Correlates and consequences of atrial fibrillation in a prospective study of 25 000 participants in the China Kadoorie Biobank.

Aims: The prevalence of atrial fibrillation (AF) is positively correlated with prior cardiovascular diseases (CVD) and CVD risk factors but is lower in Chinese than Europeans despite their higher burden of CVD. We examined the prevalence and prognosis of AF and other electrocardiogram (ECG) abnormalities in the China Kadoorie Biobank. Methods and results: A random sample of 25 239 adults (mean age 59.5 years, 62% women) had a 12-lead ECG recorded and interpreted using a Mortara VERITAS™ algorithm in 2013-14. Participants were followed up for 5 years for incident stroke, ischaemic heart disease, heart failure (HF), and all CVD, overall and by CHA2DS2-VASc scores, age, sex, and area. Overall, 1.2% had AF, 13.6% had left ventricular hypertrophy (LVH), and 28.1% had ischaemia (two-thirds of AF cases also had ischaemia or LVH). The prevalence of AF increased with age, prior CVD, and levels of CHA2DS2-VASc scores (0.5%, 1.3%, 2.1%, 2.9%, and 4.4% for scores <2, 2, 3, 4, and ≥5, respectively). Atrial fibrillation was associated with two-fold higher hazard ratios (HR) for CVD (2.15; 95% CI, 1.71-2.69) and stroke (1.88; 1.44-2.47) and a four-fold higher HR for HF (3.79; 2.21-6.49). The 5-year cumulative incidence of CVD was comparable for AF, prior CVD, and CHA2DS2-VASc scores ≥ 2 (36.7% vs. 36.2% vs. 37.7%, respectively) but was two-fold greater than for ischaemia (19.4%), LVH (18.0%), or normal ECG (14.1%), respectively. Conclusion: The findings highlight the importance of screening for AF together with estimation of CHA2DS2-VASc scores for prevention of CVD in Chinese adults.

Predictive value of 8-year blood pressure measures in intracerebral hemorrhage risk over 5 years.

AIMS: The relationships between long-term blood pressure (BP) measures and intracerebral hemorrhage (ICH), as well as their predictive ability on ICH, were unclear. We aimed to investigate the independent associations of multiple BP measures with subsequent 5-year ICH risk, as well as the incremental value of these measures over a single-point BP measurement in ICH risk prediction. METHODS: We included 12,398 participants from the China Kadoorie Biobank (CKB) who completed three surveys every four to five years. The following long-term BP measures were calculated: mean, minimum, maximum, standard deviation, coefficient of variation, average real variability, and cumulative BP exposure (cumBP). Cox proportional hazard models were used to examine the associations between these measures and ICH. The potential incremental value of these measures in ICH risk prediction was assessed using Harrell's C statistics, continuous net reclassification improvement (cNRI), and relative integrated discrimination improvement (rIDI). RESULTS: The hazard ratios (95% confidence intervals) of incident ICH associated with per SD increase in cumSBP and cumDBP were 1.62 (1.25, 2.10) and 1.59 (1.23, 2.07), respectively. When cumBP was added to the conventional 5-year ICH risk prediction model, the C-statistic change was 0.009 (-0.001, 0.019), the cNRI was 0.267 (0.070, 0.464), and the rIDI was 18.2% (5.8%, 30.7%). Further subgroup analyses revealed a consistent increase in cNRI and rIDI in men, rural residents, and participants without diabetes. Other long-term BP measures showed no statistically significant associations with incident ICH and generally did not improve model performance. CONCLUSION: The nearly 10-year cumBP was positively associated with an increased 5-year risk of ICH and could significantly improve risk reclassification for the ICH risk prediction model that included single-point BP measurement.

This prospective cohort study of Chinese adults investigated the independent associations of multiple blood pressure (BP) measures with subsequent 5-year intracerebral hemorrhage (ICH) risk, as well as the incremental value of these measures over a single-point BP measurement in ICH risk prediction. The cumulative BP exposure (cumBP) was positively associated with subsequent 5-year risk of ICH, independent of the recent single-point SBP and DBP levels.The cumBP could improve the risk reclassification of the conventional 5-year ICH risk prediction model that included single-point BP measurement for all participants, as well as for men, rural residents, and participants without diabetes.

