Sampson, J. | bioRxiv Science

bioRxiv2018

A Simple Approximation To The Bias Of Gene-Environment Interactions In Case/Control Studies With Silent Disease

One of the most important research areas in case-control Genome-Wide Association Studies is to determine how the effect of a genotype varies across the environment or to measure the gene-environment interaction (GxE). We consider the scenario when some of the \"healthy\" controls actually have the disease and when the frequency of these latent cases varies by the environmental variable of interest. In this scenario, performing logistic regression of clinically defined case status on the genetic variant, environmental variable, and their interaction will result in biased estimates of GxE interaction. Here, we derive a general theoretical approximation to the bias in the estimates of the GxE interaction and show, through extensive simulation, that this approximation is accurate in finite samples. Moreover, we apply this approximation to evaluate the bias in the effect estimates of the genetic variants related to mitochondrial proteins a large-scale Prostate Cancer study.

genetics↗

bioRxiv2016

Dynamical System Modeling to Simulate Donor T Cell Response to Whole Exome Sequencing-Derived Recipient Peptides: Understanding Randomness in Clinical Outcomes Following Stem Cell Transplantation

The quantitative relationship between the magnitude of variation in minor histocompatibility antigens (mHA) and graft versus host disease (GVHD) pathophysiology in stem cell transplant (SCT) donor-recipient pairs (DRP) is not established. In order to elucidate this relationship, whole exome sequencing (WES) was performed on 27 HLA matched related (MRD), & 50 unrelated donors (URD), to identify nonsynonymous single nucleotide polymorphisms (SNPs). An average 2,463 SNPs were identified in MRD, and 4,287 in URD DRP (p<0.01); resulting peptide antigens that may be presented on HLA class I molecules in each DRP were derived in silico (NetMHCpan ver2.0) and the tissue expression of proteins these were derived from determined (GTex). MRD DRP had an average 3,670 HLA-binding-alloreactive peptides, putative mHA (pmHA) with an IC50 of <500 nM, and URD, had 5,386 (p<0.01). To simulate an alloreactive donor cytotoxic T cell response, the array of pmHA in each patient was considered as an operator matrix modifying a hypothetical cytotoxic T cell clonal vector matrix; each responding T cell clones proliferation was determined by the logistic equation of growth, accounting for HLA binding affinity and tissue expression of each alloreactive peptide. The resulting simulated organ-specific alloreactive T cell clonal growth revealed marked variability, with the T cell count differences spanning orders of magnitude between different DRP. Despite an estimated, uniform set of constants used in the model for all DRP, and a heterogeneously treated group of patients higher total and organ-specific T cell counts were associated with cumulative incidence of GVHD in recipients in Cox proportional hazard models. In conclusion, exome wide sequence differences and the variable alloreactive peptide binding to HLA in each DRP yields a large range of possible alloreactive donor T cell responses. Our findings also help understand the apparent randomness observed in the development of alloimmune responses.

immunology↗