Ophthalmology (Eye & Ear Hospital) - Theses
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ItemAssessment of environmental and genetic risk factors for age-related macular degeneration( 2012)This thesis consists of two sections. Section one presents the results of associations found between environmental factors and age-related macular degeneration (AMD) in a prospective cohort study, Section 2 presents genetic associations and interactions found between AMD risk genes and environmental risk factors from a case-control study nested in the cohort. Section One Aim: To investigate associations between environmental factors and age-related macular degeneration (AMD) in the Melbourne Collaborative Cohort Study (MCCS). Material & Methods: Participants included 21 287 men and women, who were aged 40–69 years at baseline (1990–1994 (48 to 86 years at follow up). Participant's body compositions were measured and alcohol and nutrient intakes were estimated from a food frequency questionnaire at baseline in 1990-94. At follow up from 2003-2007, digital macula photographs of both eyes were taken and evaluated for signs of early and late AMD. Section Two Aim: Associations between genotype and AMD were assessed using a nested case-control study (2,287 cases, 2,287 controls individually matched on age, sex and country-of-origin), selected from the Melbourne Collaborative Cohort Study. Statistical interactions between selected environmental and genetic risk factors were evaluated.
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ItemDevelopment of an “item bank” to assess the impact of diabetic retinopathy on quality of life: the RetBank project( 2012)Diabetic retinopathy and diabetic macular oedema are common ocular complications of diabetes that can lead to significant vision impairment and have a devastating impact on quality of life. However, our understanding of the impact of diabetic retinopathy on quality of life is limited by the lack of an appropriate patient reported outcome measure. Most instruments tend to focus primarily on activity limitation rather than the holistic concept of quality of life. Moreover, most outcome measures have undergone minimal validation using classical test theory rather than modern psychometric theory such as Rasch analysis. With the emergence of new treatment modalities for diabetic retinopathy and diabetic macular oedema such as anti-vascular endothelial growth factor intraocular injections, the time is propitious for an instrument that can accurately yet quickly quantify the quality of life impact of diabetic retinopathy. This doctoral work developed an item bank – Retbank – to comprehensively assess the impact of diabetic retinopathy, diabetic macular oedema and associated vision impairment on all relevant quality of life parameters. The domains and items for Retbank were developed following a thorough literature review including a survey of extant functioning and quality of life questionnaires, and qualitative interviews with diabetic retinopathy patients and retinal and diabetes specialists. The large initial item pool was reduced to 314 items across nine quality of life domains, namely visual symptoms; ocular surface symptoms; activity limitation; mobility; emotional; health concerns; social; convenience; and economic via the systematic processes of binning and winnowing based on key criteria and expert panel consensus and cognitive interviewing. The pilot instrument was tested in a large sample of patients (n=466) with diabetic retinopathy and diabetic macular oedema using face to face and telephone interviews. The psychometric properties of the nine domains were explored using Rasch analysis according to key parameters, including rating scales performance, measurement precision, item fit, unidimensionality, differential item functioning and scale targeting. For most domains, precision was excellent and multidimensionality and differential item functioning were negligible. However, targeting and measurement range were frequently suboptimal, and the rating scales of some of the domains demonstrated disordered or bunched thresholds. These trends are most likely due to the large proportion of the pilot sample with no or unilateral vision impairment and/or those with non-vision threatening stages of diabetic retinopathy and diabetic macular oedema. As the performance of these parameters should improve in a more visually impaired sample, a lenient approach to category collapse and other major modifications was applied throughout the analysis. Finally, the impact of diabetic retinopathy, diabetic macular oedema and associated vision impairment on patients’ quality of life was explored using preliminary Retbank data. The findings indicated a strong association between worsening bilateral vision impairment and reduced quality of life outcomes. Vision-threatening diabetic retinopathy (i.e. severe non-proliferative diabetic retinopathy, proliferative diabetic retinopathy and severe diabetic macular oedema) was also associated with poorer quality of life outcomes overall. Retbank demonstrates a promising capacity to provide accurate and precise measurement of the impact of diabetic retinopathy and diabetic macular oedema on a range of important quality of life parameters. Ultimately, Retbank will allow researchers to assess the outcomes of traditional and novel treatment therapies for diabetic retinopathy from the patient’s perspective. It may also benefit policy planners in the design and evaluation of interventions and allocation of funding and resources. Finally, as it can be easily implemented into clinical settings via a computerised system which produces quick results with few items, clinicians will be able to track ongoing patient progress and assess the longitudinal effectiveness of treatments.
