Collaborative Applied Statistics

我与马修·布林博士和他在NCSU的研究小组进行了长期的合作。我们已经完成了一些关于了解犬类癌症病因的遗传和环境因素的研究，作为更好地理解人类癌症的模型。犬组织细胞恶性肿瘤(HM)在普通犬种中很少见，但在某些品种中过于常见，如伯恩山犬和扁平毛寻回犬。准确的诊断依赖于免疫组织化学染色，以排除预后和治疗策略不同的组织学相似的癌症(例如淋巴瘤和血管肉瘤)。HM一般是难治性的，总生存期不到6个月。缺乏对疾病发展和进展机制的了解阻碍了新疗法的发展。虽然对人类肿瘤的研究可以帮助兽医，但所建议的直系疾病(树突状细胞肉瘤)的罕见排除了这一点。这项研究旨在通过对几个品种的自发性HM进行全基因组DNA拷贝数和基因表达分析来提高对潜在疾病机制的理解。广泛的DNA拷贝数破坏明显，分别在93%和72%的肿瘤中检测到16和31号染色体片段的丢失。液滴数字聚合酶链式反应(DdPCR)对大量癌症标本中这些区域的评估有效地将HM与其他常见的圆形细胞肿瘤区分开来，包括淋巴瘤和血管肉瘤，从而为兽医提供了一种新的、快速的诊断辅助手段。转录分析表明，纺锤体组装复合体被破坏，这与基因组不稳定和降低对人类的治疗效果有关。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与人类的快速转移和肿瘤侵袭有关，本研究的数据提供了HM侵袭的可能机制。与他的团队正在进行的其他工作是评估被动硅胶跟踪器与尿液、脚趾甲等更传统采样技术测量的狗体内毒素暴露的一致性。我还与另一位使用犬类模型的合作者合作。我还与威斯康星大学的Lauren Trepanier博士合作，在犬模型中检测淋巴瘤病因学背后的基因-环境相互作用。 我还在一家评估阿尔茨海默氏症代谢变化的协会工作。与ADNI代谢组学联盟合作，领导我的Rima Kaddurah-Doak，我们评估了胆汁酸代谢物和疾病的相关性。我以前的博士生是这个项目的带头人。越来越多的证据表明，肠道微生物群在中枢神经系统疾病中发挥了作用，肠道-脑轴在神经退化中发挥了特定作用。胆汁酸(BAS)是胆固醇代谢和清除的产物，在肝脏中产生，并由肠道细菌进一步代谢。它们具有重要的调节和信号功能，在阿尔茨海默病(AD)中似乎调节失调。检测了1464例受试者血清中15种主要和继发性BA及其结合形式，包括370例认知正常老年人、284例早期轻度认知损害、505例晚期轻度认知损害和305例参加AD神经影像研究的AD患者。我们评估了BA图谱的相关性，包括选定的比率与诊断、认知和AD相关遗传变异的关系，调整了混杂因素和多重测试。在AD患者中，我们观察到与认知正常的老年人相比，初级BA(胆酸CA)的血清浓度显著降低，细菌产生的次级BA、脱氧胆酸及其甘氨酸和牛磺酸结合形式的水平增加。脱氧胆酸：CA的比率增加，反映肠道细菌对CA的7-脱羟基，与认知能力下降密切相关，这一发现在Rush宗教秩序和记忆与老龄化项目的血清和大脑样本中得到了重复。与阿尔茨海默病有关的免疫反应相关基因中的几个遗传变异与BA谱有关。 由于这是我在NIEHS的第一年，我正在建立令人兴奋的新合作。特别是，我曾与斯蒂芬妮·伦敦博士合作，对吸烟反应的甲基化数据进行适当的路径分析。我们有一篇提交的论文。我还在与克利伯格博士合作，希望在接触柴油的淋巴母细胞系模型中复制他的一些发现。我还真的越来越多地参与到环境多态登记处。我计划在该项目的统计遗传学方面发挥领导作用。

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.