Fiona Bragg

Variation in rates of caesarean section among English NHS trusts after accounting for maternal and clinical risk: cross sectional study.

Objective To determine whether the variation in unadjusted rates of caesarean section derived from routine data in NHS trusts in England can be explained by maternal characteristics and clinical risk factors. Design A cross sectional analysis using routinely collected hospital episode statistics was performed. A multiple logistic regression model was used to estimate the likelihood of women having a caesarean section given their maternal characteristics (age, ethnicity, parity, and socioeconomic deprivation) and clinical risk factors (previous caesarean section, breech presentation, and fetal distress). Adjusted rates of caesarean section for each NHS trust were produced from this model. Setting 146 English NHS trusts. Population Women aged between 15 and 44 years with a singleton birth between 1 January and 31 December 2008. Main outcome measure Rate of caesarean sections per 100 births (live or stillborn). Results Among 620 604 singleton births, 147 726 (23.8%) were delivered by caesarean section. Women were more likely to have a caesarean section if they had had one previously (70.8%) or had a baby with breech presentation (89.8%). Unadjusted rates of caesarean section among the NHS trusts ranged from 13.6% to 31.9%. Trusts differed in their patient populations, but adjusted rates still ranged from 14.9% to 32.1%. Rates of emergency caesarean section varied between trusts more than rates of elective caesarean section. Conclusion Characteristics of women delivering at NHS trusts differ, and comparing unadjusted rates of caesarean section should be avoided. Adjusted rates of caesarean section still vary considerably and attempts to reduce this variation should examine issues linked to emergency caesarean section.

Association Between Diabetes and Cause-Specific Mortality in Rural and Urban Areas of China.

Importance In China, diabetes prevalence has increased substantially in recent decades, but there are no reliable estimates of the excess mortality currently associated with diabetes. Objectives To assess the proportional excess mortality associated with diabetes and estimate the diabetes-related absolute excess mortality in rural and urban areas of China. Design, Setting, and Participants A 7-year nationwide prospective study of 512 869 adults aged 30 to 79 years from 10 (5 rural and 5 urban) regions in China, who were recruited between June 2004 and July 2008 and were followed up until January 2014. Exposures Diabetes (previously diagnosed or detected by screening) recorded at baseline. Main Outcomes and Measures All-cause and cause-specific mortality, collected through established death registries. Cox regression was used to estimate adjusted mortality rate ratio (RR) comparing individuals with diabetes vs those without diabetes at baseline. Results Among the 512 869 participants, the mean (SD) age was 51.5 (10.7) years, 59% (n = 302 618) were women, and 5.9% (n = 30 280) had diabetes (4.1% in rural areas, 8.1% in urban areas, 5.8% of men, 6.1% of women, 3.1% had been previously diagnosed, and 2.8% were detected by screening). During 3.64 million person-years of follow-up, there were 24 909 deaths, including 3384 among individuals with diabetes. Compared with adults without diabetes, individuals with diabetes had a significantly increased risk of all-cause mortality (1373 vs 646 deaths per 100 000; adjusted RR, 2.00 [95% CI, 1.93-2.08]), which was higher in rural areas than in urban areas (rural RR, 2.17 [95% CI, 2.07-2.29]; urban RR, 1.83 [95% CI, 1.73-1.94]). Presence of diabetes was associated with increased mortality from ischemic heart disease (3287 deaths; RR, 2.40 [95% CI, 2.19-2.63]), stroke (4444 deaths; RR, 1.98 [95% CI, 1.81-2.17]), chronic liver disease (481 deaths; RR, 2.32 [95% CI, 1.76-3.06]), infections (425 deaths; RR, 2.29 [95% CI, 1.76-2.99]), and cancer of the liver (1325 deaths; RR, 1.54 [95% CI, 1.28-1.86]), pancreas (357 deaths; RR, 1.84 [95% CI, 1.35-2.51]), female breast (217 deaths; RR, 1.84 [95% CI, 1.24-2.74]), and female reproductive system (210 deaths; RR, 1.81 [95% CI, 1.20-2.74]). For chronic kidney disease (365 deaths), the RR was higher in rural areas (18.69 [95% CI, 14.22-24.57]) than in urban areas (6.83 [95% CI, 4.73-9.88]). Among those with diabetes, 10% of all deaths (16% rural; 4% urban) were due to definite or probable diabetic ketoacidosis or coma (408 deaths). Conclusions and Relevance Among adults in China, diabetes was associated with increased mortality from a range of cardiovascular and noncardiovascular diseases. Although diabetes was more common in urban areas, it was associated with greater excess mortality in rural areas.

