Genetic association studies under the population stratification, family pedigree and application to genome-wide association studies

This dissertation has three separate parts: the first part deals with the general pedigree association testing incorporating continuous covariates; the second part deals with the association tests under population stratification using the conditional likelihood tests; the third part deals with the genome-wide association studies based on the real rheumatoid arthritis (RA) disease data sets from Genetic Analysis Workshop 16 (GAW16) problem 1. Many statistical tests are developed to test the linkage and association using either case-control status or phenotype covariates for family data structure, separately. Those univariate analyses might not use all the information coming from the family members in practical studies. On the other hand, the human complex disease do not have a clear inheritance pattern, there might exist the gene interactions or act independently. In part I, the new proposed approach MPDT is focused on how to use both the case control information as well as the phenotype covariates. This approach can be applied to detect multiple marker effects. Based on the two existing popular statistics in family studies for case-control and quantitative traits respectively, the new approach could be used in the simple family structure data set as well as general pedigree structure. The combined statistics are calculated using the two statistics; A permutation procedure is applied for assessing the p-value with adjustment from the Bonferroni for the multiple markers. We use simulation studies to evaluate the type I error rates and the powers of the proposed approach. Our results show that the combined test using both case-control information and phenotype covariates not only has the correct type I error rates but also is more powerful than the other existing methods. For multiple marker interactions, our proposed method is also very powerful. Selective genotyping is an economical strategy in detecting and mapping quantitative trait loci in the genetic dissection of complex disease. When the samples arise from different ethnic groups or an admixture population, all the existing selective genotyping methods may result in spurious association due to different ancestry distributions. The problem can be more serious when the sample size is large, a general requirement to obtain sufficient power to detect modest genetic effects for most complex traits. In part II, I describe a useful strategy in selective genotyping while population stratification is present. Our procedure used a principal component based approach to eliminate any effect of population stratification. The paper evaluates the performance of our procedure using both simulated data from an early study data sets and also the HapMap data sets in a variety of population admixture models generated from empirical data. There are one binary trait and two continuous traits in the rheumatoid arthritis dataset of Problem 1 in the Genetic Analysis Workshop 16 (GAW16): RA status, AntiCCP and IgM. To allow multiple traits, we suggest a set of SNP-level F statistics by the concept of multiple-correlation to measure the genetic association between multiple trait values and SNP-specific genotypic scores and obtain their null distributions. Hereby, we perform 6 genome-wide association analyses using the novel one- and two-stage approaches which are based on single, double and triple traits. Incorporating all these 6 analyses, we successfully validate the SNPs which have been identified to be responsible for rheumatoid arthritis in the literature and detect more disease susceptibility SNPs for follow-up studies in the future. Except for chromosome 13 and 18, each of the others is found to harbour susceptible genetic regions for rheumatoid arthritis or related diseases, i.e., lupus erythematosus. This topic is discussed in part III.

A FIREWALL MODEL OF FILE SYSTEM SECURITY

File system security is fundamental to the security of UNIX and Linux systems since in these systems almost everything is in the form of a file. To protect the system files and other sensitive user files from unauthorized accesses, certain security schemes are chosen and used by different organizations in their computer systems. A file system security model provides a formal description of a protection system. Each security model is associated with specified security policies which focus on one or more of the security principles: confidentiality, integrity and availability. The security policy is not only about “who” can access an object, but also about “how” a subject can access an object. To enforce the security policies, each access request is checked against the specified policies to decide whether it is allowed or rejected. The current protection schemes in UNIX/Linux systems focus on the access control. Besides the basic access control scheme of the system itself, which includes permission bits, setuid and seteuid mechanism and the root, there are other protection models, such as Capabilities, Domain Type Enforcement (DTE) and Role-Based Access Control (RBAC), supported and used in certain organizations. These models protect the confidentiality of the data directly. The integrity of the data is protected indirectly by only allowing trusted users to operate on the objects. The access control decisions of these models depend on either the identity of the user or the attributes of the process the user can execute, and the attributes of the objects. Adoption of these sophisticated models has been slow; this is likely due to the enormous complexity of specifying controls over a large file system and the need for system administrators to learn a new paradigm for file protection. We propose a new security model: file system firewall. It is an adoption of the familiar network firewall protection model, used to control the data that flows between networked computers, toward file system protection. This model can support decisions of access control based on any system generated attributes about the access requests, e.g., time of day. The access control decisions are not on one entity, such as the account in traditional discretionary access control or the domain name in DTE. In file system firewall, the access decisions are made upon situations on multiple entities. A situation is programmable with predicates on the attributes of subject, object and the system. File system firewall specifies the appropriate actions on these situations. We implemented the prototype of file system firewall on SUSE Linux. Preliminary results of performance tests on the prototype indicate that the runtime overhead is acceptable. We compared file system firewall with TE in SELinux to show that firewall model can accommodate many other access control models. Finally, we show the ease of use of firewall model. When firewall system is restricted to specified part of the system, all the other resources are not affected. This enables a relatively smooth adoption. This fact and that it is a familiar model to system administrators will facilitate adoption and correct use. The user study we conducted on traditional UNIX access control, SELinux and file system firewall confirmed that. The beginner users found it easier to use and faster to learn then traditional UNIX access control scheme and SELinux.