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ItemThe “segment knockout” survey method for large trachoma-endemic districts( 2012)Prevalence surveys are mandatory before new trachoma control projects are funded and existing ones continued. When a large administrative district with >200,000 people is surveyed as one trachoma intervention unit, the survey clusters are widely spaced and it is difficult to establish the distribution of the disease at the sub-district level with certainty. As a result, some trachoma-endemic areas in Kenya have been missed out and non-endemic areas included in mass antibiotic treatment. The other challenge is the large sample size required in standard trachomatous trichiasis (TT) surveys that include participants aged ≥15 years. The main objective of this study was to develop an effective and efficient survey method to justify administration of mass antibiotic treatment for active trachoma. The other objective was to establish the optimum lower age limit of TT survey participants, to ensure that the time required to complete a TT survey was the same as the time required to complete a TF survey, while ensuring that the sample was adequately representative of the TT backlog. The costs of surveys and administration of mass antibiotic treatment were determined for comparison of the standard and new survey methods. Data sets for previous surveys were re-analysed to calculate the optimum lower age limit of TT survey participants and correction factors to extrapolate the total backlog of TT. A “Trachoma Survey by Segment” (TSS) method was developed to justify and reduce the cost of mass antibiotic treatment. It was tested in Turkana, a large hyper-endemic district with 543,199 people and Narok, a meso-endemic district with 576,388 people. Each district was divided into five geographical areas (segments). A segment had a population of 100,000–200,000 people. Areas with similar risk of trachoma were aggregated in the same segment. The segments with <10% prevalence of TF in children 1-9 years were excluded (knocked-out) from mass treatment, 10%-30% treated for 3 years and >30% treated for 5 years. An efficient TT40 survey method was also developed where the backlog of TT was estimated in people ≥40 years old and correction factors used to extrapolate the total backlog. A TT40 survey required a smaller survey sample than a standard TT survey. The backlog correction factor for the lower age limit of 40 years was 1.1. In Turkana district 3,962 children aged 1-9 years were examined and the prevalence of TF in the whole district was 38.0% (95%CI: 32.2%-43.9%). If the survey was conducted using the standard survey by administrative district method the whole population would have been treated for 5 years. However, the TSS method revealed that two segments needed treatment for 3 years and three segments for 5 years. After mass treatment the areas will be re-surveyed to justify further treatment. In Narok district 3,998 children aged 1-9 years were examined and the prevalence of TF was 11.0% (95%CI: 8.0%-14.0%). The entire district had received three rounds of mass antibiotic treatment prior to this study. If this study was conducted by administrative district method, the whole population could have been treated for another three years. The TSS method identified three non-endemic segments which were excluded (knocked-out) from further treatment. In Turkana district 2,962 people ≥40 years were examined and 7.8% (95%CI: 6.8%-8.8%) had TT while in Narok 2,996 people ≥40 years were examined and 2.9% (95%CI: 2.2%-3.6%) had TT. All the segments in both districts needed TT surgical services. The cost of a survey by the administrative district method was $15,726 to $28,905, while by the TSS method it was $31,917 to $40,610 ($6,383 to $8,122 per segment). In 2009, the unit cost of administration of mass treatment was $0.20 to $0.42 per person treated. In Turkana district (hyper-endemic setting), the total cost of a survey and administration of mass treatment by the TSS method was $11,705 (1.7%) more expensive that by the administrative district method. In Narok district (meso-endemic setting with clustered trachoma) the survey by TSS method and administration of mass treatment was cheaper by $168,275 (53.2%). It was concluded that the TSS is an effective trachoma survey method to identify the areas that need mass antibiotic treatment. For short term (<3 years) mass treatment in a hyper-endemic district like Turkana, the TSS method has no advantage over the administrative district method. For long term treatment, the TSS method is recommended because some segments may not require treatment for >3 years. The TT40 is an efficient trachoma survey method to determine the backlog of people with TT.
