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、影像学和内镜结果

• 批准号: 10292286
• 负责人: LEE ARMISTEAD DENSON
• 金额: $ 39.12万
• 依托单位: CONNECTICUT CHILDREN'S MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-07 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10292286
• 关键词: Adult; Algorithms; Anti-Tumor Necrosis Factor Therapy; Biological; Biological Response Modifier Therapy; Budgets; Characteristics; Child; Childhood; Classification; Clinical; Clinical Treatment; Clinical/Radiologic; Cohort Studies; Colon; Crohn' s disease; Data; Data Management Resources; Diagnosis; Disease Progression; Disease remission; Dose; Drug Monitoring; Exhibits; Future; Gene Expression; Gene Expression Profile; Genes; Genomics; Genotype; Goals; Health Expenditures; Hospitalization; IL17 Signaling Pathway; Image; Immune response; Immunomodulators; Inflammatory; Institutional Review Boards; Interleukin-10; Intestines; Logistic Regressions; Machine Learning; Magnetic Resonance; Manuals; Measures; Metabolic; Microbe; Microbial Taxonomy; Modeling; Mononuclear; Newly Diagnosed; Nutritional status; Operative Surgical Procedures; Outcome; Patients; Pediatric Crohn' s disease; Phagocytes; Pharmaceutical Preparations; Probability; Procedures; Process; Prospective cohort study; Protocols documentation; Quality of life; Reading; Rectum; Reporting; Ruminococcus; Sedimentation process; Serology; Services; Severities; Specific qualifier value; Standardization; Steroids; TNF gene; Testing; Therapeutic; Translating; Validation; alpha-Defensins; antimicrobial; base; clinical practice; clinical remission; clinical research site; epigenome; experience; genetic signature; healing; hospitalization rates; ileum; improved; infliximab; machine learning method; metabolomics; microbial; microbial genomics; microbiota; novel; operation; operational taxonomic units; predictive modeling; primary endpoint; radiomics; rectal; response; secondary endpoint; seropositive; single-cell RNA sequencing; targeted treatment; transcriptome

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). This shift happened because patients who achieve complete healing (CH, TH and EH) experience lower rates of subsequent hospitalization, therapy escalation, or surgery than those with EH alone or no healing. We hypothesize that specific pre-treatment clinical, radiologic, 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 570 newly diagnosed pediatric-onset CD subjects who initiate treatment with anti-TNF medication within 6 months of diagnosis. We will administer personalized anti-TNF biologic therapy guided by therapeutic drug monitoring (TDM) using a novel dosing algorithm which we developed. 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 CH 52 weeks after anti-TNF start. Formal hypothesis tests will be carried out to confirm the predictive power of a set of pre-specified measures using a logistic regression model. We will also conduct exploratory analyses of novel predictors, identified via machine learning methods, to assess their relationship with CH after adjusting for the confirmed primary predictors. Aim 2. Evaluate putative associations and explore novel associations between CH and baseline host and microbial genomic and metabolic factors. We hypothesize that pre-treatment gene expression signatures and microbial factors will be associated with year 1 CH. We will characterize the host genotype, longitudinal microbial taxonomic and metabolomic profiles, and ileal and colon host epigenome and transcriptome at baseline and at 52 weeks after anti-TNF start. 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 significant clinical and imaging predictors from Aim 1 and the subset of baseline host and microbial characteristics found to be potentially explanatory in Aim 2. Impact. The proposed inception cohort study, CAMEO, will be unique in providing a robust, novel platform to study factors that contribute to healing in pediatric CD that can then be immediately translated into clinical practice, as well as guiding future therapies targeting the microbiota and host immune responses in patients unlikely to achieve healing with current approaches.

项目摘要/摘要 小儿克罗恩病（CD）的治疗目标已从临床改善或缓解转移到 内窥镜愈合（EH）通过磁性共振娱乐进行回肠造影镜和透壁愈合（Th） （MRE）。发生这种转变是因为实现完全康复的患者（CH，TH和EH）经历了较低的经历 随后的住院治疗，治疗升级或手术率比单独使用EH或没有治愈的率。我们 假设特定的预处理临床，放射学，基因组和微生物因子以及成就 靶向抗TNF生物学暴露与主要终点和主要次要相关 抗TNF开始后52周，我们将在一项前瞻性队列研究中检验该假设 在570个新诊断的小儿发作的CD受试者中，他们在6次内使用抗TNF药物进行治疗 几个月的诊断。我们将管理通过治疗药物指导的个性化抗TNF生物疗法 使用我们开发的新剂量算法进行监测（TDM）。 目标1。评估推定的关联并探索CH和基线之间的新型关联 临床和放射学严重程度的度量。我们假设治疗前的营养状况， 抗TNF启动后52周，抗菌血清学和MRE发现将与CH相关。正式的 将进行假设检验，以确认使用A组预先指定措施的预测能力 逻辑回归模型。我们还将对通过机器确定的新型预测变量进行探索性分析 学习方法，以评估他们在调整确认的主要预测因子后与CH的关系。 AIM 2。评估推定的关联并探索CH和基线宿主之间的新型关联和 微生物基因组和代谢因子。我们假设预处理基因表达特征 微生物因素将与1年级有关。我们将表征宿主基因型，纵向 微生物分类学和代谢组概况，基线时的回肠和结肠宿主表观基因组和转录组 抗TNF开始后52周。 AIM 3。使用K折的交叉验证程序来确定1年级的最佳预测模型。 我们假设包括宿主基因特征和微生物在内的模型将改善CH的预测 仅仅基于临床和成像因子。该模型将包括重要的临床和成像 AIM 1的预测因子以及基线宿主的子集和微生物特征的子集可能是潜在的 AIM 2中的解释。 影响。拟议的Inception队列研究Cameo将在提供一个健壮，新颖的平台上是独一无二的 可导致小儿CD愈合的研究因素，然后立即转化为临床 练习，以及指导针对菌群和宿主免疫反应的未来疗法 目前的方法不太可能实现治愈。