NATURAL HISTORY STUDY OF THE DEVELOPMENT OF TYPE I DIABETES

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 目的：本研究的总体目标是对T1D高危个体的代谢和免疫状态进行基线和随时间的重复评估，以便： A)描述他们罹患T1D的风险， B)描述T1D的致病进化，以及 C)增加对T1D发病因素的认识。 摘要： T1D发展的TrialNet自然历史研究分为三个阶段：筛查(阶段1)、基线风险评估(阶段2)和后续风险评估(阶段3)。这些阶段中的每一个阶段都需要单独的知情同意才能进入。这项研究将采用前瞻性队列设计。 第一阶段包括筛查与T1D相关的自身抗体的存在。在筛查过程中，在两个不同的血样上检测出一种或多种相同的生化自身抗体(抗GAD65、抗ICA512或IAA)的个人(即确认的自身抗体阳性)将有资格进入研究的第二阶段，即基线风险评估。此外，在筛查过程中获得的第一个血液样本中至少有两个生化自身抗体呈阳性的个人将有资格进入第二阶段。这些受试者将可以选择在第二阶段期间提供第二个样本以供自身抗体确认，或在进入第二阶段之前提供第二个样本。 由于TrialNet是一个将继续开发研究T1D病因和预防的方案的联盟，因此不符合第二阶段资格的个人可能仍然有资格参加其他研究。因此，将来可能会联系他们，以便向他们通报新的研究。此外，还将定期与他们联系，了解他们是否已经开发出T1D。18岁以下不符合第二阶段资格的个人，将被邀请每年重新进行筛查，直到他们达到18岁生日。基线风险评估将包括OGTT、HbA1c测量、ICA测试和人类白细胞抗原配型(在参与者同意的情况下)。具有保护性HLA等位基因的参与者不会被排除在这项研究之外。在某些情况下，还将进行20分钟的第一相胰岛素反应(FPIR)的IVGTT。 第二阶段完成后，参与者将被归类为五年内发生T1D的三个风险类别之一：50%。风险类别将根据OGTT结果、确认的生化自身抗体阳性数、ICA阳性以及必要时的IVGTT结果来确定。当所有测试结果可用时，参与者将被告知他们的风险类别。 参与第二阶段的个人也将有机会(通过书面同意)进入第三阶段进行后续风险评估。他们将在五年内每隔六个月接受一次检查，或直到研究结束。在每次就诊时，程序将包括OGTT、采集血液进行自身抗体检测和测量HbA1c水平。IVGTTS将不会进行。虽然每次评估后不会对风险进行正式分类，但参与者将在提出要求时被告知其测试结果。 在研究的每个阶段，来自同意参与者的剩余血液样本(和第二阶段的DNA样本)将被无限期地存储在TrialNet核心实验室和/或NIDDK储存库站点，用于未来与x细胞破坏机制有关的免疫学和新陈代谢评估，并获得与T1D风险相关的遗传标记的更多信息。受试者仍然可以参与研究的所有阶段，即使他们选择不同意储存。还将在第二阶段和第三阶段在参与《议定书修正案》的临床中心收集机械性样本，以便为机械性研究收集样本。 根据风险评估有资格参加预防试验的个人将被邀请参加这些试验。参加预防试验的个人将根据该试验的方案进行跟踪。然而，在试验期间积累的相关数据(取决于试验中的治疗状态)，如T1D的发展，可能会被纳入本研究的数据库。 主要研究结果是美国糖尿病协会(ADA)标准定义的糖尿病(T1D)。对于大多数受试者，这将基于没有症状性高血糖的OGTT结果。需要对无症状的个体进行第二次OGTT测试，以确认糖尿病的诊断。确诊时住院的个人将通过医疗记录进行评估。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. OBJECTIVE: The overall objective of this study is to perform baseline and repeat assessments over time of the metabolic and immunologic status of individuals at risk for T1D in order: a) To characterize their risk for developing T1D, b) To describe the pathogenetic evolution of T1D, and c) To increase the understanding of the pathogenetic factors involved in the development of T1D. SUMMARY: The TrialNet Natural History Study of the Development of T1D is divided into three phases: Screening (Phase 1), Baseline Risk Assessment (Phase 2) and Follow-up Risk Assessments (Phase 3). Each of these phases will require separate informed consent for entry. A prospective cohort design will be used for the study. Phase 1 involves screening for the presence of autoantibodies associated with T1D. Individuals who are positive for one or more of the same biochemical autoantibodies (anti-GAD65, anti-ICA512 or IAA) on two separate blood samples during screening (i.e., confirmed autoantibody positive) will be eligible for entry into Phase 2 of the study, the baseline risk assessment. In addition, individuals who are positive for at least two biochemical autoantibodies on the first blood sample obtained during screening will be eligible for entry into Phase 2. These subjects will have the option of providing the second sample for autoantibody confirmation during Phase 2 or providing the second sample before proceeding to Phase 2. Since TrialNet is a consortium that will continue to develop protocols for studying the etiology and prevention of T1D, it is possible that individuals who do not qualify for Phase 2 might still be eligible for other studies. Therefore, they may be contacted in the future so that they can be informed of new studies. In addition, they will be contacted periodically to learn if they have developed T1D. Individuals under the age of 18 years, who do not qualify for Phase 2, will be invited back for rescreening on an annual basis until they reach their 18th birthday. The baseline risk assessment will include an OGTT, the measurement of HbA1c, testing for ICA, and HLA typing (in consenting participants). Participants with protective HLA alleles will not be excluded from this study. In certain cases, a 20 minute IVGTT for First Phase Insulin Response (FPIR) will also be performed. Upon completion of Phase 2, participants will be classified into one of three risk categories for the occurrence of T1D within five years: 50%. The risk categories will be defined according to the OGTT results, number of confirmed positive biochemical autoantibodies, ICA positivity, and when required, IVGTT results. Participants will be informed of their risk categories when all test results are available. Individuals who participate in Phase 2 will also be offered the opportunity (through written consent) to enter Phase 3 for follow-up risk assessments. They will be seen at six-month intervals for five years or until the end of the study. At each visit, procedures will include an OGTT, collection of blood for autoantibody testing and measurement of HbA1c levels. IVGTTs will not be performed. Although there will not be a formal categorization of risk following each assessment, participants will be informed of their test results upon request. During each phase of the study, residual blood samples (and DNA samples in Phase 2) from consenting participants will be stored indefinitely at a TrialNet core laboratory and/or an NIDDK repository site for future immunologic and metabolic assessments that bear upon mechanisms of ¿x-cell destruction, and to obtain additional information about genetic markers associated with risk for the development of T1D. Subjects may still participate in all phases of the study even if they choose not to give consent for storage. Mechanistic samples will also be collected at Phases 2 and 3 at Clinical Centers participating in the Protocol Amendment for the collection of samples for storage for mechanistic studies. Individuals who qualify for prevention trials based on their risk assessments will be invited to participate in those trials as they become available. Individuals who enter a prevention trial will be followed according to the protocol of that trial. However, pertinent data accrued during the trial (conditional upon treatment status in the trial) such as the development of T1D, may be incorporated into the database for this study. The primary study outcome is diabetes mellitus (T1D) as defined by the American Diabetes Association (ADA) criteria. For most subjects, this will be based upon the results of an OGTT in the absence of symptomatic hyperglycemia. Confirmation of a diagnosis of diabetes by a second OGTT test in asymptomatic individuals will be required. Individuals who are hospitalized at diagnosis will be assessed through medical records.