Proteomic Analyses in Diverse Populations Improved Risk Prediction and Identified New Drug Targets for Type 2 Diabetes.

OBJECTIVE: Integrated analyses of plasma proteomics and genetic data in prospective studies can help assess the causal relevance of proteins, improve risk prediction, and discover novel protein drug targets for type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS: We measured plasma levels of 2,923 proteins using Olink Explore among ∼2,000 randomly selected participants from China Kadoorie Biobank (CKB) without prior diabetes at baseline. Cox regression assessed associations of individual protein with incident T2D (n = 92 cases). Proteomic-based risk models were developed with discrimination, calibration, reclassification assessed using area under the curve (AUC), calibration plots, and net reclassification index (NRI), respectively. Two-sample Mendelian randomization (MR) analyses using cis-protein quantitative trait loci identified in a genome-wide association study of CKB and UK Biobank for specific proteins were conducted to assess their causal relevance for T2D, along with colocalization analyses to examine shared causal variants between proteins and T2D. RESULTS: Overall, 33 proteins were significantly associated (false discovery rate < 0.05) with risk of incident T2D, including IGFBP1, GHR, and amylase. The addition of these 33 proteins to a conventional risk prediction model improved AUC from 0.77 (0.73-0.82) to 0.88 (0.85-0.91) and NRI by 38%, with predicted risks well calibrated with observed risks. MR analyses provided support for the causal relevance for T2D of ENTR1, LPL, and PON3, with replication of ENTR1 and LPL in Europeans using different genetic instruments. Moreover, colocalization analyses showed strong evidence (pH4 > 0.6) of shared genetic variants of LPL and PON3 with T2D. CONCLUSIONS: Proteomic analyses in Chinese adults identified novel associations of multiple proteins with T2D with strong genetic evidence supporting their causal relevance and potential as novel drug targets for prevention and treatment of T2D.

Safety and Toxicity Profiles of CAR T Cell Therapy in Non-Hodgkin Lymphoma: A Systematic Review and Meta-Analysis.

BACKGROUND: The application of CD19-directed chimeric antigen receptor T (CAR T) cell therapy has improved outcomes for thousands of patients with non-Hodgkin B cell lymphoma (NHL). The toxicities associated with various CAR T cell products, however, can be severe and difficult to anticipate. METHODS: In this systematic review and meta-analysis, we set out to determine whether there are measurable differences in common toxicities, including cytokine release syndrome (CRS), immune effector cell associated neurotoxicity syndrome (ICANS), cytopenias, and infections, between CAR T products that are commercially available for the treatment of NHL. RESULTS: After a stringent study selection process, we used a cohort of 1364 patients enrolled in 15 prospective clinical trials investigating the use of axicabtagene ciloleucel (axi-cel), lisocabtagene maraleucel (liso-cel), and tisagenlecleucel (tisa-cel). We found that the rates of CRS and ICANS were significantly higher with axi-cel as compared to both liso-cel and tisa-cel. Conversely, we demonstrated that rates of all-grade and severe neutropenia were significantly greater with liso-cel. Febrile neutropenia and all-grade infection rates did not differ significantly between products though rates of severe infection were increased with axi-cel. CONCLUSIONS: Overall, this study serves as the first to delineate toxicity profiles associated with various available CAR T products. By better understanding associated toxicities, it may become possible to tailor therapies towards individual patients and anticipate the development of toxicities at earlier stages.

Benchmarking multi-ancestry prostate cancer polygenic risk scores in a real-world cohort.

Prostate cancer is a heritable disease with ancestry-biased incidence and mortality. Polygenic risk scores (PRSs) offer promising advancements in predicting disease risk, including prostate cancer. While their accuracy continues to improve, research aimed at enhancing their effectiveness within African and Asian populations remains key for equitable use. Recent algorithmic developments for PRS derivation have resulted in improved pan-ancestral risk prediction for several diseases. In this study, we benchmark the predictive power of six widely used PRS derivation algorithms, including four of which adjust for ancestry, against prostate cancer cases and controls from the UK Biobank and All of Us cohorts. We find modest improvement in discriminatory ability when compared with a simple method that prioritizes variants, clumping, and published polygenic risk scores. Our findings underscore the importance of improving upon risk prediction algorithms and the sampling of diverse cohorts.

