NATURAL HISTORY STUDY OF THE DEVELOPMENT OF TYPE I DIABETES

该子项目是利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得主要资金， 因此可以在其他CRISP条目中表示。所列机构为 中心，不一定是研究者的机构。 目的：本研究的总体目的是对T1 D风险个体的代谢和免疫状态进行基线和重复评估，以： a）、 为了描述他们患T1 D的风险， B） 描述T1 D的发病演变， c）、 增加对T1 D发病因素的认识。 总结： T1 D发展的TrialNet自然史研究分为三个阶段：筛选（第1阶段），基线风险评估（第2阶段）和随访风险评估（第3阶段）。每个阶段都需要单独的知情同意书才能进入。本研究将采用前瞻性队列设计。 第1阶段包括筛查与T1 D相关的自身抗体的存在。在筛选期间，在两个单独的血液样本中对一种或多种相同的生化自身抗体（抗GAD 65、抗ICA 512或IAA）呈阳性的个体（即，确认自身抗体阳性）将有资格进入研究的第2阶段，即基线风险评估。此外，筛选期间获得的首份血液样本中至少两种生化自身抗体阳性的个体将有资格进入II期。这些受试者可以选择在II期期间提供第二份样本用于自身抗体确认，或在进入II期之前提供第二份样本。 由于TrialNet是一个联盟，将继续开发研究T1 D病因和预防的方案，因此不符合II期研究资格的个人可能仍有资格参加其他研究。因此，将来可能会与他们联系，以便他们能够了解新的研究。此外，他们将定期联系，以了解他们是否已开发T1 D。18岁以下的个人，谁不符合第二阶段，将被邀请回来重新筛选，每年一次，直到他们达到18岁生日。基线风险评估将包括OGTT、HbA 1c测量、伊卡检测和HLA分型（在知情同意的参与者中）。本研究不排除具有保护性HLA等位基因的受试者。在某些情况下，还将进行20分钟IVGTT用于第一时相胰岛素应答（FPIR）。 在第二阶段完成后，参与者将被分为三个风险类别之一，在五年内发生T1 D：50%。将根据OGTT结果、确认的阳性生化自身抗体数量、伊卡阳性和IVGTT结果（如需要）定义风险类别。当所有测试结果可用时，将告知参与者他们的风险类别。 参与第2阶段的个人也将有机会（通过书面同意）进入第3阶段进行随访风险评估。他们将在五年内每隔六个月进行一次观察，或直到研究结束。每次访视时，程序将包括OGTT、采集血液进行自身抗体检测和测量HbA 1c水平。将不进行IVGTT。虽然每次评估后不会对风险进行正式分类，但将根据要求告知参与者他们的测试结果。 在研究的每个阶段，来自知情同意受试者的残留血液样本（和第2阶段的DNA样本）将无限期储存在TrialNet核心实验室和/或NIDDK储存库中，用于未来的免疫学和代谢评估，这些评估与X细胞破坏机制有关，并获得与T1 D发生风险相关的遗传标记物的其他信息。即使受试者选择不同意储存，他们仍然可以参加研究的所有阶段。还将在参与方案修订的临床中心的2期和3期采集机械样本，以采集用于储存的样本用于机械研究。 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。进入预防试验的个体将根据该试验的方案进行随访。然而，试验期间积累的相关数据（取决于试验中的治疗状态），例如T1 D的发生，可纳入本研究的数据库中。 主要研究结局是美国糖尿病协会（ADA）标准定义的糖尿病（T1 D）。对于大多数受试者，这将基于无症状性高血糖的OGTT结果。在无症状个体中，需要通过第二次OGTT试验确诊糖尿病。诊断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.