Confounded association between proton pump inhibitor use and risk of biliary tract cancer: Result from three cohorts

Recent epidemiological studies suggested that proton pump inhibitor (PPI) use was associated with an increased risk of biliary tract cancer (BTC), however, confounders were not adequately controlled. Our study aimed to evaluate PPI use and subsequent risk of BTC and its subtypes in three well-established cohorts. We conducted a pooled analysis of the subjects free of cancers in UK Biobank (n = 463 643), Nurses' Health Study (NHS, n = 80 235) and NHS II (n = 95 869). Propensity score weighted Cox models were used to estimate marginal HRs of PPIs use on BTC risk, accounting for potential confounders. We documented 284 BTC cases in UK Biobank (median follow-up: 7.6 years), and 91 cases in NHS and NHS II cohorts (median follow-up: 15.8 years). In UK biobank, PPI users had a 96% higher risk of BTC compared to nonusers in crude model (HR 1.96, 95% CI 1.44-2.66), but the effect was attenuated to null after adjusting for potential confounders (HR 0.95, 95% CI 0.60-1.49). PPI use was not associated with risk of BTC in the pooled analysis of three cohorts (HR 0.93, 95% CI 0.60-1.43). We also observed no associations between PPI use with risk of intrahepatic (HR 1.00, 95% CI 0.49-2.04), extrahepatic bile duct (HR 1.09, 95% CI 0.52-2.27) and gallbladder cancers (HR 0.66, 95% CI 0.26-1.66) in UK Biobank. In summary, regular use of PPIs was not associated with the risk of BTC and its subtypes.     

Loss of function,missense, and intronic variants in NOTCH1 confer different risks for left ventricular outflow tract obstructive heart defects in two European cohorts

Loss of function variants in NOTCH1 cause left ventricular outflow tract obstructive defects (LVOTO). However, the risk conferred by rare and noncoding variants in NOTCH1 for LVOTO remains largely uncharacterized. In a cohort of 49 families affected by hypoplastic left heart syndrome, a severe form of LVOTO, we discovered predicted loss of function NOTCH1 variants in 6% of individuals. Rare or low-frequency missense variants were found in 16% of families. To make a quantitative estimate of the genetic risk posed by variants in NOTCH1 for LVOTO, we studied associations of 400 coding and noncoding variants in NOTCH1 in 1,085 cases and 332,788 controls from the UK Biobank. Two rare intronic variants in strong linkage disequilibrium displayed significant association with risk for LVOTO amongst European-ancestry individuals. This result was replicated in an independent analysis of 210 cases and 68,762 controls of non-European and mixed ancestry. In conclusion, carrying rare predicted loss of function variants in NOTCH1 confer significant risk for LVOTO. In addition, the two intronic variants seem to be associated with an increased risk for these defects. Our approach demonstrates the utility of population-based data sets in quantifying the specific risk of individual variants for disease-related phenotypes.     

Relationship between Serum 25(OH)D and Depression: Causal Evidence from a Bi-Directional Mendelian Randomization Study

The relationship between depression and vitamin D deficiency is complex, with evidence mostly from studies affected by confounding and reverse causality. We examined the causality and direction of the relationship between 25-hydroxyvitamin D (25(OH)D) and depression in bi-directional Mendelian randomization (MR) analyses using information from up to 307,618 white British participants from the UK Biobank and summary results from the SUNLIGHT (n = 79,366) and Psychiatric Genomics consortia (PGC 113,154 cases and 218,523 controls). In observational analysis, the odds of depression decreased with higher 25(OH)D concentrations (adjusted odds ratio (OR) per 50% increase 0.95, 95%CI 0.94–0.96). In MR inverse variance weighted (IVW) using the UK Biobank, there was no association between genetically determined serum 25(OH)D and depression (OR per 50% higher 0.97, 95%CI 0.90–1.05) with consistent null association across all MR approaches and in data from PGC consortium. In contrast, genetic liability to depression was associated with lower 25(OH)D concentrations (MR IVW −3.26%, −4.94%–−1.55%), with the estimates remaining generally consistent after meta-analysing with the consortia. In conclusion, we found genetic evidence for a causal effect of depression on lower 25(OH)D concentrations, however we could not confirm a beneficial effect of nutritional vitamin D status on depression risk.     

