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Chronological age of healthy people is able to be predicted accurately using deep neural networks from neuroimaging data, and the predicted brain age could serve as a biomarker for detecting aging-related diseases. In this paper, a novel 3D convolutional network, called two-stage-age-network (TSAN), is proposed to estimate brain age from T1-weighted MRI data. Compared with existing methods, TSAN has the following improvements. First, TSAN uses a two-stage cascade network architecture, where the first-stage network estimates a rough brain age, then the second-stage network estimates the brain age more accurately from the discretized brain age by the first-stage network. Second, to our knowledge, TSAN is the first work to apply novel ranking losses in brain age estimation, together with the traditional mean square error (MSE) loss. Third, densely connected paths are used to combine feature maps with different scales. The experiments with $6586$ MRIs showed that TSAN could provide accurate brain age estimation, yielding mean absolute error (MAE) of $2.428$ and Pearson's correlation coefficient (PCC) of $0.985$, between the estimated and chronological ages. Furthermore, using the brain age gap between brain age and chronological age as a biomarker, Alzheimer's disease (AD) and Mild Cognitive Impairment (MCI) can be distinguished from healthy control (HC) subjects by support vector machine (SVM). Classification AUC in AD/HC and MCI/HC was $0.904$ and $0.823$, respectively. It showed that brain age gap is an effective biomarker associated with risk of dementia, and has potential for early-stage dementia risk screening. The codes and trained models have been released on GitHub: https://github.com/Milan-BUAA/TSAN-brain-age-estimation., Comment: Accepted by IEEE transactions on Medical Imaging, 13 pages, 6 figures

Clinical visual field testing is performed with commercial perimetric devices and employs psychophysical techniques to obtain thresholds of the differential light sensitivity (DLS) at multiple retinal locations. Current thresholding algorithms are relatively inefficient and tough to get satisfied test accuracy, stability concurrently. Thus, we propose a novel Bayesian perimetric threshold method called the Trail-Traced Threshold Test (T4), which can better address the dependence of the initial threshold estimation and achieve significant improvement in the test accuracy and variability while also decreasing the number of presentations compared with Zippy Estimation by Sequential Testing (ZEST) and FT. This study compares T4 with ZEST and FT regarding presentation number, mean absolute difference (MAD between the real Visual field result and the simulate result), and measurement variability. T4 uses the complete response sequence with the spatially weighted neighbor responses to achieve better accuracy and precision than ZEST, FT, SWeLZ, and with significantly fewer stimulus presentations. T4 is also more robust to inaccurate initial threshold estimation than other methods, which is an advantage in subjective methods, such as in clinical perimetry. This method also has the potential for using in other psychophysical tests.

AimTo reassess the association between near work, outdoor exposure and myopia in children through an objective approach.MethodsEighty-six children (10.13±0.48 years) were asked to wear Clouclip, a newly developed wearable device that is able to measure working distance and eye-level illuminance, for a complete week to obtain information on near work and outdoor exposure. The mean daily Clouclip wearing time was 11.72±1.14 hour. The spherical equivalent refraction was determined by cycloplegic autorefraction.ResultsThe myopic children were found to be exposed to light intensities >3000 lux (0.68±0.50 hour vs 1.02±0.53 hour, p=0.012) and >5000 lux (0.42±0.35 hour vs 0.63±0.31 hour, p=0.004) for shorter durations on average each day than the non-myopic children. Additionally, the myopic children spent more time on average each day on activities at a distance of 3000 lux (OR=0.27, 95% CI: 0.10 to 0.72, p=0.009); >5000 lux (OR=0.11, 95% CI: 0.02 to 0.56, p=0.008)) and a working distance of 3000 lux (OR=1.17, 95% CI: 1.09 to 1.86, p=0.038) or in that of >5000 lux (OR=1.12, 95% CI: 1.03 to 1.77, p=0.046)) were the independent protective factors and risk factors, respectively.ConclusionThe current study provides novel evidence, based on objective data, to support the association between the intensity of near work, light intensity and myopia. However, the causality and the dose-effect relationship need to be investigated further.

Objective: To facilitate the analysis and diagnosis of X-ray coronary angiography in interventional surgery, it is necessary to extract vessel from X-ray coronary angiography. However, vessel images of angiography suffer from low quality with large artefacts, which challenges the existing vascular technology. Methods: In this paper, we propose a avessel framework to detect vessels and segment vessels in angiographic vessel data. In this framework, we develop a new matrix decomposition model with gradient sparse in the tensor representation. Then, the energy function with the input of the hierarchical vessel is used in vessel detection and vessel segmentation. Results: Through experiments conducted on angiographic data, we have demonstrated the good performance of the proposed method in removing background structure. Conclusion: We evaluated our method for vessel detection and segmentation in different clinical settings, including LAO/RAO with cranial and caudal angulation, and showed its competitive results compared with eight state-of-the-art methods in terms of extensive qualitative and quantitative evaluation. Significance: Our method can remove a large number of background artefacts and obtain a better vascular structure, which has contributed to the clinical diagnosis of coronary artery diseases.

Fetal congenital heart disease (FHD) is a common and serious congenital malformation in children. In Asia, FHD birth defect rates have reached as high as 9.3%. For the early detection of birth defects and mortality, echocardiography remains the most effective method for screening fetal heart malformations. However, standard echocardiograms of the fetal heart, especially four-chamber view images, are difficult to obtain. In addition, the pathophysiological changes in fetal hearts during different pregnancy periods lead to ever-changing two-dimensional fetal heart structures and hemodynamics, and it requires extensive professional knowledge to recognize and judge disease development. Thus, research on the automatic screening for FHD is necessary. In this paper, we proposed a new model named DGACNN that shows the best performance in recognizing FHD, achieving a rate of 85%. The motivation for this network is to deal with the problem that there are insufficient training datasets to train a robust model. There are many unlabeled video slices, but they are tough and time-consuming to annotate. Thus, how to use these un-annotated video slices to improve the DGACNN capability for recognizing FHD, in terms of both recognition accuracy and robustness, is very meaningful for FHD screening. The architecture of DGACNN comprises two parts, that is, DANomaly and GACNN (Wgan-GP and CNN). DANomaly, similar to the ALOCC network, but incorporates cycle adversarial learning to train an end-to-end one-class classification (OCC) network that is more robust and has a higher accuracy than ALOCC in screening video slices. For the GACNN architecture, we use FCH (four chamber heart) video slices at around the end-systole, as screened by DANomaly, to train a WGAN-GP for the purpose of obtaining ideal low-level features that can robustly improve the FHD recognition accuracy. A few annotated video slices, as screened by DANomaly, can also be used for data augmentation so as to improve the FHD recognition further. The experiments show that the DGACNN outperforms other state-of-the-art networks by 1%-20% in recognizing FHD. A comparison experiment shows that the proposed network already outperforms the performance of expert cardiologists in recognizing FHD, reaching 84% in a test. Thus, the proposed architecture has high potential for helping cardiologists complete early FHD screenings.

