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Optic nerve head parameters and their relevance in glaucoma
diagnosis
Author:
Jonnadula, Ganesh Babu
Publication Date:
2019
DOI:
https://doi.org/10.26190/unsworks/21467
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OPTIC NERVE HEAD PARAMETERS AND THEIR RELEVANCE IN
GLAUCOMA DIAGNOSIS
Jonnadula Ganesh Babu
A thesis in fulfilment of the requirements for the degree of
Doctor of Philosophy
School of Optometry and Vision Science, Sydney, Australia
Brien Holden Vision Institute, Sydney, Australia
The University of New South Wales
March 2019
Thesis/Dissertation Sheet
Thesis/Dissertation Sheet
OPTIC NERVE HEAD PARAMETERS AND THEIR RELEVANCE IN GLAUCOMA DIAGNOSIS ii

Originality statement
Originality statement
OPTIC NERVE HEAD PARAMETERS AND THEIR RELEVANCE IN GLAUCOMA DIAGNOSIS iii
Inclusion of Publications Statement
Inclusion of Publications Statement
OPTIC NERVE HEAD PARAMETERS AND THEIR RELEVANCE IN GLAUCOMA DIAGNOSIS iv

Copyright and Authenticity statement
Copyright and Authenticity statement
OPTIC NERVE HEAD PARAMETERS AND THEIR RELEVANCE IN GLAUCOMA DIAGNOSIS v

TABLE OF CONTENTS
TABLE OF CONTENTS
Thesis/Dissertation Sheet .............................................................................................................. ii
Originality statement .................................................................................................................... iii
Inclusion of Publications Statement ............................................................................................. iv
Copyright and Authenticity statement .......................................................................................... v
TABLE OF CONTENTS..................................................................................................................... vi
LIST OF FIGURES ............................................................................................................................ ix
LIST OF TABLES .............................................................................................................................. xi
LIST OF SYMBOLS AND ABBREVIATIONS ..................................................................................... xiii
ACKNOWLEDGEMENTS ............................................................................................................... xiv
ABSTRACT xvi
1 INTRODUCTION................................................................................................................... 1
1.1 Glaucoma.................................................................................................................. 1
1.2 Prevalence ................................................................................................................ 3
1.3 Risk factors for glaucoma ......................................................................................... 6
Demographic risk factors ............................................................................... 6
Systemic diseases associated with glaucoma ................................................ 9
Ocular risk factors associated with glaucoma .............................................. 10
Family history and genetics as a risk factor for glaucoma ........................... 12
1.4 Identifying glaucoma in the clinical setting ............................................................ 13
Tonometry.................................................................................................... 13
Visual field .................................................................................................... 14
Optic nerve head evaluation ........................................................................ 15
Modern tools to aid in glaucoma diagnosis ................................................. 18
1.5 Detection of glaucoma: Role of optic disc size ....................................................... 18
1.6 Techniques to measure optic disc size ................................................................... 20
Histo-morphometry ..................................................................................... 21
Slit-lamp biomicroscopy ............................................................................... 21
Digital planimetry ......................................................................................... 22
OPTIC NERVE HEAD PARAMETERS AND THEIR RELEVANCE IN GLAUCOMA DIAGNOSIS vi
TABLE OF CONTENTS
Template of circles ....................................................................................... 27

Imaging ......................................................................................................... 27
1.7 Detection of glaucoma: Role of RNFL optical coherence tomography .................. 29
Factors affect RNFL analysis ......................................................................... 29
Diagnostic ability .......................................................................................... 34
1.8 Determination of retinal image size ....................................................................... 38
1.9 Rationale for research ............................................................................................ 40
1.10 Thesis aims ............................................................................................................. 43
1.11 Thesis hypotheses .................................................................................................. 44
Hypothesis I .................................................................................................. 44
Hypothesis II ................................................................................................. 44
1.12 Thesis overview ...................................................................................................... 44
2 MATERIALS AND METHODS .............................................................................................. 45
2.1 Introduction ............................................................................................................ 45

2.2 Data collection ........................................................................................................ 45
2.3 Glaucoma Epidemiology and Molecular Genetics Study ....................................... 46
Sample size ................................................................................................... 46
Ethics ............................................................................................................ 47
Project staff .................................................................................................. 48
Examination procedures .............................................................................. 48
Stereo optic disc photography and grading ................................................. 51
Spectral-domain optical coherence tomography ........................................ 51
2.4 Overall characteristics of the study sample ........................................................... 52
2.5 Determining the size of retinal features ................................................................ 53
The Zeiss fundus camera .............................................................................. 54
The Topcon fundus camera.......................................................................... 56
Determining the size of a retinal feature by fundus photography .............. 57
The reliability of the formula compared to other methods for calculating the
true size of a retinal feature......................................................................... 60
Determining the magnification of fundus photographs taken with the
fundus camera ............................................................................................. 61
2.6 Summary................................................................................................................. 63
3 OPTIC NERVE HEAD PARAMETERS- NORMATIVE VALUES AND DETECTION OF
GLAUCOMA....................................................................................................................... 64
OPTIC NERVE HEAD PARAMETERS AND THEIR RELEVANCE IN GLAUCOMA DIAGNOSIS vii
TABLE OF CONTENTS
3.1 Background ............................................................................................................. 64

3.2 Aims ........................................................................................................................ 65
3.3 Methods ................................................................................................................. 66
Participants .................................................................................................. 66
Definitions .................................................................................................... 69
Procedures ................................................................................................... 69
3.4 Statistical analysis ................................................................................................... 72
Reproducibility of measurements ................................................................ 74
3.5 Results .................................................................................................................... 76
3.6 Diagnostic ability of the predictive normative database ....................................... 88
3.7 Discussion ............................................................................................................... 96
Optic nerve head parameters ...................................................................... 96
Diagnostic accuracy of ONH parameters in diagnosing glaucomatous eyes
101
Limitations.................................................................................................. 104
4 OPTICAL COHERENCE TOMOGRAPHY RETINAL NERVE FIBRE LAYER PARAMETERS ...... 107
4.1 Background ........................................................................................................... 107

4.2 Aims ...................................................................................................................... 109
4.3 Methods ............................................................................................................... 110
Participants ................................................................................................ 110
4.4 Statistical analysis ................................................................................................. 112
4.5 Results .................................................................................................................. 113
4.6 Discussion ............................................................................................................. 124
RNFL thickness at 3.4mm circumpapillary scan circle and influence of disc
area on RNFL thickness .............................................................................. 125
Limitations.................................................................................................. 128
5 DISCUSSION AND CONCLUSION ..................................................................................... 131
5.1 Introduction .......................................................................................................... 131

5.2 Population based study and key findings ............................................................. 132
6 REFERENCES .................................................................................................................... 137
7 APPENDIX ........................................................................................................................ 167
Appendix – A ................................................................................................................... 168
OPTIC NERVE HEAD PARAMETERS AND THEIR RELEVANCE IN GLAUCOMA DIAGNOSIS viii
LIST OF FIGURES
LIST OF FIGURES
Figure 1.1.1: Colour fundus photograph showing the normal ONH and a glaucomatous ONH ... 2
Figure 2.1: Map showing the study area as published in Addepalli et al., 2013 ........................ 46
Figure 2.2: Flowchart of examination procedures as published in Addepalli et al., 2013