Dietary factors and patterns in relation to risk of later-onset ulcerative colitis in Chinese: A prospective study of 0.5 million people.

BACKGROUND: There is limited evidence on the associations of dietary factors and patterns with risk of later-onset ulcerative colitis (UC) in Chinese adults. AIMS: To investigate the associations of dietary factors and patterns with risk of later-onset UC in Chinese. METHODS: The prospective China Kadoorie Biobank cohort study recruited 512,726 participants aged 30-79. Dietary habits were assessed using food frequency questionnaires. Dietary patterns were derived by factor analysis with a principal component method. Cox regression analysis was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: During a median follow-up of 12.1 years, 312 cases of newly diagnosed UC were documented (median age of diagnosis 60.1 years). Egg consumption was associated with higher risk of UC (HR for daily vs. never or rarely: 2.29 [95% CI: 1.26-4.16]), while spicy food consumption was inversely associated with risk of UC (HR: 0.63 [0.45-0.88]). The traditional northern dietary pattern, characterised by high intake of wheat and low intake of rice, was associated with higher risk of UC (HR for highest vs. lowest quartile of score: 2.79 [1.93-4.05]). The modern dietary pattern, characterised by high intake of animal-origin foods and fruits, was associated with higher risk of UC (HR: 2.48 [1.63-3.78]). Population attributable fraction was 13.04% (7.71%-19.11%) for daily/almost daily consumption of eggs and 9.87% (1.94%-18.22%) for never/rarely consumption of spicy food. CONCLUSIONS: The findings highlight the importance of evaluating dietary factors and patterns in the primary prevention of later-onset UC in Chinese adults.

AutoNet-Generated Deep Layer-Wise Convex Networks for ECG Classification.

The design of neural networks typically involves trial-and-error, a time-consuming process for obtaining an optimal architecture, even for experienced researchers. Additionally, it is widely accepted that loss functions of deep neural networks are generally non-convex with respect to the parameters to be optimised. We propose the Layer-wise Convex Theorem to ensure that the loss is convex with respect to the parameters of a given layer, achieved by constraining each layer to be an overdetermined system of non-linear equations. Based on this theorem, we developed an end-to-end algorithm (the AutoNet) to automatically generate layer-wise convex networks (LCNs) for any given training set. We then demonstrate the performance of the AutoNet-generated LCNs (AutoNet-LCNs) compared to state-of-the-art models on three electrocardiogram (ECG) classification benchmark datasets, with further validation on two non-ECG benchmark datasets for more general tasks. The AutoNet-LCN was able to find networks customised for each dataset without manual fine-tuning under 2 GPU-hours, and the resulting networks outperformed the state-of-the-art models with fewer than 5% parameters on all the above five benchmark datasets. The efficiency and robustness of the AutoNet-LCN markedly reduce model discovery costs and enable efficient training of deep learning models in resource-constrained settings.

Reproductive factors and risk of lung cancer among 300,000 Chinese female never-smokers: evidence from the China Kadoorie Biobank study.

BACKGROUND: Lung cancer is the leading cause of cancer mortality among Chinese females despite the low smoking prevalence among this population. This study assessed the roles of reproductive factors in lung cancer development among Chinese female never-smokers. METHODS: The prospective China Kadoorie Biobank (CKB) recruited over 0.5 million Chinese adults (0.3 million females) from 10 geographical areas in China in 2004-2008 when information on socio-demographic/lifestyle/environmental factors, physical measurements, medical history, and reproductive history collected through interviewer-administered questionnaires. Cox proportional hazard regression was used to estimate adjusted hazard ratios (HRs) of lung cancer by reproductive factors. Subgroup analyses by menopausal status, birth year, and geographical region were performed. RESULTS: During a median follow-up of 11 years, 2,284 incident lung cancers occurred among 282,558 female never-smokers. Ever oral contraceptive use was associated with a higher risk of lung cancer (HR = 1.16, 95% CI: 1.02-1.33) with a significant increasing trend associated with longer duration of use (p-trend = 0.03). Longer average breastfeeding duration per child was associated with a decreased risk (0.86, 0.78-0.95) for > 12 months compared with those who breastfed for 7-12 months. No statistically significant association was detected between other reproductive factors and lung cancer risk. CONCLUSION: Oral contraceptive use was associated with an increased risk of lung cancer in Chinese female never-smokers. Further studies are needed to assess lung cancer risk related to different types of oral contraceptives in similar populations.