Background and objectives To analyze echocardiographic parameters of fetal large ventricular septal defect (VSD) and tetralogy of Fallot (TOF) in the context of multicenter data and big data analysis because these two diseases are often misdiagnosed in fetuses, and to find the key parameters for the differential diagnosis of these two diseases. Methods A total of 305 cases of large VSD and 192 cases of TOF diagnosed by fetal echocardiography from August 2010 to July 2016 from the database of Beijing Key Laboratory of Fetal Heart Defects were analyzed. Quantile regression of the 48 echocardiographic parameters of the 6272 normal fetuses from seven Chinese medical institutions was performed to determine the Q-score. The forward selection method and the naive Bayesian classification method were used to analyze the core differential diagnostic variables of fetal TOF and VSD. Results The Q-score of the internal diameter of the aorta (AO Q-score), the ratio of the diameter of the pulmonary artery to the internal diameter of the aorta (PA/AO), and the Q-score of the ratio of the diameter of the pulmonary artery to the internal diameter of the aorta (PA/AO Q-score) were key parameters for the differential diagnosis of fetal large VSD and TOF. PA/AO was the primary parameter, with an area under the receiver operating characteristic curve of 0.951. Conclusions These findings provide a new method for the prenatal diagnosis of large VSD and TOF and a theoretical basis for the intelligent diagnosis of large VSD and TOF.

Automatic analysis of fetal heart and related components in fetal echocardiography can help cardiologists to reach a diagnosis for Congenital Heart Disease (CHD). Previous studies mainly focused on cardiac chamber segmentation, while few researches deal with the cardiac component detection. In this paper, we tackle the task of simultaneous detection of the fetal heart and descending aorta in four-chamber view of fetal echocardiography, which is useful to analyze some kinds of CHD, such as left/right atrial isomerism, dextroversion of heart, etc. Several CNN-based object detection methods with different backbones are thoroughly evaluated, and finally, the Hybrid Task Cascade method with HRNet is selected as the detection method. Experiments on a fetal echocardiography dataset show that the method can achieve superior performance according to common-used evaluation metrics.Clinical relevance-This can be used to help the cardiologists to estimate the position of the fetal heart and the descending aorta, which is also useful to estimate the direction of the cardiac axis and apex and analyze some kinds of CHD, such as left/right atrial isomerism, dextroversion of heart, etc.

Accurate segmentation of cardiac chambers is helpful for the diagnosis of Congenital Heart Disease (CHD) in fetal echocardiography. Previous studies mainly focused on single cardiac chamber segmentation, which cannot provide sufficient information for the cardiologists. In this paper, we present an instance segmentation approach capable of segmenting four cardiac chambers accurately and simultaneously. A novel object proposal recovery strategy is further deployed to retrieve possible missing objects. To alleviate the shortage of medical data and further improve the segmentation performance, we utilize a rotation and distortion method for data augmentation. Experiments on a fetal echocardiography dataset of 319 fetuses demonstrate that the proposed approach can achieve superior performance according to common-used evaluation metrics.Clinical relevance-This can be used to help the cardiologists to better analyze the structure and function of the fetal heart.

To validate a novel wearable device that can measure both viewing distance and light exposure, Clouclip, and compare questionnaire estimates regarding near-work and outdoor time with the objective measures obtained using Clouclip.Fifteen Clouclips were selected to measure different distances and levels of illuminance. With each Clouclip, five measurements at different distances and light intensities were measured and recorded. Eighty participants wore Clouclips for a week and completed an activity questionnaire afterwards.The intra- and inter-Clouclip coefficients were 1.00 and 0.99 for measuring distance and 1.00 and 1.00 for illuminance, respectively. Within the measurement limit, the maximum relative error was 2.07% for distance and 2.23% for illuminance. Assuming that30 cm was the typical distance for near-work activities and1000 Lux was the typical cut-off for outdoor environments, the questionnaire showed a trend of overestimation for both. The greatest overestimation of near-work occurred during the school period [Questionnaire: 4.73 hr (4.73, 5.07) versus Clouclip: 2.16 hr (1.74, 2.78); p 0.01]. The greatest overestimation of outdoor activity also occurred during the school period [Questionnaire: 1.60 hr (1.33, 1.85) versus Clouclip: 1.21 hr (0.96, 1.50); p 0.01]. Based on Clouclip, the total time spent outdoors was estimated to be 1.55 hr on school days, of which 0.34 hr occurred after school. For weekend days, however, the duration was only 0.17 hr.Clouclip had excellent precision and accuracy. Although the agreement between the questionnaire and Clouclip was relatively poor, they were able to complement each other to provide a more logical and feasible assessment of exposure to near-work and outdoor activity. Indoor-oriented lifestyles were found to predominate in Chinese children.

Background 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). Objective 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. Design 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). Setting Ten university and general ophthalmology units (UKGTS) and a single university ophthalmology unit (RAPID). Participants 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. Interventions 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). Main outcome measures 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. Results 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 p ≤ 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; p = 0.016] for GPA, 0.59 (95% CI 0.42 to 0.83; p = 0.002) for PoPLR, 0.76 (95% CI 0.56 to 1.02; p = 0.065) for ANSWERS and 0.70 (95% CI 0.53 to 0.93; p = 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. Limitations 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. Conclusions 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. Trial registration Current Controlled Trials ISRCTN96423140. Funding This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; 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.

