External quality assurance for image grading in the Scottish Diabetic Retinopathy Screening Programme.

AIMS: To develop and evaluate an image grading external quality assurance system for the Scottish Diabetic Retinopathy Screening Programme. METHOD: A web-based image grading system was developed which closely matches the current Scottish national screening software. Two rounds of external quality assurance were run in autumn 2008 and spring 2010, each time using the same 100 images. Graders were compared with a consensus standard derived from the top-level graders' results. After the first round, the centre lead clinicians and top-level graders reviewed the results and drew up guidance notes for the second round. RESULTS: Grader sensitivities ranged from 60.0 to 100% (median 92.5%) in 2008, and from 62.5 to 100% (median 92.5%) in 2010. Specificities ranged from 34.0 to 98.0% (median 86%) in 2008, and 54.0 to 100% (median 88%) in 2010. There was no difference in sensitivity between grader levels, but first-level graders had a significantly lower specificity than level-two and level-three graders. In 2008, one centre had a lower sensitivity but higher specificity than the majority of centres. Following the feedback from the first round, overall agreement improved in 2010 and there were no longer any significant differences between centres. CONCLUSIONS: A useful educational tool has been developed for image grading external quality assurance.

Costs and consequences of automated algorithms versus manual grading for the detection of referable diabetic retinopathy.

AIMS: To assess the cost-effectiveness of an improved automated grading algorithm for diabetic retinopathy against a previously described algorithm, and in comparison with manual grading. METHODS: Efficacy of the alternative algorithms was assessed using a reference graded set of images from three screening centres in Scotland (1253 cases with observable/referable retinopathy and 6333 individuals with mild or no retinopathy). Screening outcomes and grading and diagnosis costs were modelled for a cohort of 180 000 people, with prevalence of referable retinopathy at 4%. Algorithm (b), which combines image quality assessment with detection algorithms for microaneurysms (MA), blot haemorrhages and exudates, was compared with a simpler algorithm (a) (using image quality assessment and MA/dot haemorrhage (DH) detection), and the current practice of manual grading. RESULTS: Compared with algorithm (a), algorithm (b) would identify an additional 113 cases of referable retinopathy for an incremental cost of pound 68 per additional case. Compared with manual grading, automated grading would be expected to identify between 54 and 123 fewer referable cases, for a grading cost saving between pound 3834 and pound 1727 per case missed. Extrapolation modelling over a 20-year time horizon suggests manual grading would cost between pound 25,676 and pound 267,115 per additional quality adjusted life year gained. CONCLUSIONS: Algorithm (b) is more cost-effective than the algorithm based on quality assessment and MA/DH detection. With respect to the value of introducing automated detection systems into screening programmes, automated grading operates within the recommended national standards in Scotland and is likely to be considered a cost-effective alternative to manual disease/no disease grading.

Cost-effectiveness of implementing automated grading within the national screening programme for diabetic retinopathy in Scotland.

AIMS: National screening programmes for diabetic retinopathy using digital photography and multi-level manual grading systems are currently being implemented in the UK. Here, we assess the cost-effectiveness of replacing first level manual grading in the National Screening Programme in Scotland with an automated system developed to assess image quality and detect the presence of any retinopathy. METHODS: A decision tree model was developed and populated using sensitivity/specificity and cost data based on a study of 6722 patients in the Grampian region. Costs to the NHS, and the number of appropriate screening outcomes and true referable cases detected in 1 year were assessed. RESULTS: For the diabetic population of Scotland (approximately 160,000), with prevalence of referable retinopathy at 4% (6400 true cases), the automated strategy would be expected to identify 5560 cases (86.9%) and the manual strategy 5610 cases (87.7%). However, the automated system led to savings in grading and quality assurance costs to the NHS of 201,600 pounds per year. The additional cost per additional referable case detected (manual vs automated) totalled 4088 pounds and the additional cost per additional appropriate screening outcome (manual vs automated) was 1990 pounds. CONCLUSIONS: Given that automated grading is less costly and of similar effectiveness, it is likely to be considered a cost-effective alternative to manual grading.

The efficacy of automated "disease/no disease" grading for diabetic retinopathy in a systematic screening programme.

