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.

项目总结/摘要 儿童克罗恩病（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镜下愈合（EH），通过磁共振小肠造影检查进行透壁愈合（TH （MRE）。这种转变的发生是因为实现完全愈合的患者（CH，TH和EH）经历了更低的 随后住院、治疗升级或手术的发生率高于单纯EH患者或未治愈者。我们 假设特定治疗前临床、放射学、基因组和微生物因素沿着 的靶向抗TNF生物制剂暴露将与主要终点CH和主要次要终点CH相关。 终点，EH和TH，抗TNF治疗开始后52周。我们将在一项前瞻性队列研究中检验这一假设 570例新诊断的儿童发病CD受试者在6天内开始抗TNF药物治疗， 数月的诊断。我们将在治疗药物的指导下实施个性化的抗TNF生物治疗 监测（TDM）使用我们开发的一种新的给药算法。 目标1。评估CH和基线之间的假定关联并探索新的关联 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TNF治疗开始后52周，抗微生物血清学和MRE结果将与CH相关。正式 将进行假设检验，以确认一组预先指定的测量方法的预测能力， Logistic回归模型我们还将对通过机器识别的新预测因子进行探索性分析。 学习方法，以评估其与CH的关系后，调整确认的主要预测因素。 目标二。评估CH和基线宿主之间的假定关联并探索新的关联， 微生物基因组和代谢因子。我们假设治疗前的基因表达特征 和微生物因素将与1年CH。我们将表征宿主基因型，纵向 基线时的微生物分类学和代谢组学特征以及回肠和结肠宿主表观基因组和转录组 开始抗TNF治疗后52周。 目标3。使用k折交叉验证程序确定第1年CH的最佳预测模型。 我们假设一个包括宿主基因签名和微生物的模型将改善CH的预测 而不仅仅是基于临床和成像因素。该模型将包括重要的临床和成像 目标1中的预测因子以及基线宿主和微生物特征的子集被发现可能 目标2中的解释。 冲击拟议的初始队列研究CAMEO将是独一无二的，它提供了一个强大的、新颖的平台， 研究有助于儿童CD愈合的因素，然后可以立即转化为临床 实践，以及指导未来针对患者微生物群和宿主免疫反应的疗法 用目前的方法不太可能治愈。