(n=3,833) ..................................................................................................................................... 49
Figure 2.3: Ray tracing diagram of an eye in front of a fundus camera. The camera components
of a telecentric imaging system nearest the subject´s eye is represented as a thick lens and its
anterior and posterior principal points denoted with Pc and Pc’ respectively. Figure adapted
from Rudnicka et al., 1998 .......................................................................................................... 55
Figure 2.4: Model Eye used to calculate the size of the object of interest measured in pixels
from a digital photograph. .......................................................................................................... 62
Figure 3.1: Flowchart demonstrating derivation of normal, test samples – I and II .................. 68
Figure 3.2: Snapshot of the customized MATLAB Software for planimetry ............................... 71
Figure 3.3: Sketch showing the description of ONH parameters. .............................................. 71
Figure 3.4: Frequency distribution of optic disc area in mm2 (n=1,650) .................................... 79
Figure 3.5: Plot between disc area in mm2 versus cup disc area ratio, cup area, cup height and
cup width parameters (n=1,650) ................................................................................................ 83
Figure 3.6: Plot between disc area versus rim area from 7,8,10 and 11 clock hours (n=1,650) 84
Figure 4.1: Sketch showing the gap between disc margin to scan circle in large disc size and
small disc size ............................................................................................................................ 108
Figure 4.2: Flowchart showing the selection of eyes from LVPEI-GLEAM study ...................... 111
Figure 4.3: Plot showing the difference in RNFL thickness between small(n=228),
medium(n=1,042), and large(n=203) 95th, 5th and 1st percentiles measured on 3.4 mm circle
diameter.................................................................................................................................... 119
Figure 4.4: Scatterplot showing Disc area in mm2 and average RNFL thickness between small,
medium and large disc sizes ..................................................................................................... 120
Figure 4.5: Bland-Altman plot between disc area measured by OCT and planimetry ............. 123
Figure 7.1: Plot showing the ROC curve of all disc size A. Cup-disc ratio in the clinic by an
optometrist, B. Average cup-disc ratio of the horizontal and vertical disc and cup diameter
measured by planimetry, C. Cup-disc ratio of disc and cup area measured by planimetry, D.
Cup-disc ratio of disc and cup area measured by planimetry .................................................. 171
OPTIC NERVE HEAD PARAMETERS AND THEIR RELEVANCE IN GLAUCOMA DIAGNOSIS ix

LIST OF FIGURES
Figure 7.2: Plot showing the ROC curve of all disc size A. Rim area at 6 o clock hour measured
by planimetry, B. Rim-disc area ratio at 6 o clock hour measured by planimetry, C. Rim area at
12 o clock hour measured by planimetry, D. Rim-disc area ratio at 12 o clock hour measured by
planimetry ................................................................................................................................. 172
Figure 7.3: Plot showing the ROC curve of small disc size A. Cup-disc ratio in the clinic by an
Figure 7.4: Plot showing the ROC curve of small disc size A. Rim area at 6 o clock hour
measured by planimetry, B. Rim-disc area ratio at 6 o clock hour measured by planimetry, C.
Rim area at 12 o clock hour measured by planimetry, D. Rim-disc area ratio at 12 o clock hour
measured by planimetry ........................................................................................................... 177
Figure 7.5: Plot showing the ROC curve of medium disc size A. Cup-disc ratio in the clinic by an
Figure 7.6: Plot showing the ROC curve of medium disc size A. Rim area at 6 o clock hour
Figure 7.7: Plot showing the ROC curve of large disc size A. Cup-disc ratio in the clinic by an
Figure 7.8: Plot showing the ROC curve of large disc size A. Rim area at 6 o clock hour
OPTIC NERVE HEAD PARAMETERS AND THEIR RELEVANCE IN GLAUCOMA DIAGNOSIS x

LIST OF TABLES
LIST OF TABLES
Table 1.1: The prevalence of glaucoma in population-based studies .......................................... 4
Table 1.2: Planimetric optic disc data from different studies ..................................................... 23
Table 1.3: Summary of studies about the diagnostic ability of OCT ........................................... 35
Table 2.1: Demographic distribution of participants in LVPEI-GLEAM study population

(n=3,833) ..................................................................................................................................... 52
Table 2.2: Age and gender distribution of the study population (n=3,833) ............................... 53
Table 3.1: Normative database: Demographic and clinical characteristics of participants

(n=1,650) ..................................................................................................................................... 76
Table 3.2: Demographic and clinical characteristics of participants in test sample I & normative
database sample ......................................................................................................................... 77
Table 3.3: Morphometric parameters of optic disc data (n=1,650) ........................................... 80
Table 3.4: Linear regression intercept, slope coefficient, standard error of slope, p-values and r-
squared value of optic disc parameters with optic disc area ..................................................... 85
Table 3.5: Demographic and clinical characteristics of participants from the test sample I & II 88
Table 3.6: Comparison of the diagnostic ability of the ONH parameters unadjusted for disc size
versus 95% predicted intervals of ONH parameters after adjusting for disc size ...................... 90
versus 95% predicted intervals of ONH parameters after adjusting for disc size in small disc size
cohort .......................................................................................................................................... 92
versus 95% predicted intervals of ONH parameters after adjusting for disc size in medium disc
size cohort ................................................................................................................................... 93
versus 95% predicted intervals of ONH parameters after adjusting for disc size in large disc size
cohort .......................................................................................................................................... 94
Table 3.10: Bland-Altman plot between A) OCT and planimetry cup area in mm2 B) OCT and
planimetry rim area in mm2 C) OCT and planimetry disc area in mm2 ....................................... 98
Table 4.1: Demographic and clinical characteristics of normative database sample (n=1,473)
.................................................................................................................................................. 113
OPTIC NERVE HEAD PARAMETERS AND THEIR RELEVANCE IN GLAUCOMA DIAGNOSIS xi

LIST OF TABLES
Table 4.2: Distribution of RNFL and ONH parameters (n=1,473). ............................................ 114
Table 4.3: Comparison of mean RNFL thickness in optic disc size groups ................................ 116
Table 4.4: Table showing 95th, 5th and 1st percentiles of all(n=1,473), small(n=228),
medium(n=1,042), and large(n=203) RNFL thickness parameters. .......................................... 118
Table 4.5: Correlation of optic disc parameters, age, gender, axial length and RNFL parameters
with optic disc area ................................................................................................................... 121
versus 95% predicted intervals of ONH parameters after adjusting for disc size- with all
parameters ................................................................................................................................ 168
versus 95% predicted intervals of ONH parameters after adjusting for disc size in small disc size
cohort- with all parameters ...................................................................................................... 173
size cohort- with all parameters ............................................................................................... 178
cohort- with all parameters ...................................................................................................... 183
OPTIC NERVE HEAD PARAMETERS AND THEIR RELEVANCE IN GLAUCOMA DIAGNOSIS xii
LIST OF SYMBOLS AND ABBREVIATIONS
LIST OF SYMBOLS AND ABBREVIATIONS
OCT : Optical coherence tomography

