Phenotypes and familiality in speech disorders

描述（由申请人提供）：在过去的二十年中，语音分析和语音模式识别技术取得了重大进展，然而，这些进展对语言障碍研究领域的渗透滞后，对临床的渗透几乎不存在。我们建议通过适应和扩展基于隐马尔可夫建模（HMM）的语音识别技术来分析来源不明的语音延迟儿童的语音来解决这一滞后问题。我们将通过(a)建立提出的分析技术在识别声学定义的片段扭曲类别（内表型）方面的有效性，(b)检查这些声学定义的内表型以寻找遗传力的证据，以及(c)寻找所获得的内表型与与语言障碍有关的3号染色体区域的遗传联系的证据，来证明这种方法的有效性。也就是说，三个目标将被解决：目标1：扩展和验证一个新的基于hmm的方法来识别和分类被诊断为发育性语音延迟的儿童。我们将建立一个新的数据库，收集与75对5至9岁的兄弟姐妹有关的信息，这些兄弟姐妹中至少有一人被诊断为自闭症。声学语音数据和感知数据将在数据库中提供特征集，用于识别可能的内表型。目的2：检查发展性语音障碍患者对声学和知觉测量的熟悉程度，以确定这些测量是否定义了可遗传的数量特征。我们将使用聚类和兄弟相关分析来评估声学和感知变量的遗传能力，并将其与更经典的语言变量进行比较，以确定更精细的表型是否比语言遗传学研究中通常使用的表型更具遗传性。我们假设，声学表型将定义一个可遗传的数量性状，可用于未来的基因组筛选研究，以确定与语言有关的基因。目的3：评估语言障碍兄弟姐妹中3号染色体的连锁关系。最近的研究表明，SD与3号染色体的中心点周围区域有关联（Stein et al., 2004）。我们将对语音、声学和感知表型进行定量性状连锁分析，以确定在该患者队列中是否存在与该区域相关的证据。

DESCRIPTION (provided by applicant): Over the past two decades, significant advances have been made in speech analysis and speech pattern recognition techniques, however, the penetration of these advances into the speech disorders research arena has lagged, and penetration into the clinic is virtually non-existent. We propose to address this lag by adapting and extending speech recognition technology based on Hidden Markov Modeling (HMM) to an analysis of speech from children with speech delay of unknown origin. We will demonstrate the efficacy of this approach by (a) establishing the effectiveness of the proposed analysis techniques in identifying acoustically defined categories of segmental distortions (endophenotypes), (b) examining these acoustically-defined endophenotypes for evidence of heritability and (c) searching for evidence of genetic linkage of the obtained endophenotypes to a region of chromosome 3 that has been implicated in speech disorders. That is, three aims will be addressed: Aim 1: Extension and validation of a new HMM-based approach to the identification and classification of children who are diagnosed with developmental phonological delays. We will develop a new database of information associated with 75 five to nine year old sibling pairs, at least one of whom is diagnosed with SD. Acoustic speech data and perceptual data will provide feature sets in the database for use in identifying possible endophenotypes. Aim 2: Examination of familiarity of acoustic and perceptual measures in developmental phonological disorders to determine whether these measures define heritable quantitative traits. We will assess heritability of the acoustic and perceptual variables as compared with more classically defined speech variables using cluster and sibling correlation analysis to determine whether the more refined phenotypes are more/less heritable that those typically used in speech genetics studies. We hypothesize that the acoustic phenotypes will define a heritable quantitative trait that can be used for future genome screening studies to identify genes involved in speech. Aim 3: Assessment of linkage to chromosome 3 in speech-disordered sibling pairs. Recent studies have shown evidence for linkage of SD to the pericentromeric region of chromosome 3 (Stein et al., 2004). We will use quantitative trait linkage analyses for the speech, acoustic and perceptual phenotypes to determine whether there is evidence for linkage to this region in this patient cohort.