Associations of blood glucose and prevalent diabetes with risk of cardiovascular disease in 500 000 adult Chinese: the China Kadoorie Biobank

To examine the relationship of self‐reported diabetes, and of random blood glucose levels among individuals without known diabetes, with the prevalence of cardiovascular disease in Chinese adults.

Evaluation of type 2 diabetes genetic risk variants in Chinese adults: findings from 93,000 individuals from the China Kadoorie Biobank.

Aims/hypothesisGenome-wide association studies (GWAS) have discovered many risk variants for type 2 diabetes. However, estimates of the contributions of risk variants to type 2 diabetes predisposition are often based on highly selected case–control samples, and reliable estimates of population-level effect sizes are missing, especially in non-European populations.MethodsThe individual and cumulative effects of 59 established type 2 diabetes risk loci were measured in a population-based China Kadoorie Biobank (CKB) study of 93,000 Chinese adults, including >7,100 diabetes cases.ResultsAssociation signals were directionally consistent between CKB and the original discovery GWAS: of 56 variants passing quality control, 48 showed the same direction of effect (binomial test, p = 2.3 × 10−8). We observed a consistent overall trend towards lower risk variant effect sizes in CKB than in case–control samples of GWAS meta-analyses (mean 19–22% decrease in log odds, p ≤ 0.0048), likely to reflect correction of both ‘winner’s curse’ and spectrum bias effects. The association with risk of diabetes of a genetic risk score, based on lead variants at 25 loci considered to act through beta cell function, demonstrated significant interactions with several measures of adiposity (BMI, waist circumference [WC], WHR and percentage body fat [PBF]; all pinteraction < 1 × 10−4), with a greater effect being observed in leaner adults.Conclusions/interpretationOur study provides further evidence of shared genetic architecture for type 2 diabetes between Europeans and East Asians. It also indicates that even very large GWAS meta-analyses may be vulnerable to substantial inflation of effect size estimates, compared with those observed in large-scale population-based cohort studies.Access to research materialsDetails of how to access China Kadoorie Biobank data and details of the data release schedule are available from www.ckbiobank.org/site/Data+Access.

A Review on Metaanalysis of Biomarkers: Promises and Pitfalls

BACKGROUND The last 30 years have seen an exponential increase in metaanalyses. By combining multiple studies, metaanalysis can provide an overview of the totality of evidence on a particular question and the statistical power needed to reduce random error and produce precise estimates of even modest effect sizes. This capability is of particular value when many small studies address similar questions [such as in the investigation of novel cardiovascular disease (CVD) biomarkers]. To provide reliable evidence, however, metaanalyses must be undertaken robustly. CONTENT In this review, we describe the major issues to consider when designing and conducting metaanalyses, including the design of constituent studies, selection criteria, assessment of exposures and disease outcomes, and control of bias and confounding. Some of the potential challenges and pitfalls associated with metaanalysis are examined, and their consequences are considered. We use 2 examples of novel biomarkers for CVD-homocysteine and triglycerides-to illustrate how metaanalyses of observational studies have contributed to, and on occasion hindered, our understanding; and how subsequent work has built upon these findings. SUMMARY Metaanalyses of observational studies, particularly metaanalyses of individual-participant data, have the power to provide robust evidence to support our understanding of the role of novel biomarkers for disease. The characteristic limitations and challenges of these studies, including their inability to detect causal associations, must be considered, however, and additional evidence from randomized controlled trials and genetic studies is frequently required to elucidate fully the role of novel biomarkers in predicting cardiovascular risk.

Diabetes, plasma glucose and incidence of pancreatic cancer: A prospective study of 0.5 million Chinese adults and a meta-analysis of 22 cohort studies.

Diabetes is associated with an increased risk of pancreatic cancer (PC) in Western populations. Uncertainty remains, however, about the relevance of plasma glucose for PC among people without diabetes and about the associations of diabetes and high blood glucose with PC in China where the increase in diabetes prevalence has been very recent. The prospective China Kadoorie Biobank (CKB) study recruited 512,000 adults aged 30‐79 years from 10 diverse areas of China during 2004‐2008, recording 595 PC cases during 8 years of follow‐up. Cox regression yielded adjusted hazard ratios (HRs) for PC associated with diabetes (previously diagnosed or screen‐detected) and, among those without previously diagnosed diabetes, with levels of random plasma glucose (RPG). These were further meta‐analysed with 22 published prospective studies. Overall 5.8% of CKB participants had diabetes at baseline. Diabetes was associated with almost twofold increased risk of PC (adjusted HR = 1.87, 95% CI 1.48‐2.37), with excess risk higher in those with longer duration since diagnosis (p for trend = 0.01). Among those without previously diagnosed diabetes, each 1 mmol/L higher usual RPG was associated with a HR of 1.12 (1.04‐1.21). In meta‐analysis of CKB and 22 other studies, previously diagnosed diabetes was associated with a 52% excess risk (1.52, 1.43‐1.63). Among those without diabetes, each 1 mmol/L higher blood glucose was associated with a 15% (1.15, 1.09‐1.21) excess risk. In Chinese and non‐Chinese populations, diabetes and higher blood glucose levels among those without diabetes are associated with an increased risk of PC.