ONH : Optic nerve head
IOP : Intraocular pressure
APEDS : Andhra Pradesh eye disease study
CGS : Chennai glaucoma study
POAG : Primary open angle glaucoma
PACG : Primary angle closure glaucoma
CCT : Central corneal thickness
OHTS : Ocular hypertension treatment study
RNFL : Retinal nerve fibre layer
HoV : Hill of vision
CDR : Cup to disc ratio
SDOCT : Spectral-domain optical coherence tomography
mm : Millimeter
HRT : Heidelberg retinal tomography
3-D : Three dimensional
µm : Micrometers
TDOCT : Time-domain optical coherence tomography
AUROC : Area under the receiver operating characteristic curve
LVPEI-GLEAM : L V Prasad Eye Institute-Glaucoma Epidemiology And Molecular-genetics
VTs : Vision technicians
VGs : Vision guardians
ROC : Receiver operated characteristic
ICC : Intra-class correlation
OPTIC NERVE HEAD PARAMETERS AND THEIR RELEVANCE IN GLAUCOMA DIAGNOSIS xiii
ACKNOWLEDGEMENTS
ACKNOWLEDGEMENTS
I would like to thank Dr Garudadri Chandrasekhar Vice-chair at L V Prasad Eye Institute and
Professor Padmaja Sankaridurg at Brien Holden Vision Institute and the School of Optometry
and Vision Science, University of New South Wales for their excellent supervision during this
project. They not only offered enormous support and enthusiasm but also encouraged me to
have confidence in my scientific abilities and to continuously increase my expertise in all facets
of scientific research. Over the years they taught me the importance of thinking through the
subject matter from all angles , considering various points of view and not jumping into
conclusions and to think like a researcher and stay focused on the subject. A special thanks to
Professor Padmaja Sankaridurg for her commitment, patience and constructive criticism during
the preparation of the thesis. Most of all, I would like to thank my family, who supported me
with love and patience through this whole experience. I could not have got this far without their
encouragement.
Also deserving a special mention are Mr Hasnat Ali, Dr Thomas Naduvilath, Dr Harsha B L, Dr
Shrikant Bharadwaj, Prof Arthur Ho and Ms S Banu for their advice and invaluable time spent to
teach me statistics, R-Programme, building model eye, verifying magnification correction of
planimetry software, correcting the results and providing valuable support.
My gratitude goes to complete LVPEI-GLEAM study team for their support throughout the
duration of the Study.
Funding: I express my sincere thanks and gratitude to Hyderabad Eye Research Foundation for
funding to conduct L V Prasad Eye Institute-Glaucoma Epidemiology And Molecular Genetic
study and the Vision Cooperative Research Centre, the School of Optometry and Vision Sciences,
OPTIC NERVE HEAD PARAMETERS AND THEIR RELEVANCE IN GLAUCOMA DIAGNOSIS xiv
ACKNOWLEDGEMENTS
University of New South Wales, who supported me with a scholarship and other infrastructure
needs.
Finally, I want to dedicate this thesis to my GURU and my mentor Dr G Chandrasekhar for his
love and for having made me what I am.
OPTIC NERVE HEAD PARAMETERS AND THEIR RELEVANCE IN GLAUCOMA DIAGNOSIS xv

ABSTRACT
ABSTRACT
Purpose: To measure optic nerve head (ONH) and retinal nerve fibre layer (RNFL) thickness
parameters in normal and glaucomatous eyes in a South Indian population and to determine if
ability to detect glaucoma can be improved with a) planimetric assessment of ONH parameters
compared to subjective assessment and b) consideration of disc size in assessment of ONH
parameters and RNFL thickness.
Methods: In a population-based study conducted in South India (2011-2013), 3,833 participants
were enrolled, and a complete ocular assessment conducted including posterior segment optical
coherence tomography (OCT). ONH parameters (disc, cup and neuro-retinal rim) were
extracted, measured and analysed using planimetric techniques and custom software. From the
OCT images, RNFL data for the 3.4mm scan circle was extracted. The eyes were divided into 3
sets: normative, test (normal) and test (glaucomatous) eyes. ONH parameters were categorized
using the normative dataset. Using the test sets, the area under the receiver operating
characteristic curves (AUROC) for the ONH parameters in detecting glaucoma was determined
and compared against a subjective assessment of cup-to-disc ratio. The RNFL measurement and
ONH parameters were adjusted for disc size to determine if the accuracy in diagnosing glaucoma
could be improved.
Results: The mean optic disc, cup and rim area for normal eyes were 1.90 ± 0.35, 0.66 ± 0.25
and 1.24 ± 0.23 mm2 respectively and disc area was highly correlated to cup area, rim area, cup
height and width respectively (r2 = 0.564, 0.515, 0.511, 0.505 respectively, p<0.001). For
detection of glaucoma, cup-to-disc area, cup area, cup width and height and sectoral neuro-
retinal rim areas (8, 9, 10 and 11) had a better discriminatory ability (AUROC >0.9) over
OPTIC NERVE HEAD PARAMETERS AND THEIR RELEVANCE IN GLAUCOMA DIAGNOSIS xvi
ABSTRACT
subjective cup-to-disc ratio (AUROC 0.83) and improved further when adjusted for disc area. The
average RNFL thickness (3.4mm scan circle) was 94 ± 9 µm and thinnest in the temporal followed
by nasal, superior and inferior quadrants. Optic disc area/disc size had no significant influence
on the RNFL thickness.
Conclusion: In this large cohort, assessment of ONH parameters especially cup-to-disc area ratio
and cup width when adjusted for disc area was superior to subjective assessment of cup-to-disc
ratio in detecting glaucoma.
OPTIC NERVE HEAD PARAMETERS AND THEIR RELEVANCE IN GLAUCOMA DIAGNOSIS xvii
CHAPTER 1: INTRODUCTION
1 INTRODUCTION
This chapter begins with a description of glaucoma, classification and its prevalence. This
is followed by a detailed review of the literature on risk factors for glaucoma and
assessment of structural damage of the retinal layers and optic disc in glaucoma using
the optical coherence tomography (OCT). The chapter concludes with the aims and
hypothesis of my thesis based on the existing literature and the gaps in the knowledge
of the optic disc size and optic nerve head (ONH) parameters.
1.1 Glaucoma
Glaucoma is an optic neuropathy characterized by a loss of optic nerve fibres that result
in characteristic changes to the ONH and accompanied by visual field loss. It was
estimated that there were 60.5 million people with glaucoma worldwide in 2010 and
predicted to increase to 79.6 million by 2020, glaucoma worldwide will increase to 111.8
million in 2040, disproportionally affecting people residing in Asia and Africa[1]. In 2002,
an international consensus panel published a definition of glaucoma that is now widely
accepted[2]. The term ‘glaucoma’ covers a few diseases with varying clinical
presentations. Glaucoma leads to distinctive changes in the shape or morphology of the
ONH(Figure 1.1) called ‘cupping’. This damage to the ONH results in loss to some or
much of the visual field, which is “that portion of space simultaneously visible during the
steady state of fixation with either one or both eyes open”[3]. The resulting loss of visual
field and visual impairment is irreversible. If untreated, the damage to the affected eye
OPTIC NERVE HEAD PARAMETERS AND THEIR RELEVANCE IN GLAUCOMA DIAGNOSIS 1

will result in, measurable loss of visual function[4]. The pathogenesis of glaucoma is not
well understood but it has been said that the primary sites of insult in glaucoma are
somas, axons, and dendrites of retinal ganglion cells [5-8]. A detailed review of the sub-
types of glaucoma and the pathogenesis of glaucoma is outside the scope of this thesis.
Figure 1.1.1: Colour fundus photograph showing the normal ONH and a glaucomatous
ONH