Associations of traditional cardiovascular risk factors with 15-year blood pressure change and trajectories in Chinese adults: a prospective cohort study.

OBJECTIVE: How traditional cardiovascular disease (CVD) risk factors are related to long-term blood pressure change (BPC) or trajectories remain unclear. We aimed to examine the independent associations of these factors with 15-year BPC and trajectories in Chinese adults. METHODS: We included 15 985 participants who had attended three surveys, including 2004-2008 baseline survey, and 2013-2014 and 2020-2021 resurveys, over 15 years in the China Kadoorie Biobank (CKB). We measured systolic and diastolic blood pressure (SBP and DBP), height, weight, and waist circumference (WC). We asked about the sociodemographic characteristics and lifestyle factors, including smoking, alcohol drinking, intake of fresh vegetables, fruits, and red meat, and physical activity, using a structured questionnaire. We calculated standard deviation (SD), cumulative blood pressure (cumBP), coefficient of variation (CV), and average real variability (ARV) as long-term BPC proxies. We identified blood pressure trajectories using the latent class growth model. RESULTS: Most baseline sociodemographic and lifestyle characteristics were associated with cumBP. After adjusting for other characteristics, the cumSBP (mmHg × year) increased by 116.9 [95% confidence interval (CI): 111.0, 122.7] for every 10 years of age. The differences of cumSBP in heavy drinkers of ≥60 g pure alcohol per day and former drinkers were 86.7 (60.7, 112.6) and 48.9 (23.1, 74.8) compared with less than weekly drinkers. The cumSBP in participants who ate red meat less than weekly was 29.4 (12.0, 46.8) higher than those who ate red meat daily. The corresponding differences of cumSBP were 127.8 (120.7, 134.9) and 70.2 (65.0, 75.3) for BMI per 5 kg/m2 and WC per 10 cm. Most of the findings of other BPC measures by baseline characteristics were similar to the cumBP, but the differences between groups were somewhat weaker. Alcohol drinking was associated with several high-risk trajectories of SBP and DBP. Both BMI and WC were independently associated with all high-risk blood pressure trajectories. CONCLUSIONS: Several traditional CVD risk factors were associated with unfavorable long-term BPC or blood pressure trajectories in Chinese adults.

Genome-wide characterization of circulating metabolic biomarkers.

Genome-wide association analyses using high-throughput metabolomics platforms have led to novel insights into the biology of human metabolism1-7. This detailed knowledge of the genetic determinants of systemic metabolism has been pivotal for uncovering how genetic pathways influence biological mechanisms and complex diseases8-11. Here we present a genome-wide association study for 233 circulating metabolic traits quantified by nuclear magnetic resonance spectroscopy in up to 136,016 participants from 33 cohorts. We identify more than 400 independent loci and assign probable causal genes at two-thirds of these using manual curation of plausible biological candidates. We highlight the importance of sample and participant characteristics that can have significant effects on genetic associations. We use detailed metabolic profiling of lipoprotein- and lipid-associated variants to better characterize how known lipid loci and novel loci affect lipoprotein metabolism at a granular level. We demonstrate the translational utility of comprehensively phenotyped molecular data, characterizing the metabolic associations of intrahepatic cholestasis of pregnancy. Finally, we observe substantial genetic pleiotropy for multiple metabolic pathways and illustrate the importance of careful instrument selection in Mendelian randomization analysis, revealing a putative causal relationship between acetone and hypertension. Our publicly available results provide a foundational resource for the community to examine the role of metabolism across diverse diseases.

A genome-wide association study based on the China Kadoorie Biobank identifies genetic associations between snoring and cardiometabolic traits.

