Collaborative Applied Statistics

National Institute Of Environmental Health Sciences

Investigators

Linked publications & trials

Abstract

I have had a long-term collaboration with Dr. Matthew Breen and his research group at NCSU. We have completed a number of studies in this last related to understanding the genetic and environmental factors that underlie the etiology of cancer in canines as a model for better understanding cancer in humans. Canine histiocytic malignancies (HM) are rare across the general dog population, but overrepresented in certain breeds, such as Bernese mountain dog and flat-coated retriever. Accurate diagnosis relies on immunohistochemical staining to rule out histologically similar cancers with different prognoses and treatment strategies (e.g., lymphoma and hemangiosarcoma). HM are generally treatment refractory with overall survival of less than 6 months. A lack of understanding regarding the mechanisms of disease development and progression hinders development of novel therapeutics. While the study of human tumors can benefit veterinary medicine, the rarity of the suggested orthologous disease (dendritic cell sarcoma) precludes this. This study aims to improve the understanding of underlying disease mechanisms using genome-wide DNA copy number and gene expression analysis of spontaneous HM across several dog breeds. Extensive DNA copy number disruption was evident, with losses of segments of chromosomes 16 and 31 detected in 93% and 72% of tumors, respectively. Droplet digital PCR (ddPCR) evaluation of these regions in numerous cancer specimens effectively discriminated HM from other common round cell tumors, including lymphoma and hemangiosarcoma, resulting in a novel, rapid diagnostic aid for veterinary medicine. Transcriptional analysis demonstrated disruption of the spindle assembly complex, which is linked to genomic instability and reduced therapeutic impact in humans. A key signature detected was up-regulation of Matrix Metalloproteinase 9 (MMP9), supported by an immunohistochemistry-based assessment of MMP9 protein levels. Since MMP9 has been linked with rapid metastasis and tumor aggression in humans, the data in this study offer a possible mechanism of aggression in HM. Additional ongoing work with his group is evaluating the consistency of toxin exposure in dogs measured by passive silicone trackers versus more traditional sampling techniques like urine, toenails, etc. I also work with another collaborator using the canine model. I also work with Dr. Lauren Trepanier at the University of Wisconsin on detecting gene-environment interactions underlying the etiology of lymphoma in the canine model. I also work in a consortium that evaluates metabolomic changes in Alzheimers Disease. Working with the ADNI Metabolomics Consortia, led my Rima Kaddurah-Doak, we evaluated associations of bile acid metabolites and disease. My former PhD student was the lead on this project. Increasing evidence suggests a role for the gut microbiome in central nervous system disorders and a specific role for the gut-brain axis in neurodegeneration. Bile acids (BAs), products of cholesterol metabolism and clearance, are produced in the liver and are further metabolized by gut bacteria. They have major regulatory and signaling functions and seem dysregulated in Alzheimer's disease (AD). Serum levels of 15 primary and secondary BAs and their conjugated forms were measured in 1464 subjects including 370 cognitively normal older adults, 284 with early mild cognitive impairment, 505 with late mild cognitive impairment, and 305 AD cases enrolled in the AD Neuroimaging Initiative. We assessed associations of BA profiles including selected ratios with diagnosis, cognition, and AD-related genetic variants, adjusting for confounders and multiple testing. In AD compared to cognitively normal older adults, we observed significantly lower serum concentrations of a primary BA (cholic acid CA) and increased levels of the bacterially produced, secondary BA, deoxycholic acid, and its glycine and taurine conjugated forms. An increased ratio of deoxycholic acid:CA, which reflects 7-dehydroxylation of CA by gut bacteria, strongly associated with cognitive decline, a finding replicated in serum and brain samples in the Rush Religious Orders and Memory and Aging Project. Several genetic variants in immune response-related genes implicated in AD showed associations with BA profiles. As this is my first year at NIEHS, I am building exciting new collaborations. In particular I have worked with Dr. Stephanie London on implementing appropriate pathway analysis for methylation data in response to smoking. We have a paper in submission. I am also working with Dr. Kleeberger looking to replicate some of his findings in the lymphoblastoid cell line model of diesel fuel exposure. I am also really growing my involvement in the Environmental Polymorphisms Registry. I plan to take a leadership role in the statistical genetics aspects of the project.