PurposeThe laser in glaucoma and ocular hypertension (LiGHT) trial aims to establish whether initial treatment with selective laser trabeculoplasty (SLT) is superior to initial treatment with topical medication for primary open angle glaucoma (POAG) or ocular hypertension (OHT).DesignLiGHT is a prospective unmasked, multicentre, pragmatic, randomised controlled trial (RCT).Participants718 previously untreated patients with POAG or OHT were recruited at 6 UK centres between 2012 and 2014.MethodsPatients were randomised to initial SLT followed by medical therapy or medical therapy without laser. Participants will be monitored for 3 years, according to routine clinical practice. The primary outcome is EQ-5D-5L. Secondary outcomes are treatment pathway cost and cost-effectiveness, Glaucoma Utility Index (GUI), Glaucoma Symptom Scale, Glaucoma Quality of Life (GQL), pathway effectiveness, visual function, safety and concordance.ResultsA total of 555 patients had POAG and 163 OHT; 518 patients had both eyes eligible. The mean age for patients with POAG was 64 years and for OHT 58 years. 70% of all participants were white. Median IOP for OHT eyes was 26 mm Hg and 23 mm Hg for POAG eyes. Median baseline visual field mean deviation was −0.81 dB for OHT eyes and −2.82 dB for POAG eyes. There was no difference between patients with POAG and patients with OHT on the EQ-5D-5DL; the difference between OHT and POAG on the GUI was −0.02 and 1.23 on the GQL.ConclusionsThe LiGHT trial is the first RCT to compare the two treatment options in a real-world setting. The baseline characteristics of the LiGHT cohort compare well with other landmark glaucoma studies.Trial registration numberISRCTN32038223, Pre-results.

To report clinical efficacy, predictors of success, and safety of primary selective laser trabeculoplasty (SLT) used in treatment-naive patients with open-angle glaucoma (OAG) or ocular hypertension (OHT).Post hoc analysis of a multicenter, prospective, randomized, controlled trial.Treatment-naive patients with OAG or OHT.Patients randomized to SLT or topical medication and treated to predefined target intraocular pressures (IOPs) requiring ≥20% IOP reduction from baseline for all disease severity levels.Initial (early) absolute IOP-lowering at 2 months. Achievement of drop-free disease-control: meeting target IOP without disease progression or need for additional topical medication over 36 months after SLT. Predictors of early absolute IOP-lowering and drop-free disease-control after single initial SLT. Frequency of laser-related complications.A total of 611 eyes (195 OHT and 416 OAG) of 355 patients received SLT, and 622 eyes (185 OHT and 437 OAG) of 362 patients received topical medication at baseline. Early absolute IOP-lowering after SLT was no different between OHT and OAG eyes (adjusted mean difference = -0.05 mmHg; 95% confidence interval [CI], -0.6 to 0.5 mmHg; P = 0.85). No difference was noted in early absolute IOP-lowering between topical medication and primary SLT (adjusted mean difference = -0.1 mmHg; 95% CI, -0.6 to 0.4 mmHg; P = 0.67). Early absolute IOP-lowering with primary SLT was positively associated with baseline IOP (coefficient 0.58; 95% CI, 0.53-0.63; P0.001) and negatively with female gender (coefficient -0.63; 95% CI, -1.23 to -0.02; P = 0.04). At 36 months, 536 eyes (87.7% of 611 eyes) of 314 patients (88.5% of 355 patients) were available for analysis. Some 74.6% of eyes (400 eyes) treated with primary SLT achieved drop-free disease-control at 36 months; 58.2% (312 eyes) after single SLT. Total SLT power and 2-month IOP were predictors of drop-free disease-control at 36 months after single SLT. Six eyes of 6 patients experienced immediate post-laser IOP spike (5 mmHg from pretreatment IOP) with 1 eye requiring treatment.Primary SLT achieved comparable early absolute IOP-lowering in OHT versus OAG eyes. Drop-free disease-control was achieved in approximately 75% eyes at 36 months after 1 or 2 SLTs, the majority of these after single SLT. These analyses are exploratory but support primary SLT to be effective and safe in treatment-naive OAG and OHT eyes.

Purpose To develop a practical approach to quantify the exposure to environmental risk factors of myopia. Methods In total, 179 children (age, mean ± standard deviation [SD] 9.17 ± 0.52 years) were requested to wear Clouclip, designed to measure working distance (WD) and light intensity (LI), for a whole week. The spherical equivalent refraction (SER) was determined by cycloplegic autorefraction. The raw data of WD and LI were preprocessed through several steps, including data denoising, constructing a two-dimensional WD-LI space, and data sparseness disposing. Weighted linear regression was used to explore the relationship between WD/LI and SER. A novel parameter visual behaviour index (VBI) was developed to summarize the overall impact of WD/LI on SER. Results The mean ± SD SER of 179 participants was 0.22 ± 1.18 D. WD and LI were positively associated with SER. However, their magnitude of effect on SER varied with the relative level between them. When WD and LI were split up, the detrimental threshold was approximately 40 cm for WD and 6300 lux for LI. VBI was significantly positively associated with SER (β = 0.0623, R 2 = 0.031, P Conclusions The current study provides a novel approach to quantify environmental risk factors of myopia. Despite the complexity of the interaction between these risk factors and their impact on SER, this information can be summarized as one single-parameter VBI, which provides a useful tool to investigate the effect of environmental factors on myopia development and progression. Translational relevance We developed a novel approach to quantify environmental risk factors of myopia.