Risks and Population Burden of Cardiovascular Diseases Associated with Diabetes in China: A Prospective Study of 0.5 Million Adults

Background In China, diabetes prevalence is rising rapidly, but little is known about the associated risks and population burden of cardiovascular diseases. We assess associations of diabetes with major cardiovascular diseases and the relevance of diabetes duration and other modifiable risk factors to these associations. Methods and Findings A nationwide prospective study recruited 512,891 men and women aged 30–79 y between 25 June 2004 and 15 July 2008 from ten diverse localities across China. During ~7 y of follow-up, 7,353 cardiovascular deaths and 25,451 non-fatal major cardiovascular events were recorded among 488,760 participants without prior cardiovascular disease at baseline. Cox regression yielded adjusted hazard ratios (HRs) comparing disease risks in individuals with diabetes to those without. Overall, 5.4% (n = 26,335) of participants had self-reported (2.7%) or screen-detected (2.7%) diabetes. Individuals with self-reported diabetes had an adjusted HR of 2.07 (95% CI 1.90–2.26) for cardiovascular mortality. There were significant excess risks of major coronary event (2.44, 95% CI 2.18–2.73), ischaemic stroke (1.68, 95% CI 1.60–1.77), and intracerebral haemorrhage (1.24, 95% CI 1.07–1.44). Screen-detected diabetes was also associated with significant, though more modest, excess cardiovascular risks, with corresponding HRs of 1.66 (95% CI 1.51–1.83), 1.62 (95% CI 1.40–1.86), 1.48 (95% CI 1.40–1.57), and 1.17 (95% CI 1.01–1.36), respectively. Misclassification of screen-detected diabetes may have caused these risk estimates to be underestimated, whilst lack of data on lipids may have resulted in residual confounding of diabetes-associated cardiovascular disease risks. Among individuals with diabetes, cardiovascular risk increased progressively with duration of diabetes and number of other presenting modifiable cardiovascular risk factors. Assuming a causal association, diabetes now accounts for ~0.5 million (489,676, 95% CI 335,777–681,202) cardiovascular deaths annually in China. Conclusions Among Chinese adults, diabetes is associated with significantly increased risks of major cardiovascular diseases. The increasing prevalence and younger age of onset of diabetes foreshadow greater diabetes-attributable disease burden in China.

Fresh fruit consumption in relation to incident diabetes and diabetic vascular complications: A 7-y prospective study of 0.5 million Chinese adults.

Background Despite the well-recognised health benefits of fresh fruit consumption, substantial uncertainties remain about its potential effects on incident diabetes and, among those with diabetes, on risks of death and major vascular complications. Methods and findings Between June 2004 and July 2008, the nationwide China Kadoorie Biobank study recruited 0.5 million adults aged 30–79 (mean 51) y from ten diverse localities across China. During ~7 y of follow-up, 9,504 new diabetes cases were recorded among 482,591 participants without prevalent (previously diagnosed or screen-detected) diabetes at baseline, with an overall incidence rate of 2.8 per 1,000 person-years. Among 30,300 (5.9%) participants who had diabetes at baseline, 3,389 deaths occurred (overall mortality rate 16.5 per 1,000), along with 9,746 cases of macrovascular disease and 1,345 cases of microvascular disease. Cox regression yielded adjusted hazard ratios (HRs) associating each disease outcome with self-reported fresh fruit consumption, adjusting for potential confounders such as age, sex, region, socio-economic status, other lifestyle factors, body mass index, and family history of diabetes. Overall, 18.8% of participants reported consuming fresh fruit daily, and 6.4% never/rarely (non-consumers), with the proportion of non-consumers about three times higher in individuals with previously diagnosed diabetes (18.9%) than in those with screen-detected diabetes (6.7%) or no diabetes (6.0%). Among those without diabetes at baseline, higher fruit consumption was associated with significantly lower risk of developing diabetes (adjusted HR = 0.88 [95% CI 0.83–0.93] for daily versus non-consumers, p < 0.001, corresponding to a 0.2% difference in 5-y absolute risk), with a clear dose–response relationship. Among those with baseline diabetes, higher fruit consumption was associated with lower risks of all-cause mortality (adjusted HR = 0.83 [95% CI 0.74–0.93] per 100 g/d) and microvascular (0.72 [0.61–0.87]) and macrovascular (0.87 [0.82–0.93]) complications (p < 0.001), with similar HRs in individuals with previously diagnosed and screen-detected diabetes; estimated differences in 5-y absolute risk between daily and non-consumers were 1.9%, 1.1%, and 5.4%, respectively. The main limitation of this study was that, owing to its observational nature, we could not fully exclude the effects of residual confounding. Conclusion In this large epidemiological study in Chinese adults, higher fresh fruit consumption was associated with significantly lower risk of diabetes and, among diabetic individuals, lower risks of death and development of major vascular complications.

