software for Integrated Linkage and Association Analysis

描述（由申请人提供）：本提案的目标是继续开发新的连锁和关联分析方法，并将新方法与核心家庭的现有连锁和关联方法联合收割机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个软件程序，用于复杂性状的遗传分析，包括受影响的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通用模拟包，以探索这些和其他软件包的特性。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包可用于模拟一般家系，其中可以包括观察到的标记图和观察到的等位基因频率。我们的目标是扩展该软件包以模拟观察到的谱系结构，包括观察到的表型和基因型的指标。2)开发和分发软件，以便在有联系的情况下建立以家庭为基础的联系。在我们的模拟研究的过程中，比较可用的软件包，以家庭为基础的协会，我们观察到严重膨胀的I型错误的区域的联系的一个测试。我们提出了一个新的测试，调整家庭中存在的连锁，并给出适当的1型错误率。3)继续开发有序子集分析方法和软件，通过递归划分方法将一个以上的性状纳入其中，使用有序子集分析划分连锁证据，并将此方法应用于基于家族的关联分析。4)开发方法，整合各种统计测试、表达和蛋白质组学结果，并整合人类基因组计划中出现的遗传特征，例如已识别的基因、单倍型块、重组热点和高危序列。我们的研究方法的发展，评估和比较已经得到了这些新方法的应用程序的各种正在进行的应用联系和协会项目的帮助。我们的合作者已经测试了新的软件，并讨论了在方法开发和软件编程过程中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.