National Institute for Health Research (NIHR) Biomedical Research Centre, Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London, UK.
Division of Optometry and Visual Science, School of Health Sciences, City, University of London, London, UK.
Health Technol Assess. 2018 Jan;22(4):1-106. doi: 10.3310/hta22040.
Progressive optic nerve damage in glaucoma results in vision loss, quantifiable with visual field (VF) testing. VF measurements are, however, highly variable, making identification of worsening vision ('progression') challenging. Glaucomatous optic nerve damage can also be measured with imaging techniques such as optical coherence tomography (OCT).
To compare statistical methods that combine VF and OCT data with VF-only methods to establish whether or not these allow (1) more rapid identification of glaucoma progression and (2) shorter or smaller clinical trials.
Method 'hit rate' (related to sensitivity) was evaluated in subsets of the United Kingdom Glaucoma Treatment Study (UKGTS) and specificity was evaluated in 72 stable glaucoma patients who had 11 VF and OCT tests within 3 months (the RAPID data set). The reference progression detection method was based on Guided Progression Analysis™ (GPA) Software (Carl Zeiss Meditec Inc., Dublin, CA, USA). Index methods were based on previously described approaches [Analysis with Non-Stationary Weibull Error Regression and Spatial enhancement (ANSWERS), Permutation analyses Of Pointwise Linear Regression (PoPLR) and structure-guided ANSWERS (sANSWERS)] or newly developed methods based on Permutation Test (PERM), multivariate hierarchical models with multiple imputation for censored values (MaHMIC) and multivariate generalised estimating equations with multiple imputation for censored values (MaGIC).
Ten university and general ophthalmology units (UKGTS) and a single university ophthalmology unit (RAPID).
UKGTS participants were newly diagnosed glaucoma patients randomised to intraocular pressure-lowering drops or placebo. RAPID participants had glaucomatous VF loss, were on treatment and were clinically stable.
24-2 VF tests with the Humphrey Field Analyzer and optic nerve imaging with time-domain (TD) Stratus OCT™ (Carl Zeiss Meditec Inc., Dublin, CA, USA).
Criterion hit rate and specificity, time to progression, future VF prediction error, proportion progressing in UKGTS treatment groups, hazard ratios (HRs) and study sample size.
Criterion specificity was 95% for all tests; the hit rate was 22.2% for GPA, 41.6% for PoPLR, 53.8% for ANSWERS and 61.3% for sANSWERS (all comparisons ≤ 0.042). Mean survival time (weeks) was 93.6 for GPA, 82.5 for PoPLR, 72.0 for ANSWERS and 69.1 for sANSWERS. The median prediction errors (decibels) when the initial trend was used to predict the final VF were 3.8 (5th to 95th percentile 1.7 to 7.6) for PoPLR, 3.0 (5th to 95th percentile 1.5 to 5.7) for ANSWERS and 2.3 (5th to 95th percentile 1.3 to 4.5) for sANSWERS. HRs were 0.57 [95% confidence interval (CI) 0.34 to 0.90; = 0.016] for GPA, 0.59 (95% CI 0.42 to 0.83; = 0.002) for PoPLR, 0.76 (95% CI 0.56 to 1.02; = 0.065) for ANSWERS and 0.70 (95% CI 0.53 to 0.93; = 0.012) for sANSWERS. Sample size estimates were not reduced using methods including OCT data. PERM hit rates were between 8.3% and 17.4%. Treatment effects were non-significant in MaHMIC and MaGIC analyses; statistical significance was altered little by incorporating imaging.
TD OCT is less precise than current imaging technology; current OCT technology would likely perform better. The size of the RAPID data set limited the precision of criterion specificity estimates.
The sANSWERS method combining VF and OCT data had a higher hit rate and identified progression more quickly than the reference and other VF-only methods, and produced more accurate estimates of the progression rate, but did not increase treatment effect statistical significance. Similar studies with current OCT technology need to be undertaken and the statistical methods need refinement.
Current Controlled Trials ISRCTN96423140.
This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in ; Vol. 22, No. 4. See the NIHR Journals Library website for further project information. Data analysed in the study were from the UKGTS. Funding for the UKGTS was provided through an unrestricted investigator-initiated research grant from Pfizer Inc. (New York, NY, USA), with supplementary funding from the NIHR Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London, UK. Imaging equipment loans were made by Heidelberg Engineering, Carl Zeiss Meditec and Optovue (Fremont, CA, USA). Pfizer, Heidelberg Engineering, Carl Zeiss Meditec and Optovue had no input into the design, conduct, analysis or reporting of any of the UKGTS findings or this work. The sponsor for both the UKGTS and RAPID data collection was Moorfields Eye Hospital NHS Foundation Trust. David F Garway-Heath, Tuan-Anh Ho and Haogang Zhu are partly funded by the NIHR Biomedical Research Centre based at Moorfields Eye Hospital and UCL Institute of Ophthalmology. David F Garway-Heath's chair at University College London (UCL) is supported by funding from the International Glaucoma Association.