Normative ranges of fetal echocardiographic measurements are important for quantitative diagnosis of fetal cardiovascular disease. The current normative ranges were derived from small samples and were based on the hypothesis of a normal distribution of these measurements during fetal cardiovascular growth. The aims of this study were to test the hypothesis of a normal distribution of fetal echocardiographic measurements in a large multicenter cohort and to propose a reference system without the normal distribution hypothesis to improve accuracy of fetal echocardiographic measurements.Fifty-two variables from 6,343 normal fetal echocardiographic examinations were acquired from seven Chinese centers. The hypothesis of a normal distribution used in ordinary least squares regression was tested with the Jarque-Bera test. The quantile score (q score) derived from quantile regression without normal distribution hypothesis was compared with the Z score derived from ordinary least squares regression. A total of 288 fetuses with outflow tract and great artery abnormalities and 300 normal fetuses were used to compare the diagnostic accuracy of q and Z scores.All fetal echocardiographic measurements showed non-normal distributions (P .001). The normal range was underestimated by ordinary least squares regression compared with quantile regression by 30 ± 11%. The partial normalized areas under the receiver operating characteristic curve within the 20% false-positive rate were 0.62 and 0.50 for the q and Z scores, respectively.The q score provides a more robust system for determining normative ranges of fetal echocardiographic measurements. The improved sensitivity of matched false-positive rates makes the q score a more accurate reference for prenatal diagnosis, assessment, and prognosis of fetal cardiovascular disease.

AIM To assess the rate of 'treatment-requiring diabetic macular oedema (DMO)' in eyes for the two years before and after cataract surgery. METHODS Multicentre national diabetic retinopathy (DR) database study with anonymised data extraction across 19 centres from an electronic medical record system. INCLUSION CRITERIA eyes undergoing cataract surgery in patients with diabetes with no history of DMO prior to study start. The minimum dataset included: age, visual acuity (all time-points), injection episodes, timing of cataract surgery and ETDRS grading of retinopathy and maculopathy. MAIN OUTCOME MEASURE rate of developing first episode of treatment-requiring DMO in relation to timing of cataract surgery in the same eye. RESULTS 4850 eyes met the inclusion criteria. The rate of developing treatment-requiring DMO in this cohort was 2.9% in the year prior to surgery versus 5.3% in the year after surgery (p

To assess the association of single nucleotide polymorphisms of hsa-miR-196a2, hsa-miR-149, hsa-miR-146a, hsa-miR-499 with susceptibility to ischemic stroke.Taqman-PCR and DNA sequencing assays were employed to determine the genotypes of the 4 loci among 510 patients and 523 controls. And their association with the disease was assessed.Analysis showed that smoking, diabetes, hypertension, BMI index and abnormal serum lipid metabolism were significantly associated with ischemic stroke, and that rs2910164 was significantly associated with the disease in codominant (CG vs. CC: P=0.002, OR=1.878, 95%CI=1.269-2.789), dominant (P=0.012, OR=1.325, 95%CI=1.110-1.580), recessive (P=0.008, OR=1.630, 95%CI=1.130-2.342) and allele (P=0.002, OR=1.449, 95%CI=1.210-1.731) genetic models. Stratified analysis further showed that the significant association only existed in population with smoking and hypertension. By contrast, no association was found between hsa-miR-196a2 rs11614913, hsa-miR-149 rs2292832 and hsa-miR-499 rs3746444 with the disease.Our study indicated that smoking, diabetes, hypertension, fat and hyperlipidemia are risk factors for ischemic stroke. Hsa-miR-146a rs2910164 is significantly associated with the disease in those with smoking and hypertension in Dongyang region and may be involved in the process of the disease. The G allele G, GG and CG+GG genotypes of the locus may underlie the susceptibility to the disease in Dongyang region.

Aims: To describe baseline characteristics and visual outcome for eyes treated with ranibizumab for diabetic macular oedema (DMO) from a multicentre database.\ud \ud Methods: Structured clinical data were anonymised and extracted from an electronic medical record from 19 participating UK centres: age at first injection, ETDRS visual acuity (VA), number of injections, ETDRS diabetic retinopathy (DR) and maculopathy grade at baseline and visits. The main outcomes were change in mean VA from baseline, number of injections and clinic visits and characteristics affecting VA change and DR grade.\ud \ud Results: Data from 12 989 clinic visits was collated from baseline and follow-up for 3103 eyes. Mean age at first treatment was 66 years. Mean VA (letters) for eyes followed at least 2 years was 51.1 (SD=19.3) at baseline, 54.2 (SD: 18.6) and 52.5 (SD: 19.4) at 1 and 2 years, respectively. Mean visual gain was five letters. The proportion of eyes with VA of 72 letters or better was 25% (baseline) and 33% (1 year) for treatment naïve eyes. Eyes followed for at least 6 months received a mean of 3.3 injections over a mean of 6.9 outpatient visits in 1 year.\ud \ud Conclusions: In a large cohort of eyes with DMO treated with ranibizumab injections in the UK, 33% of patients achieved better than or equal to 6/12 in the treated eye at 12 months compared with 25% at baseline. The mean visual gain was five letters. Eyes with excellent VA at baseline maintain good vision at 18 months.

Glaucoma is the most common optic neuropathy in humans and the leading cause of irreversible blindness worldwide. Its prevalence and incidence increase exponentially with ageing and raised intraocular pressure (IOP), while increasing evidence suggests that systemic mitochondrial abnormalities may also be implicated in its pathogenesis. We have recently shown that patients who have not developed glaucoma despite being exposed for many years to high IOP (ocular hypertension - OHT) have more efficient mitochondria, measured in peripheral blood lymphocytes, when compared to age-similar controls and fast progressing normal tension glaucoma (NTG) patients. In this prospective case series we aimed to explore some of the molecular pathways involved in mitochondrial efficiency in glaucoma resistance by measuring the systemic activity (in peripheral blood) of key mitochondrial regulators: the mammalian target of rapamycin (mTOR) and its major upstream regulators and downstream effectors that form the PTEN-Akt1-mTOR signalling pathway. We found no statistically significant difference in the systemic mTOR activity between the three groups (control, NTG and OHT). In line with the mTOR results, there was no significant difference in the activity of both the two major upstream mTOR regulators (PTEN and Akt1) and its two main downstream effectors (S6K and 4EBP1). In a single NTG patient, with history of Raynaud's, significantly higher mTOR activity was noted. We conclude that the PTEN-Akt1-mTOR pathway does not appear to play a central role in mitochondrial efficiency in OHT.

