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Developing retinal biomarkers of neurological disease: an analytical perspective

Ian JC MacCormick, Gabriela Czanner, Brian Faragher
2015 Biomarkers in Medicine  
MacCormick et al. Page 17 Biomark Med. Author manuscript; available in PMC 2016 April 06. MacCormick et al. Page 18 MacCormick et al. Page 19 table.  ... 
doi:10.2217/bmm.15.17 pmid:26174843 pmcid:PMC4822679 fatcat:6jcywmid7replceer5fcbosbtu

Malarial retinopathy affecting visual function in a Malawian adult with cerebral malaria

Katherine Piddock, Nicholas Beare, Ian MacCormick
2014 IDCases  
Conflicts of interest Drs MacCormick and Piddock report grants from The Wellcome Trust, during the conduct of the study. Dr.  ... 
doi:10.1016/j.idcr.2014.10.003 pmid:26839781 pmcid:PMC4735036 fatcat:zfhqeobr7razboxzbhuuxn36pm

Spatial statistical modelling of capillary non-perfusion in the retina

Ian J. C. MacCormick, Yalin Zheng, Silvester Czanner, Yitian Zhao, Peter J. Diggle, Simon P. Harding, Gabriela Czanner
2017 Scientific Reports  
Manual grading of lesions in retinal images is relevant to clinical management and clinical trials, but it is time-consuming and expensive. Furthermore, it collects only limited information -such as lesion size or frequency. The spatial distribution of lesions is ignored, even though it may contribute to the overall clinical assessment of disease severity, and correspond to microvascular and physiological topography. Capillary non-perfusion (CNP) lesions are central to the pathogenesis of major
more » ... causes of vision loss. Here we propose a novel method to analyse CNP using spatial statistical modelling. This quantifies the percentage of CNP-pixels in each of 48 sectors and then characterises the spatial distribution with goniometric functions. We applied our spatial approach to a set of images from patients with malarial retinopathy, and found it compares favourably with the raw percentage of CNP-pixels and also with manual grading. Furthermore, we were able to quantify a biological characteristic of macular CNP in malaria that had previously only been described subjectively: clustering at the temporal raphe. Microvascular location is likely to be biologically relevant to many diseases, and so our spatial approach may be applicable to a diverse range of pathological features in the retina and other organs. The retinal microcirculation is exquisitely accessible to clinical observation, and unlike other organs, the retinal vasculature is arranged perpendicular to an optical axis. Consequently alterations to small vessel flow can be easily mapped using techniques such as fluorescein angiography (FA) and optical coherence tomography angiography (OCT-A). Capillary non-perfusion (CNP) appears as distinctive dark areas with geographic boundaries, and develops when blood fails to reach areas of the capillary bed (Fig. 1a-c) . It is a feature of several major causes of blindness including diabetic maculopathy, retinal vein occlusion, and retinal artery occlusion 1 . CNP also occurs in malarial retinopathy, and can be graded manually according to a validated scheme 2 . Malarial retinopathy is seen in children and adults with cerebral malaria, which has a high mortality rate. The retina and brain sustain similar damage in cerebral malaria, and several retinal signs are associated with death (reviewed in 3 ). As with grading schemes for retinal vein occlusion 4,5 the malarial retinopathy grading scheme assesses the overall area of CNP in various large retinal regions. Manual grading is necessarily semi-quantitative, time consuming and costly. These and other constraints mean that manual grading is impractical for large image datasets, and at best captures only a tiny fraction of the biological information contained in a retinal image. Beyond lesion type, frequency, and area, spatial characteristics may be a particularly relevant aspect of a retinal image. This is because the retinal microvasculature is not homogenous but rather composed of regions with different vascular topology, geometry, and corresponding haemorheology and physiology. For example, the foveal avascular zone is a unique region where the retina is supplied solely from the underlying choriocapillaris. The perifoveal region has one capillary layer, which forms an oxygen diffusion watershed with the choriocapillaris. The temporal macula and horizontal raphe contain a further watershed between superior and inferior temporal arcades 3 . Therefore, the biological meaning of CNP in one sub-region of the macula may be different from that of a lesion of similar size in an adjacent region. Current grading techniques are too coarse to allow such distinctions.
doi:10.1038/s41598-017-16620-x pmid:29196702 pmcid:PMC5711887 fatcat:hfvvgjx5hvfhfescn5xiwmk4li

What Happens to Intraocular Pressure at High Altitude?

