Collaborative Applied Statistics

我与马修·布林博士和他在NCSU的研究小组有着长期的合作。 我们已经完成了一些研究，在这最后一个相关的理解的遗传和环境因素，作为一个模型，更好地了解癌症在人类中的犬癌症的病因。犬组织细胞恶性肿瘤（HM）在一般犬种群中很少见，但在某些品种中比例过高，如伯尔尼山地犬和平毛寻回犬。准确的诊断依赖于免疫组织化学染色，以排除具有不同病变和治疗策略的组织学相似的癌症（例如，淋巴瘤和血管肉瘤）。HM通常是治疗难治性的，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开发。虽然对人类肿瘤的研究可以使兽医学受益，但所提出的骨科疾病（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个犬种的自发性HM进行全基因组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号和31号染色体片段的丢失。液滴数字PCR（ddPCR）评价这些地区在许多癌症标本有效区分HM从其他常见的圆形细胞肿瘤，包括淋巴瘤和血管肉瘤，从而在兽医学的一种新的，快速的诊断援助。转录分析表明纺锤体组装复合物的破坏，这与基因组不稳定性和人类治疗效果降低有关。检测到的一个关键特征是基质金属蛋白酶9（MMP 9）的上调，这得到了MMP 9蛋白水平的基于荧光化学的评估的支持。由于MMP 9与人类的快速转移和肿瘤侵袭有关，因此本研究中的数据提供了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追踪器与更传统的采样技术（如尿液，脚趾甲等）测量的狗毒素暴露的一致性。 我还与威斯康星州大学的Lauren Trepanier博士合作，在犬模型中检测淋巴瘤病因学的基因-环境相互作用。 我还在一个评估老年痴呆症代谢组学变化的协会工作。 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关联。 我以前的博士生是这个项目的负责人。越来越多的证据表明肠道微生物组在中枢神经系统疾病中的作用以及肠-脑轴在神经变性中的特定作用。胆汁酸（BA）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传导功能，在阿尔茨海默病（AD）中似乎失调。在1464例受试者中测定了15种原发性和继发性BA及其结合形式的血清水平，其中包括370例认知正常的老年人，284例早期轻度认知障碍，505例晚期轻度认知障碍，以及305例AD神经影像学研究中登记的AD病例。我们评估了BA谱的相关性，包括诊断、认知和AD相关遗传变异的选定比例，调整了混杂因素和多重检验。在AD认知正常的老年人相比，我们观察到显着降低血清浓度的主要BA（胆酸CA）和细菌产生的，二级BA，脱氧胆酸，其甘氨酸和牛磺酸共轭形式的水平增加。脱氧胆酸：CA的比率增加，这反映了肠道细菌对CA的7-脱羟基作用，与认知能力下降密切相关，这一发现在拉什宗教秩序和记忆与衰老项目的血清和大脑样本中得到了复制。与AD相关的免疫应答相关基因的几种遗传变异与BA谱相关。 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，我与Stephanie伦敦博士合作，对吸烟引起的甲基化数据进行了适当的途径分析。 我们提交了一篇论文。 我还与Kleeberger博士合作，希望在柴油暴露的淋巴母细胞系模型中复制他的一些发现。 我也真正增加了我在环境多态性登记处的参与。 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.