Resources being amassed for genome-wide association (GWA) studies include "control databases" genotyped with a large-scale SNP array. How to use these databases effectively is an open question. We develop a method to match, by genetic ancestry, controls to affected individuals (cases). The impact of this method, especially for heterogeneous human populations, is to reduce the false-positive rate, inflate other spuriously small p values, and have little impact on the p values associated with true positive loci. Thus, it highlights true positives by downplaying false positives. We perform a GWA by matching Americans with type 1 diabetes (T1D) to controls from Germany. Despite the complex study design, these analyses identify numerous loci known to confer risk for T1D.

Phase II clinical trials in oncology are used for initial evaluation of the therapeutic efficacy of a new treatment regimen. Simon's two-stage design based on total response (TR) rate is commonly used for such trials. Several authors have proposed alternative strategies to consider either response and toxicity or response and early progression. Because TR consists of both partial response (PR) and complete response (CR) and these two types of responses have different effects on subsequent patient outcome, Lin and Chen proposed a flexible design that is based on a weighted average of PR and CR rates as a way to recognize the differential significance of the two levels of response. Panageas and colleagues, on the other hand, used a trinomial model and direct search to consider a rejection region for PR and CR separately. In this paper, we reformat their hypotheses to assess efficacy based on TR and CR. A new two-stage optimum phase II trial design based on TR and CR is developed. We provide guides on searching the stopping and rejecting regions and on determining sample size. An example of a phase II trial for glioblastomas treatment is presented. In this trial, physicians would be interested in either stable disease (SD), PR, or CR as an indication of efficacy. However, because PR and CR rarely occur, observation of any PR or CR will lean towards acceptance of the treatment. Our design has the advantage of being close to the traditional Simon two-stage design while still having the flexibility to treat responses (PR and CR in this example) differently than SD.

The major histocompatibility complex (MHC) on chromosome 6p is an established risk locus for ulcerative colitis (UC) and Crohn’s disease (CD). We aimed to better define MHC association signals in UC and CD by combining data from dense single nucleotide polymorphism (SNP) genotyping and from imputation of classical HLA types, their constituent SNPs and corresponding amino acids in 562 UC, 611 CD, and 1,428 control subjects. Univariate and multivariate association analyses were performed, controlling for ancestry. In univariate analyses, absence of the rs9269955 C allele was strongly associated with risk for UC (P = 2.67×10−13). rs9269955 is a SNP in the codon for amino acid position 11 of HLA-DRβ1, located in the P6 pocket of the HLA-DR antigen binding cleft. This amino acid position was also the most significantly UC-associated amino acid in omnibus tests (P = 2.68×10−13). Multivariate modeling identified rs9269955-C and 13 other variants in best predicting UC versus control status. In contrast, there was only suggestive association evidence between the MHC and CD. Taken together, these data demonstrate that variation at HLA-DRβ1, amino acid 11 in the P6 pocket of the HLA-DR complex antigen binding cleft is a major determinant of chromosome 6p association with ulcerative colitis.

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