John E. A. Somner, Daniel S. Morris, Kirsten M. Scott, Ian J. C. MacCormick, Peter Aspinall, Baljean Dhillon
2007 Investigative Ophthalmology and Visual Science  
MacCormick, None; P. Aspinall, None; B. Dhillon, None FIGURE 1 . 1 Ascent profile of volunteers. FIGURE 2 . 2 The changes in recorded IOP Ϯ SEM. author: John E. A.  ... 
doi:10.1167/iovs.06-1238 pmid:17389492 fatcat:ccustg6eafhoxhqvl2nlpvlu7e

Grading fluorescein angiograms in malarial retinopathy

Ian J. C. MacCormick, Richard J. Maude, Nicholas A. V. Beare, Shyamanga Borooah, Simon Glover, David Parry, Sophie Leach, Malcolm E. Molyneux, Baljean Dhillon, Susan Lewallen, Simon P. Harding
2015 Malaria Journal  
Malarial retinopathy is an important finding in Plasmodium falciparum cerebral malaria, since it strengthens diagnostic accuracy, predicts clinical outcome and appears to parallel cerebral disease processes. Several angiographic features of malarial retinopathy have been described, but observations in different populations can only be reliably compared if consistent methodology is used to capture and grade retinal images. Currently no grading scheme exists for fluorescein angiographic features
more » ... f malarial retinopathy. Methods: A grading scheme for fluorescein angiographic images was devised based on consensus opinion of clinicians and researchers experienced in malarial retinopathy in children and adults. Dual grading were performed with adjudication of admission fluorescein images from a large cohort of children with cerebral malaria. Results: A grading scheme is described and standard images are provided to facilitate future grading studies. Intergrader agreement was >70 % for most variables. Intravascular filling defects are difficult to grade and tended to have lower inter-grader agreement (>57 %) compared to other features. Conclusions: This grading scheme provides a consistent way to describe retinal vascular damage in paediatric cerebral malaria, and can facilitate comparisons of angiographic features of malarial retinopathy between different patient groups, and analysis against clinical outcomes. Inter-grader agreement is reasonable for the majority of angiographic signs. Dual grading with expert adjudication should be used to maximize accuracy.
doi:10.1186/s12936-015-0897-7 pmid:26403288 pmcid:PMC4583163 fatcat:6hsfz4q65jdstniz76jh2nzlbq

Automated Detection of Vessel Abnormalities on Fluorescein Angiogram in Malarial Retinopathy