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ItemThe heritability of optic disc shape( 2012)Aim: Morphologic appearance is an important aspect of the structural integrity of the optic disc. While factors influencing the size of the optic disc have been studied, there is relatively little information explaining underlying causes of variation in its shape. Recent work has suggested that the shape may be heritable and this has implications for disorders of the optic nerve head that have a genetic basis. The aim of my thesis was to disentangle and quantify the relative contributions of genetic and environmental factors to the variation in optic disc shape in the population. Methods: Stereoscopic optic disc photographs were obtained from twins (n = 1,858) and their non-twin siblings (n = 194), recruited through the Australian Twins Eye Study. The two-dimensional contours of the optic cup and disc were planimetrically delineated using specialised imaging instrumentation and the outline information converted to coordinate data. A novel method of shape analysis employed in geometric morphometric studies of biological form was then used to normalise optic cup and disc configurations for position, size and orientation, thereby removing all non-shape-related geometric variation. The remaining shape information was subjected to principal components analysis in order to describe the main features of shape variation and quantify the magnitude of each. The heritability of three optic disc shape phenotypes was evaluated: optic disc shape, optic cup shape and a combined shape phenotype (cup and disc outlines analysed simultaneously). The proportion of phenotypic variance attributable to genetic factors in each case was estimated by structural equation modelling applied within a multivariate framework. Genome-wide association studies were also conducted for optic cup and disc shape in an effort to identify prospective genes related to these traits. Results: The principal mode of shape variation for both the optic cup and disc was interpreted as differences in vertical/horizontal ovality of the configuration outline and accounted for 52.1% and 56.7% of the total shape variance, respectively. For the combined shape phenotype, covariation of cup and disc size explained 65% of the total variance and represented the dominant shape characteristic. Of the three shape traits considered, the combined shape phenotype was the most heritable, followed by the optic disc and optic cup shapes (maximum additive heritabilities - 0.87, 0.70 and 0.43, respectively). The best-fitting genetic model in each case was the AE model, with the residual variance in each trait due to unique environmental factors. The dominant heritable shape features reflected those of the phenotypic shape analysis. The genome-wide association study failed to identify any molecular variants either reaching conventional thresholds of significance or with a plausible biological basis for association. Conclusions: Genetic factors influence inter-individual shape variation of the optic nerve head in humans. However, the results of my work indicate that when looking for associated genes, it is better to focus on the shape of optic disc rather than the optic cup, for which environmental factors play a greater role. This is important information in the study of all disorders of the optic disc, especially those underpinned by genetic differences. My thesis is directly relevant for studying glaucoma, a complex disease with a genetic architecture that can be distilled into a simpler form by evaluating individual, underlying traits. Thus, by unravelling the genetic epidemiology of optic disc shape, my work fits into place one piece of that metaphorical jigsaw puzzle.
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ItemRetinal vascular geometry and its relationships to diabetes and diabetic retinopathy( 2012)PURPOSE: Diabetic retinopathy (DR) is a major cause of visual disability worldwide. Retinal vessel diameter, measured from fundus photographs, has been shown to be predictive of DR. However, other parameters reflecting the geometry of the retinal vasculature (e.g. vessel tortuosity, branching angle) in DR are unexplored. This doctoral work presents the associations between traditional DR risk factors and retinal vascular geometry (aim 1), associations of retinal vascular geometry with DR (aim 2), and with novel markers of DR including the relative contribution of these markers and retinal vascular geometry to DR (aim 3). METHODS: This study used two specific clinical samples of children and adolescents (aged 12 to 20 years) with type 1 diabetes (N=1200) and adults (aged 18 to 70 years) with type 1 and 2 diabetes (N=244). Retinal vascular geometric parameters (tortuosity, branching angle, length to diameter ratio, optimality deviation) were measured from disc-centred fundus photographs using semi-automated computer software following standardized protocol. DR was also assessed from fundus photographs (7-field for the children sample and 2-field for the adult sample), according to modified Airlie House Classification, and categorized into mild, moderate, and vision-threatening DR (VTDR, including severe non-proliferative and proliferative DR, with or without clinically significant macular oedema). Detailed clinical characteristics (e.g. duration of diabetes, blood pressure, body mass index [BMI], the use of insulin and other medications, history of cardiovascular or other diseases) were obtained via interview with a specific questionnaire and clinical examinations. Traditional and novel biomarkers were assessed from fasting blood sample, including concurrent HbA1c level, fasting blood glucose, cholesterol and other lipid profiles, serum creatinine, apolipoprotein (Apo) AI and B, high sensitivity C-reactive proteins [CRP], soluble e-selectin, inter-cellular adhesion molecule-1 [ICAM-1], vascular adhesion molecule-1 [VCAM-1], total nitrite, and endothelin-1 [ET-1] levels. Measures of dynamic retinal and skin microvascular function were also obtained using dynamic retinal vessel analyser and skin iontophoresis. Associations of traditional and novel risk factors with retinal vascular geometry were assessed using analysis of covariance and generalized linear models. Associations of retinal vascular geometry with DR and