AIM: To assess the efficacy of automated "disease/no disease" grading for diabetic retinopathy within a systematic screening programme. METHODS: Anonymised images were obtained from consecutive patients attending a regional primary care based diabetic retinopathy screening programme. A training set of 1067 images was used to develop automated grading algorithms. The final software was tested using a separate set of 14 406 images from 6722 patients. The sensitivity and specificity of manual and automated systems operating as "disease/no disease" graders (detecting poor quality images and any diabetic retinopathy) were determined relative to a clinical reference standard. RESULTS: The reference standard classified 8.2% of the patients as having ungradeable images (technical failures) and 62.5% as having no retinopathy. Detection of technical failures or any retinopathy was achieved by manual grading with 86.5% sensitivity (95% confidence interval 85.1 to 87.8) and 95.3% specificity (94.6 to 95.9) and by automated grading with 90.5% sensitivity (89.3 to 91.6) and 67.4% specificity (66.0 to 68.8). Manual and automated grading detected 99.1% and 97.9%, respectively, of patients with referable or observable retinopathy/maculopathy. Manual and automated grading detected 95.7% and 99.8%, respectively, of technical failures. CONCLUSION: Automated "disease/no disease" grading of diabetic retinopathy could safely reduce the burden of grading in diabetic retinopathy screening programmes.

The scanning laser ophthalmoscope--a review of its role in bioscience and medicine.

The scanning laser ophthalmoscope (SLO) offers the potential for retinal imaging that is complementary both to that of the fundus camera and also the newly developing technique of optical coherence tomography (OCT). It has the ability to produce rapid images at low light levels using light of specific wavelengths. This permits temporal studies of fluorescent-labelled cells which offer a unique insight into inflammatory processes in the eye. The facility to image with several different wavelengths simultaneously offers the potential for spectral imaging of retinal tissue with the aim of revealing those early changes in tissue perfusion that indicate the onset of retinal disease, so increasing the probability of successful therapy.

The value of digital imaging in diabetic retinopathy.

OBJECTIVES: To assess the performance of digital imaging, compared with other modalities, in screening for and monitoring the development of diabetic retinopathy. DESIGN: All imaging was acquired at a hospital assessment clinic. Subsequently, study optometrists examined the patients in their own premises. A subset of patients also had fluorescein angiography performed every 6 months. SETTING: Research clinic at the hospital eye clinic and optometrists' own premises. PARTICIPANTS: Study comprised 103 patients who had type 1 diabetes mellitus, 481 had type 2 diabetes mellitus and two had secondary diabetes mellitus; 157 (26.8%) had some form of retinopathy ('any') and 58 (9.9%) had referable retinopathy. INTERVENTIONS: A repeat assessment was carried out of all patients 1 year after their initial assessment. Patients who had more severe forms of retinopathy were monitored more frequently for evidence of progression. MAIN OUTCOME MEASURES: Detection of retinopathy, progression of retinopathy and determination of when treatment is required. RESULTS: Manual grading of 35-mm colour slides produced the highest sensitivity and specificity figures, with optometrist examination recording most false negatives. Manual and automated analysis of digital images had intermediate sensitivity. Both manual grading of 35-mm colour slides and digital images gave sensitivities of over 90% with few false positives. Digital imaging produced 50% fewer ungradable images than colour slides. This part of the study was limited as patients with the more severe levels of retinopathy opted for treatment. There was an increase in the number of microaneurysms in those patients who developed from mild to moderate. There was no difference between the turnover rate of either new or regressed microaneurysms for patients with mild or with sight-threatening retinopathy. It was not possible in this study to ascertain whether digital imaging systems determine when treatment is warranted. CONCLUSIONS: In the context of a national screening programme for referable retinopathy, digital imaging is an effective method. In addition, technical failure rates are lower with digital imaging than conventional photography. Digital imaging is also a more sensitive technique than slit-lamp examination by optometrists. Automated grading can improve efficiency by correctly identifying just under half the population as having no retinopathy. Recommendations for future research include: investigating whether the nasal field is required for grading; a large screening programme is required to ascertain if automated grading can safely perform as a first-level grader; if colour improves the performance of grading digital images; investigating methods to ensure effective uptake in a diabetic retinopathy screening programme.

A comparative evaluation of digital imaging, retinal photography and optometrist examination in screening for diabetic retinopathy.