Age at menopause,body mass index,and risk of type 2 diabetes mellitus in postmenopausal Chinese women: The Henan Rural Cohort study

Background and aimThe present study was conducted to explore the stratified and joint effects of age at menopause and body mass index (BMI) with the risk of type 2 diabetes mellitus (T2DM) in Chinese rural adults.Methods and resultsA total of 15,406 postmenopausal Chinese women were included in this study. Multivariable logistic regression analysis was used to quantify the stratified and joint effects of age at menopause and BMI on T2DM. Overall, the mean age at menopause and BMI was 48.8 ± 4.7 years and 25.1 ± 3.6 kg/m², respectively. In general, data suggest that: 1) women with BMI ≥ 24 had a higher risk of T2DM, irrespective of age at menopause; 2) in women with BMI < 24, later menopause had a higher risk of T2DM (OR, 1.52; 95% CI, 1.16–2.01); 3) the risk of T2DM was higher only in patients with early or normal age at menopause and BMI ≥ 24, with 0R (95% CI) of (1.58, 1.28–1.94) and (1.48, 1.31–1.67), respectively.ConclusionOur findings suggest that: 1) women with BMI ≥ 24 had a higher risk of T2DM, irrespective of age at menopause; 2) in women with BMI < 24, a higher risk of T2DM was found only in those with later menopause; 3) women with later menopause had a higher risk of T2DM, irrespective of BMI; 4) in patients with early or normal age at menopause, a higher risk of T2DM was found only in patients with BMI ≥ 24.The Chinese Clinical Trial RegistrationChiCTR–OOC–1500669(URL:http://www.chictr.org.cn/showproj.aspx?proj=11375)     

Cross‐sex shifts in two brain imaging phenotypes and their relation to polygenic scores for same‐sex sexual behavior: A study of 18,645 individuals from the UK Biobank

Genetic and hormonal factors have been suggested to influence human sexual orientation. Previous studied proposed brain differences related to sexual orientation and that these follow cross‐sex shifted patterns. However, the neurobiological correlates of sexual orientation and how genetic factors relate to brain structural variation remains largely unexplored. Using the largest neuroimaging‐genetics dataset available on same‐sex sexual behavior (SSB) (n = 18,645), we employed a data‐driven multivariate classification algorithm (PLS) on magnetic resonance imaging data from two imaging modalities to extract brain covariance patterns related to sex. Through analyses of latent variables, we tested for SSB‐related cross‐sex shifts in such patterns. Using genotype data, polygenic scores reflecting the genetic predisposition for SSB were computed and tested for associations with neuroimaging outcomes. Patterns important for classifying between males and females were less pronounced in non‐heterosexuals. Predominantly in non‐heterosexual females, multivariate brain patterns as represented by latent variables were shifted toward the opposite sex. Complementary univariate analyses revealed region specific SSB‐related differences in both males and females. Polygenic scores for SSB were associated with volume of lateral occipital and temporo‐occipital cortices. The present large‐scale study demonstrates multivariate neuroanatomical correlates of SSB, and tentatively suggests that genetic factors related to SSB may contribute to structural variation in certain brain structures. These findings support a neurobiological basis to the differences in human sexuality.     

脑血管病生物样本库建设标准研究

目的 开发适合我国脑血管病精准医学研究的生物样本库建设及管理标准,为建设可开发共享的 脑血管病生物样本库提供技术保障。 方法 参考国际大型生物样本库建设经验,基于国际标准化组织等机构的标准化思路,形成我国 脑血管病生物样本库建设标准框架,从场地设施、设备、操作规程、数据标准、信息化等多个维度, 对样本库的建设提出技术要求。 结果 依据本研究提出的建设标准,建立了符合国际标准的天坛脑血管病生物样本库运行及质量 管理体系,建成标准化采集、处理、保藏的10万人次脑血管病临床研究生物样本资源平台。 结论 天坛脑血管病生物样本库具有样本量充足、多样、多时点采集的生物样本资源,并实现了标 准化的信息存储,可为对接脑血管病多组学研究,脑血管病精准筛查、预警、诊断与干预等精准医学 研究提供技术支撑。     

