DO BIOMARKERS PREDICT RESPONSE TO A PEDIATRIC CHRONIC PAIN SYMPTOM MANAGEMENT PROGRAM?

功能性腹痛、胃肠道疾病(FGID)影响15%-20%的学龄儿童和 美国和世界各地的成年人。FGID的特征是间歇性腹痛，通常与 严重残疾。在高达60%的病例中，FGID持续到成年期，估计成年人的成本 美国每年近300亿美元。尽管FGID无处不在，其巨大的国际经济， 在社会和情感负担方面，找到广泛有效的管理策略一直难以捉摸。我们在中国的学习 儿童和成人中的其他人支持认知行为疗法(CBT)作为我们目前治疗的最佳策略 但腹痛仅在40%的患者中得到改善。考虑到所需的费用和时间投资 对于CBT，需要解决哪些患者可能反应最好的知识差距。最近， 饮食管理(低FODMAP饮食)正在显示出希望，但它也只对50%的患者有效。 我们小组最近的研究表明，生物因素(通过生物标记物衡量)在 确定对CBT的反应。同样，我们最近的工作表明，肠道微生物组组成出现了 以影响腹痛是否会对低FODMAP饮食产生反应。尽管潜在的危急 这些高信息量的生理生物标志物的重要性，到目前为止还没有在儿童或成人中进行的CBT试验 测量了它们。因此，根据我们迄今在CBT和饮食干预方面的经验， FGID，我们建议对7-12岁的儿童进行分类。患有FGID的年龄(n=200)是否 有/没有下列一种或多种异常生理变化： (1)以低心率变异性衡量的自主神经系统失衡；和/或(2) 肠道生理异常：肠道屏障功能受损(通透性增加)；和/或降低 类杆菌的丰度(通过鸟枪式元基因组测序测量)；和/或(3)肠道神经免疫 功能障碍(粪便嗜铬颗粒素A和分泌颗粒素2浓度升高)。 我们建议将这些儿童按是否存在生理异常进行随机分组 CBT或低FODMAP饮食使用我们之前测试的程序，并比较 对那些有/没有异常生理生物标志物的人进行治疗。我们假设CBT将会比 对那些没有生理异常的人有效，而饮食对有异常的儿童更有效 生理学。主要结果指标将是：1)症状改善(腹痛频率或 严重程度(由预期日记衡量)和2)健康相关生活质量(PedsQL)的改善 这项创新的多学科研究将是第一次解决识别生理学 可以缓和对管理层的反应的特征，潜在地减轻了这些 通过及时应用干预措施，最有可能使个别患者受益。的目标 此应用程序符合Precision Medicine Initiative和NINR PA-16-188和PA-14-029。

Functional abdominal pain gastrointestinal disorders (FGIDs) affect 15-20% of school age children and adults in the US and worldwide. FGIDs are characterized by intermittent abdominal pain, often associated with significant disability. FGIDs continue into adulthood in up to 60% of cases and estimated costs for adults in the US are near $30 billion per year. Despite the ubiquity of FGIDs and their tremendous international economic, social, and emotional burden, finding widely effective management strategies has been elusive. Our studies in children and others in adults support cognitive behavioral therapy (CBT) as our current best strategy to treat FGIDs but abdominal pain only improves in 40% of patients. Given the expense and time investment required for CBT, the knowledge gap of which patients are likely to respond best needs to be addressed. More recently, dietary management (low FODMAP diet) is showing promise but it too, is effective in only 50% of patients. Recent studies from our group suggest that biologic factors (measured by biomarkers) play a role in determining the response to CBT. Similarly, our recent work shows that gut microbiome composition appears to influence whether abdominal pain will respond to a low FODMAP diet. Despite the potential critical importance of these highly informative physiologic biomarkers, no CBT trials to date in children or adults have measured them. Thus, building on our experience to date with CBT and dietary interventions in children with FGIDs, we propose to categorize children ages 7-12 yrs. of age with FGIDs (n=200) as to whether they have/do not have one or more of the following abnormal physiologic changes: (1) Autonomic Nervous System imbalance as measured by low heart rate variability; and/or (2) Abnormalities in gut physiology: Impaired gut barrier function (increased permeability); and/or Decreased abundance of Bacteroides (measured by shotgun metagenomic sequencing); and/or (3) Gut neuroimmune dysfunction (increased fecal chromogranin A and secretogranin 2 concentrations). We propose to randomize these children, stratified by presence/absence of physiologic abnormalities to CBT or a low FODMAP diet using our previously tested programs and compare the effectiveness of the treatments in those with/without abnormal physiologic biomarkers. We Hypothesize that CBT will be more effective in those without abnormal physiology whereas Diet will be more effective in children with abnormal physiology. Primary outcome measures will be: 1) Symptom improvement (abdominal pain frequency or severity measured by prospective diary) and 2) Improvement in health related quality of life (PedsQL) This innovative multidisciplinary study will be the first addressing the critical need to identify physiological characteristics that may moderate the response to management, potentially reducing the burden of these disorders through timely application of the intervention most likely to benefit an individual patient. The goals of this application fit with the Precision Medicine Initiative and NINR PA-16-188 and PA-14-029.