AIMS: To compare the respective performances of digital retinal imaging, fundus photography and slit-lamp biomicroscopy performed by trained optometrists, in screening for diabetic retinopathy. To assess the potential contribution of automated digital image analysis to a screening programme. METHODS: A group of 586 patients recruited from a diabetic clinic underwent three or four mydriatic screening methods for retinal examination. The respective performances of digital imaging (n=586; graded manually), colour slides (n=586; graded manually), and slit-lamp examination by specially trained optometrists (n=485), were evaluated against a reference standard of slit-lamp biomicroscopy by ophthalmologists with a special interest in medical retina. The performance of automated grading of the digital images by computer was also assessed. RESULTS: Slit-lamp examination by optometrists for referable diabetic retinopathy achieved a sensitivity of 73% (52-88) and a specificity of 90% (87-93). Using two-field imaging, manual grading of red-free digital images achieved a sensitivity of 93% (82-98) and a specificity of 87% (84-90), and for colour slides, a sensitivity of 96% (87-100) and a specificity of 89% (86-91). Almost identical results were achieved for both methods with single macular field imaging. Digital imaging had a lower technical failure rate (4.4% of patients) than colour slide photography (11.9%). Applying an automated grading protocol to the digital images detected any retinopathy, with a sensitivity of 83% (77-89) and a specificity of 71% (66-75) and diabetic macular oedema with a sensitivity of 76% (53-92) and a specificity of 85% (82-88). CONCLUSIONS: Both manual grading methods produced similar results whether using a one- or two-field protocol. Technical failures rates, and hence need for recall, were lower with digital imaging. One-field grading of fundus photographs appeared to be as effective as two-field. The optometrists achieved the lowest sensitivities but reported no technical failures. Automated grading of retinal images can improve efficiency of resource utilization in diabetic retinopathy screening.

True colour imaging of the fundus using a scanning laser ophthalmoscope.

Currently retinal imaging is performed with the fundus camera. This has a number of limitations, in particular the high level of illuminations required for imaging. The scanning laser ophthalmoscope (SLO) has been proposed as an alternative imaging device but to date one of its main limitations has been that it gives only monochromatic images. In this paper we describe an SLO which uses low power red, green and blue lasers to image the human fundus. Using three lasers simultaneously to produce a colour image will increase the fundus exposure by a factor of three. To overcome this problem, a technique has been developed for multiplexing the lasers so that each point on the retina is imaged by the three lasers pulsed rapidly in sequence. The total exposure is thus kept to the same level as for a single laser and total imaging time is not increased. An example is shown of the image from a patient with diabetic retinopathy.

Clinical investigation of a true color scanning laser ophthalmoscope.

OBJECTIVE: To show true color scanning laser ophthalmoscope (SLO) images produced by simultaneously imaging the retina with red, green, and blue lasers. METHODS: Low-power red, green, and blue lasers were combined using fiber optics. By rapidly pulsing the lasers, each point on the fundus is illuminated by the 3 colors in quick succession, with the total power level being similar to that from a single laser. The reflected light is then decoded to extract the red, green, and blue color information and the true color fundus image is displayed live on a computer monitor. RESULTS: Comparison was made between the color SLO images from 5 patients and their digitized fundus photographs. The background fundus and retinal vasculature showed a similar appearance. The SLO gave better quality information in patients with ocular histoplasmosis, macular dystrophy, and optic disc drusen. By operating the color SLO in the indirect mode, macular edema could be clearly seen as lines and ridges surrounding the fovea. CONCLUSION: The color SLO offers all the advantages of the present commercially available monochromatic device, with the added advantage of true color representation of the fundus without increasing either imaging time or the level of exposure.

Automated detection of microaneurysms in digital red-free photographs: a diabetic retinopathy screening tool.

AIMS: To develop a technique to detect microaneurysms automatically in 50 degrees digital red-free fundus photographs and evaluate its performance as a tool for screening diabetic patients for retinopathy. METHODS: Candidate microaneurysms are extracted, after the image has been modified to remove variations in background intensity, by algorithms that enhance small round features. Each microaneurysm candidate is then classified according to its intensity and size by the application of a set of rules derived from a training set of 102 images. RESULTS: When 3,783 individual images were analysed and the results compared with the opinion of a clinical research fellow examining the same images, the program achieved a sensitivity of 81% and a specificity of 93% for the detection of images containing microaneurysms. Nine hundred and twenty-five sets of 4 images per patient were then analysed and the total number of microaneurysms detected compared with the overall patient retinopathy grade derived by the clinician examining the same images. In this context, intended to mimic a screening situation, the program achieved a sensitivity of 85% and a specificity of 76% for the detection of patients with (any) retinopathy (positive predictive value 0.71, negative predictive value 0.88). CONCLUSIONS: An automated technique was developed to detect retinopathy in digital red-free fundus images that can form part of a diabetic retinopathy screening programme. It is believed that it can perform a useful role in this context identifying images worthy of closer inspection or eliminating 50% or more of the screening population who have no retinopathy.

Positron emission tomography using [(18)F]-fluorodeoxy-D-glucose to predict the pathologic response of breast cancer to primary chemotherapy.