1.2 Prevalence
In many of the earlier reports, glaucoma and ocular hypertension were considered to be
synonymous and therefore there were no clear definitions or criteria used to define the disease
[9, 10]. One of the first adequately designed and well-conducted studies to determine the
prevalence of glaucoma was the Welsh Glaucoma Survey [11]; 92% of the town’s eligible
population i.e. persons aged between 40 and 75 were included in the study. Using a diagnostic
criterion of intraocular pressure (IOP) above 20 mmHg, cupping of the optic disc and visual field
defects, the prevalence of chronic simple glaucoma was found to be 0.28%. Since the Welsh
Glaucoma Survey, many other studies were conducted in different populations and include, the
Rotterdam Eye Study [12], Roscommon Eye Study [13], and the Reykjavik Eye Study [14] from
Europe. Studies from Australia include The Blue Mountains Eye Study [15] and the Melbourne
Visual Impairment Project [16]. Studies from the United States include the Beaver Dam Eye
Study [17], Baltimore Eye Survey [18], Salisbury Eye Evaluation Project [19], and the Los Angeles
Latino Eye Study [20]. Studies from the Caribbean include the Barbados Eye Study [21]. Studies
are now emerging from Asian countries such as The Andhra Pradesh Eye Disease Study (APEDS)
[22], The Aravind Comprehensive Eye Study [23], Chennai Glaucoma Study (CGS) [24], Dhaka Eye
Study [25], Singapore Tanjong Pagar Survey [26] and Singapore Malays Eye Study [27] and China
Beijing Eye Study [28], Liwan Eye Study [29]. Data from these studies have been reviewed for
inclusion in the Global Burden of Disease prevalence data and the area specific to glaucoma. The
prevalence of glaucoma as reported in these studies is summarized in Table 1.1

Table 1.1: The prevalence of glaucoma in population-based studies
% %
Study
Population Country Age POAG PACG
Welsh glaucoma survey White Wales 40+ 0.4 0.1
caucasian
Rotterdam eye study White Netherlands 55+ 1.1 0
caucasian
Roscommon eye study White Ireland 50+ 1.9 0.1
caucasian
Reykjavik eye study White Iceland 50+ 0.4 NA
caucasian
Blue mountains eye study White Australia 50+ 3 0.3
caucasian
Melbourne visual impairment White Australia 40+ 1.7 0.1
study caucasian
Beaver dam eye study White USA 43+ 2.1 0.1
caucasian
Baltimore eye survey Black USA 40+ 1.3 NA
Americans,
White
caucasian
Salisbury eye evaluation project Black USA 73+ 8.5 NA
Americans,
White
caucasian

Los Angeles Latino eye study Black USA 40+ 4.7 NA
Americans,
White
caucasian
Barbados eye study African- West Indies 40+ 0.8 NA
caribbean
Andhra Pradesh eye disease study Indian India 40+ 2.6 1.1
Aravind comprehensive eye study Indian India 40+ 1.2 0.5
Chennai glaucoma study Indian India 40+ 1.6 0.9
Dhaka eye study Indian Bangladesh 35+ 1.9 0.3
Singapore Tanjong Pagar survey Singaporean Singapore 40+ 1.8 1.1
Chinese
Singapore Malays eye study Malay Singapore 40+ 2.5 0.12
China Beijing eye study Chinese China 40+ 0.03 1.4
Liwan eye study Chinese China 50+ 2.1 1.5
[NA- Not Applicable, POAG – Primary open-angle glaucoma; PACG – Primary angle-closure
glaucoma]
In Table 1.1, the age of the study population included was 35 years and above, with the majority
being 40 years and above. All the studies were carried out from 1965–2006 and had varying
criteria for diagnosing glaucoma. Overall, the prevalence of primary open-angle glaucoma
(POAG) was low ranging from 0.03 to 3.0% with a higher prevalence in certain populations such
as Americans and Latinos. Similarly, the prevalence of primary angle closure glaucoma (PACG)
was also low ranging from no prevalence to 1.0 but was relatively higher in those of Chinese
ethnicity.

1.3 Risk factors for glaucoma
Risk factors have been identified to play a role in the onset and progression of glaucoma. These
can be categorised as demographic, systemic, ocular and genetic and their role are summarised
below.
Demographic risk factors
1.3.1.1 Age
Age is the main demographic factor associated with an increased risk of glaucoma with
increasing age found to be consistently associated with an increased risk of developing the
condition [30, 31]. The magnitude of risk also consistently increases with increasing age,
increasing several times from the 40-50 year age group to the over 80 age group [32, 33]. Other
than ancestry, discussed below, no other demographic factor has been consistently associated
with this increased risk.
Increasing age is associated with a multitude of changes to the eye and its associated blood
supply, changes that may promote the pathogenesis of glaucoma. The trabecular meshwork is
the key route of aqueous outflow in the eye [34]. Aqueous formed in the ciliary body, courses
through the posterior to the anterior chamber then drains through the trabecular meshwork
and the uveoscleral pathways. Both pathways show a decrease in outflow with age [35, 36].
Trabecular meshwork cells are lost and accrual of extracellular substances within the meshwork
has been noted with increasing age [37]. These changes may contribute to the observed age-
related increase in IOP observed in a number of population-based studies [17, 38-41].

Glial cells of the retina and optic nerve play a multitude of roles and contribute towards many
aspects of retinal ganglion cell function [42]. This includes structural and functional support for
retinal ganglion cells including the provision of basic metabolic support, regulation of the
extracellular environment and the production of neurotrophins. Microglia provides immune
regulatory functions and assists in maintaining the perivascular barriers and attempt to protect
neurones from destructive inflammatory cytokines. Aging has an unfavourable effect on the
viability and regenerative capacity of microglial cells of the central nervous system [43]. Similar
age-dependent attrition may be seen in glial cells of the retina and optic nerve and it is possible
that these changes may adversely affect their neuro-supportive and neuroprotective functions
[44]. With age, endothelial cells of blood vessels demonstrate increasing levels of apoptosis and
a reduced ability to regenerate. These changes have obvious derogatory effects on
autoregulation. ONH blood flow also declines with age [45].
1.3.1.2 Gender
The relationship between gender and glaucoma is inconsistent across the literature, with a few
prevalence studies reporting an increased frequency in men, others in women and others
demonstrating little difference between the genders. For example, the Baltimore and Beaver
Dam studies found no significant difference in glaucoma risk between males and females [17,
46], the Rotterdam and Barbados Eye studies found an increased risk in males [21, 47] whilst
the Blue Mountains Eye Study found an increased prevalence of POAG amongst women[15].
Similar inconsistencies can be observed amongst incidence studies. For example, the Rotterdam
and Skelleftea studies found no significant difference between males and females in the
incidence of glaucoma [48, 49]. However, the Dalby study found a higher incidence amongst
women[50]. Hence, there appears to be some evidence for a higher risk of POAG in some
populations in males and in others in females.