DR severity were assessed using binary, ordinal, and multinomial logistic regression models. RESULTS: Aim 1: Associations between traditional DR risk factors and retinal vascular geometry Longer diabetes duration was associated with larger arteriolar branching angle and increased arteriolar optimality deviation; higher HbA1c was associated with increased arteriolar tortuosity; higher SBP was associated with decreased arteriolar LDR; and higher total cholesterol levels was associated with increased arteriolar LDR and decreased venular optimality deviation in the children sample. In the adult sample, longer diabetes duration was associated with increased arteriolar tortuosity. Aim 2: Associations of retinal vascular geometry with DR DR was present in 170 (18%) of the children, and in 114 (44%) of the adults. Retinal arteriolar tortuosity showed significant associations with DR, in both children (odds ratio [OR] 1.42, 95% confidence interval [CI] 1.11 – 1.83; P=0.005; per standard deviation [SD] increase in arteriolar tortuosity) and adults (OR for mild DR 1.53, 1.03 – 2.05; P=0.014; OR for moderate DR 1.67, 1.10 – 2.55; P=0.016; per SD increase). Aim 3: Associations of novel markers for DR with retinal vascular geometry and the relative contribution of retinal vascular geometry to DR Among the adults, ApoAI level was inversely associated with DR (OR 0.76, 95% CI 0.59–0.98; per SD increase), while ApoB and ApoB/AI (OR 1.31, 1.02–1.68 and OR 1.48, 1.13–1.95; per SD increase in ApoB and ApoB/AI respectively) were positively associated with DR. Increasing CRP levels were positively associated only with the presence of VTDR (OR 1.38, 1.07–1.68, per SD increase), which was more pronounced in subjects with BMI≥30 kg/m2 (OR 2.9; P=0.019 for interaction). Per SD increase in ApoAI level was inversely (mean difference in arteriolar tortuosity -2.83 x 10-5 ; P=0.044), while ApoB was positively (mean difference 1.75 x 10-5; P=0.050) associated with arteriolar tortuosity. Reduced flicker-light induced retinal vasodilation was related to more tortuous arterioles and venules (mean difference in arteriolar tortuosity 5.62 x 10-5, 4.50 – 6.72 x 10-5; P<0.001 and in venules 5.94 x 10-5, 3.33 – 8.55 x 10-5; P<0.001; comparing highest vs. lowest tertile of flicker-light vasodilation). Finally, diabetes duration contributed the most (51%) to the risk of DR, followed by ApoAI (16%), SBP (13%), retinal arteriolar tortuosity (8%), and flicker-light induced venular and arteriolar dilation (3% and 0.5% respectively). CONCLUSIONS: Key diabetes-related factors (e.g. duration of diabetes, HbA1c level) are associated with retinal microvascular geometry, mainly arteriolar tortuosity. In line with this, increased arteriolar tortuosity is also consistently associated with early stages of DR in both study samples. Furthermore, we demonstrate relationships between retinal arteriolar tortuosity and a number of novel risk markers for DR found in this study (serum ApoAI and ApoB) and also to novel markers for DR found in other studies (flicker-light induced retinal vascular function). Retinal arteriolar tortuosity and ApoAI is shown to have considerable contribution to DR risk and substantially improved the clinical performance of DR prediction model in terms of the specificity, independent of traditional risk markers. These findings provide novel evidence that variations in retinal vascular tortuosity may be markers of diabetes-related vascular damage due to adverse exposure of diabetic milieu, reflecting increased person’s susceptibility to DR.
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ItemMitochondrial dysfunction in the retina contributes to vision loss( 2012)Mitochondrial impairment in ocular disease pathogenesis has been well recognised since the first disease-linked mitochondrial DNA mutation was described for Leber’s Hereditary Optic Neuropathy in 1988. Our increased understanding of mitochondrial function and dynamics since then has suggested that mitochondrial dysfunction may be a key underlying factor contributing to retinal ganglion cell loss in a range of optic neuropathies. Mitochondrial dysfunction is traditionally attributed to heritable nuclear and mitochondrial DNA mutations but may be exacerbated by aging, oxidative stress and environmental factors. Mitochondrial impairment limits endogenous energy production and sensitises cells to stress and injury. Understanding how impairment of this key organelle can lead to loss of specific neuronal populations provides possibilities for neuroprotective intervention to prevent retinal ganglion cell degeneration. To address mechanisms of disease pathogenesis associated with vision loss we performed a detailed analysis of mitochondrial function using human cell lines from Autosomal Dominant Optic Atrophy family pedigrees bearing an identical mutation of the OPA1 gene. These patients may suffer specific loss of retinal ganglion cells, but the disease phenotype varies dramatically within family pedigrees. We compared patients with severe vision loss and patients with relatively preserved vision and found a clear defect in mitochondrial energy production and respiration in patients with poor vision. In Autosomal Dominant Optic Atrophy patients with normal vision numerous components of oxidative phosphorylation were increased. These data suggest that OPA1 deficiency impairs oxidative phosphorylation efficiency, but compensation through increases in the distal complexes of the respiratory chain may preserve mitochondrial energy production in patients who maintain normal vision. Evaluation of in vivo retinal mitochondrial function provides insight into early events occurring in optic nerve degeneration during aging and with mitochondrial impairment. We demonstrated that mitochondrial capacity decreased in the aging rodent retina, and was further decreased in the presence of a heritable mitochondrial dysfunction (xenomitochondrial mouse). These mitochondrial impairments (heritable and with aging) sensitised retinal ganglion cells to intraocular pressure elevation. Novel findings from dietary restriction demonstrated that improved mitochondrial function provided a resistance of the retinal ganglion cells to stress. Therapies that promote enhanced mitochondrial function may protect neurons against injury the detrimental effects of aging.