PURPOSE: To determine whether [(18)F]-fluorodeoxy-D-glucose ([(18)F]-FDG) positron emission tomography (PET) can predict the pathologic response of primary and metastatic breast cancer to chemotherapy. PATIENTS AND METHODS: Thirty patients with noninflammatory, large (> 3 cm), or locally advanced breast cancers received eight doses of primary chemotherapy. Dynamic PET imaging was performed immediately before the first, second, and fifth doses and after the last dose of treatment. Primary tumors and involved axillary lymph nodes were identified, and the [(18)F]-FDG uptake values were calculated (expressed as semiquantitative dose uptake ratio [DUR] and influx constant [K]). Pathologic response was determined after chemotherapy by evaluation of surgical resection specimens. RESULTS: Thirty-one primary breast lesions were identified. The mean pretreatment DUR values of the eight lesions that achieved a complete microscopic pathologic response were significantly (P =.037) higher than those from less responsive lesions. The mean reduction in DUR after the first pulse of chemotherapy was significantly greater in lesions that achieved a partial (P =.013), complete macroscopic (P =.003), or complete microscopic (P =.001) pathologic response. PET after a single pulse of chemotherapy was able to predict complete pathologic response with a sensitivity of 90% and a specificity of 74%. Eleven patients had pathologic evidence of lymph node metastases. Mean pretreatment DUR values in the metastatic lesions that responded did not differ significantly from those that failed to respond (P =.076). However, mean pretreatment K values were significantly higher in ultimately responsive cancers (P =.037). The mean change in DUR and K after the first pulse of chemotherapy was significantly greater in responding lesions (DUR, P =.038; K, P =.012). CONCLUSION: [(18)F]-FDG PET imaging of primary and metastatic breast cancer after a single pulse of chemotherapy may be of value in the prediction of pathologic treatment response.

The preprocessing of retinal images for the detection of fluorescein leakage.

Images of the human retina are routinely used in clinical practice for the diagnosis and management of eye disease. Increased permeability of retinal blood vessels, which is a clinically significant feature, can be visualized with a process known as fluorescein angiography as leakage of fluorescence dye into the surrounding tissues. Analyses of such images can be quantified but significant degradation of images due to uneven illumination or occluded optical pathways is often incurred during image capture. We describe a procedure to restore fluorescein angiographic retinal images so that quantitative computation can be reliably performed. Analysis of the image acquisition system reveals that captured images are composed of two functions, one describing the true underlying image and the other the degradation incurred. These two functions are independent of one another and it is possible to estimate the degradation from an isolated captured image and restore it appropriately. Any leakage of fluorescein dye is then detected by analysing the restored angiographic sequence over time and finding areas of the image that do not have the usual decrease in fluorescence intensity.

Balancing patient dose and image quality.

The formation of images in diagnostic radiology involves a complex interdependence of many factors. The ideal balance is to obtain an image which is adequate for the clinical purpose with the minimum radiation dose. Factors which affect radiation dose and image quality can be grouped under three headings; radiation quality, photon fluence and removal of scattered radiation. If optimal performance is to be achieved, it is necessary to understand how these factors influence image formation and affect radiation dose, and apply methodology for image quality and dose analysis at each stage in the development and use of X-ray equipment.

Measurement of image quality in diagnostic radiology.

The aim in radiology is to obtain images which are adequate for the clinical purpose with the minimum radiation dose to the patient. If optimum performance is to be achieved, assessments of image quality must be made to balance against patient dose. The subjective nature of image interpretation makes an objective approach to such assessment difficult. Methods widely applied involve the use of test objects, which although providing a measure of imaging performance may be difficult to link to clinical image formation. The ideal method for evaluation of imaging techniques is through clinical trials and this should be used to address major questions. Scoring of quality criteria, relating to features observed in a normal clinical radiograph, provides a simple method through which image quality can be assessed in every hospital department.

A comparison of computer based classification methods applied to the detection of microaneurysms in ophthalmic fluorescein angiograms.

We compared the performance of three computer based classification methods when applied to the problem of detecting microaneurysms on digitised angiographic images of the retina. An automated image processing system segmented 'candidate' objects (microaneurysms or spurious objects), and produced a list of features on each candidate for use by the classifiers. We compared an empirically derived rule based system with two automated methods, linear discriminant analysis and a learning vector quantiser artificial neural network, to classify the objects as microaneurysms or otherwise. ROC analysis shows that the rule based system gave a higher performance than the other methods (p = 0.92) although a much greater development time is required.

In vivo cell tracking by scanning laser ophthalmoscopy: quantification of leukocyte kinetics.