Despite the high prevalence of snoring in Asia, little is known about the genetic etiology of snoring and its causal relationships with cardiometabolic traits. Based on 100,626 Chinese individuals, a genome-wide association study on snoring was conducted. Four novel loci were identified for snoring traits mapped on SLC25A21, the intergenic region of WDR11 and FGFR, NAA25, ALDH2, and VTI1A, respectively. The novel loci highlighted the roles of structural abnormality of the upper airway and craniofacial region and dysfunction of metabolic and transport systems in the development of snoring. In the two-sample bi-directional Mendelian randomization analysis, higher body mass index, weight, and elevated blood pressure were causal for snoring, and a reverse causal effect was observed between snoring and diastolic blood pressure. Altogether, our results revealed the possible etiology of snoring in China and indicated that managing cardiometabolic health was essential to snoring prevention, and hypertension should be considered among snorers.

Mediating Effect of Tobacco Dependence on the Association Between Maternal Smoking During Pregnancy and Chronic Obstructive Pulmonary Disease: Case-Control Study.

BACKGROUND: Maternal smoking during pregnancy (MSDP) is a known risk factor for offspring developing chronic obstructive pulmonary disease (COPD), but the underlying mechanism remains unclear. OBJECTIVE: This study aimed to explore whether the increased COPD risk associated with MSDP could be attributed to tobacco dependence (TD). METHODS: This case-control study used data from the nationwide cross-sectional China Pulmonary Health study, with controls matched for age, sex, and smoking status. TD was defined as smoking within 30 minutes of waking, and the severity of TD was assessed using the Fagerstrom Test for Nicotine Dependence. COPD was diagnosed when the ratio of forced expiratory volume in 1 second to forced vital capacity was <0.7 in a postbronchodilator pulmonary function test according to the 2017 Global Initiative for Chronic Obstructive Lung Disease criteria. Logistic regression was used to examine the correlation between MSDP and COPD, adjusting for age, sex, BMI, educational attainment, place of residence, ethnic background, occupation, childhood passive smoking, residential fine particulate matter, history of childhood pneumonia or bronchitis, average annual household income, and medical history (coronary heart disease, hypertension, and diabetes). Mediation analysis examined TD as a potential mediator in the link between MSDP and COPD risk. The significance of the indirect effect was assessed through 1000 iterations of the "bootstrap" method. RESULTS: The study included 5943 participants (2991 with COPD and 2952 controls). Mothers of the COPD group had higher pregnancy smoking rates (COPD: n=305, 10.20%; controls: n=211, 7.10%; P<.001). TD was more prevalent in the COPD group (COPD: n=582, 40.40%; controls: n=478, 33.90%; P<.001). After adjusting for covariates, MSDP had a significant effect on COPD (ß=.097; P<.001). There was an association between MSDP and TD (ß=.074; P<.001) as well as between TD and COPD (ß=.048; P=.007). Mediation analysis of TD in the MSDP-COPD association showed significant direct and indirect effects (direct: ß=.094; P<.001 and indirect: ß=.004; P=.03). The indirect effect remains present in the smoking population (direct: ß=.120; P<.001 and indirect: ß=.002; P=.03). CONCLUSIONS: This study highlighted the potential association between MSDP and the risk of COPD in offspring, revealing the mediating role of TD in this association. These findings contribute to a deeper understanding of the impact of prenatal tobacco exposure on lung health, laying the groundwork for the development of relevant prevention and treatment strategies.

Testing Conditional Independence Between Latent Variables by Independence Residuals.

Conditional independence (CI) testing is an important problem, especially in causal discovery. Most testing methods assume that all variables are fully observable and then test the CI among the observed data. Such an assumption is often untenable beyond applications dealing with, e.g., psychological analysis about the mental health status and medical diagnosing (researchers need to consider the existence of latent variables in these scenarios); and typically adopted latent CI test schemes mainly suffer from robust or efficient issues. Accordingly, this article investigates the problem of testing CI between latent variables. To this end, we offer an auxiliary regression-based CI (AReCI) test by taking the measured variable as the surrogate variable of the latent variables to conduct the regression over the latent variables under the linear causal models, in which each latent variable has some certain measured variables. Specifically, given a pair of latent variables LX and LY , and a corresponding latent variable set LO , [Formula: see text] holds if and only if [Formula: see text] and [Formula: see text] are statistically independent, where A' and A'' are the two disjoint subset of the measured variable for the corresponding latent variables, A'{LO} ∩A''{LO} = ∅ , and ω1 is a parameter vector characterized from the cross covariance between A{LX} and A'{LO} , and ω2 is a parameter vector characterized from the cross covariance between A{LY} and A''{LO} . We theoretically show that the AReCI test is capable of addressing both Gaussian and non-Gaussian data. In addition, we find that the well-known partial correlation test can be seen as a special case of the AReCI test. Finally, we devise a causal discovery method by using the AReCI test as the CI test. The experimental results on synthetic and real-world data illustrate the effectiveness of our method.

