Type 1 diabetes genetic risk scores for the diagnosis of diabetes type in children of diverse racial and ethnic background

项目概要 大量且不断增加的儿童糖尿病病例无法按照现行标准进行诊断分类， 尤其是在非白人儿童中。通常对临床病程进行纵向观察 对糖尿病进行分类所需的信息会导致正确治疗的有害延误。诊断和治疗中的误区 可能导致少数种族/族裔中糖尿病并发症的发生率较高。因此，有一个关键的 需要可用于诊断的强有力的标准，为所有种族/族裔儿童的临床决策提供信息 背景。长期目标是确定儿童糖尿病的发病特征，为临床提供信息 及时管理，从而最终改善种族/民族多样化儿童的结果。作为 初步数据显示，申请人已经开发并验证了 1 型糖尿病 (T1D) 遗传风险评分 (GRS)，在患有不明糖尿病的成人中，识别患有 T1D 的患者，其定义为快速胰岛素依赖；和 还证明，T1D GRS 改进了当前进展为 T1D 的预测模型 处于危险之中的个人。本申请的中心假设是 T1D GRS 与胰岛相结合 糖尿病发病时的自身抗体和其他因素，可用于种族/民族多样化的儿童，以识别 患有 T1D 的人，定义为 C 肽（β 细胞功能的测量）快速丧失，因为这是 T1D 具有最大临床影响的特征。该提案的基本原理是及时描述 糖尿病对于少数民族儿童来说尤其困难，这将有助于及早建立正确的治疗方法 治疗、改善糖尿病结果并降低糖尿病费用，目前费用超过 3,270 亿美元 每年。在强有力的初步数据的指导下，这一假设将在种族/民族多样化的儿童中进行检验 通过评估 T1D GRS 的能力并结合其他因素来识别患有糖尿病的患者 T1D，定义为胰岛素缺乏（低 C 肽），在横断面（具体目标 1）和前瞻性（具体目标 目标2）方式。该项目意义重大，因为它最终有望改善儿科的治疗 糖尿病及其临床结果，特别是对弱势种族/族裔群体的影响。这个项目 具有创新性，因为它试图通过提议利用遗传学来改变当前的临床和研究实践 作为一种新颖、经济实惠、与时间无关的 T1D 诊断策略，由临床相关专家确定 特点。

PROJECT SUMMARY A large and growing number of pediatric diabetes cases cannot be classified at diagnosis with the current criteria, particularly among non-Caucasian children. The longitudinal observation of the clinical course that is often needed to classify diabetes causes harmful delays in the correct treatment. Mistakes in diagnosis and treatment may contribute to the higher frequency of diabetic complications in racial/ethnic minorities. Thus, there is a critical need for robust criteria that can be applied at diagnosis to inform clinical decisions in children of all racial/ethnic backgrounds. The long-term objective is to characterize pediatric diabetes at onset to inform clinical management in a timely fashion and thus, ultimately improve outcomes in racially/ethnically diverse children. As preliminary data, the applicants have developed and validated type 1 diabetes (T1D) Genetic Risk Scores (GRSs) that, in adults with unclear diabetes, identify those with T1D, defined by rapid insulin dependence; and have also demonstrated that a T1D GRS improves the current predictive model for progression to T1D in individuals at risk. The central hypothesis of this application is that T1D GRSs, in combination with islet autoantibodies and other factors at diabetes onset, can be used in racially/ethnically diverse children to identify those who have T1D, defined by rapid loss of C-peptide (measure of beta-cell function), as this is the T1D characteristic with the largest clinical impact. The rationale for this proposal is that timely characterization of diabetes, which is particularly difficult in minority children, will facilitate early establishment of the correct treatment, improve diabetes outcomes and lower the costs of diabetes, which are currently over $327 billion yearly. Guided by strong preliminary data, this hypothesis will be tested in racially/ethnically diverse children with diabetes by assessing the ability of T1D GRSs, in combination with other factors, to identify those who have T1D, defined as insulin deficiency (low C-peptide), in a cross-sectional (Specific Aim 1) and prospective (Specific Aim 2) manner. This project is significant because it is ultimately expected to improve the treatment of pediatric diabetes and thus its clinical outcomes, with particular impact on disadvantaged racial/ethnic groups. This project is innovative because it seeks to shift the current clinical and research practices by proposing to utilize genetics as a novel, affordable, time-independent strategy to diagnose T1D, identified by a clinically relevant characteristic.