基于纵向随访队列的儿童非酒精性脂肪肝预测模型的构建和验证

With the epidemic of childhood obesity, the prevalence pediatric nonalcoholic fatty liver disease (NAFLD) had rapidly increased and it is the most common liver disease in children worldwide. Pediatric NAFLD can increase the risk of liver cirrhosis and cardiovascular disease both in childhood and adulthood. There is no guidelines referring to pediatric NAFLD in China, but guidelines in other countries recommend developing predictive tools for screening in pediatric population at high risk. Thus, our study is based on the baseline data from the National Science-technology Support Plan Project named “Cardiovascular disease early warning, diagnosis and treatment technology research in childhood” in June, 2014. A total of 3895 children aged 6-12 years old were included and all participants have completed physical examination, blood pressure measurements, serum biochemical profile, and a validated questionnaire (including lifestyle and dietary information) in baseline and fist follow up (finished in 2016).We plan to conduct two time points of follow up during the period of September, 2018 to September, 2020. The outcome is newly diagnosed NAFLD during 6 years of follow up by ultrasound test. In the setting of longitudinal cohort study, we aim to develop predictive model of NAFLD based on independent variables including the anthropometric, biochemical profiles and lifestyle factors in Chinese children. In addition, we will conduct external validation of the predictive model in anther childhood cohort. Finally, we will develop a simple assessment tool of NAFLD that could be used in child health care practice, in order to identify high risk children at an early stage, thereby decreasing risk of liver damage and cardiovascular disease in the future.

随着儿童肥胖的流行，儿童非酒精性脂肪肝（NAFLD）患病率不断增加，现已成为儿童最常见的肝脏疾病。儿童NAFLD会增加近期及远期肝硬化和心血管疾病风险。国外相关指南一致建议研发预警工具对高危儿童进行筛查，而我国尚无儿童NAFLD诊疗指南及预警模型。本研究以2014年完成的国家科技支撑项目“儿童心血管疾病的预警、诊治技术研究”济南调查点3895名6-12岁儿童为对象，现已完成基线调查及第1次随访，均包括身体和血压测量、血生化检测、问卷调查（包括生活行为和膳食习惯）及超声检查，计划于2018-2020年再进行两次随访。在纵向随访队列的设计框架下，本研究拟以6年内随访的超声诊断的新发NAFLD为结局，构建基于人体测量指标、生活方式和生化指标的儿童NAFLD早期预测模型，并进行外部队列验证。同时，开发出简易筛查工具，实现对NAFLD高危儿童的早识别和早干预，从而降低成年期肝脏疾病及心血管疾病风险。

伴随着儿童超重和肥胖的流行，儿童非酒精性脂肪肝（NAFLD）患病率不断增加，已成为儿童最常见的肝脏疾病。儿童NAFLD会增加近期及远期肝硬化和心血管疾病风险。国外相关指南一致建议研发预警工具对高危儿童进行筛查，而我国尚无儿童NAFLD诊疗指南及其预警模型。本研究2017年建立的“淄博桓台儿童心血管健康队列”为依托，共纳入了1516名6-11岁的儿童，在项目进行期内分别于2019年10月及2021年10月共进行了两次随访，基线及随访均包括身体和血压测量、血生化检测、问卷调查（包括生活行为和膳食习惯）及超声检查，其中第一次随访观察到新发NAFLD26例，第二次55例，以第二次随访观察到的新发NAFLD为结局构建NAFLD的预测模型，并在十二五“儿童心血管疾病的预警、诊治技术研究”的队列中对预测效果进行评估。结果显示纳入年龄、性别、BMI和ALT的预测模型效果良好，AUC为0.963。同时还对2019年随访新发的20例NAFLD儿童按照年龄、性别匹配对照，进行了基于UHPLC-QTOFMS 的非靶向代谢组学检测和肠道菌群16sRNA测序,以期发现NAFLD新的标志物。而以Alpha-N-Phenylacetyl-L-glutamine、S-Methyl-5'-thioadenosine及M642T280_POS三个代谢物构建的模型其AUC为0.988，效果优于传统预测因素。同时肠道菌群16sRNA测序结果表明与正常对照组相比， NAFLD 组α多样性显著下降，物种差异分析显示 NAFLD 组变形菌门、伯克氏菌显著高于对照组，而理研菌科、瘤胃菌科显著低于对照组。目前初步完成了项目计划书中的内容，建立了儿童NAFLD的两个筛查模型并评估了筛查效果，同时通过代谢组学和肠道菌群研究发现了NAFLD新的生物标记物，一方面为NAFLD的早识别和早诊断提供了循证依据，一方面也为后续机制研究和干预靶点的选择提供了线索。