New Reference Values for Body Composition by Bioelectrical Impedance Analysis in the General Population: Results From the UK Biobank

BackgroundLow fat-free mass (FFM) is a risk factor for morbidity and mortality in elderly and patient populations. Therefore, measurement of FFM is important in nutritional assessment. Bioelectrical impedance analysis (BIA) is a convenient method to assess FFM and FFM index (FFMI; FFM/height²). Although reference values have been established for individuals with normal body weight, no specific cutoff values are available for overweight and obese populations. Also, limited studies accounted for the age-related decline in FFM.ObjectiveTo determine BMI- and age-specific reference values for abnormal low FFM(I) in white-ethnic men and women free of self-reported disease from the general population.DesignThe UK Biobank is a prospective epidemiological study of the general population from the United Kingdom. Individuals in the age category 45 to 69 years were analyzed. In addition to body weight, FFM and FFMI were measured using a Tanita BC-418MA. Also, self-reported chronic conditions and ethnic background were registered, and lung function was assessed using spirometry.ResultsAfter exclusion of all individuals with missing data, nonwhite ethnicity, self-reported disease, body mass index (BMI) less than 14 or 36 kg/m² or higher, and/or an obstructive lung function, reference values for FFM and FFMI were derived from 186,975 individuals (45.9% men; age: 56.9 ± 6.8 years; BMI: 26.5 ± 3.6 kg/m²; FFMI 18.3 ± 2.4 kg/m²). FFM and FFMI were significantly associated with BMI and decreased with age. Percentiles 5, 10, 25, 50, 75, 90, and 95 were calculated for FFM, FFMI, and fat mass (index), after stratification for gender, age, and BMI.ConclusionsUsing the UK Biobank dataset, new reference values for body composition assessed with BIA were determined in white-ethnic men and women aged 45 to 69 years. Because these reference values are BMI specific, they are of broad interest for overweight and obese populations.     

我国生物样本库建设现状与对策

生物样本库作为临床治疗和医学科学研究的基础设施,是推动临床医学学科创新与诊疗技术创新的关键。目前我国生物样本库行业处于加速发展阶段,但存在缺乏统一的标准化流程,生物样本学科尚未建成、缺乏专业的人才队伍、各个样本库之间相互独立缺乏资源共享机制、样本库的成本效益低,样本使用率低等问题。针对上述问题,应加强生物样本库标准化建设,建立生物样本学,培养高素质专业人才,整合样本资源,实现信息共享,提高样本使用率,促进可持续发展。     

中国的生物信息库和伦理问题

1998年,科技部在上海成立了国家南方和北方人类基因研究中心,两个研究中心建立了与疾病有关的信息库;2007年,泰州市开展了人群健康追踪研究项目;温州市于2008年建立了温州医学院中心生物信息库;中国法医DNA数据库自1998年开始建设,并发挥了具体作用;中国慢性病kadoorle研究与肿瘤基因组学研究项目也得以开展;香港建成了几个遗传信息库,台湾生物数据的研究也已开展。但有一些生物数据库在具体的实践中,也遇到了许多伦理难题,应随着生物信息库的建立和使用尽快解决。     

Biobanking in the digital pathology era

Digital Pathology is becoming more and more important to achieve the goal of precision medicine. Advances in whole-slide imaging, software integration, and the accessibility of storage solutions have changed the pathologists’ clinical practice, not only in terms of laboratory workflow but also for diagnosis and biomarkers analysis. In parallel with the pathology setting advancement, translational medicine is approaching the unprecedented opportunities unrevealed by artificial intelligence (AI). Indeed, the increased usage of biobanks’ datasets in research provided new challenges for AI applications, such as advanced algorithms, and computer-aided techniques. In this scenario, machine learning-based approaches are being propose in order to improve biobanks from biospecimens collection repositories to computational datasets. To date, evidence on how to implement digital biobanks in translational medicine is still lacking. This viewpoint article summarizes the currently available literature that supports the biobanks’ role in the digital pathology era, and to provide possible practical applications of digital biobanks.