PURPOSE: To image peripheral blood leukocyte traffic in the normal retinal and choroidal vasculature and to quantify the differences in the circulation dynamics between normal and concanavalin A (ConA)-activated leukocytes. METHODS: Normal or ConA-activated splenocytes were fluorescently labeled in vitro with 6-carboxyfluorescein diacetate (CFDA) and reinfused in vivo where they were tracked in the retinal and choroidal circulations of syngeneic rats by means of a scanning laser ophthalmoscope (SLO). Simultaneous digital and video images were captured for as long as 30 minutes, and the initial 15 seconds of image sequences and leukocyte dynamics were analyzed from digitized images by recording the velocity of trafficking cells and the number of stationary cells that accumulated with time, using a customized software package. RESULTS: Mean velocity (+/-SD) was 29.8 +/- 15.3 mm/sec in the retinal arteries, 14.7 +/- 7.2 mm/sec in the retinal veins, and 3.0 +/- 3.6 mm/sec in the retinal capillaries. Mean velocity in the choroidal vessels was 6.1 +/- 6.0 mm/sec. No significant difference in leukocyte velocity was found between activated and normal leukocytes in any of the vessel systems. However, activated leukocytes were observed to accumulate more within the choroidal vasculature (P < 0.001) and the retinal capillaries (P < 0.001) than in control animals, but not in larger retinal vessels. CONCLUSIONS: A technique to measure the kinetics of circulating leukocytes in vivo has been developed. Although leukocyte activation itself is insufficient to cause slowing of leukocyte velocity, the data indicate that leukocyte adherence to endothelium can be induced in the absence of local or systemic activating stimuli.

Novel approach towards colour imaging using a scanning laser ophthalmoscope.

AIMS: Conventional fundus imaging using a fundus camera produces colour fundus pictures. The scanning laser ophthalmoscope (SLO) has the advantages of lower levels of light exposure, improved contrast, and direct digital imaging but until now has produced monochromatic images as a laser of single wavelength is used. True representation of the fundus is possible by combining images taken using blue, green, and red lasers. METHODS: A custom built SLO was used to capture blue, green, and red fundus images from suitable volunteers and patients with fundus disease. Images were corrected for eye movement and combined to form a colour image. Colour fundus photographs were taken using a fundus camera for comparison with the SLO image. RESULTS: The background fundus and retinal vasculature had similar appearances with the two imaging modalities. Internal limiting membrane reflections were prominent with the SLO. Identification of new vessels in the diabetic fundus was easier with the SLO than the colour fundus photographs. CONCLUSION: A colour SLO offers all the advantages of the present monochromatic imaging system with the added advantage of true colour representation of the fundus.

Quantifying changes in retinal circulation: the generation of parametric images from fluorescein angiograms.

Fluorescein angiography is an established technique for examining the functional integrity of the retinal circulation. The ability to quantify this function offers the possibility of early detection of changes due to retinopathy. We have developed a technique to generate functional, parametric images of the retinal circulation. A given angiogram is first registered to align consecutive frames. At each point in the retina, a graph of fluorescein intensity versus time is then constructed and fitted with a gamma variate curve. Parameters are extracted from these curves and formed into parametric images showing the variation in fluorescein passage across the entire area of the angiogram. Parameters examined to date include time to maximum intensity, time of arrival and rise time. The technique has been demonstrated using photographic and scanning laser ophthalmoscopic angiograms of both normal subjects and patients with a variety of retinopathies. The time to maximum images of the normal subjects reveals a similar fillings pattern in each case, whilst the pathologies present in the abnormal angiograms are clearly identified. The generation of functional time to maximum images enables the health of the retinal circulation to be quantified with respect to the rate at which the vasculature fills with fluorescein. This offers a potential tool for detecting the onset of retinopathy and monitoring its progression.

Imaging of optic nerve head drusen with the scanning laser ophthalmoscope.

BACKGROUND: Optic nerve head drusen may present diagnostic difficulties in cases of disc swelling. Imaging of the nerve in a search for drusen is often inconclusive, especially in children, where drusen may be buried below the surface of the nerve head. METHODS: A small study was carried out using a scanning laser ophthalmoscope (SLO) with an infrared confocal facility to scan deep within optic discs in an attempt to image drusen. RESULTS: The SLO was able to demonstrate superficial and buried drusen (using the infrared confocal facility). The superiority of the SLO over ultrasound in the presence of lens opacity was revealed, as the SLO simultaneously demonstrated both drusen and the associated anomalous disc features which are not detected by ultrasound. CONCLUSION: The SLO can help in the diagnosis of optic disc drusen especially in difficult cases where lens opacity or buried drusen hinders their definitive diagnosis.