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)项目旨在推进一个长期目标，即通过遗传学、神经科学和行为学研究为诊断系统做出贡献。我们正在响应的对应用程序的请求鼓励应用程序研究跨越传统诊断类别的RDoC结构。由于RDoC结构是由行为和神经生物学评估实例化的理论实体，它们的验证(在缺乏已知黄金标准的情况下)需要一个经验框架。本提案试图将这样的框架应用于RDoC构造的正价系统。我们将应用Robins和Guze提出的验证系统的更新版本，该系统几十年来一直被用作验证精神病学结构的工具。我们将重点讨论该方法提出的五个问题中的四个：结构是否连贯？是家族性的吗？它与神经生物学指标有关吗？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。本着RDoC的精神，我们将对病因学采取不可知论的方法，通过转诊到我们的普通儿童精神病学诊所来确定孩子患有任何精神障碍的家庭。我们还将从社区中抽取非精神病学比较对象，以确保我们在研究中所代表的RDoC结构上有广泛的分数，并评估构建措施的临床意义。我们采用以临床为基础的方法和适当匹配的社区对照，因为虽然RDoC领域并不是为了定义特定的障碍，但在研究样本时，对这些领域的任何研究都应该更强大，因为样本丰富了在这些特征上具有极端价值的个人(即，那些有或没有精神障碍的人)2，因此，我们可以在一项研究中同时评估RDoC的结构和主要的传统定义的儿童精神障碍。我们的做法显然也与NIMH的目标人群和RDoC倡议有关；即，表现出损害精神症状的儿童和成人。利用这个样本，我们将完成以下具体目标：1)确定NIMH工作组提出的正价系统结构域中的结构是否是同质理论结构；2)确定正价系统结构是否具有家族性；3)确定正价系统结构是否预测精神疾病和损伤；4)确定正价系统结构是否与构建的候选基因、最近发现的全基因组显著的跨障碍候选基因以及跨障碍多基因分数相关；以及5)建立登记家庭的数据库并保持与他们的年度联系，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.