The reasons for these inconsistencies are not clear. It may reflect the influence of gender in the
pathogenesis of glaucoma in different populations. A meta-analysis of 46 studies by Rudnicka et
al. (2006) demonstrated a higher risk of POAG amongst men compared to women [32].
However, in certain subgroups of POAG, such as normal tension glaucoma, the prevalence is
consistently higher in women [51]. There is evidence to suggest that female sex hormones may
be protective against raised IOP[52, 53]. Oestrogen receptors can be found in the ciliary body
and outflow tract and it is possible it could influence glaucoma via aqueous formation and
vascular factors [54, 55]. Evidence from population-based studies, however, are inconsistent
[55-57].
1.3.1.3 Ancestry (Population /Ethnicity /Race)
The third demographic risk that has been consistently associated with glaucoma is ancestry. A
meta-analysis of variations in the prevalence of POAG by age, gender and ancestry by Rudnicka
et al. (2006) showed that prevalence of POAG is highest amongst populations of African-
Caribbean (“black”) ethnicity at all ages, compared to White-Caucasian and Asian. The estimated
overall prevalence of 16% in those over the age of 70 amongst African Americans compared to
6% and 3% respectively in Caucasians and Asians [32]. Not only are individuals of African
ancestry at a greater risk of developing POAG, but the course of the disease also tends to be
more aggressive and blindness more likely to ensue in these individuals. Inter-population
differences in optic nerve structure, central corneal thickness (CCT), IOP levels and the
prevalence of other putative glaucoma associated risk factors such as refractive error, blood
pressure, diabetes, as well as differences in response to medication, uptake of treatment have
been cited as possible explanations for this difference, but these findings have not been
consistent across studies [58]. Hence these overall figures should be interpreted with caution as
using umbrella descriptions such as “Black”, “White” or “Asian” oversimplifies human diversity
[59]. Individuals of African descent, for example, belong to one of the most genetically varied
populations in the world. If the prevalence of POAG in populations deemed to be of “the same
race” is analysed in greater detail, there can be significant variations in POAG prevalence
between populations [60]. POAG prevalence is significantly lower in South Africa, Nigeria,
Tanzania and Baltimore compared to Ghana, St. Lucia or Barbados, ranging from as low as 2.9%
in South Africa and rural Nigeria to as high as 8.3% in Ghana, amongst individuals of African
ancestry. Amongst “white” populations the prevalence of POAG is significantly higher in white
Australians than in the Dutch [60].
Systemic diseases associated with glaucoma
Systemic diseases associated with glaucoma include: diabetes [61-64], blood pressure [65-69],
cardiovascular disease [70], thyroid disease [71] and migraine [51, 72-74]. However, these
findings have not always been consistent across large cross-sectional population-based studies
as well as longitudinal trials. Studies which also suggest the effects of these factors are
potentially modified by the presence of other risk factors [51, 66, 74-80]. These as well as a
multitude of other factors – autoimmune, neurodegenerative, endocrine, vascular – have been
reviewed in detail by Pache and Flammer (2006) [80], Flammer and Mozaffarieh (2007) [81] and
Grieshaber et al. (2007) [82, 83], Coleman and Caprioli (2008-2010) [84-86] and more recently
by Schmidl et al. (2011) [87].

Ocular risk factors associated with glaucoma
1.3.3.1 Intraocular pressure
Evidence indicates that IOP is strongly associated with glaucoma. Population-based, cross-
sectional studies from different regions of the world such as the Beaver Dam, Blue Mountains,
Tanjong Pagar, Tajimi and Chennai glaucoma study [15, 88-91] show higher IOP to be associated
with an increased prevalence of glaucoma. This relationship between IOP and glaucoma is a
dose-dependent one [18]. Randomized clinical trials have proven that lowering IOP, whether by
means of medication, surgery or argon laser trabeculoplasty, slows the onset/progression of
glaucomatous optic neuropathy and visual field deterioration [92-96]. Overall, it is believed that
raised IOP induces a series of events that eventually leads to the death of retinal ganglion cells
by apoptosis [97].
1.3.3.2 Central corneal thickness
Though cross-sectional studies had reported [98-103] an association between CCT and ocular
hypertension, normal tension glaucoma, and POAG. The Ocular hypertension treatment study
(OHTS) was the first prospective study to demonstrate that thinner central cornea is a risk factor
for the progression of ocular hypertension to POAG. Participants with thin cornea (555μm or
less) had a three-fold increased risk of developing POAG compared with those who had a corneal
thickness of more than 588μm. Since then, others have supported this finding [69, 104]. It is now
widely accepted that in best clinical practice, the assessment of the risk of a glaucoma suspect
should include the measurement of CCT[105-107].

The evidence for CCT as a risk factor for the presence of glaucoma is more equivocal. A number
of studies, including population-based studies in Barbados and Rotterdam, have found a thinner
CCT to be associated with the occurrence of glaucoma [108-110]. Furthermore, a thinner central
cornea has been associated with increased glaucomatous visual field loss as well as increased
ONH damage [111-114]. However, these findings are not supported by all studies [89, 91, 99].
There is little evidence so far to suggest that a thinner central corneal is a risk factor for the
progression of glaucoma [69, 115-118].
1.3.3.3 Myopia
Cross-sectional and case-control studies from across the continents have found associations
between glaucoma and myopia [23, 77, 119-124]. Analogous to studies in glaucoma, studies on
refractive error are difficult to compare as definitions for myopia and hyperopia depend on
demarcating values with no clear consensus. Not all studies, however, have supported the
association between glaucoma and myopia. In the follow-up of 647 ocular hypertensive
subjects, Quigley et al. (1994) did not find myopia to be a risk factor for the development of
glaucomatous visual field loss in ocular hypertension [125]. The results of randomized clinical
trials have also been inconsistent [30, 126].
The exact biological reason for the possible association between myopia and glaucoma is
unclear. There is evidence that the increased risk (at least in myopia ≥ 4D) is not due to an
increased association with raised IOP [127] but is an independent risk factor for glaucoma. This
association may be related to the structure of the myopic eye which differs from emmetropic
eyes [128]. Myopic eyes have longer axial lengths and deeper anterior chambers. The lamina
cribrosa is thinner and shows greater deformability in myopia than in emmetropia [128]. This

architecture of myopic eyes will make the ONH more vulnerable to fluctuations in IOP and
subsequent retinal ganglion cell damage.
Family history and genetics as a risk factor for glaucoma
Family history is now recognized as an important risk factor for the development of glaucoma.
Cross-sectional epidemiological studies have demonstrated that 10 to 50% of POAG patients
have a reported family history of the disease [129] though nearly a third of cases may be under-
reported. The risk of developing the disease amongst first-degree relatives is 2 to 10 fold [16,
130]. Furthermore, several large population-based studies have demonstrated that the
prevalence of glaucoma varies between populations of self-reported ethnicity. A recent meta-
analysis [32] calculated the average estimated prevalence of POAG in those over 70 years of age
was 3% in Asian populations, 6% in white Caucasian populations and 16% in populations of black
African and Caribbean origin. POAG, for example, shows more rapid and early progression in
blacks than white Caucasians, with the risk of irreversible blindness, also being greater amongst
the former [58, 131]. The predominant type of glaucoma also varies across ethnic groups, with
population-based studies suggesting that PACG predominates amongst East Asians and Eskimos
whilst POAG is the more dominant form found in white Caucasians and those of Afro- Caribbean
origin [29, 111].
The genetic basis of glaucoma is further supported by twin studies [132, 133]. A prospective
study by Gottfredsdottir et al. (1999), for example, looking at 50 monozygotic twin pairs and
their spouses, found concordance rates of open-angle glaucoma in twin pairs (98%) exceeded
that of spouse-twin pairs (72%). Since then, several genetic loci associated with POAG have been
described and several genes implicated.