Yitian Zhao, Ian J. C. MacCormick, David G. Parry, Nicholas A. V. Beare, Simon P. Harding, Yalin Zheng
2015 Scientific Reports  
The detection and assessment of intravascular filling defects is important, because they may represent a process central to cerebral malaria pathogenesis: neurovascular sequestration. We have developed and validated a framework that can automatically detect intravascular filling defects in fluorescein angiogram images. It first employs a state-of-the-art segmentation approach to extract the vessels from images and then divide them into individual segments by geometrical analysis. A feature
more » ... r based on the intensity and shape of saliency maps is generated to represent the level of abnormality of each vessel segment. An AdaBoost classifier with weighted cost coefficient is trained to classify the vessel segments into normal and abnormal categories. To demonstrate its effectiveness, we apply this framework to 6,358 vessel segments in images from 10 patients with malarial retinopathy. The test sensitivity, specificity, accuracy, and area under curve (AUC) are 74.7%, 73.5%, 74.1% and 74.2% respectively when compared to the reference standard of human expert manual annotations. This performance is comparable to the agreement that we find between human observers of intravascular filling defects. Our method will be a powerful new tool for studying malarial retinopathy. Cerebral malaria (CM) is a major cause of death and disability, especially in children in sub-Saharan Africa. CM is characterised by sequestration of parasitised erythrocytes in cerebral vessels 1 , but despite much research the mechanisms by which the intravascular malaria parasite causes coma and death remain unclear 2,3 . Malarial retinopathy (MR) has been identified as an important clinical sign in the diagnosis and prognosis of cerebral malaria 4 . The retina and brain are affected in similar ways in CM, and so the photographic features of MR are likely to give further valuable information about CM disease process, diagnosis, treatment and prognosis 2 . Intravascular filling defects (IVFD) are a feature of MR that can be observed in fluorescein angiogram (FA) images. IVFD may represent sequestration of parasitised erythrocytes in the microvasculature 5 . Sequestration is the pathological hallmark of cerebral malaria 6,7 , but as yet, it has only been possible to quantify it histopathologically at post mortem. IVFD can be seen in large and small venules, arterioles and capillaries, but appear to be most prominent in venules. As shown in Fig. 1 , the appearance ranges from mottling and slight irregularities of the vessel wall, to more obvious lesions that look as if small bites have been taken from the vessel 4,8 . Cerebral and retinal sequestration is always seen in fatal cases of CM with MR 2,9 , and the histopathological appearance of sequestration is similar to IVFD 2,10 . Moreover, IVFD often resolve the day after treatment with anti-malarial drugs is started (personal observation). This is consistent with resolution of sequestration and clinical recovery. It is plausible that IVFD represent this fundamental pathological process, and this lesion merits further investigation.
doi:10.1038/srep11154 pmid:26053690 pmcid:PMC4459173 fatcat:6s5xwd4gzjgp5i3mmmd5ahk6d4

Evidence from a natural experiment that malaria parasitemia is pathogenic in retinopathy-negative cerebral malaria

Dylan S Small, Terrie E Taylor, Douglas G Postels, Nicholas AV Beare, Jing Cheng, Ian JC MacCormick, Karl B Seydel
2017 eLife  
Cerebral malaria (CM) can be classified as retinopathy-positive or retinopathy-negative, based on the presence or absence of characteristic retinal features. While malaria parasites are considered central to the pathogenesis of retinopathy-positive CM, their contribution to retinopathy-negative CM is largely unknown. One theory is that malaria parasites are innocent bystanders in retinopathy-negative CM and the etiology of the coma is entirely non-malarial. Because hospitals in malaria-endemic
more » ... reas often lack diagnostic facilities to identify non-malarial causes of coma, it has not been possible to evaluate the contribution of malaria infection to retinopathy-negative CM. To overcome this barrier, we studied a natural experiment involving genetically inherited traits, and find evidence that malaria parasitemia does contribute to the pathogenesis of retinopathy-negative CM. A lower bound for the fraction of retinopathy-negative CM that would be prevented if malaria parasitemia were to be eliminated is estimated to be 0.93 (95% confidence interval: 0.68, 1).
doi:10.7554/elife.23699 pmid:28590246 pmcid:PMC5462542 fatcat:zpuhedmtcrgfjpdar3ijndqjg4

Automated Detection of Leakage in Fluorescein Angiography Images with Application to Malarial Retinopathy

Yitian Zhao, Ian J. C. MacCormick, David G. Parry, Sophie Leach, Nicholas A. V. Beare, Simon P. Harding, Yalin Zheng
2015 Scientific Reports  
The detection and assessment of leakage in retinal fluorescein angiogram images is important for the management of a wide range of retinal diseases. We have developed a framework that can automatically detect three types of leakage (large focal, punctate focal, and vessel segment leakage) and validated it on images from patients with malarial retinopathy. This framework comprises three steps: vessel segmentation, saliency feature generation and leakage detection. We tested the effectiveness of
more » ... his framework by applying it to images from 20 patients with large focal leak, 10 patients with punctate focal leak, and 5,846 vessel segments from 10 patients with vessel leakage. The sensitivity in detecting large focal, punctate focal and vessel segment leakage are 95%, 82% and 81%, respectively, when compared to manual annotation by expert human observers. Our framework has the potential to become a powerful new tool for studying malarial retinopathy, and other conditions involving retinal leakage.
doi:10.1038/srep10425 pmid:26030010 pmcid:PMC4450752 fatcat:tnnpfu2ubjdcrottzqj2dy237y