Investigating multiple research questions, or hypotheses, within one study is a common scenario in biomedical research with many examples in ophthalmology. As the number of statistical tests increases, the overall chance that we draw an erroneous conclusion in our study gets higher in a predictable manner. Each statistical test conducted at the conventional 5% significance level (α) has a one in 20 chance (or 0.05 probability) of appearing significant simply due to chance (a type I error) and a 1−0.05=0.95 probability of being non-significant. If we test two independent true null hypotheses, the probability that neither test will be significant is 0.95×0.95=0.90. Likewise, if we test 14 independent hypotheses, the probability that none will be significant is 0.9514=0.49, and the probability that at least one will be significant is 1−0.49=0.51, that is, we are more likely than not to find at least one test significant. In other words, if we go on carrying out tests of significance we are very likely to find a spurious significant result. In the field of statistics, this phenomenon is known as the problem of multiple testing or the multiplicity problem .1 Consider the ABC study which compared bevacizumab for neovascular age-related macular degeneration (nAMD) with standard National Health Service (NHS) care.2 This study was conducted on 131 patients and found that 21 (32%) of patients treated with bevacizumab gained ≥15 letters compared with two (3%) of those in the standard care group with an OR of 18.1 (95% CI 3.6 to 91.2; p

To derive macular thickness measures and their associations by performing rapid, automated segmentation of spectral-domain optical coherence tomography (SD OCT) images collected and stored as part of the UK Biobank (UKBB) study.Large, multisite cohort study in the United Kingdom. Analysis of cross-sectional data.Adults from the United Kingdom aged 40 to 69 years.Participants had nonmydriatic SD OCT (Topcon 3D OCT-1000 Mark II; Topcon GB, Newberry, Berkshire, UK) performed as part of the ocular assessment module. Rapid, remote, automated segmentation of the images was performed using custom optical coherence tomography (OCT) image analysis software (Topcon Advanced Boundary Segmentation [TABS]; Topcon GB) to generate macular thickness values. We excluded people with a history of ocular or systemic disease (diabetes or neurodegenerative diseases) and eyes with reduced vision (0.1 logarithm of the minimum angle of resolution) or with low SD OCT signal-to-noise ratio and low segmentation success certainty.Macular thickness values across 9 Early Treatment of Diabetic Retinopathy Study (ETDRS) subfields.The SD OCT scans of 67 321 subjects were available for analysis, with 32 062 people with at least 1 eye meeting the inclusion criteria. There were 17 274 women and 14 788 men, with a mean (standard deviation [SD]) age of 55.2 (8.2) years. The mean (SD) logarithm of the minimum angle of resolution visual acuity was -0.075 (0.087), and the refractive error was -0.071 (+1.91) diopters (D). The mean (SD) central macular thickness (CMT) in the central 1-mm ETDRS subfield was 264.5 (22.9) μm, with 95% confidence limits of 220.8 and 311.5 μm. After adjusting for covariates, CMT was positively correlated with older age, female gender, greater myopia, smoking, body mass index (BMI), and white ethnicity (all P0.001). Of note, macular thickness in other subfields was negatively correlated with older age and greater myopia.We report macular thickness data derived from SD OCT images collected as part of the UKBB study and found novel associations among older age, ethnicity, BMI, smoking, and macular thickness.

Purpose To report the methodology and findings of a large scale investigation of burden and distribution of refractive error, from a contemporary and ethnically diverse study of health and disease in adults, in the UK. Methods U K Biobank, a unique contemporary resource for the study of health and disease, recruited more than half a million people aged 40–69 years. A subsample of 107,452 subjects undertook an enhanced ophthalmic examination which provided autorefraction data (a measure of refractive error). Refractive error status was categorised using the mean spherical equivalent refraction measure. Information on socio-demographic factors (age, gender, ethnicity, educational qualifications and accommodation tenure) was reported at the time of recruitment by questionnaire and face-to-face interview. Results Fifty four percent of participants aged 40–69 years had refractive error. Specifically 27% had myopia (4% high myopia), which was more common amongst younger people, those of higher socio-economic status, higher educational attainment, or of White or Chinese ethnicity. The frequency of hypermetropia increased with age (7% at 40–44 years increasing to 46% at 65–69 years), was higher in women and its severity was associated with ethnicity (moderate or high hypermetropia at least 30% less likely in non-White ethnic groups compared to White). Conclusions Refractive error is a significant public health issue for the UK and this study provides contemporary data on adults for planning services, health economic modelling and monitoring of secular trends. Further investigation of risk factors is necessary to inform strategies for prevention. There is scope to do this through the planned longitudinal extension of the UK Biobank study.

Distributions of measured data are often well modelled by known probability distributions, which provide a useful description of their underlying properties such as location (average), spread (variation) and shape. Statisticians use probability distributions to interpret and attribute meaning, draw conclusions and answer research questions using the measurements or data that researchers gather during their studies. Different types of data follow different probability distributions, and these distributions are characterised by certain features called parameters. Even the most statistically averse of researchers is likely to have heard of the normal distribution, which is often used to approximate the distribution of continuous or measurement data such as intraocular pressure, central retinal thickness and degree of proptosis. The normal distribution follows a ‘bell-shaped curve’ (although with a rim stretching to ±infinity) the shape of which is specified by the mean and SD, with different values of each, giving rise to different bell-shaped curves (see figure 1). Figure 1 Examples of the normal N (µ, σ) distributions parameterised by different values of mean (µ) and SD (σ). Other distributions such as the binomial and Poisson probability distributions are less commonly reported in ophthalmic research and are characterised by different parameters. The binomial distribution is used for dichotomous data and is characterised by the probability of success, that is, the number of ‘successes’ out of a total number of observed events, for example, the proportion of graft transplants that fail within 6 months of transplantation. The Poisson distribution is used for counts data and is characterised by the mean number of events, for example, endophthalmitis rates. The assumption that the observed data follow such probability distributions allows a statistician to apply appropriate statistical tests, which are known as parametric tests. The normal distribution is a powerful tool provided the data plausibly arise from that distribution or can be …