1.4 Identifying glaucoma in the clinical setting
Tonometry, visual field testing, and ophthalmoscopy have been used for glaucoma screening
[134] and form the mainstay of glaucoma detection. However, surprisingly, there have been few
studies on the power of these three tests, especially when used in a combination to detect
glaucoma. Harper & Reeves (1999), considered the sensitivity and specificity of a range of
glaucoma screening tests, both singly and in combination and found visual field screening, optic
disc cupping, and IOP (in rank order) to be the most significant discriminants of glaucoma [135].
Furthermore, significantly greater sensitivity was found when the tests were used in
combination than when used alone. In addition, to provide high levels of sensitivity and
specificity in excess of 0.90 a visual field screening test was essential to be included [136]. Testing
of visual fields is more time consuming and definite standards for mass visual field screening
with automated perimetry have not been fully defined[137]. In this regard, evaluating the ONH
might be satisfactory from a sensitivity point of view but requires highly trained individuals
and/or expensive devices. In this respect, photography to capture images of the ONH and
evaluation of the retinal nerve fibre layer (RNFL) thickness with various instruments such as
OCT[138] have been able to overcome the problem of cataloguing the state of the ONH and
RNFL thickness without the need for qualified personnel during mass screening [139].
Tonometry
Measurement of IOP is probably the most common method employed by practitioners for
diagnosis and monitoring of glaucoma. Although high IOP remains a risk factor for the
development of glaucoma [30], it must also be noted that there is no absolute value of IOP
which, if a person has a value lower, they are safe from the development of the disease.

The accepted value for the mean IOP in the population is around 16 mmHg with no evidence of
an independent age effect on IOP [140]. However, there are many sources of error in the
procedure of recording IOP, some of which are dependent on the type of tonometer used, while
others are general errors that could influence the measurement irrespective of the device used
such as the biological attributes of the examined patient.
Even the technique considered the ‘Gold Standard’, i.e. Goldmann tonometry is not without its
problems. Indeed, in a major review of errors when using a Goldmann type tonometer there
were shown to be six main areas which could be sub-divided into forty-two possible sources of
error [141]. There has been great debate regarding corneal thickness as a source of error
following the publication of the OHTS [30], where it was found that corneal thickness was a
powerful predictor for the development of POAG. The OHTS showed that there are many
patients being misclassified as ‘at risk’ through erroneous IOP readings because of increased
corneal thickness when their true reading is probably normal [142]. Fundamentally, IOP
measurements are subject to numerous errors, many of which can be being ignored by
practitioners. We misclassify IOP for glaucoma patients, glaucoma suspects and those patients
classified as normal on a basis of tonometry investigation without accurate procedure and
correction of IOP based on corneal thickness measurement.
Visual field
The visual field is defined as the portion of space simultaneously visible during the steady state
of fixation with either one or both eyes open. The visual field of one eye can be described as a
“Hill of Vision” (HoV) surrounded by a sea of blindness [3]. The height of the HoV corresponds
to retinal sensitivity and it has its peak centred at the fovea where the retina has its maximum
sensitivity. The HoV has a bottomless pit that corresponds to the blind spot location of the
retina. The blind spot has no photoreceptors, causing an absolute defect or absolute scotoma in
the visual field. Any localized depression in the HoV causes a relative scotoma. An overall
reduction in height of the HoV without changing its shape is known as the generalized loss. The
extent of the normal visual field is approximately 60 degrees nasally, 60 degrees superiorly, 70
to 75 degrees inferiorly and 100 to 110 degrees temporally. Glaucomatous visual field defects
follow the course of the retinal nerve fibre defects. The characteristic glaucomatous visual field
defects are generalized depression, nasal step, paracentral scotoma and arcuate defects [3, 143-
145].
Optic nerve head evaluation
Evaluation of the ONH is important as the structural damage of the ONH is central to the
diagnosis of glaucoma and is extremely important for monitoring if a patient is at or established
disc damage. The ONH is the location where the axons from the retinal ganglion cells converge
to exit the eye through the scleral canal. Besides axons, the ONH consists of blood vessels, glia
and connective tissue.
The edges of the scleral canal define the optic disc margin, which is clinically visible as a whitish
circular band at the edge of the optic disc. Optic disc cupping is one of the most important
features in the diagnosis of glaucoma. The cup to disc ratio (CDR), defined as a ratio of cup
diameter to disc diameter, exhibits a similar variability with a range between 0.0 and 0.9 in
normal populations although screening studies showed that less than 10 to 11 % have a CDR
more than 0.5 [146, 147]. Because of the predilection of the superior and inferior neuroretinal
rim area in glaucomatous optic nerve damage, the vertical CDR increases faster than the
horizontal CDR. Evaluation of vertical CDR is a more sensitive way to detect glaucomatous
change [148]. However, the assessment of CDR is limited by the fact that it provides little
information about focal neuroretinal rim damage manifested as thinning and notching. In
normal eyes, the neuroretinal rim is intact for 360 degrees and thickest in the inferior sector,
followed by the superior, nasal and temporal regions of the optic disc [149]. In glaucomatous
eyes, neuroretinal rim loss is essentially diffuse even though localized damage can be found
depending on the stages of the disease. In early glaucoma, neuroretinal rim loss is preferentially
located at the inferotemporal and supero-temporal sectors of the optic disc [150, 151]. The
temporal followed by the nasal neuroretinal rim is subsequently affected as glaucomatous
damages progress to moderate and advanced stages [150]. This contrasts with non-
glaucomatous optic neuropathy in which neuroretinal rim pallor, rather than rim thinning, is
more pronounced.
Optic disc haemorrhage is a clinical sign with high specificity. In the population without signs of
glaucoma, the frequency of disc haemorrhage has been reported as only about 1% [152]. In a
recent screening study of 14,779 participants, the prevalence of disc haemorrhages was
estimated to be 8.2% in glaucoma patients and 0.2% in non-glaucoma cases [153]. Disc
haemorrhage usually appears in splinter-shaped located in the prelaminar and superficial nerve
fibre layers. It was reported that 92% of disc haemorrhages were found between 4 weeks and 2
months after the first presentation [154]. It is associated closely with a RNFL defect in location
and the size of the peripapillary atrophy [155]. Because of the relatively short duration of disc
haemorrhage, the probability of finding one would be low if examination frequency is low.
Peripapillary atrophy is another structural feature associated with glaucoma. Peripapillary
atrophy can be divided into the β zone, located close to the optic disc border and characterized
by a complete loss of retinal pigment epithelium, and the α zone, located peripherally and
characterized by irregular hypopigmentation and hyperpigmentation in the retinal pigment