Association between health insurance cost-sharing and choice of hospital tier for cardiovascular diseases in China: a prospective cohort study.

Background: Hospitals in China are classified into tiers (1, 2 or 3), with the largest (tier 3) having more equipment and specialist staff. Differential health insurance cost-sharing by hospital tier (lower deductibles and higher reimbursement rates in lower tiers) was introduced to reduce overcrowding in higher tier hospitals, promote use of lower tier hospitals, and limit escalating healthcare costs. However, little is known about the effects of differential cost-sharing in health insurance schemes on choice of hospital tiers. Methods: In a 9-year follow-up of a prospective study of 0.5 M adults from 10 areas in China, we examined the associations between differential health insurance cost-sharing and choice of hospital tiers for patients with a first hospitalisation for stroke or ischaemic heart disease (IHD) in 2009-2017. Analyses were performed separately in urban areas (stroke: n = 20,302; IHD: n = 19,283) and rural areas (stroke: n = 21,130; IHD: n = 17,890), using conditional logit models and adjusting for individual socioeconomic and health characteristics. Findings: About 64-68% of stroke and IHD cases in urban areas and 27-29% in rural areas chose tier 3 hospitals. In urban areas, higher reimbursement rates in each tier and lower tier 3 deductibles were associated with a greater likelihood of choosing their respective hospital tiers. In rural areas, the effects of cost-sharing were modest, suggesting a greater contribution of other factors. Higher socioeconomic status and greater disease severity were associated with a greater likelihood of seeking care in higher tier hospitals in urban and rural areas. Interpretation: Patient choice of hospital tiers for treatment of stroke and IHD in China was influenced by differential cost-sharing in urban areas, but not in rural areas. Further strategies are required to incentivise appropriate health seeking behaviour and promote more efficient hospital use. Funding: Wellcome Trust, Medical Research Council, British Heart Foundation, Cancer Research UK, Kadoorie Charitable Foundation, China Ministry of Science and Technology, and National Natural Science Foundation of China.

A wide landscape of morbidity and mortality risk associated with marital status in 0.5 million Chinese men and women: a prospective cohort study.

Background: A comprehensive depiction of long-term health impacts of marital status is lacking. Methods: Sex-stratified phenome-wide association analyses (PheWAS) of marital status (living with vs. without a spouse) were performed using baseline (2004-2008) and follow-up information (ICD10-coded events till Dec 31, 2017) from the China Kadoorie Biobank (CKB). We estimated adjusted hazard ratios (aHRs) to evaluate the associations of marital status with morbidity risks of phenome-wide significant diseases or sex-specific top-10 death causes in China documented in 2017. Additionally, the association between marital status and mortality risks among participants with major chronic diseases at baseline was assessed. Findings: During up to 11.1 years of the median follow-up period, 1,946,380 incident health events were recorded among 210,202 men and 302,521 women aged 30-79. Marital status was found to have phenome-wide significant associations with thirteen diseases among men (p < 9.92 × 10-5) and nine diseases among women (p < 9.33 × 10-5), respectively. After adjusting for all disease-specific covariates in the final model, participants living without a spouse showed increased risks of schizophrenia, schizotypal and delusional disorders (aHR [95% CI]: 2.55, [1.83-3.56] for men; 1.49, [1.13-1.97] for women) compared with their counterparts. Additional higher risks in overall mental and behavioural disorder (1.31, 1.13-1.53), cardiovascular disease (1.07, 1.04-1.10) and cancer (1.06, 1.00-1.12) were only observed among men without a spouse, whereas women living without a spouse were at lower risks of developing genitourinary diseases (0.89, 0.85-0.93) and injury & poisoning (0.93, 0.88-0.97). Among 282,810 participants with major chronic diseases at baseline, 39,166 deaths were recorded. Increased mortality risks for those without a spouse were observed in 12 of 21 diseases among male patients and one of 23 among female patients. For patients with any self-reported disease at baseline, compared with those living with a spouse, the aHRs (95% CIs) of mortality risk were 1.29 (1.24-1.34) and 1.04 (1.00-1.07) among men and women without a spouse (pinteraction<0.0001), respectively. Interpretation: Long-term associations of marital status with morbidity and mortality risks are diverse among middle-aged Chinese adults, and the adverse impacts due to living without a spouse are more profound among men. Marital status may be an influential factor for health needs. Funding: The National Natural Science Foundation of China, the Kadoorie Charitable Foundation, the National Key R&D Program of China, the Chinese Ministry of Science and Technology, and the UK Wellcome Trust.

