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

优化儿童急性肌肉骨骼感染的诊断策略：评估无创诊断技术的临床表现和比较成本

• 批准号: 10664298
• 负责人: Justin Benjamin Searns
• 金额: $ 18.78万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-03 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10664298
• 关键词: Acute; Address; Agreement; Algorithms; Award; Biological Testing; Biopsy; Blood; Blood specimen; Caring; Child; Child Care; Childhood; Clinical; Code; Collection; Colorado; Communicable Diseases; Consumption; Cost Analysis; DNA; Data; Database Management Systems; Databases; Dedications; Diagnostic; Diagnostic Procedure; Diagnostic Trial; Diagnostic tests; Disease; Enrollment; Equilibrium; Frequencies; Future; Goals; Guidelines; Health Information System; Hematogenous; Hospitalization; Hospitals; Infection; Inpatients; Institution; Interventional radiology; Intravenous; Investigation; Joints; Length; Length of Stay; Life; Mentorship; Microbiological Techniques; Microbiology; Modality; Molecular Diagnostic Testing; Morbidity - disease rate; Musculoskeletal; Operative Surgical Procedures; Osteomyelitis; Outcome; Pathogen detection; Patients; Pediatric Hospitals; Performance; Population; Procedures; Prospective Studies; Prospective, cohort study; Publishing; Recommendation; Reference Standards; Research; Research Personnel; Resources; Risk; Sedation procedure; Societies; Source; Specimen; Techniques; Testing; Training; United States; Variant; antimicrobial; bone; career; case finding; cell free DNA; clinical care; comparative; cost; cost comparison; cost estimate; diagnostic strategy; disability; hospital readmission; improved; innovation; interest; liquid biopsy; microbial; microcosting; minimally invasive; multidisciplinary; next generation sequencing; noninvasive diagnosis; novel diagnostics; pathogen; pathogenic bacteria; peripheral blood; prevent; primary outcome; relative cost; sample collection; skills; standard of care; standardized care; targeted treatment

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.

项目概要/摘要 小儿肌肉骨骼感染 (MSKI) 是一种负担重的疾病，需要大量的医院资源。 源并需要及时进行抗菌治疗，以防止全身发病和改变生活的残疾。 识别 MSKI 的致病细菌可以通过快速靶向治疗来改善护理。然而，许多 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。 尼克斯。血培养是一种微创且廉价的方法，但只能在 30-50% 的 MSKI 中发现病原体。 通过手术采集的受感染肌肉骨骼样本（即“源培养物”）活检可提高诊断率 产率提高了 30%，但需要侵入性且昂贵的诊断程序，并可能因镇静和 外科手术。需要研究来确定 MSKI 的最佳诊断策略（即常规使用侵入性方法） 程序与单独的血培养相比）。儿科健康信息系统 (PHIS) 数据库包含 来自数百万住院病人的管理数据可用于有效地研究诊断 美国 52 家儿科医院 MSKI 的临床变异性。此外，新的诊断方式 已经出现了对儿科 MSKI 有希望的药物，但需要在这些患者中进行进一步研究。具体来说，接下来—— 外周血样本中微生物无细胞 DNA (mcfDNA) 的世代测序是一种新的技术 先进的非侵入性诊断测试，使用“液体活检”来检测 1000 多种潜在病原体。 尽管 mcfDNA 检测已获准用于临床，但该检测尚未在患有 MSKI 的儿童中得到验证 具体来说。缺乏证据证明 mcfDNA 与侵入性诊断程序的比较限制了其临床 在这个人群中的效用。美国传染病学会 (IDSA) 最近呼吁开展新研究 确定 mcfDNA 检测是否可以改善儿科 MSKI 的护理。此外，mcfDNA 有一个估计 配套成本超过 2000 美元，需要进行成本分析来证明其使用的合理性。该提案旨在解决 通过 (1) 描述儿童 MSKI 的国家差异，迫切需要优化儿科 MSKI 诊断策略 急性儿科 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 检测与手术微生物检测的性能比较 采集骨骼和关节标本； (3) 描述与现有诊断相比 mcfDNA 的成本 儿科 MSKI 的选择。该项目是该候选人致力于改善临床的巅峰之作 因 MSKI 住院的儿童的结果。该奖项的目的是让候选人发展 实现成为一名研究诊断的独立研究者的长期目标所需的技能 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体验式培训。候选人 精心组建了一支在上述目标方面具有丰富专业知识的多学科指导团队 帮助他成功完成职业培训目标和研究具体目标。