Migchelsen Stephanie J, Martin Diana L, Southisombath Khamphoua, Turyaguma Patrick, Heggen Anne, Rubangakene Peter Paul, Joof Hassan, Makalo Pateh, Cooley Gretchen, Gwyn Sarah, Solomon Anthony W, Holland Martin J, Courtright Paul, Willis Rebecca, Alexander Neal D E, Mabey David C W, Roberts Chrissy H
Clinical Research Department, London School of Hygiene & Tropical Medicine, London, United Kingdom.
Division of Parasitic Diseases and Malaria, Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America.
PLoS Negl Trop Dis. 2017 Jan 18;11(1):e0005230. doi: 10.1371/journal.pntd.0005230. eCollection 2017 Jan.
Efforts are underway to eliminate trachoma as a public health problem by 2020. Programmatic guidelines are based on clinical signs that correlate poorly with Chlamydia trachomatis (Ct) infection in post-treatment and low-endemicity settings. Age-specific seroprevalence of anti Ct Pgp3 antibodies has been proposed as an alternative indicator of the need for intervention. To standardise the use of these tools, it is necessary to develop an analytical approach that performs reproducibly both within and between studies.
Dried blood spots were collected in 2014 from children aged 1-9 years in Laos (n = 952) and Uganda (n = 2700) and from people aged 1-90 years in The Gambia (n = 1868). Anti-Pgp3 antibodies were detected by ELISA. A number of visual and statistical analytical approaches for defining serological status were compared.
Seroprevalence was estimated at 11.3% (Laos), 13.4% (Uganda) and 29.3% (The Gambia) by visual inspection of the inflection point. The expectation-maximisation algorithm estimated seroprevalence at 10.4% (Laos), 24.3% (Uganda) and 29.3% (The Gambia). Finite mixture model estimates were 15.6% (Laos), 17.1% (Uganda) and 26.2% (The Gambia). Receiver operating characteristic (ROC) curve analysis using a threshold calibrated against external reference specimens estimated the seroprevalence at 6.7% (Laos), 6.8% (Uganda) and 20.9% (The Gambia) when the threshold was set to optimise Youden's J index. The ROC curve analysis was found to estimate seroprevalence at lower levels than estimates based on thresholds established using internal reference data. Thresholds defined using internal reference threshold methods did not vary substantially between population samples.
Internally calibrated approaches to threshold specification are reproducible and consistent and thus have advantages over methods that require external calibrators. We propose that future serological analyses in trachoma use a finite mixture model or expectation-maximisation algorithm as a means of setting the threshold for ELISA data. This will facilitate standardisation and harmonisation between studies and eliminate the need to establish and maintain a global calibration standard.
目前正在努力到2020年消除沙眼这一公共卫生问题。项目指南基于临床体征，但在治疗后和低流行率环境中，这些体征与沙眼衣原体（Ct）感染的相关性较差。抗Ct Pgp3抗体的年龄特异性血清流行率已被提议作为干预需求的替代指标。为了规范这些工具的使用，有必要开发一种在研究内部和研究之间都能可重复执行的分析方法。
2014年从老挝1至9岁儿童（n = 952）、乌干达1至9岁儿童（n = 2700）以及冈比亚1至90岁人群（n = 1868）中采集干血斑。通过酶联免疫吸附测定法检测抗Pgp3抗体。比较了多种用于定义血清学状态的视觉和统计分析方法。
通过观察拐点进行目视检查，估计血清流行率在老挝为11.3%、在乌干达为13.4%、在冈比亚为29.3%。期望最大化算法估计血清流行率在老挝为10.4%、在乌干达为24.3%、在冈比亚为29.3%。有限混合模型估计值在老挝为15.6%、在乌干达为17.1%、在冈比亚为26.2%。使用针对外部参考标本校准的阈值进行的受试者工作特征（ROC）曲线分析，当阈值设定为优化约登指数时，估计血清流行率在老挝为6.7%、在乌干达为6.8%、在冈比亚为20.9%。发现ROC曲线分析估计的血清流行率水平低于基于使用内部参考数据建立的阈值的估计值。使用内部参考阈值方法定义的阈值在不同人群样本之间变化不大。
内部校准的阈值设定方法具有可重复性和一致性，因此比需要外部校准物的方法更具优势。我们建议未来沙眼的血清学分析使用有限混合模型或期望最大化算法作为设定酶联免疫吸附测定数据阈值的方法。这将促进研究之间的标准化和协调，并消除建立和维护全球校准标准的必要性。
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