Causal association between snoring and stroke: a Mendelian randomization study in a Chinese population.

Background: Previous observational studies established a positive relationship between snoring and stroke. We aimed to investigate the causal effect of snoring on stroke. Methods: Based on 82,339 unrelated individuals with qualified genotyping data of Asian descent from the China Kadoorie Biobank (CKB), we conducted a Mendelian randomization (MR) analysis of snoring and stroke. Genetic variants identified in the genome-wide association analysis (GWAS) of snoring in CKB and UK Biobank (UKB) were selected for constructing genetic risk scores (GRS). A two-stage method was applied to estimate the associations of the genetically predicted snoring with stroke and its subtypes. Besides, MR analysis among the non-obese group (body mass index, BMI <24.0 kg/m2), as well as multivariable MR (MVMR), were performed to control for potential pleiotropy from BMI. In addition, the inverse-variance weighted (IVW) method was applied to estimate the causal association with genetic variants identified in CKB GWAS. Findings: Positive associations were found between snoring and total stroke, hemorrhagic stroke (HS), and ischemic stroke (IS). With GRS of CKB, the corresponding HRs (95% CIs) were 1.56 (1.15, 2.12), 1.50 (0.84, 2.69), 2.02 (1.36, 3.01), and the corresponding HRs (95% CIs) using GRS of UKB were 1.78 (1.30, 2.43), 1.94 (1.07, 3.52), and 1.74 (1.16, 2.61). The associations remained stable in the MR among the non-obese group, MVMR analysis, and MR analysis using the IVW method. Interpretation: This study suggests that, among Chinese adults, genetically predicted snoring could increase the risk of total stroke, IS, and HS, and the causal effect was independent of BMI. Funding: National Natural Science Foundation of China, Kadoorie Charitable Foundation Hong Kong, UK Wellcome Trust, National Key R&D Program of China, Chinese Ministry of Science and Technology.

Using routinely collected data to determine care cascades of hypertension and type-2 diabetes management in China: a cross-sectional study.

Background: China's National Essential Public Health Service Package (NEPHSP) aims to promote health for all at the primary health care level and includes a focus on hypertension and type-2 diabetes mellitus (T2DM). However, there are limited contemporary data to quantify the care cascades of hypertension and T2DM in primary health care. Methods: This cross-sectional study involved individual level linkage of routinely collected data from the NEPHSP, health insurance claims and hospital electronic health records, from four diverse regions in China, including Xiling District (central China), Wenchuan County (western), Acheng District and Jiao District (northern). We first compared numbers of people aged ≥35 with a recorded diagnosis of hypertension and T2DM against expected numbers derived from epidemiological data. We then constructed care cascades to assess the percentages (1) enrolled in the NEPHSP, (2) adherent to the follow-up care of NEPHSP, (3) receiving medication treatment, and (4) having hypertension and/or T2DM controlled. Findings: In the four regions, the total numbers of people aged ≥35 diagnosed of hypertension and T2DM from any data source were 149,176 and 50,828, respectively. This was estimated to be 46.0% (95% confidence interval [CI]: 45.8%-46.2%) and 45.6% (95% CI: 45.3%-45.9%) of the expected totals for hypertension and T2DM, respectively. Among those diagnosed, 65.4% (95% CI: 65.1%-65.6%) with hypertension and 66.1% (95% CI: 65.7%-66.5%) with T2DM were enrolled in the NEPHSP, respectively, in which 54.8% (95% CI: 54.5%-55.2%) with hypertension and 64.7% (95% CI: 64.1%-65.2%) with T2DM were adherent to the required services. Among those enrolled, the overall treatment rates were 70.8% (95% CI: 70.6%-71.1%) for hypertension and 82.2% (95% CI: 81.8%-82.6%) for T2DM. Among those treated, a further 80.9% (95% CI: 80.6%-81.2%) with hypertension and 73.9% (95% CI: 73.3%-74.4%) with T2DM achieved control. These results varied considerably across regions, with the northern sites showing relatively higher enrolment rates while the central site had higher control rates. Interpretation: Detection and control rates for hypertension and T2DM are suboptimal in these four regions of China. Further strategies are needed to improve people's enrolment in and adherence to the NEPHSP and strengthen care delivery processes. Of note, our estimations of the diagnosis rates for each region are based on national level large epidemiological data. The interpretation of these data needs caution due to potential bias caused by regional variations. Funding: This study is funded by National Health and Medical Research Council (NHMRC) Global Alliance for Chronic Diseases funding (APP1169757), and National Natural Science Foundation of China (72074065).