Background Vigabatrin (VGB) is an anti-epileptic medication which has been linked to peripheral constriction of the visual field. Documenting the natural history associated with continued VGB exposure is important when making decisions about the risk and benefits associated with the treatment. Due to its speed the Swedish Interactive Threshold Algorithm (SITA) has become the algorithm of choice when carrying out Full Threshold automated static perimetry. SITA uses prior distributions of normal and glaucomatous visual field behaviour to estimate threshold sensitivity. As the abnormal model is based on glaucomatous behaviour this algorithm has not been validated for VGB recipients. We aim to assess the clinical utility of the SITA algorithm for accurately mapping VGB attributed field loss. Methods The sample comprised one randomly selected eye of 16 patients diagnosed with epilepsy, exposed to VGB therapy. A clinical diagnosis of VGB attributed visual field loss was documented in 44% of the group. The mean age was 39.3 years ± 14.5 years and the mean deviation was -4.76 dB ±4.34 dB. Each patient was examined with the Full Threshold, SITA Standard and SITA Fast algorithm. Results SITA Standard was on average approximately twice as fast (7.6 minutes) and SITA Fast approximately 3 times as fast (4.7 minutes) as examinations completed using the Full Threshold algorithm (15.8 minutes). In the clinical environment, the visual field outcome with both SITA algorithms was equivalent to visual field examination using the Full Threshold algorithm in terms of visual inspection of the grey scale plots , defect area and defect severity. Conclusions Our research shows that both SITA algorithms are able to accurately map visual field loss attributed to VGB. As patients diagnosed with epilepsy are often vulnerable to fatigue, the time saving offered by SITA Fast means that this algorithm has a significant advantage for use with VGB recipients. Electronic supplementary material The online version of this article (doi:10.1186/1471-2415-14-166) contains supplementary material, which is available to authorized users.

Glaucomatous optic neuropathy, an important neurodegenerative condition and the commonest optic neuropathy in humans, is the leading cause of irreversible blindness worldwide. Its prevalence and incidence increase exponentially with ageing and raised intraocular pressure (IOP). Using glaucomatous optic neuropathy as an exemplar for neurodegeneration, this study investigates putative factors imparting resistance to neurodegeneration. Systemic mitochondrial function, oxidative stress and vascular parameters were compared from isolated lymphocytes, whole blood and urine samples between 30 patients who have not developed the neuropathy despite being exposed for many years to very high IOP ('resistant'), 30 fast deteriorating glaucoma patients despite having low IOP ('susceptible'), and 30 age-similar controls. We found that 'resistant' individuals showed significantly higher rates of ADP phosphorylation by mitochondrial respiratory complexes I, II and IV, hyperpolarised mitochondrial membrane potential, higher levels of mitochondrial DNA, and enhanced capacity to deal with cytosolic calcium overload and exogenous oxidative stress, as compared to both controls and glaucoma patients. While it has been known for some years that mitochondrial dysfunction is implicated in neurodegeneration, this study provides a fresh perspective to the field of neurodegeneration by providing, for the first time, evidence that systemic mitochondrial efficiency above normal healthy levels is associated with an enhanced ability to withstand optic nerve injury. These results demonstrate the importance of cellular bioenergetics in glaucomatous disease progression, with potential relevance for other neurodegenerative disorders, and raise the possibility for new therapeutic targets in the field of neurodegeneration.

Visual fields measured with standard automated perimetry are a benchmark test for determining retinal function in ocular pathologies such as glaucoma. Their monitoring over time is crucial in detecting change in disease course and, therefore, in prompting clinical intervention and defining endpoints in clinical trials of new therapies. However, conventional change detection methods do not take into account non-stationary measurement variability or spatial correlation present in these measures. An inferential statistical model, denoted ‘Analysis with Non-Stationary Weibull Error Regression and Spatial enhancement’ (ANSWERS), was proposed. In contrast to commonly used ordinary linear regression models, which assume normally distributed errors, ANSWERS incorporates non-stationary variability modelled as a mixture of Weibull distributions. Spatial correlation of measurements was also included into the model using a Bayesian framework. It was evaluated using a large dataset of visual field measurements acquired from electronic health records, and was compared with other widely used methods for detecting deterioration in retinal function. ANSWERS was able to detect deterioration significantly earlier than conventional methods, at matched false positive rates. Statistical sensitivity in detecting deterioration was also significantly better, especially in short time series. Furthermore, the spatial correlation utilised in ANSWERS was shown to improve the ability to detect deterioration, compared to equivalent models without spatial correlation, especially in short follow-up series. ANSWERS is a new efficient method for detecting changes in retinal function. It allows for better detection of change, more efficient endpoints and can potentially shorten the time in clinical trials for new therapies.

Purpose To investigate the influence of intersubject variation in ocular parameters on the mapping of retinal locations to the retinal nerve fiber layer and optic nerve head. Methods One hundred retinal nerve fiber layer (RNFL) bundle photographs from 100 subjects were optimized digitally and single RNFL bundles manually traced back to the ONH where their entry point was noted. A 24-2 visual field (VF) grid pattern was superimposed onto the photographs in order to relate VF test points to intersecting RNFL bundles and their entry angles into the ONH. Axial length, spherical equivalent, the position of the ONH in relation to the fovea, size, orientation, tilt, and shape of the ONH were assessed. Multilevel linear models were generated for predicting the entry angle of RNFL bundles, based on ocular parameters. Results A total of 6388 RNFL bundles were traced. The influence of ocular parameters could be evaluated for 33 out of 52 VF locations. The position of the ONH in relation to the fovea was the most prominent predictor for variations in the mapping of retinal locations to the ONH, followed by disc area, axial length, spherical equivalent, disc shape, disc orientation, and disc tilt. Conclusions Mapping of retinal locations to the optic nerve head varies between patients according to a given patient's ocular parameters. By considering these parameters, patient-tailored, structure-function maps can be built and structural and functional measurements can be correlated more accurately. Individualized maps may assist clinicians detecting glaucoma and monitoring glaucomatous progression.

