Improving Outcomes Assessment for Microbial Keratitis

摘要 这个K23指导职业发展奖的首要研究目标是改善结果 评估微生物角膜炎(MK)或感染性角膜溃疡。MK每年影响200万人 并对视力和生活质量造成严重损害。MK对临床和临床有意义的测量 研究目的仍然具有挑战性。MK严重性和反应性的传统临床评估 治疗是主观的和不精确的，这使得在临床研究中很难比较治疗的效果。 由于重复性低和样本量要求增加而导致的研究。之前的MK临床试验已经使用了 结果指标，如最佳眼镜矫正视力，这些指标不是疾病特有的，可能无法 捕捉有关MK造成的角膜损伤的关键信息。这些测量限制减少了 MK研究的质量和影响。到目前为止，大多数MK的大规模前瞻性随机试验都失败了 证明治疗反应在临床上有意义或在统计学上有显著差异 组。单中心MK研究也可能缺乏对其他医疗保健环境的适用性，因为 患者特征和人群中的微生物分布。开发更客观、可重现、 与临床相关的、可推广的MK结果度量和预测因素将提高临床 未来多中心MK研究的相关性和统计能力。新的成像模式，如Scheimpflg 断层扫描和眼前段光学相干断层扫描(ASOCT)可以提供客观、精确、 可重复性的和临床相关的角膜结构评估，但这些模式还没有 使用前瞻性研究对MK临床护理或研究进行严格评估。此应用程序建议 在约翰霍普金斯大学对MK患者进行前瞻性队列研究。我们将收集详细的临床和 微生物学数据，并使用裂隙灯摄影执行连续多模式成像，Scheimpflug 体层摄影术和6个月以上的ASOCT检查。目标1将比较超声的重复性和一致性 角膜厚度测量、Scheimpflg断层扫描和ASOCT用于客观量化MK患者的角膜变薄。目标2 将评估Scheimpflg密度测量法作为客观量化角膜纵向变化的手段 瘢痕密度：MK。目标3将评估某些早期解剖或临床特征是否可以改善预测 MK的后续视觉结果以及这些预测指标是否适用于不同的MK 人群和感染亚组，表明这些新的结果指标适用于 协作性多中心临床试验。这项建议将为应聘者提供高级培训和 需要成为临床试验方法学专家和独立资助的研究经验 临床医生--角膜和外部疾病领域的科学家。候选人提出了一项全面的 将严格的正规课程、研讨会和研讨会结合在一起的培训计划 在约翰霍普金斯大学的环境；在Douglas Jabs博士，Thomas Lietman博士的世界级指导下， 伊丽莎白·苏格和阿尔伯特·君；正在进行的前瞻性多中心临床试验的身临其境体验；以及 应用研究经验。具体培训领域包括：(1)先进的临床试验方法；(2) 实际的临床试验实施；(3)先进的生物统计学；(4)微生物的临床和研究专长 角膜炎；以及(5)作为临床医生-科学家的职业发展。候选人的研究结果将被用于 为R01或UG1资助的临床试验制定建议，以改善以证据为基础的治疗 角膜和外部疾病。

ABSTRACT The overarching research goal of this K23 Mentored Career Development Award is to improve outcomes assessment for microbial keratitis (MK), or infectious corneal ulceration. MK affects 2 million people per year and causes significant harm to vision and quality of life. Meaningful measurement of MK for clinical and research purposes remains challenging. Traditional clinical assessments of MK severity and response to treatment are subjective and imprecise, making it difficult to compare efficacy of treatments in clinical research studies due to low reproducibility and increased sample size requirements. Prior MK clinical trials have used outcome metrics such as best spectacle-corrected visual acuity which are not disease-specific and may fail to capture key information about corneal damage caused by MK. These measurement limitations reduce the quality and impact of MK research. To date, most large-scale prospective randomized trials in MK have failed to demonstrate clinically meaningful or statistically significant differences in treatment response between groups. Single-center MK studies can also lack applicability to other healthcare settings due to differences in patient characteristics and microbial distributions across populations. Developing more objective, reproducible, clinically relevant, and generalizable outcome metrics and predictors for MK would enhance the clinical relevance and statistical power of future multicenter MK studies. New imaging modalities such as Scheimpflug tomography and anterior segment optical coherence tomography (ASOCT) can provide objective, precise, reproducible, and clinically relevant assessments of corneal structure, but these modalities have not been critically evaluated for MK clinical care or research using prospective studies. This application proposes to conduct a prospective cohort study of MK patients at Johns Hopkins. We will collect detailed clinical and microbiologic data and perform serial multimodal imaging using slit lamp photography, Scheimpflug tomography, and ASOCT over 6 months. Aim 1 will compare the reproducibility and concordance of ultrasound pachymetry, Scheimpflug tomography, and ASOCT for objective quantification of corneal thinning in MK. Aim 2 will evaluate Scheimpflug densitometry as a means of objectively quantifying longitudinal changes in corneal scar density in MK. Aim 3 will assess whether certain early anatomic or clinical features can improve prediction of subsequent visual outcomes in MK and whether these predictors are applicable across different MK populations and infection subgroups, indicating the suitability of these novel outcome metrics for use in collaborative multicenter clinical trials. This proposal will provide the candidate with the advanced training and research experience needed to become an expert in clinical trials methodology and an independently funded clinician-scientist in the field of cornea and external diseases. The candidate proposes a comprehensive training plan combining rigorous formal coursework, seminars, and workshops in the intellectually rich environment at Johns Hopkins University; world-class mentorship under Drs. Douglas Jabs, Thomas Lietman, Elizabeth Sugar, and Albert Jun; immersive experience with ongoing prospective multicenter clinical trials; and applied research experience. Specific training areas include: (1) advanced clinical trial methodology; (2) practical clinical trial implementation; (3) advanced biostatistics; (4) clinical and research expertise in microbial keratitis; and (5) career development as a clinician-scientist. Results from the candidate’s research will be used to develop a proposal for a R01 or UG1 funded clinical trial that will improve evidence-based treatment for cornea and external diseases.