Measurement of Cardiometabolic Risk in Antipsychotic-Treated Children

描述（由申请人提供）：此K23奖申请与最近IOM研究优先列表中的多个主题领域相关，以及最近IOM报告简报和白宫关注儿童肥胖的“让我们动起来”运动。该奖项将支持指导、教学培训和额外的职业发展活动，为特别适合在患有精神健康障碍的儿童肥胖和代谢风险领域发展专业知识的候选人提供支持。申请人的近期职业目标是进一步发展肥胖和心脏代谢风险的代谢机制测量方面的专业知识。申请人的长期职业目标是成为一名独立的研究者，研究儿童肥胖和精神病人群的心脏代谢风险。从计划的活动中产生的专业综合知识将是儿童精神病学领域中独一无二的，并将为未来几十年在这一高度优先、服务不足的主题领域所需的研究提供资源。近几十年来，美国儿童期肥胖和2型糖尿病的患病率（两者都是心血管风险的预测因子）已经上升到流行病的程度。患有精神疾病的儿童，特别是那些接受抗精神病药物治疗的儿童，患肥胖和相关疾病的风险更高。尽管已知儿童期与成年期肥胖相关的肥胖相关结果（包括过早死亡）增加，但儿童对这些风险的认识仍然不足。各种评估心脏代谢风险的无创技术已经开始应用于儿童，包括超声测量颈动脉内膜中膜厚度（IMT）， 1H磁共振波谱（MRS）测量肝脏和心脏甘油三酯含量。这些措施允许对代谢风险进行早期、无创的研究。不幸的是，这些有希望的方法都没有应用于患有精神疾病的高危儿童人群，并且心脏甘油三酯含量根本没有在儿童中进行评估，这妨碍了对风险的准确描述或干预措施的有效性，从而降低了这一弱势人群的风险。该应用的研究部分侧重于使用敏感的疾病风险早期生物标志物，包括肝脏甘油三酯含量（HTGC）、心脏甘油三酯含量（CTGC）和颈动脉IMT，它们分别与糖尿病和心血管疾病风险直接相关。这项两项研究计划的总体目标是利用这些敏感标记来表征治疗和未治疗的患有精神健康障碍的儿童的可测量风险水平，并评估在接受完善的行为减肥干预的儿童中使用这些生物标记可以观察到的风险变化幅度。这将通过两项研究来完成：1)三组年龄、性别和体重指数（BMI）百分位数匹配的超重/肥胖儿童的CTGC、HTCG和IMT值的病例对照横断面比较：接受抗精神病药物治疗的精神病儿童；未接受抗精神病药物治疗的精神疾病儿童和未接受抗精神病药物治疗的无精神疾病儿童（一小部分瘦弱健康参与者也将包括在内）和2)12周行为减肥干预（与饮食和运动教育相比）对超重/肥胖接受抗精神病药物治疗的儿童的CTGC、HTGC和IMT的影响的随机对照试验（一小部分健康超重/肥胖儿童将仅接受积极干预）。主要的分析计划将分别利用方差分析和方差分析来测试一组关于研究样本中心脏代谢风险水平的假设，以及已知的减肥干预措施可以在多大程度上改变这些敏感的风险生物标志物。)

DESCRIPTION (provided by applicant): This K23 award application is relevant to multiple topic areas in the recent IOM research priority list, as well as the recent IOM report brief and White House "Let's Move" Campaign focused on childhood obesity. The award will support mentoring, didactic training and additional career development activities for a candidate uniquely suited to develop expertise in the area of obesity and metabolic risk in children with mental health disorders. The applicant's immediate career goals are to further develop expertise in the measurement of metabolic mechanisms underlying obesity and cardiometabolic risk. The applicant's long-term career goal is to establish herself as an independent investigator studying childhood obesity and cardiometabolic risk in psychiatric populations. The specialized combined expertise that will emerge from the planned activities will be unique in the field of child psychiatry and will provide a resource for needed research in this high-priority, underserved topic area for decades to come. The US prevalence of childhood-onset obesity and type 2 diabetes, both predictors of cardiovascular risk, have increased to epidemic proportions in recent decades. Children with mental illness, especially those treated with antipsychotic medications, are at additional risk for obesity and related risk conditions. Despite known increases in obesity-related outcomes, including premature mortality, associated with childhood-onset versus adult-onset obesity, there remains an under-appreciation of these risks in children. A variety of noninvasive techniques to assess cardiometabolic risk have begun to be applied in children, including carotid intima media thickness (IMT) measured by ultrasound, and hepatic and cardiac triglyceride content measured by 1H Magnetic Resonance Spectroscopy (MRS). These measures allow for the early, noninvasive study of metabolic risk. Unfortunately, none of these promising methods have been applied to the high-risk population of children with psychiatric disorders, and cardiac triglyceride content has not been evaluated in children at all, preventing accurate characterization of risk or the effectiveness of interventions the reduce risk in this vulnerable population. The research portion of this application focuses on the use of sensitive, early biomarkers of disease risk, including hepatic triglyceride content (HTGC), as well as cardiac triglyceride content (CTGC) and carotid IMT, directly relevant to diabetes and cardiovascular disease risk, respectively. The overall aim of this two-study research plan is to characterize the level of measurable risk using these sensitive markers in treated and untreated children with mental health disorders, and to evaluate the magnitude of change in risk that can be observed using these biomarkers in children receiving a well- established behavioral weight-loss intervention. This will be accomplished using two studies: 1) A case control cross sectional comparison of CTGC, HTCG and IMT values in three groups of overweight/obese children who are age-, gender- and body mass index (BMI) percentile-matched: antipsychotic treated mentally ill children; mentally ill children not treated with antipsychotics and untreated children with no mental illness (a small reference group of lean healthy participants will also be included) and 2) A randomized controlled test of the effects of a 12-week behavioral weight loss intervention (versus diet and exercise education) on CTGC, HTGC and IMT in overweight/obese antipsychotic-treated children (a small reference group of healthy overweight/obese children will receive the active intervention only). The primary analytic plan will utilize ANOVA and ANCOVA, respectively, to test a focused set of hypotheses concerning the level of cardiometabolic risk in the study samples and the extent to which known weight loss interventions can modify these sensitive risk biomarkers. )