Optimizing the Diagnostic Strategy for Acute Musculoskeletal Infections in Children: Evaluating the Clinical Performance and Comparative Cost of a Noninvasive Diagnostic Technique

项目总结/摘要 小儿肌肉骨骼感染（MSKI）是一种负担沉重的疾病，消耗大量的医院资源， 这是一个严重的疾病来源，需要及时的抗菌治疗，以防止全身发病和改变生活的残疾。 确定MSKI的致病细菌罪犯通过快速靶向治疗改善护理。但不少 患有MSKI的儿童从未使用现有的微生物技术确定其细菌原因- 尼克。血培养是微创和廉价的，但只发现30-50%的MSKI的病原体。 手术收集的受感染肌肉骨骼样本的活检（即，“源培养物”）增加诊断 产率提高30%，但需要侵入性和昂贵的诊断程序，具有镇静的潜在危害， 手术需要进行研究以确定MSKI的最佳诊断策略（即，常规使用侵入性 程序与单独的血培养）。儿科健康信息系统（PHIS）数据库包含 管理数据从数百万住院病人的遭遇，并可以利用有效地研究诊断， 美国52家儿科医院的MSKI的统计变异性。此外，新的诊断方法 已经出现了对儿童MSKI的承诺，但需要在这些患者中进行进一步研究。具体来说，接下来- 从外周血标本中获得微生物无细胞DNA（mcfDNA）的代测序是一种新的方法， 使用“液体活检”检测1000多种潜在病原体的非侵入性诊断测试。 尽管mcfDNA检测已被批准用于临床，但该检测尚未在MSKI儿童中得到验证 具体来说缺乏mcfDNA与侵入性诊断程序相比的证据限制了其临床应用。 在这个人群中的效用。美国传染病协会（IDSA）最近呼吁进行新的研究， 确定mcfDNA检测是否可以改善儿科MSKI的护理。此外，mcfDNA还拥有一个... 交配成本超过2000美元，需要进行成本分析，以证明其使用的合理性。该提案旨在解决 迫切需要通过以下方式优化儿科MSKI的诊断策略：（1）描述 急性小儿MSKI的诊断测试和相关临床结果;（2）确定临床 MSKI的非侵入性mcfDNA检测与手术微生物学检测相比的性能 收集的骨和关节标本;（3）描述与现有诊断相比，mcfDNA的成本 儿童MSKI的选择。该项目是这位候选人致力于改善临床 因MSKI住院的儿童的结局。该奖项的目的是让候选人发展 他的长期目标是成为一名独立的研究诊断的研究者， 儿科感染的创新。候选人将通过专家指导建立他的研究技能， 教学课程，以及诊断试验和描述性成本分析的经验培训。候选 经过深思熟虑，组建了一个多学科的导师团队，在上述目标方面具有广泛的专业知识， 帮助他顺利完成职业培训目标和研究具体目标。

PROJECT SUMMARY/ABSTRACT Pediatric musculoskeletal infections (MSKIs) are burdensome disorders that consume significant hospital re- sources and require prompt antimicrobial treatment to prevent systemic morbidity and life-altering disability. Identifying the causative bacterial culprit for MSKIs improves care by quickly targeting therapy. However, many children suffering from MSKIs never have their bacterial cause identified using existing microbiological tech- niques. Blood cultures are minimally invasive and inexpensive but only find the pathogen in 30-50% of MSKIs. Surgically-collected biopsies of infected musculoskeletal specimens (i.e., “source cultures”) increase diagnostic yield by 30% but require invasive and expensive diagnostic procedures with potential harm from sedation and surgery. Studies are needed to identify the optimal diagnostic strategy for MSKIs (i.e., routine use of invasive procedures versus blood culture alone). The Pediatric Health Information System (PHIS) database contains administrative data from millions of inpatient encounters and could be leveraged to efficiently study the diag- nostic variability for MSKIs at 52 pediatric hospitals in the United States. In addition, new diagnostic modalities have emerged that hold promise for pediatric MSKIs but need further study in these patients. Specifically, next- generation sequencing of microbial cell-free DNA (mcfDNA) from a peripheral blood specimen is a newly de- veloped non-invasive diagnostic test that uses a “liquid biopsy” to detect more than 1000 potential pathogens. Although mcfDNA testing is approved for clinical use, this test has not been validated in children with MSKIs specifically. The lack of evidence for how mcfDNA compares to invasive diagnostic procedures limits its clinical utility in this population. The Infectious Diseases Society of America (IDSA) recently called for new studies to determine whether mcfDNA testing could improve care for pediatric MSKIs. In addition, mcfDNA has an esti- mated cost of more than $2000, and cost analyses are needed to justify its use. This proposal aims to address the critical need for an optimized diagnostic strategy in pediatric MSKIs by (1) describing national variability in diagnostic testing and associated clinical outcomes for acute pediatric MSKIs; (2) determining the clinical performance of non-invasive mcfDNA testing for MSKIs compared to microbiological testing of surgically collected bone and joint specimens; (3) describe the cost of mcfDNA as compared to existing diagnostic options for pediatric MSKIs. This project is the culmination of this candidate’s dedication to improving clinical outcomes for children hospitalized with MSKIs. The objective of this award is for the candidate to develop the skills needed to meet his long-term goal of becoming an independent investigator studying diagnostic innovation for pediatric infections. The candidate will build on his research skillset through expert mentorship, didactic coursework, and experiential training in diagnostic trials and descriptive cost analyses. The candidate has thoughtfully assembled a multidisciplinary mentorship team with extensive expertise in the above aims to help him successfully complete his career training goals and research specific aims.