epithelium [156]. Although both α and β zones are present in normal eyes, in glaucoma patients,
the β zone is significantly larger and occurred more frequently [157]. In addition, the presence
and the size of peripapillary atrophy were demonstrated to be related to the development of
subsequent optic disc or visual field damage in patients with ocular hypertension suggesting it
is an important sign of early glaucomatous damage [158].
The RNFL is the innermost layer of the retina that is composed of retinal ganglion cells axons
covered by astrocytes and a process of Muller cells. These axons converge on the optic disc and
form the optic nerve. In glaucomatous eyes, because of retinal ganglion cell loss, the reflectivity
of RNFL decreases, with focal areas where RNFL reflectivity is absent. The frequency of localized
RNFL defects has been reported to be 20% or more of all glaucoma patients [159, 160]. The
frequency of detection of localized RNFL defect increases from early to moderate glaucoma but
decreases again in advanced glaucoma because of diffuse RNFL loss. Localized RNFL defects are
most often detected in the inferotemporal and/or supero-temporal sectors of the ONH. Diffuse
RNFL loss has been reported to be more common than a localized RNFL defect in patients with
glaucoma [161]. Detection of a diffuse RNFL defect is a challenge although a clearer and sharper
image of retinal vessels would assist to indicate the presence of diffuse RNFL loss.
Early structural damage in glaucoma remains a hallmark of the diagnosis of glaucoma and
detection of progression. The interpretation is subjective and requires complex consideration of
numerous factors, emphasizing the importance of a person able to undertake a high-quality
clinical examination. While newer technologies show promise in offering better detection of
glaucomatous change over time, the subjective examination remains vital in managing in clinical
practice as the newer technologies lack the wide range of a normative database to discriminate
glaucomatous optic disc to normal optic disc.

Modern tools to aid in glaucoma diagnosis
Since glaucoma causes irreversible loss of vision, the main goal of glaucoma management is early
diagnosis and intervention. [126, 162]. In addition to the asymptomatic nature of the condition
that limits early diagnosis, the standard clinical methods for diagnosing glaucoma (i.e., visual
field-testing) are able to detect glaucomatous vision loss only after significant field loss, that is
after up to 40% of the nerve tissue is lost [163, 164]. In addition, the subjective nature of these
tests, reliance on patient responses and the subjective interpretation of the clinicians, make
them a less than ideal method to diagnose glaucoma. Imaging methods such as Scanning laser
polarimetry, Confocal scanning laser ophthalmoscopy and Spectral-domain optical coherence
tomography (SDOCT) have been developed to objectively and quantitatively measure changes
in both the ONH and RNFL, both of which undergo structural changes with glaucoma.
1.5 Detection of glaucoma: Role of optic disc size
Quigley et al. (1992) have emphasized that identification of early damage in glaucoma
involves examination of the disc, the nerve fibre layer and an automated visual field test
[165]. Detection of characteristic glaucomatous optic disc damage involves the
measurement of the size and shape of the neuroretinal rim and optic cup [147, 166-168]
relative to the disc size. Interestingly, most of the techniques are focussed on measuring
the size of the cup relative to the disc. Although these techniques help in assessing
whether a cup size is small or large, they most commonly do not consider the size and
relevance of the disc size in diagnosing the condition. [169-172]. Till date all clinicians
in their routine practice do not measure the exact numerical values of the disc size,

instead use a crude estimate of whether the size of the disc in question is of average
size, smaller than average or a larger than average disc. In clinics, the combination of
multiple measurements is currently often an art rather than a science and can usually
only be mastered by experienced glaucoma specialists. The interpretation can be
susceptible to interobserver differences due to variances in training and experience.
According to Joseph Caprioli (1994) “Discontent with the qualitative and subjective
nature of optic disc evaluation prompted researchers to seek other methods to detect
early structural damage from glaucoma”[173]. Examination of the RNFL, stereo-
photogrammetry, computerized image analysis of digitized images, and scanning
confocal laser imaging have all been used to recognize early structural abnormalities
from glaucoma. Some of these methods required use of expensive instruments, which
generally remove them from the realm of the community practitioners and even from
using in multicentre clinical trials. The incorporation of appropriate outcome measures
of structural optic nerve damage into clinical trials of glaucoma has generally been
problematic. In the Glaucoma Laser Trial, a combination of qualitative and
semiquantitative techniques was used to interpret non-simultaneous, stereoscopic disc
photographs at a central reading centre[174]. In the Advanced Glaucoma Intervention
Study, the only record of optic nerve appearance is the examiner's subjective estimate
of CDR; ONH photographs are not acquired. The OHTS randomised ocular hypertensive
patients to treatment or no treatment. The optic nerve experience is used as an
outcome measure and was evaluated qualitatively by a central reading centre and not
measurements of fundus[175]. To summarize, The OHTS and the Rotterdam population-
based study have identified a larger CDR as a significant predictive factor in the
development of POAG[30, 176]. The disc size of subjects with normal-tension glaucoma
is significantly larger than POAG eyes whilst pseudoexfoliative glaucoma subjects had
smaller discs though not significantly smaller than POAG counterparts[177]. Cost-
effective measures with established sensitivity and specificity must be defined for better
glaucoma detection, management and cost savings for patients, public healthcare
providers and the government[178]. Moreover, the new imaging modalities have
constant updates making it difficult for clinician to compare with older versions of
imaging. The principal advantage of optic disc photographs over other imaging
modalities is that it is close to what clinician are used to see in clinical examination. This
method allows for direct comparison within the clinical setting. ONH stereo photographs
are readily available and are easily reproducible. They provide a baseline image against
which all the comparisons can be made for judging progression. These advantages do
not necessarily mean that stereophotographs are superior to any imaging modalities or
clinical drawings.
1.6 Techniques to measure optic disc size
The methods used to measure optic disc parameters have been many and range from simple
measurement techniques used at the slit lamp to the assessment of optic disc photographs by
custom software and automated ONH analysers. The standard of practice to most clinicians
since a long time is to use a direct ophthalmoscope and graticule incorporated in the instrument,
allowing an estimate of cup parameters such as cup disc ratio and disc size. The smallest round
white light spot of the Welch Alleyn direct ophthalmoscope projects a 1.5 mm diameter spot on
the retina, it is a little size of medium disc size. Scots eyes of Welch Alleyn direct ophthalmoscope

is compared with subjects’ disc size. As detailed below, each method has its own advantages
and limitations. The following sections describe methods to obtain retinal parameters.
Histo-morphometry
Qualitative histology measurements of optic disc remain the gold standard. Histo-morphometry
is a technique to obtain quantitative information from histologic tissue section in two-
dimensional morphometry. The major advantages of this direct measurement method are its
independence from magnification correction error [179]. Disadvantages are dependent on
histological techniques used, cost and availability of post-mortem eyes [180]. Morphologic
evaluation of histological sections is used in both RNFL characteristics and topological features
of the ONH[181-183].
Slit-lamp biomicroscopy
Slit-lamp biomicroscopy is an easy, rapid and inexpensive method to estimate the size of the
optic disc [184] and involves the use of a fundus viewing lens - +90 D [169], +78 D [185], +60 D
[186], Goldmann lens [187] or the Zeiss 4-mirror lens [188]. Using either a slit beam of adjustable
length or an eyepiece graticule, and appropriate correction factors (x1.0 for + 60D lens, x1.1 for
78D lens and x1.3 for the 90D lens), the vertical and horizontal diameters of the optic disc and
optic cup can be measured. Using the formula for the area of an ellipse, measurements of the
optic disc and cup area can be obtained with the neural rim area calculated as the difference
between disc area and cup area [187]. The development of several lens specific correction
factors allows estimation of the size of the optic disc. A limitation of using indirect lenses is that
the distance from the lens to the eye may vary and influence the accuracy of the magnification

correction, particularly in the presence of high refractive error[189]. Significant inter-observer
variation has been reported for clinical disc size measurement[190].
Digital planimetry
Digital photography is widespread in its use due to the inherent advantages of easy storage,
retrieval and low cost. Additionally, several centres have developed their own software for
digital analysis of the photographs [191-198]. Digital planimetry involves plotting disc stereo
photographs on a computer monitor and measuring them manually or with the help of
computerized techniques for quantitative measurements of the optic disc [199]. Digital stereo
pair images of the optic disc photographs are obtained either by sequential or simultaneous
photographs that are then displayed either side by side. A stereo viewer is used to view these
images stereoscopically and the margins of the optic disc and optic cup are marked. Depending
on the software features and capabilities, various measurements are generated. Table 1.2
summarizes the data obtained using a variety of methods. However, there exist a number of
limitations with optic disc planimetry [200] and include lengthy process with time-consuming
technique, the subjective nature of judging the contour/edge of the optic disc and in addition,
using spherical error as the correction factor may underestimate the size of the disc in large eyes
and vice versa overestimate for small eyes [201].