Measurement of retinal nerve fiber layer (RNFL) thickness using optical coherence tomography (OCT) is commonly used in the detection and management of glaucoma. The Stratus OCT (Carl Zeiss Meditec, Inc., Dublin, CA) is widely used, but image acquisition is subject to artifacts, such as those caused by normal fixational eye movements, and this leads to unreliable measurements. Novel analytical methods have been developed to estimate the amount of misalignment of the circular scanning protocol used by the Stratus OCT. A computer program with a graphical user interface implementing these methods has been written by some of the authors. A case example is presented in this report that shows the effect that vertical displacements of the OCT scan have on measured RNFL thickness. The example is used to demonstrate how the software can be used for estimating the positional alignment of the scan circle. This software can potentially improve the identification of unreliable RNFL thickness measurements and is freely available from the authors.

Optical coherence tomography (OCT) is widely used in the assessment of retinal nerve fibre layer thickness (RNFLT) in glaucoma. Images are typically acquired with a circular scan around the optic nerve head. Accurate registration of OCT scans is essential for measurement reproducibility and longitudinal examination. This study developed and evaluated a special image registration algorithm to align the location of the OCT scan circles to the vessel features in the retina using probabilistic modelling that was optimised by an expectation-maximization algorithm. Evaluation of the method on 18 patients undergoing large numbers of scans indicated improved data acquisition and better reproducibility of measured RNFLT when scanning circles were closely matched. The proposed method enables clinicians to consider the RNFLT measurement and its scan circle location on the retina in tandem, reducing RNFLT measurement variability and assisting detection of real change of RNFLT in the longitudinal assessment of glaucoma.

Objective To evaluate a new method of quantifying and visualizing discordance between structural and functional measurements in glaucomatous eyes by predicting the visual field (VF) from retinal nerve fiber layer thickness (RNFLT) using a bayesian radial basis function. Methods Five GDx VCC RNFLT scans and 5 Humphrey 24-2 Swedish Interactive Thresholding Algorithm VF tests were performed for 50 glaucomatous eyes from 50 patients. A best-available estimate (BAE) of the true VF was calculated as the pointwise median of these 5 replications. This BAE VF was compared with every RNFLT-predicted VF from the bayesian radial basis function and every measured VF. Predictability of VFs from RNFLT was established from previous data. A structure-function pattern discordance map and a structure-function discordance index (scores of 0-1) were established from the predictability limits for each structure-function measurement pair to quantify and visualize the discordance between the structure-predicted and measured VFs. Results The mean absolute difference between the structure-predicted and BAE VFs was 3.9 dB. The mean absolute difference between measured and BAE VFs was 2.6 dB. The mean (SD) structure-function discordance index score was 0.34 (0.11). Ninety-seven (39%) of the structure-predicted VFs showed significant discordance (structure-function discordance index score >0.3) from measured VFs. Conclusions On average, the bayesian radial basis function predicts the BAE VF from RNFLT slightly less well than a measured VF from the 5 VFs composing the BAE VF. The pattern discordance map highlights locations with structure-function discordance, with the structure-function discordance index providing a summary index. These tools may help clinicians trust the mutually confirmatory structure-function measurements with good concordance or identify unreliable ones with poor concordance.

Spectral-domain optical coherence tomography (SD-OCT) provides volumetric images of retinal structures with unprecedented detail. Accurate segmentation algorithms and feature quantification in these images, however, are needed to realize the full potential of SD-OCT. The fully automated segmentation algorithm, FloatingCanvas, serves this purpose and performs a volumetric segmentation of retinal tissue layers in three-dimensional image volume acquired around the optic nerve head without requiring any pre-processing. The reconstructed layers are analyzed to extract features such as blood vessels and retinal nerve fibre layer thickness. Findings from images obtained with the RTVue-100 SD-OCT (Optovue, Fremont, CA, USA) indicate that FloatingCanvas is computationally efficient and is robust to the noise and low contrast in the images. The FloatingCanvas segmentation demonstrated good agreement with the human manual grading. The retinal nerve fibre layer thickness maps obtained with this method are clinically realistic and highly reproducible compared with time-domain StratusOCT(TM).

Purpose: To develop and validate a method for predicting visual function from retinal nerve fibre layer (RNFL) structure in glaucoma.\ud \ud Methods: RNFL thickness (RNFLT) measurements from GDxVCC scanning laser polarimetry (SLP) and visual field (VF) sensitivity from standard automated perimetry were made available from 535 eyes from three centres. In a training dataset, structure-function relationships were characterized using linear regression and a type of neural network: Radial Basis Function customised under a Bayesian framework (BRBF). These two models were used in a test dataset to 1) predict sensitivity values at individual VF locations from RNFLT measurements and 2) predict the spatial relationship between VF locations and positions at a peripapillary RNFLT measurement annulus. Predicted spatial relationships were compared with a published anatomical structure-function map.\ud \ud Results: Compared with linear regression, BRBF yielded a nearly two-fold improvement (P

Background and Objective: The purpose of this study was to examine the hypothesis that retinal nerve fiber layer (RNFL) birefringence increases following surgical reduction of intraocular pressure (IOP). Patients and Methods: Twenty-six glaucomatous eyes requiring trabeculectomy or drainage implant were enrolled. Optical coherence tomography (OCT), scanning laser polarimetry (SLP), and IOP measurements were performed preoperatively and 3 months postoperatively. The OCT and SLP images were aligned using a new algorithm that aligns the vessels in an OCT image to those in the corresponding SLP reflectance image. The SLP retardance values at the location of the OCT scan circle were then extracted using the OCT scan circle position inferred by the algorithm. Sixty-four corresponding RNFL segments were extracted from SLP and OCT to calculate RNFL birefringence. A significant birefringence change was defined as 1.96 times the weighted test–retest standard deviation in four contiguous segments. Results: Preoperative IOP (19.3 ± 6.1 mm Hg) was significantly ( P < .001) lower than postoperative IOP (10.4 ± 3.7 mm Hg). Average birefringence magnitude did not change ( P = .19) postoperatively. Localized birefringence magnitude increased significantly in 6 (23%) eyes and decreased significantly in 7 (27%) eyes. Conclusion: In this cohort, variable changes in localized birefringence were observed following surgical reduction of IOP.

