Clinical, Imaging, and Endoscopic Outcomes of Children Newly Diagnosed with Crohn's Disease

新诊断克罗恩病儿童的临床、影像学和内窥镜结果

基本信息

批准号：
10560015
负责人：
LEE ARMISTEAD DENSON
金额：
$ 280万
依托单位：
CONNECTICUT CHILDREN'S MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-01 至 2028-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10560015
关键词：
Algorithms Ancillary Study Anti-Tumor Necrosis Factor Therapy Biological Biological Factors Budgets Characteristics Child Childhood Clinical Clinical Treatment Clinical/Radiologic Cohort Studies Colon Colonoscopy Crohn&apos s disease Data Data Management Resources Data Set Development Diagnosis Disease Disease remission Dose Drug Exposure Drug Monitoring Erythrocyte Sedimentation Rate Exhibits Fibroblasts Future Gene Expression Gene Expression Profile Genetic Transcription Genomics Genotype Goals Health Expenditures Hospitalization Image Immune response Inflammatory Institutional Review Boards Intestines Logistic Regressions Macrophage Magnetic Resonance Manuals Measures Microbe Microbial Taxonomy Modeling Mucous Membrane Multiomic Data Neoadjuvant Therapy Newly Diagnosed Nutritional status Operative Surgical Procedures Outcome Pathogenesis Patients Pediatric Crohn&apos s disease Pharmaceutical Preparations Predictive Factor Probability Procedures Process Prospective, cohort study Protocols documentation Quality of life Radiology Specialty Reading Refractory Regimen Reporting Risk Serology Services Severities Specific qualifier value TNF gene Testing Therapeutic Translating Validation antimicrobial biobank clinical practice clinical remission clinical research site experience genetic signature genotyped patients healing hospitalization rates image archival system improved infliximab insight microbial microbial community microbial genomics microbiota novel operation predictive modeling primary endpoint response secondary endpoint seropositive targeted treatment transcriptome transcriptomics

项目摘要

PROJECT SUMMARY/ABSTRACT Therapeutic goals in pediatric Crohn's Disease (CD) have shifted from clinical improvement or remission to endoscopic healing (EH) by ileocolonoscopy and transmural healing (TH) by magnetic resonance enterography (MRE). Patients achieving complete healing (CH, EH and TH) experience fewer hospitalizations or surgery. We hypothesize that specific pre-treatment clinical, radiologic, transcriptomic, genomic, and microbial factors along with attainment of targeted anti-TNF biologic exposure will be associated with the primary endpoint, CH, and the major secondary endpoints, EH and TH, 52 weeks after anti-TNF start. We will test this hypothesis in a prospective cohort study of 550 newly diagnosed pediatric-onset CD subjects treated with anti-TNF medication within 6 months of diagnosis guided by therapeutic drug monitoring (TDM). Aim 1. Evaluate putative associations and explore novel associations between CH and baseline measures of clinical and radiologic severity. We hypothesize that pre-treatment nutritional status, antimicrobial serologies, and MRE findings will be associated with year 1 CH. Formal hypothesis tests will be carried out with appropriately controlled Type I error probabilities to confirm the predictive power of a set of pre- specified baseline measures using a logistic regression model based on the year 1 CH outcome. Aim 2. Evaluate putative associations and explore novel associations between anti-TNF drug levels, CH, and host and microbial genomic and transcriptomic factors. We hypothesize that pre-treatment gene expression signatures and microbial factors will be associated with early anti-TNF drug levels and year 1 CH. We will characterize the host genotype, baseline mucosal and longitudinal fecal microbial taxonomic profile, and baseline ileal and colon host transcriptome. Those variables identified as significantly associated will be candidates for the final prediction model determined in Aim 3. Aim 3. Use a k-fold cross-validation procedure to determine the optimal predictive model of year 1 CH. We hypothesize that a model which includes host gene signatures and microbes will improve prediction of CH beyond one based on clinical and imaging factors alone. The model will include clinical and imaging predictors from Aim 1 and host and microbial characteristics found to be potentially explanatory in Aim 2. Impact. The proposed inception cohort study, CAMEO, will provide a robust platform to study factors that contribute to healing in pediatric CD that can then be translated into practice, as well as guiding future therapies targeting the host immune response and microbiota in patients unlikely to achieve healing. .

项目概要/摘要儿科克罗恩病 (CD) 的治疗目标已从临床改善或缓解转向通过回结肠镜检查进行内窥镜愈合（EH），通过磁共振肠造影进行透壁愈合（TH）（MRE）。完全康复的患者（CH、EH 和 TH）住院或手术次数较少。我们假设特定的治疗前临床、放射学、转录组学、基因组和微生物因素达到靶向抗 TNF 生物制剂暴露将与主要终点 CH 和主要次要终点 EH 和 TH，在抗 TNF 治疗开始后 52 周。我们将在以下情况中检验这个假设： 550 名新诊断的儿科发病 CD 受试者接受抗 TNF 药物治疗的前瞻性队列研究在治疗药物监测 (TDM) 指导下诊断后 6 个月内。目标 1. 评估假定的关联并探索 CH 与基线之间的新关联临床和放射学严重程度的测量。我们假设治疗前的营养状况，抗菌血清学和 MRE 结果将与第一年的 CH 相关。正式的假设检验将是以适当控制的 I 类错误概率进行，以确认一组预预测的预测能力使用基于第一年 CH 结果的逻辑回归模型指定基线测量。目标 2. 评估假定的关联并探索抗 TNF 药物水平、CH、以及宿主和微生物基因组和转录组因素。我们假设预处理基因表达特征和微生物因素将与早期抗 TNF 药物水平和第 1 年 CH 相关。我们将描述宿主基因型、基线粘膜和纵向粪便微生物分类学特征，以及基线回肠和结肠宿主转录组。那些被确定为显着相关的变量将被目标 3 中确定的最终预测模型的候选者。目标 3. 使用 k 倍交叉验证程序确定第 1 年 CH 的最佳预测模型。我们假设包含宿主基因特征和微生物的模型将改善 CH 的预测超出了仅基于临床和影像学因素的一种。该模型将包括临床和影像预测因子目标 1 中的宿主和微生物特征被发现对目标 2 具有潜在的解释作用。影响。拟议的初始队列研究 CAMEO 将为研究以下因素提供一个强大的平台：有助于儿科 CD 的治愈，然后可以转化为实践，并指导未来的治疗针对不太可能治愈的患者的宿主免疫反应和微生物群。。