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， 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。高达60%的病例中，FGID持续到成年， 美国每年近300亿美元。尽管FGID无处不在，而且它们具有巨大的国际经济效益， 社会和情感负担，找到广泛有效的管理策略一直难以捉摸。我们的研究在 儿童和其他成人支持认知行为疗法（CBT）作为我们目前治疗的最佳策略。 FGIDs但腹痛仅在约40%的患者中改善。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做出最佳反应的知识差距。最近， 饮食管理（低FODMAP饮食）显示出希望，但它也仅对50%的患者有效。 我们小组最近的研究表明，生物因素（通过生物标志物测量）在 确定对CBT的反应。同样，我们最近的研究表明，肠道微生物组的组成似乎 以影响腹痛是否会对低FODMAP饮食产生反应。尽管潜在的危险 这些高度信息化的生理生物标志物的重要性，迄今为止在儿童或成人中没有CBT试验 测量它们。因此，根据我们迄今为止在儿童CBT和饮食干预方面的经验， FGID，我们建议将7-12岁的FGID儿童（n=200）进行分类， 有/没有以下一种或多种异常生理变化： (1)通过低心率变异性测量的自主神经系统失衡;和/或（2） 肠道生理学异常：肠道屏障功能受损（通透性增加）;和/或 类杆菌的丰度（通过鸟枪法宏基因组测序测量）;和/或（3）肠道神经免疫 功能障碍（粪便嗜铬粒蛋白A和分泌粒蛋白2浓度增加）。 我们建议对这些儿童进行随机分组，根据是否存在生理异常进行分层， CBT或低FODMAP饮食使用我们以前测试的程序，并比较的有效性， 在具有/不具有异常生理生物标志物的那些中进行治疗。我们假设CBT将更多 对于那些没有异常生理的孩子有效，而对于那些有异常生理的孩子， physiology.主要结果测量将是：1）症状改善（腹痛频率或 通过前瞻性日记测量的严重程度）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个解决关键需要，以确定生理 可能缓和对管理的反应的特征，可能减轻这些负担 通过及时应用干预措施，最有可能使个别患者受益。的目标 该应用符合精密医学倡议和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.