemorrhage). Interpretation In Chinese adults, adiposity was strongly positively associated with ischaemic stroke, chiefly through its effect on blood pressure. For intracerebral haemorrhage, leanness, either per se or through some other factor (or factors), might increase risk, offsetting the protective effects of lower blood pressure. Funding UK Wellcome Trust, UK Medical Research Council, British Heart Foundation, Cancer Research UK, Kadoorie Charitable Foundation, Chinese Ministry of Science and Technology, Chinese National Natural Science Foundation.

Background Population-based studies of ultrasound measures of carotid atherosclerosis are informative about future risks of cardiovascular disease. Design Cross-sectional studies of carotid artery atherosclerosis in 24,822 Chinese adults from the China Kadoorie Biobank and 2579 Europeans from the UK Biobank. Methods Mean intima-media thickness of the common carotid arteries and presence of carotid artery plaque were examined in the China Kadoorie Biobank study. The carotid intima-media thickness (cIMT) findings in Chinese (mean age 59 years) were compared with a European population (mean age 62 years). Results Overall, the mean cIMT in Chinese was 0.70 mm (SD 0.16) and increased with age by 0.08 mm (SE 0.008) per 10-years older age. About 31% of the Chinese had carotid plaques and the prevalence varied 10-fold with age (6% at 40-49 to 63% at 70-89 years) and four-fold by region (range, 14%-57%). After adjustment for age, sex and region, plaque prevalence was higher in smokers than in non-smokers (36% vs. 28%) and two-fold higher in individuals with systolic blood pressure ≥160 mmHg than those with systolic blood pressure120 mmHg (44% vs. 22%) in the China Kadoorie Biobank study. Mean cIMT was similar in the younger Chinese and European adults, but increased more steeply with age in the Chinese ( p = 0.002). Conclusions About one-third of Chinese adults had carotid plaques. The rate of progression of carotid atherosclerosis with age was more extreme in the Chinese compared with the European population, highlighting the need for more intensive strategies for cardiovascular disease prevention in China.

Lowering LDL cholesterol reduces the risk of developing atherosclerotic events in CKD, but the effects of such treatment on progression of kidney disease remain uncertain. Here, 6245 participants with CKD (not on dialysis) were randomly assigned to simvastatin (20 mg) plus ezetimibe (10 mg) daily or matching placebo. The main prespecified renal outcome was ESRD (defined as the initiation of maintenance dialysis or kidney transplantation). During 4.8 years of follow-up, allocation to simvastatin plus ezetimibe resulted in an average LDL cholesterol difference (SEM) of 0.96 (0.02) mmol/L compared with placebo. There was a nonsignificant 3% reduction in the incidence of ESRD (1057 [33.9%] cases with simvastatin plus ezetimibe versus 1084 [34.6%] cases with placebo; rate ratio, 0.97; 95% confidence interval [95% CI], 0.89 to 1.05; P=0.41). Similarly, allocation to simvastatin plus ezetimibe had no significant effect on the prespecified tertiary outcomes of ESRD or death (1477 [47.4%] events with treatment versus 1513 [48.3%] events with placebo; rate ratio, 0.97; 95% CI, 0.90 to 1.04; P=0.34) or ESRD or doubling of baseline creatinine (1189 [38.2%] events with treatment versus 1257 [40.2%] events with placebo; rate ratio, 0.93; 95% CI, 0.86 to 1.01; P=0.09). Exploratory analyses also showed no significant effect on the rate of change in eGFR. Lowering LDL cholesterol by 1 mmol/L did not slow kidney disease progression within 5 years in a wide range of patients with CKD.

Background and objectives Because there is substantial biologic intraindividual variation in albumin excretion, randomized trials of albuminuria-reducing therapies may need multiple urine samples to estimate daily urinary albumin excretion. Mailing spot urine samples could offer a convenientand cost-effective method to collect multiple samples, but urine albumin-to-creatinine ratio stability in samples stored at ambient temperatures for several days is unknown. Design, setting, participants, & measurements Patients with kidney disease provided fresh urine samples in two tubes (with and without boric acid preservative). Reference aliquots from each participant were analyzed immediately, whereas remaining aliquots were subject to different handling/storage conditions before analysis, including delayed processing for up to 7 days at three different storage temperatures (4°C, 18°C, and 30°C), multiple freeze-thaw cycles, and long–term frozen storage at280°C,240°C, and220°C. We calculated the mean percentage change in urine albumin-to-creatinine ratio for each condition, and we considered samples stable if the 95% confidence interval was within a65% threshold. Results Ninety-three patients provided samples with detectable albuminuria in the reference aliquot. Median (interquartile range) urine albumin-to-creatinine ratio was 87 (20–499) mg/g. The inclusion of preservative had minimal effect on fresh urine albumin-to-creatinine ratio measurements but reduced the changes in albumin and creatinine in samples subject to processing delay and storage conditions.The urine albumin-to-creatinine ratio was stable for 7 days in samples containing preservative at 4°C and 18°C and 2 days when stored at 30°C. It was also stable in samples with preservative after three freeze-thaw cycles and in frozen storage for 6 months at280°C or240°C but not at220°C. Conclusions Mailed urine samples collected with preservative and received within 7 days if ambient temperature is#18°C, or within 2 days if the temperature is higher but does not exceed 30°C, are suitable for the measurement of urine albumin-to-creatinine ratioin randomized trials. Preserved samples frozen to 240°C or280°C for 6 months before analysis also seem suitable.

We set out to use machine learning techniques to analyse ECG data to improve risk evaluation of cardiovascular disease in a very large cohort study of the Chinese population. We performed this investigation by (i) detecting "abnormality" using 3 one-class classification methods, and (ii) predicting probabilities of "normality", arrhythmia, ischemia, and hypertrophy using a multiclass approach. For one-class classification, we considered 5 possible definitions for "normality" and used 10 automatically-extracted ECG features along with 4 blood pressure features. The one-class approach was able to identify abnormality with area-under-curve (AUC) 0.83, and with 75.6% accuracy. For four-class classification, we used 86 features in total, with 72 additional features extracted from the ECG. Accuracy for this four-class classifier reached 75.1%. The methods demonstrated proof-of-principle that cardiac abnormality can be detected using machine learning in a large cohort study.