Longitudinal Visuomotor Development in a Malaria Endemic Area: Cerebral Malaria and Beyond

Paul C. Knox, Ian J. C. MacCormick, Emme Mbale, Macpherson Malewa, Gabriela Czanner, Simon P. Harding, David J. Sullivan
2016 PLoS ONE  
Paediatric cerebral malaria is the most serious complication of Plasmodium falciparum infection. While the majority recover, long-term cognitive impairment has been highlighted as a significant and neglected problem. Persistent or serious deficits in processes such as attention or behavioural inhibition should be manifest in changes to performance on oculomotor tasks. Therefore we investigated the impact of cerebral malaria on the development of reflexive pro-saccades and antisaccades. In a
more » ... itudinal study, 47 children previously admitted with retinopathy-confirmed cerebral malaria (mean age at admission 54 months), were compared with 37 local healthy controls (mean ages at first study visit 117 and 110 months respectively). In each of three or four test sessions, over a period of up to 32 months, participants completed 100 prosaccade tasks and 100 antisaccade tasks. Eye movements were recorded using infrared reflectance oculography; prosaccade, correct antisaccade and error prosaccade latency, and antisaccade directional error rate were calculated. Hierarchical linear modelling was used to investigate the effect of age and the influence of cerebral malaria on these parameters. Data were also collected from an independent, older group (mean age 183 months) of 37 local healthy participants in a separate cross-sectional study. Longitudinal data exhibited the expected decrease in latency with age for all saccade types, and a decrease in the antisaccade directional error rate. Hierarchical linear modelling confirmed that age had a statistically significant effect on all parameters (p< = 0.001). However, there were no statistically significant differences between the cerebral malaria and control groups. Combining groups, comparison with the literature demonstrated that antisaccade directional error rate for the Malawi sample was significantly higher than expected, while latencies for all saccade types were indistinguishable from published. The high directional error rate was also confirmed in the older, healthy Malawian participants from the cross sectional study. Our observation of similar oculomotor performance in cerebral malaria and control groups at long follow-up periods suggests that cerebral malaria survivors are not at a generally increased risk of persistent cognitive deficits. Our data raise questions about the prevailing hypothesis that cerebral malaria has gross impacts on the development of processes such as attention and behavioural inhibition. More importantly, our novel finding of a clear difference in antisaccade performance between all of the Malawi participants and published data suggests that the Malawian paediatric population as a whole faces serious challenges to cognitive development beyond cerebral malaria. Materials and Methods Ethics Statement All experiments were performed in accordance with the ethical standards laid down in the Declaration of Helsinki and were approved by the
doi:10.1371/journal.pone.0164885 pmid:27764173 pmcid:PMC5072745 fatcat:ax3qs3cb4jhkzkjddb2t24oteq

Reply: Retinopathy, histidine-rich protein-2 and perfusion pressure in cerebral malaria

Ian J. C. MacCormick, Nicholas A. V. Beare, Terrie E. Taylor, Valentina Barrera, Valerie A. White, Paul Hiscott, Malcolm E. Molyneux, Baljean Dhillon, Simon P. Harding
2014 Brain  
context suggests inference of several distinct pathological processes from the retina to the brain is plausible, including sequestration, haemorrhage, blood-tissue barrier breakdown, and ischaemia (MacCormick  ... 
doi:10.1093/brain/awu146 pmid:24919966 pmcid:PMC4132643 fatcat:2tdhpetz5ncvrcqwprpz5aopru

Cerebrospinal fluid Plasmodium falciparum histidine-rich protein-2 in pediatric cerebral malaria