PCSK9 genetic variants and risk of vascular and non-vascular diseases in Chinese and UK populations.

AIM: Lowering low-density lipoprotein cholesterol (LDL-C) through PCSK9 inhibition represents a new therapeutic approach to preventing and treating cardiovascular disease (CVD). Phenome-wide analyses of PCSK9 genetic variants in large biobanks can help to identify unexpected effects of PCSK9 inhibition. METHODS: In the prospective China Kadoorie Biobank, we constructed a genetic score using three variants at the PCSK9 locus associated with directly-measured LDL-C (PCSK9-GS). Logistic regression gave estimated odds ratios (ORs) for PCSK9-GS associations with CVD and non-CVD outcomes, scaled to 1SD lower LDL-C. RESULTS: PCSK9-GS was associated with lower risks of carotid plaque (n=8340 cases; OR=0.61 [95%CI: 0.45-0.83]; P=0.0015), major occlusive vascular events (n=15,752; 0.80 [0.67-0.95]; P=0.011), and ischaemic stroke (n=11,467; 0.80 [0.66-0.98]; P=0.029). However, PCSK9-GS was also associated with higher risk of hospitalisation with chronic obstructive pulmonary disease (COPD: n=6836; 1.38 [1.08-1.76]; P=0.0089), and with even higher risk of fatal exacerbations among individuals with pre-existing COPD (n=730; 3.61 [1.71-7.60]; P=7.3x10-4). We also replicated associations for a PCSK9 variant, reported in UK Biobank, with increased risks of acute upper respiratory tract infection (URTI) (pooled OR after meta-analysis of 1.87 ([1.38-2.54]; P=5.4x10-5) and self-reported asthma (pooled OR 1.17 ([1.04-1.30]; P=0.0071). There was no association of a polygenic LDL-C score with COPD hospitalisation, COPD exacerbation, or URTI. CONCLUSIONS: LDL-C-lowering PCSK9 genetic variants are associated with lower risk of subclinical and clinical atherosclerotic vascular disease, but higher risks of respiratory diseases. Pharmacovigilance studies may be required to monitor patients treated with therapeutic PCSK9 inhibitors for exacerbations of respiratory diseases or respiratory tract infections.

Genetic analyses of over 100,000 participants of the China Kadoorie Biobank, mimicking the effect of new drugs intended to reduce cholesterol by targeting the PCSK9 protein, have identified potential severe effects of lower PCSK9 activity in patients with existing respiratory disease. PCSK9 genetic variants that are associated with lower cholesterol and reduced rates of cardiovascular disease are also associated with increased risk of a range of respiratory diseases, including asthma, upper respiratory tract infections, and hospitalisation with chronic obstructive respiratory disease (COPD). These genetic variants are not associated with whether or not individuals have COPD; instead they are specifically associated with an increase in the chance of those who already have COPD being hospitalised and even dying, suggesting that careful monitoring of such patients should be considered during development of and treatment with anti-PCSK9 medication.