software for Integrated Linkage and Association Analysis

说明(申请人提供)：本提案的目标是继续开发新的关联和关联分析方法，并将新方法与核心家庭的现有关联和关联方法结合成一个单一的软件包。在过去的三年中，我们开发并发布了5个用于复杂性状遗传分析的软件程序，包括受影响同胞对连锁作图软件、一般家系关联分析软件、有序子集连锁作图软件和用于探索这些软件包和其他软件包的特性的通用模拟软件包。我们建议通过以下方式继续开发这些方法和配套软件：1)继续开发经验p值方法和配套软件。我们开发和分发的模拟程序包可用于一般家系的模拟，其中可以包括观察标记图谱和观察等位基因频率。我们的目标是扩展这个包，从观察到的系谱结构模拟，包括观察到的表型和基因类型的指示器。2)在存在联系的情况下，开发和分发以家庭为基础的联系软件。在我们对现有的基于家庭的关联软件进行比较的模拟研究过程中，我们观察到其中一项测试的连锁区域出现了严重膨胀的I型错误。我们提出了一种新的测试，该测试调整了家庭中是否存在连锁，并给出了适当的第一类错误率。3)继续开发有序子集分析(OSA)方法和软件，通过使用OSA来划分连锁证据的递归划分方法合并多个性状，并将该方法应用于基于家族的关联分析。4)开发将纳入各种统计测试、表达和蛋白质组学结果的方法，以及纳入人类基因组计划中出现的遗传特征，如识别基因、单倍型区块、重组热点和风险序列。我们对方法开发、评估和比较的研究得到了这些新方法在各种正在进行的应用链接和联合项目中的应用的帮助。我们的合作者测试了新的软件，并讨论了在方法开发和软件编程期间所做选择的实际后果。我们将继续利用这一资源，为这些方法的应用制定切合实际的指导方针。

DESCRIPTION (provided by applicant): The goal of this proposal is to continue the development of new methods of linkage and association analysis, and to combine the new methods with existing linkage and association methods for nuclear families into a single software package. Over the course of the past three years we have developed and released 5 software programs for the genetic analysis of complex traits including software for affected sib-pair linkage mapping, software for association analysis in general pedigrees, software for ordered subset linkage mapping and a general simulation package to explore the properties of these and other software packages. We propose to continue the development of these methods and accompanying software in the following ways: 1) Continue development of empirical p-value methods and accompanying software. The simulation package we developed and distributed is available for simulation of general pedigrees, which can include an observed marker map and observed allele frequencies. Our goal is to expand this package to simulate from the observed pedigree structures, including indicators of the observed phenotypes and genotypes. 2) Develop and distribute software for family-based association in the presence of linkage. In the course of our simulation studies comparing available software packages for family-based association, we observed grossly inflated type I errors in regions of linkage for one of the tests. We propose a new test that adjusts for the presence of linkage in families and gives the proper type 1 error rates. 3) Continue development of the ordered subset analysis (OSA) methods and software to incorporate more than one trait through recursive partitioning methods that use OSA to partition the linkage evidence and to apply this method to family-based association analysis. 4) Develop methods that will incorporate a variety of statistical tests, expression and proteomics results as well as incorporate genetic features emerging from the Human Genome Project such as identified genes, Haplotype Blocks, hot spots of recombination and at-risk sequences. Our research into methods development, assessment and comparison has been aided by the application of these new methods to a variety of ongoing applied linkage and association projects. Our collaborators have tested new software and have discussed the practical consequences of choices made during methods development and software programming. We will continue to utilize this resource to develop realistic and practical guidelines for application of these methods.