Kiran T. Thakur, Jimmy Vareta, Kathryn A. Carson, Samuel Kampondeni, Michael J. Potchen, Gretchen L. Birbeck, Ian MacCormick, Terrie Taylor, David J. Sullivan, Karl B. Seydel
2018 Malaria Journal  
Cerebral malaria (CM) causes a rapidly developing coma, and remains a major contributor to morbidity and mortality in malaria-endemic regions. This study sought to determine the relationship between cerebrospinal fluid (CSF) Plasmodium falciparum histidine rich protein-2 (PfHRP-2) and clinical, laboratory and radiographic features in a cohort of children with retinopathy-positive CM. Methods: Patients included in the study were admitted (2009)(2010)(2011)(2012)(2013) to the Pediatric Research
more » ... rd (Queen Elizabeth Central Hospital, Blantyre, Malawi) meeting World Health Organization criteria for CM with findings of malarial retinopathy. Enzyme-linked immunosorbent assay was used to determine plasma and CSF PfHRP-2 levels. Wilcoxon rank-sum tests and multivariable logistic regression analysis assessed the association of clinical and radiographic characteristics with the primary outcome of death during hospitalization. Results: In this cohort of 94 patients, median age was 44 (interquartile range 29-62) months, 53 (56.4%) patients were male, 6 (7%) were HIV-infected, and 10 (11%) died during hospitalization. Elevated concentrations of plasma lactate (p = 0.005) and CSF PfHRP-2 (p = 0.04) were significantly associated with death. On multivariable analysis, higher PfHRP-2 in the CSF was associated with death (odds ratio 9.00, 95% confidence interval 1.44-56.42) while plasma PfHRP-2 was not (odds ratio 2.05, 95% confidence interval 0.45-9.35). Conclusions: Elevation of CSF, but not plasma PfHRP-2, is associated with death in this paediatric CM cohort. PfHRP-2 egress into the CSF may represent alteration of blood brain barrier permeability related to the sequestration of parasitized erythrocytes in the cerebral microvasculature.
doi:10.1186/s12936-018-2272-y pmid:29566695 pmcid:PMC5865338 fatcat:rx73n7h5trcjpdntj4xftf2sku

A Comprehensive Texture Segmentation Framework for Segmentation of Capillary Non-Perfusion Regions in Fundus Fluorescein Angiograms

Yalin Zheng, Man Ting Kwong, Ian J. C. MacCormick, Nicholas A. V. Beare, Simon P. Harding, Friedemann Paul
2014 PLoS ONE  
Capillary non-perfusion (CNP) in the retina is a characteristic feature used in the management of a wide range of retinal diseases. There is no well-established computation tool for assessing the extent of CNP. We propose a novel texture segmentation framework to address this problem. This framework comprises three major steps: pre-processing, unsupervised total variation texture segmentation, and supervised segmentation. It employs a state-of-the-art multiphase total variation texture
more » ... ion model which is enhanced by new kernel based region terms. The model can be applied to texture and intensity-based multiphase problems. A supervised segmentation step allows the framework to take expert knowledge into account, an AdaBoost classifier with weighted cost coefficient is chosen to tackle imbalanced data classification problems. To demonstrate its effectiveness, we applied this framework to 48 images from malarial retinopathy and 10 images from ischemic diabetic maculopathy. The performance of segmentation is satisfactory when compared to a reference standard of manual delineations: accuracy, sensitivity and specificity are 89.0%, 73.0%, and 90.8% respectively for the malarial retinopathy dataset and 80.8%, 70.6%, and 82.1% respectively for the diabetic maculopathy dataset. In terms of region-wise analysis, this method achieved an accuracy of 76.3% (45 out of 59 regions) for the malarial retinopathy dataset and 73.9% (17 out of 26 regions) for the diabetic maculopathy dataset. This comprehensive segmentation framework can quantify capillary non-perfusion in retinopathy from two distinct etiologies, and has the potential to be adopted for wider applications.
doi:10.1371/journal.pone.0093624 pmid:24747681 pmcid:PMC3991579 fatcat:t4hp2hmp6vd7nfvkazlgmtn2eu

Cerebral malaria in children: using the retina to study the brain

Ian J. C. MacCormick, Nicholas A. V. Beare, Terrie E. Taylor, Valentina Barrera, Valerie A. White, Paul Hiscott, Malcolm E. Molyneux, Baljean Dhillon, Simon P. Harding
2014 Brain  
MacCormick et al. by guest on October 6, 2016 Downloaded from Sequestration Sequestration is the histopathological hallmark of paediatric cerebral malaria .  ...  MacCormick et al. by guest on October 6, 2016 Downloaded from by guest on October 6, 2016 Downloaded from  ... 
doi:10.1093/brain/awu001 pmid:24578549 pmcid:PMC4107732 fatcat:h4yoypgaj5dbphdjng7tx2hqla

