Treatment as Prevention: Characterization of Partner Infections in the HIV Prevention Trials Network 052 Trial.

HIV Prevention Trials Network 052 demonstrated that antiretroviral therapy (ART) prevents HIV transmission in serodiscordant couples. HIV from index-partner pairs was analyzed to determine the genetic linkage status of partner infections. Forty-six infections were classified as linked, indicating that the index was the likely source of the partner's infection.

Augmented case-only designs for randomized clinical trials with failure time endpoints.

Under suitable assumptions and by exploiting the independence between inherited genetic susceptibility and treatment assignment, the case-only design yields efficient estimates for subgroup treatment effects and gene-treatment interaction in a Cox model. However it cannot provide estimates of the genetic main effect and baseline hazards, that are necessary to compute the absolute disease risk. For two-arm, placebo-controlled trials with rare failure time endpoints, we consider augmenting the case-only design with random samples of controls from both arms, as in the classical case-cohort sampling scheme, or with a random sample of controls from the active treatment arm only.

Mendelian randomization studies for a continuous exposure under case-control sampling.

In this article, we assess the impact of case-control sampling on mendelian randomization analyses with a dichotomous disease outcome and a continuous exposure. The 2-stage instrumental variables (2SIV) method uses the prediction of the exposure given genotypes in the logistic regression for the outcome and provides a valid test and an approximation of the causal effect. Under case-control sampling, however, the first stage of the 2SIV procedure becomes a secondary trait association, which requires proper adjustment for the biased sampling.

Tumor evolution and intratumor heterogeneity of an oropharyngeal squamous cell carcinoma revealed by whole-genome sequencing.

Head and neck squamous cell carcinoma (HNSCC) is characterized by significant genomic instability that could lead to clonal diversity. Intratumor clonal heterogeneity has been proposed as a major attribute underlying tumor evolution, progression, and resistance to chemotherapy and radiation. Understanding genetic heterogeneity could lead to treatments specific to resistant and metastatic tumor cells.

Effect of MHC and non-MHC donor/recipient genetic disparity on the outcome of allogeneic HCT.

The outcome of allogeneic hematopoietic cell transplantation is influenced by donor/recipient genetic disparity at loci both inside and outside the MHC on chromosome 6p. Although disparity at loci within the MHC is the most important risk factor for the development of severe GVHD, disparity at loci outside the MHC that encode minor histocompatibility (H) antigens can elicit GVHD and GVL activity in donor/recipient pairs who are otherwise genetically identical across the MHC. Minor H antigens are created by sequence and structural variations within the genome.

Sequencing genes in silico using single nucleotide polymorphisms.

Background: The advent of high throughput sequencing technology has enabled the 1000 Genomes Project Pilot 3 to generate complete sequence data for more than 906 genes and 8,140 exons representing 697 subjects. The 1000 Genomes database provides a critical opportunity for further interpreting disease associations with single nucleotide polymorphisms (SNPs) discovered from genetic association studies. Currently, direct sequencing of candidate genes or regions on a large number of subjects remains both cost- and time-prohibitive.

Evaluation of published single nucleotide polymorphisms associated with acute GVHD.

Candidate genetic associations with acute GVHD (aGVHD) were evaluated with the use of genotyped and imputed single-nucleotide polymorphism data from genome-wide scans of 1298 allogeneic hematopoietic cell transplantation (HCT) donors and recipients. Of 40 previously reported candidate SNPs, 6 were successfully genotyped, and 10 were imputed and passed criteria for analysis. Patient and donor genotypes were assessed for association with grades IIb-IV and III-IV aGVHD, stratified by donor type, in univariate and multivariate allelic, recessive and dominant models.

Empirical evaluations of analytical issues arising from predicting HLA alleles using multiple SNPs.

Background: Numerous immune-mediated diseases have been associated with the class I and II HLA genes located within the major histocompatibility complex (MHC) consisting of highly polymorphic alleles encoded by the HLA-A, -B, -C, -DRB1, -DQB1 and -DPB1 loci. Genotyping for HLA alleles is complex and relatively expensive. Recent studies have demonstrated the feasibility of predicting HLA alleles, using MHC SNPs inside and outside of HLA that are typically included in SNP arrays and are commonly available in genome-wide association studies (GWAS).

Predicting multiallelic genes using unphased and flanking single nucleotide polymorphisms.

Recent advances in genotyping technologies have enabled genomewide association studies (GWAS) of many complex traits including autoimmune disease, infectious disease, cancer and heart disease. To facilitate interpretations and establish biological basis, it could be advantageous to identify alleles of functional genes, beyond just single nucleotide polymorphisms (SNPs) within or nearby genes. Leslie et al.