Purpose: To investigate the effects of levocabastine hydrochloride on the profileration, Deoxyribonucleic acid (DNA) synthesis and induction of apoptosis, in human Tenon’s capsule fibroblasts. Methods: The maximum intoxicate concentration was determined by measuring the release of lactate dehydrogenase. Proliferation of fibroblasts was analyzed with a WST-1 method. DNA synthesis was examined by quantifying the incorporation of 5-bromo-2’-deoxyuridine into dividing cells, and apoptosis was analyzed using an Annexin-V-FLUOS Staining Kit. Results: Levocabastine hydrochloride (10−4 M), ketotifen fumarate (3 × 10−5 M) and tranilast (10−4 M) significantly inhibited proliferation of fibroblasts. Levocabastine hydrochloride (10−4 M), ketotifen fumarate (10−4 M) and tranilast (10−3 M) inhibited DNA synthesis and induced apoptosis. Conclusion: Levocabastine hydrochloride inhibited the proliferation of fibroblasts.

Purpose To validate a method for visual field (VF) progression analysis, called ANSWERS (Analysis with Non-Stationary Weibull Error Regression and Spatial Enhancement), which takes into account increasing measurement variability as glaucoma progresses and spatial correlation among test locations. Methods ANSWERS outputs both a global index of progression and a pointwise estimate of rate of change at each VF location. ANSWERS was compared with linear regression of mean deviation (MD) and permutation of pointwise linear regression (PoPLR). Visual field series of up to 2 years from the United Kingdom Glaucoma Treatment Study were used. This consists of 9104 Swedish Interactive Thresholding Algorithm Standard 24-2 VFs. ANSWERS and PoPLR rate of change were used to predict the VF at the next visit using subseries that were within 7, 13, 18, or 22 months from the baseline. The comparison was carried out on the statistical sensitivity, specificity, and accuracy of predicting future VF. Results Across all subseries, statistical sensitivity of ANSWERS in detecting VF deterioration was significantly better than the linear regression of MD and PoPLR, especially in short time series. Prediction accuracy of ANSWERS was better than PoPLR at all series lengths, and the improvement was particularly marked in shorter series. Seventy-five percent of VF series were better predicted by ANSWERS compared with PoPLR. The average prediction error of ANSWERS was 15% lower than that of PoPLR. Conclusions ANSWERS is more sensitive to detect VF progression and predicts future VF loss better than linear regression of MD and PoPLR, especially over short observation periods. (http://www.isrctn.com number, ISRCTN96423140.).

PURPOSE. The Ocular Response Analyzer (ORA) is a new instrument that measures the corneal biomechanical response (corneal hysteresis, CH) to rapid indentation by an air jet. CH is the difference in applanation pressures (P1, P2) between the rising and falling phases of the air jet. The investigation had two parts: a characterization study and a validation study. In the characterization study, the purposes were to investigate the intraocular pressure (IOP)– dependence of CH and to characterize the performance of the ORA. In the validation study, the purposes were to investigate the association between CH and both age and central corneal thickness (CCT) and the agreement between ORA and Goldmann applanation tonometer (GAT) IOP measurements. METHODS. For the characterization study, data were collected from 105 untreated subjects (45 ocular hypertensive patients and 60 normal subjects; mean age, 60 years, range, 26 – 82). GAT and ORA measurements were performed before and after IOP lowering of one randomly selected eye with apraclonidine drops. The change in P1 and P2 (arbitrary units) in relation to change in GAT IOP was analyzed to calibrate the instrument. The relation between P1, P2, and CCT was explored and ORA IOP was derived from the analyses. For the validation study, ORA and GAT IOP and CCT were measured in 144 eyes of 144 untreated subjects (mean age, 58 years; range, 19 – 83). The characterization calculations were applied to the dataset and values of CH and ORA IOP were calculated. The relationship between CH and both subject age and CCT was determined. The associations between CH and CCT and between ORA and GAT IOPs, were investigated by linear regression analysis. The agreement between measuring devices was calculated. RESULTS. In the characterization study, P1 changed by 6.41 arbitrary units for every 1-mm Hg change in GAT IOP. CH (P1 P2) changed by 1.60 arbitrary units for every 1-mm Hg change in GAT IOP. For each unit change in P2, P1 changed by 1.27 units. From this association a new IOP-independent corneal factor was derived [P1 (P2/1.27)] and is termed the corneal constant factor (CCF; mm Hg). ORA IOP normalized for CCF was defined as P2 – CCF (mm Hg). The CCF (mm Hg) was associated with CCT (micrometers) and with age: CCF [(0.036 CCT) (0.028 age)] 1.06 (adjusted r 2 0.34; P 0.0001 for CCT, P 0.007 for age). Normalized ORA IOP measurements were not associated with CCT. GAT IOP was associated with CCT and CCF—more strongly with the latter: GAT IOP (0.03 CCT)1.52 (r 2 0.06, P 0.002); GAT IOP (0.65 CCF) 4.5 (r 2 0.13, P 0.0001). The mean difference (95% limits of agreement) between GAT and normalized ORA IOP was 0.1 (6.6 to 6.8) mm Hg. CONCLUSIONS. The CCF describes an IOP-independent biomechanical property of the cornea that increases with thicker CCT and decreases with greater age. It is moderately strongly associated with CCT and yet explains more of the interindividual variation in GAT IOP than does CCT. Normalized ORA IOP measurements are not associated with CCT. (Invest Ophthalmol Vis Sci. 2006;47:5337–5347) DOI:10.1167/iovs.060557