Automated Detection of Malarial Retinopathy in Digital Fundus Images for Improved Diagnosis in Malawian Children with Clinically Defined Cerebral Malaria

Vinayak Joshi, Carla Agurto, Simon Barriga, Sheila Nemeth, Peter Soliz, Ian J. MacCormick, Susan Lewallen, Terrie E. Taylor, Simon P. Harding
2017 Scientific Reports  
Cerebral malaria (CM), a complication of malaria infection, is the cause of the majority of malariaassociated deaths in African children. The standard clinical case definition for CM misclassifies ~25% of patients, but when malarial retinopathy (MR) is added to the clinical case definition, the specificity improves from 61% to 95%. Ocular fundoscopy requires expensive equipment and technical expertise not often available in malaria endemic settings, so we developed an automated software system
more » ... o analyze retinal color images for MR lesions: retinal whitening, vessel discoloration, and white-centered hemorrhages. The individual lesion detection algorithms were combined using a partial least square classifier to determine the presence or absence of MR. We used a retrospective retinal image dataset of 86 pediatric patients with clinically defined CM (70 with MR and 16 without) to evaluate the algorithm performance. Our goal was to reduce the false positive rate of CM diagnosis, and so the algorithms were tuned at high specificity. This yielded sensitivity/specificity of 95%/100% for the detection of MR overall, and 65%/94% for retinal whitening, 62%/100% for vessel discoloration, and 73%/96% for hemorrhages. This automated system for detecting MR using retinal color images has the potential to improve the accuracy of CM diagnosis. Cerebral malaria (CM) is an often-fatal clinical complication associated with Plasmodium falciparum (Pf) malaria infection. The 2015 World Malaria Report estimates that malaria affected over 214 million people, and claimed the lives of 438,000 people worldwide, about 67% of whom were African children under 5 years of age; the majority of these pediatric deaths was attributed to CM 1 . Annually, CM results in the loss of 35.4 million disability adjusted life years due to mortality and morbidity of clinically diagnosed CM patients in Africa 1,2 . The standard WHO clinical case definition of CM (physical symptoms such as seizures, convulsions; Blantyre coma score <2, detection of Pf parasites in the peripheral blood, and exclusion of other causes of coma (e.g. meningitis, hypoglycemia) refs 3,4); may misclassify up to 25% of cases 5 . Because asymptomatic Pf infection is common parasitemia in malaria-endemic areas, CM is often over-diagnosed. The WHO clinical case definition overlooks other non-malarial illnesses with similar clinical symptoms "masquerading" as CM. The result is a significant false positive rate (FPR) for CM which leads to inaccurate epidemiological estimates of disease incidence, incorrect classifications in research and clinical settings, and potentially inadequate treatment of the underlying illness 6-8 . If non-malarial illnesses with incidental parasitaemia go undiagnosed and thus improperly treated, potentially avoidable death or neurologic disabilities may result. In summary, though the WHO criteria are highly sensitive
doi:10.1038/srep42703 pmid:28198460 pmcid:PMC5309896 fatcat:gsok7g3z7vhgvfajmzihz34a2u

Ophthalmic features of HIV associated cryptococcal meningitis in Malawian Adults: an observational study

Jayne P. Ellis, Kate Gaskell, Mary Peirse, Jack Gormley, Newton Kalata, Philip I. Burgess, Patty Mopamboli, Chatonda A. Manda, Christine A. Kiire, Ian Maccormick, Ebbie Gondwe, Sile Molloy (+3 others)
2019 Wellcome Open Research  
Data Curation, Investigation, Writing - Burgess PI Mopamboli P Review & Editing; : Data Curation, Investigation; : Data Curation, Investigation, Writing -Review & Editing; : Manda CA Kiire CA Maccormick  ... 
doi:10.12688/wellcomeopenres.15067.1 fatcat:7yusussrfndybpnrlmugfk4fgy
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