Longitudinal Family/Molecular Genetic Study to Validate Research Domain Criteria

描述（由申请人提供）：NIMH研究领域标准（RDoC）项目旨在进一步实现通过遗传学，神经科学和行为研究为诊断系统做出贡献的长期目标。我们正在响应的应用程序请求鼓励应用程序研究跨越传统诊断类别的RDoC构建。由于RDoC结构是通过行为和神经生物学评估实例化的理论实体，因此它们的验证（在缺乏已知金标准的情况下）需要经验框架。该提案旨在将这样的框架应用于正价系统的RDoC构建体。 我们将应用Robins和Guze提出的验证系统的更新版本，该系统已被用作验证精神病学结构的工具数十年。我们将集中讨论该方法提出的五个问题中的四个：结构是否连贯？是家族遗传吗？是否与神经生物学指标有关？随着时间的推移，它是否稳定？我们的工作将回答前三个问题，并将为 纵向研究回答第四个问题。在RDoC精神，我们将采取一种不可知论的方法，通过向我们的普通儿童精神病诊所转诊，确定有任何精神障碍的孩子的家庭。我们还将从社区中抽取非精神病比较受试者，以确保我们在研究中代表的RDoC结构上具有广泛的评分范围，并评估结构测量的临床意义。我们正在采用基于临床的方法，并适当匹配社区对照，因为尽管RDoC领域并不旨在定义特定的疾病，但当研究针对这些特征具有极端值的个体富集的样本时，这些领域的任何研究都应该更强大（即，2因此，我们可以在一项研究中同时评估RDoC结构和主要的传统定义的儿童精神障碍。我们的方法显然也与NIMH和RDoC倡议的目标人群相关;即，儿童和成人表现出损害精神症状。使用该样本，我们将实现以下特定目的：1）确定由NIMH工作组提出的正价系统域中的构建体是否是同质理论构建体; 2）确定正价系统构建体是否是家族性的; 3）确定正价系统构建体是否预测精神病理学和损伤; 4）确定正价系统构建体是否与构建体候选基因、与最近鉴定的全基因组显著交叉病症候选基因以及与交叉病症多基因评分相关; 5）建立登记家庭数据库，并每年与他们保持联系，以确保纵向跟踪分析的可行性。

DESCRIPTION (provided by applicant): The NIMH Research Domain Criteria (RDoC) project is intended to further a long-range goal of contributing to diagnostic systems as informed by research on genetics, neuroscience, and behavior. The Request for Applications to which we are responding encourages applications to study RDoC Constructs that cut across traditional diagnostic categories. Because RDoC Constructs are theoretical entities instantiated by behavioral and neurobiologic assessments, their validation (in the absence of a known gold standard) requires an empirical framework. This proposal seeks to apply such a framework to RDoC Constructs of the Positive Valence Systems. We will apply an updated version of the validation system proposed by Robins and Guze, which has been used for many decades as a tool for validating psychiatric constructs. We will focus on four of the five questions asked by ths method: Is the Construct coherent? Is it familial? Is it associated with neurobiologic measures? Is it stable over time? Our work will answer the first three questions and will set the stage for a longitudinal study to answer the fourth. In the RDoC spirit, we will take an agnostic approach regarding nosology by ascertaining families having a child with any psychiatric disorder through referrals to our general child psychiatry clinic. We will also sample non-psychiatric comparison subjects from the community to assure that we have a wide range of scores on the RDoC Constructs represented in our study and to assess the clinical significance of Construct measures. We are adopting a clinic-based approach with appropriately matched community controls because, although the RDoC Domains are not intended to define particular disorders, any study of these domains should be more powerful when studying a sample enriched for individuals with extreme values on these traits (i.e., those with or without psychiatric disorders)2 As a consequence, we can simultaneously evaluate RDoC constructs and the predominant traditionally defined childhood psychiatric disorders in one study. Our approach is also clearly relevant to the target population of NIMH and the RDoC initiative; i.e., children and adults exhibiting impairing psychiatric symptoms. Using this sample, we will accomplish the following Specific Aims: 1) Determine if Constructs in the Positive Valence System Domains proposed by the NIMH Working Groups are homogenous theoretical Constructs; 2) Determine if Positive Valence System Constructs are familial; 3) Determine if Positive Valence System Constructs predict psychopathology and impairment; 4) Determine if Positive Valence System Constructs are associated with Construct candidate genes, with recently identified genome-wide significant cross-disorder candidate genes, and with cross-disorder polygenic scores; and 5) Establish a database of enrolled families and maintain annual contact with them to ensure the viability of longitudinal follow-up analyses.