Longitudinal Family/Molecular Genetic Study to Validate Research Domain Criteria

纵向家族/分子遗传学研究以验证研究领域标准

• 批准号: 8691086
• 负责人: STEPHEN V FARAONE
• 金额: $ 60.79万
• 依托单位: UPSTATE MEDICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-25 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8691086
• 关键词: Adopted; Adult; Age; Behavior; Behavioral; Candidate Disease Gene; Catchment Area; Categories; Characteristics; Child; Child Psychiatry; Childhood; Clinic; Communities; Databases; Development; Diagnostic; Dimensions; Disease; Enrollment; Ensure; Exhibits; Family; Family member; Funding; Future; Genes; Genetic; Goals; Gold; Impairment; Individual; Longitudinal Studies; Measures; Mental disorders; Methods; Molecular Genetics; National Institute of Mental Health; Neurobiology; Neurosciences; Parents; Pathway interactions; Patient Self-Report; Patients; Psychopathology; Relative (related person); Request for Applications; Research; Research Domain Criteria; Research Infrastructure; Robin bird; Running; Sampling; Siblings; Single Nucleotide Polymorphism; Staging; Symptoms; System; Target Populations; Testing; Time; Update; Validation; Validity of Self Report; Work; base; clinically significant; disease classification; disorder risk; follow-up; genome wide association study; genome-wide; member; psychobiology; public health relevance; tool; trait; transmission process; working group

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 this 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.

NIMH研究领域标准（RDoC）项目旨在进一步实现长期目标， 遗传学、神经科学和行为学研究所提供的诊断系统。请求 我们正在响应的应用程序鼓励应用程序研究跨 传统的诊断方法。由于RDoC构造是由行为实例化的理论实体， 和神经生物学评估，其验证（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积极的RDoC构建 瓦朗斯系统公司 我们将应用Robins和Guze提出的验证系统的更新版本， 几十年来一直被用作验证精神病学结构的工具。我们将重点讨论五个中的四个 这种方法提出的问题：结构是连贯的吗？是家族遗传吗？是否与神经生物学有关 措施？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精神，我们将采取不可知论的方法， 疾病分类学通过确定家庭有一个孩子与任何精神疾病通过转介到我们的一般 儿童精神病诊所。我们亦会从社会上抽取非精神科的比较对象， 我们在研究中所代表的RDoC结构上有广泛的分数，并评估 结构测量的临床意义。我们采用以诊所为基础的方法， 匹配的社区控件，因为尽管RDoC域并不打算定义特定的 这些领域的任何研究都应该在研究富含 在这些特征上具有极端值的个体（即，有或没有精神疾病的人）。 因此，我们可以同时评估RDoC结构和主要的传统定义 儿童精神疾病的研究。我们的方法显然也适用于 NIMH和RDoC倡议;即，儿童和成人表现出损害精神症状。使用此 样品，我们将完成以下具体目标：1）确定是否构建在正价 由NIMH工作组提出的系统域是同质的理论结构; 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是家族性的。 构建体预测精神病理学和损伤; 4）确定正价系统构建体是否 与构建体候选基因相关，与最近鉴定的全基因组显著交叉紊乱相关， 候选基因，并与交叉疾病多基因评分;和5）建立登记的家庭数据库 并与他们保持年度联系，以确保纵向跟踪分析的可行性。