青光眼导致的进行性视神经损伤会导致视力丧失，可以通过视野（VF）测试进行量化。然而，VF 测量结果高度可变，使得识别视力恶化（“进展”）具有挑战性。青光眼视神经损伤也可以通过成像技术如光学相干断层扫描（OCT）来测量。
比较结合 VF 和 OCT 数据的统计方法与仅 VF 方法，以确定这些方法是否（1）更快速地识别青光眼进展，以及（2）缩短或减少临床试验。
在英国青光眼治疗研究（UKGTS）的子集中评估方法“命中率”（与敏感性相关），并在 72 名稳定的青光眼患者的 RAPID 数据集中评估特异性，这些患者在 3 个月内进行了 11 次 VF 和 OCT 测试（RAPID 数据集）。参考进展检测方法基于引导进展分析软件（GPA）（美国加利福尼亚州都柏林市卡尔蔡司 Meditec 公司）。索引方法基于先前描述的方法[具有非平稳威布尔误差回归的分析和空间增强（ANSWERS）、逐点线性回归的置换分析（PoPLR）和基于结构的 ANSWERS（sANSWERS）]或新开发的方法，如置换检验（PERM）、具有多个插补值的多元层次模型（MaHMIC）和具有多个插补值的多元广义估计方程（MaGIC）。
十个大学和普通眼科单位（UKGTS）和一个单一的大学眼科单位（RAPID）。
UKGTS 参与者为新诊断的青光眼患者，随机分配到降眼压滴眼液或安慰剂组。RAPID 参与者患有青光眼性 VF 丧失，正在接受治疗且临床稳定。
24-2 次 Humphrey 视野分析仪 VF 测试和时域（TD）Stratus OCT 视神经成像（美国加利福尼亚州都柏林市卡尔蔡司 Meditec 公司）。
标准命中率和特异性、进展时间、未来 VF 预测误差、UKGTS 治疗组进展的比例、危险比（HR）和研究样本量。
所有测试的标准特异性均为 95%；GPA 的命中率为 22.2%，PoPLR 为 41.6%，ANSWERS 为 53.8%，sANSWERS 为 61.3%（所有比较均≤0.042）。GPA 的平均存活时间（周）为 93.6，PoPLR 为 82.5，ANSWERS 为 72.0，sANSWERS 为 69.1。初始趋势用于预测最终 VF 时的中位预测误差（分贝）为 PoPLR 为 3.8（第 5 到 95 百分位为 1.7 到 7.6），ANSWERS 为 3.0（第 5 到 95 百分位为 1.5 到 5.7），sANSWERS 为 2.3（第 5 到 95 百分位为 1.3 到 4.5）。GPA 的 HR 为 0.57（95%置信区间[CI]0.34 至 0.90；=0.016），PoPLR 为 0.59（95%CI0.42 至 0.83；=0.002），ANSWERS 为 0.76（95%CI0.56 至 1.02；=0.065），sANSWERS 为 0.70（95%CI0.53 至 0.93；=0.012）。包括 OCT 数据在内的方法并未减少样本量估计。PERM 命中率在 8.3%至 17.4%之间。MaHMIC 和 MaGIC 分析中治疗效果不显著；纳入成像后，统计学意义变化不大。
TD OCT 不如当前的成像技术精确；当前的 OCT 技术可能表现得更好。RAPID 数据集的规模限制了标准特异性估计的精度。
sANSWERS 方法结合了 VF 和 OCT 数据，其命中率高于参考和其他仅 VF 方法，能更快地识别进展，并产生更准确的进展率估计，但并未增加治疗效果的统计学意义。需要进行类似的具有当前 OCT 技术的研究，并需要改进统计方法。
当前对照试验 ISRCTN96423140。
本项目由英国国家卫生研究院（NIHR）健康技术评估计划资助，将在；第 22 卷，第 4 期。有关该研究的更多项目信息，请访问 NIHR 期刊库网站。在研究中分析的数据来自 UKGTS。UKS 的资金由辉瑞公司（纽约州纽约市）提供的一项不受限制的由调查员发起的研究赠款提供，由 Moorfields Eye Hospital NHS 基金会信托基金和伦敦大学学院眼科学研究所的英国国家卫生研究院生物医学研究中心提供补充资金。成像设备贷款由海德堡工程公司、卡尔蔡司 Meditec 和 Optovue（加利福尼亚州弗里蒙特市）提供。辉瑞、海德堡工程、卡尔蔡司 Meditec 和 Optovue 对 UKGTS 的任何发现或本工作的设计、进行、分析或报告均无任何投入。UKGTS 和 RAPID 数据收集的赞助商均为 Moorfields Eye Hospital NHS 基金会信托基金。David F Garway-Heath、Tuan-Anh Ho 和 Haogang Zhu 部分由 Moorfields Eye Hospital 和 UCL 眼科研究所的英国国家卫生研究院生物医学研究中心资助。David F Garway-Heath 在伦敦大学学院的主席职位由国际青光眼协会提供资金支持。
