Collaborative Applied Statistics

我和Matthew Breen博士以及他在NCSU的研究小组有长期合作。我们已经完成了一些研究，这些研究与了解犬类癌症病因背后的遗传和环境因素有关，作为更好地了解人类癌症的模型。犬类组织细胞恶性肿瘤（HM）在一般犬类中是罕见的，但在某些品种中发病率过高，如伯尔尼山犬和平毛猎犬。准确的诊断依赖于免疫组织化学染色来排除组织学上相似但预后和治疗策略不同的癌症（如淋巴瘤和血管肉瘤）。HM通常是难治性的，总生存期小于6个月。缺乏对疾病发展和进展机制的理解阻碍了新疗法的发展。虽然对人类肿瘤的研究可以使兽医学受益，但所建议的同源疾病（树突状细胞肉瘤）的罕见性排除了这一点。本研究旨在通过对几种犬种自发性HM的全基因组DNA拷贝数和基因表达分析，提高对潜在疾病机制的理解。广泛的DNA拷贝数破坏是明显的，在93%和72%的肿瘤中分别检测到16和31染色体片段的丢失。液滴数字PCR （ddPCR）在许多癌症标本中对这些区域进行评估，有效地将HM与其他常见的圆形细胞肿瘤（包括淋巴瘤和血管肉瘤）区分开来，从而为兽医学提供了一种新的、快速的诊断手段。转录分析显示纺锤体组装复合物的破坏，这与基因组不稳定和降低人类治疗效果有关。检测到的一个关键特征是基质金属蛋白酶9 （MMP9）的上调，这得到了基于免疫组织化学的MMP9蛋白水平评估的支持。由于MMP9与人类肿瘤的快速转移和侵袭有关，本研究的数据为HM的侵袭提供了可能的机制。他的团队正在进行的另一项工作是评估被动硅胶追踪器与更传统的采样技术（如尿液、脚趾甲等）测量的狗体内毒素暴露的一致性。我还和另一位合作者使用犬类模型。我还与威斯康星大学的Lauren Trepanier博士合作，在犬类淋巴瘤模型中检测基因与环境的相互作用。

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.