Association of Random Plasma Glucose Levels With the Risk for Cardiovascular Disease Among Chinese Adults Without Known Diabetes

Importance Diabetes is a known risk factor for cardiovascular disease (CVD). Substantial uncertainty remains, however, about the relevance to CVD risk for blood glucose levels below the diabetes threshold. Objective To examine the association of random plasma glucose (RPG) levels with the risk for major CVD in Chinese adults without known diabetes. Design, Setting, and Participants This prospective cohort study included 467 508 men and women aged 30 to 79 years with no history of diabetes, ischemic heart disease (IHD), stroke, or transient ischemic attack. Participants were recruited from 5 urban and 5 rural diverse locations across China from June 25, 2004, to July 15, 2008, and followed up to January 1, 2014. Exposures Baseline and usual (longer-term average) RPG level. Main Outcomes and Measures Cardiovascular deaths, major coronary events (MCE) (including fatal IHD and nonfatal myocardial infarction), ischemic stroke (IS), major occlusive vascular disease (MOVD) (including MCE or IS), and intracerebral hemorrhage. Preliminary validation of stroke and IHD events demonstrated positive predictive values of approximately 90% and 85%, respectively. Cox regression yielded adjusted hazard ratios (aHRs) for CVD associated with RPG levels. Results Among the 467 508 participants (41.0% men; 59.0% women; mean [SD] age, 51 [11] years), a significant positive association of baseline RPG levels with CVD risks continued to 4.0 mmol/L (72 mg/dL). After adjusting for regression dilution bias, each 1-mmol/L (18-mg/dL) higher usual RPG level above 5.9 mmol/L (106 mg/dL) was associated with an 11% higher risk for cardiovascular death (6645 deaths; aHR, 1.11; 95% CI, 1.10-1.13). Similarly strong positive associations were seen for MCE (3270 events; aHR, 1.10; 95% CI, 1.08-1.13), IS (19 153 events; aHR, 1.08; 95% CI, 1.07-1.09), and MOVD (22 023 events; aHR, 1.08; 95% CI, 1.07-1.09). For intracerebral hemorrhage, the association was weaker, but also significant (4326 events; aHR, 1.05; 95% CI, 1.02-1.07). These associations persisted after excluding participants who developed diabetes during follow-up. Conclusions and Relevance Among adult Chinese without diabetes, lower RPG levels are associated with lower risks for major CVDs, even within a normal range of blood glucose levels.

Associations of General and Central Adiposity With Incident Diabetes in Chinese Men and Women.

OBJECTIVE We assess associations of general and central adiposity in middle age and of young adulthood adiposity with incident diabetes in adult Chinese and estimate the associated population burden of diabetes. RESEARCH DESIGN AND METHODS The prospective China Kadoorie Biobank enrolled 512,891 adults 30–79 years of age from 10 localities across China during 2004–2008. During 9.2 years of follow-up, 13,416 cases of diabetes were recorded among 482,589 participants without diabetes at baseline. Cox regression yielded adjusted hazard ratios (HRs) for incident diabetes associated with measures of general (e.g., BMI and BMI at 25 years) and central (e.g., waist circumference [WC]) adiposity. RESULTS The mean (SD) BMI was 23.6 kg/m2 (3.4 kg/m2), and 3.8% had a BMI ≥30 kg/m2. Throughout the range examined (19–32 kg/m2), BMI showed a positive log-linear relationship with diabetes, with adjusted HRs per SD higher usual BMI greater in men (1.98; 95% CI 1.93–2.04) than in women (1.77; 1.73–1.81) (P for heterogeneity <0.001). For WC, HRs per SD were 2.13 (95% CI 2.07–2.19) in men and 1.91 (1.87–1.95) in women (P for heterogeneity <0.001). Mutual adjustment attenuated these associations, especially those of BMI. BMI at age 25 years was weakly positively associated with diabetes (men HR 1.09 [95% CI 1.05–1.12]; women 1.04 [1.02–1.07] per SD), which was reversed after adjustment for baseline BMI. In China, the increase in adiposity accounted for ∼50% of the increase in diabetes burden since 1980. CONCLUSIONS Among relatively lean Chinese adults, higher adiposity—general and central—was strongly positively associated with the risk of incident diabetes. The predicted continuing increase in adiposity in China foreshadows escalating rates of diabetes.