Table 1.2: Planimetric optic disc data from different studies
Neuro
Optic Optic retinal
disc cup Cup rim

Author
area VDD HDD area VCD HCD /disc area
Sample (mm2) (mm) (mm) (mm2) (mm) (mm) VCDR HCDR area (mm2)
Country Method size (SD) (SD) (SD) (SD) (SD) (SD) (SD) (SD) ratio (SD)
Germany Zeiss 457 2.69 ± 1.92 ± 1.76 ± 0.72 ± 0.77 ± 0.83 ± 0.34 ± 0.39 ± NA 1.97 ±
Jonas et al. photography, 0.70 0.29 0.31 0.70 0.55 0.58 0.25 0.28 0.50
(1988) [149] digital
morphometry
Varma et al. United Topcon 1534 2.94 NA NA 1.04 NA NA 0.56 0.57 NA NA
(1994) States ImageNet
[202](Blacks)

Varma et al. United Topcon 1853 2.63 NA NA 0.71 NA NA 0.49 0.47 NA NA
(1994) [202] States ImageNet
(Whites)
Ramrattan et Netherlands Topcon 894 2.42 ± NA NA 0.57 ± NA NA 0.49 ± 0.40 ± NA 1.85 ±
al. (1999) ImageNet 0.47 0.34 0.14 0.14 0.39
[12]
India Digitized 143 3.37 ± 2.12 ± 1.94 ± 0.57 ± NA NA 0.37 ± 0.39 ± 0.16 ± 2.8 ±
Sekhar et al. photographs, 0.68 0.231 0.19 0.34 0.09 0.09 0.08 0.53
(2001) [197] custom
software
India Zeiss 70 2.58 ± 1.87 ± 1.77 ± 0.98 ± 1.06 ± 1.16 ± 0.56 ± 0.66 ± 0.37 ± 1.60 ±
Jonas et al. photography, 0.65 0.24 0.22 0.40 0.23 0.23 0.08 0.07 0.08 0.37
(2003) [203] digital
morphometry

Aravind et al. India Custom 623 2.82 ± 1.94 ± 1.81 ± 0.53 ± 0.72 ± 0.72 ± 0.36 ± 0.39 ± 0.17 ± 2.29 ±
(2011) [204] software 0.52 0.2 0.19 0.39 0.38 0.37 0.18 0.19 0.11 0.39
Crowston et Australia Graded circles 3323 NA 1.5 NA NA 0.63 NA 0.43 NA NA NA
al. (2004) template
[146]
Uchida et al. Japan HRT 2 223 2.16 ± NA NA 0.59 ± NA NA NA NA 0.26 ± 1.57 ±
(2005) [205] 0.49 0.36 0.12 0.33
Vernon et al. United HRT 2 918 1.98 ± NA NA 0.45 ± NA NA NA NA 0.22 ± 1.52 ±
(2005) [206] Kingdom 0.36 0.35 0.14 0.31
China Canon 4027 2.65 ± NA NA NA NA NA NA NA NA NA
Wang et al. photography, 0.57
(2006) [28] digital
morphometry
Bourne et al. Singapore Custom 622 2.17 ± 1.73 ± 1.58 ± 0.74 ± 0.97 ± 0.92 ± 0.55 ± NA 0.33 ± 1.43 ±
(2008) [207] software 0.46 0.19 0.18 0.35 0.24 0.24 0.10 0.11 0.29

Japan Topcon 1080 2.56 ± NA NA NA NA NA 0.56 ± 0.58 ± NA NA
Tsutsumi et nonmydriatic 0.51 0.08 0.09
al. (2012) photographs,
[208] custom
software
[mm – millimeter; SD – Standard Deviation; NA – Not Applicable; HRT – Heidelberg Retina Tomograph; VDD - Vertical Disc Diameter; HDD - Horizontal Disc
Diameter; VCD - Vertical Cup Diameter; HCD - Horizontal Cup Diameter; VCDR -Vertical Cup-Disc Ratio; HCDR - Horizontal Cup-Disc Ratio]

Template of circles
This method was first described by Klein et al. (1985) and was used to measure optic discs in the
Beaver Dam Eye Study [209] and the Blue Mountains Eye Study [147]. The technique involved
optic disc stereo-photography with a telecentric fundus camera, and processing of photographs
to yield a pair of 2"x2" colour slides. The slides were placed on a slide sorter and examined using
a Donaldson stereo-viewer. A plastic template with small circles ranging from 1/32 to 1 ¼ inch
in diameter in 1/64 to 1/32-inch increments was used (Pickett, small circles no.1203). The grader
placed it under the right side of the stereo pair. The circle whose diameter coincided with the
margins of the structure being measured was found for the longest and shortest disc and cup
diameters. The rim width was calculated as the difference between disc diameter and cup
diameter. The Blue Mountains Eye Study corrected for ocular magnification using spherical
equivalent correction as described by Bengtsson et al. (1992) [210]. The good inter-observer
agreement was reported for this method, [147, 209] which required no sophisticated
equipment. However, it was not possible to directly obtain area measurements using this
technique.
Imaging
Imaging devices such as scanning laser ophthalmoscopy (Heidelberg Retinal Tomography - HRT)
and OCT are widely used for optic disc measurements. HRT provides three-dimensional (3-D)
topographical assessment of the ONH and makes quantitative measurements of ONH
parameters that are reproducible [211]. Using confocal scanning principles, a 3-D topographic
image is constructed from a series of optical image sections at consecutive focal planes.
Advantages of HRT include the reduced need for dilating pupils and clear media, and the
automated analysis available. Limitations include the reliance on an operator to define the optic

disc margin. OCT provides in-vivo cross-sectional scans of retinal structures by the use of low-
coherence interferometry [212]. Advantages of the OCT include the automated determination
of the disc margin and the automated analysis of topographic parameters and RNFL thickness.
Limitations include the need for pupil dilation in some eyes to adjust the automated disc margin
in selected eyes, and poor quality scans in media opacities [213].
In conclusion, optic disc damage is a hallmark feature of glaucoma. Despite its importance, the
presence of optic disc damage is determined by a subjective evaluation of the ONH and remains
the most common way to evaluate and detect glaucoma. Although this method provides
qualitative and quantitative information, there is significant intra- and inter-observer variability
associated with the technique. More importantly, the technique focuses on the CDR and in the
process fails to take into the account the relevance of the size of the optic disc to this
measurement.
Various techniques are available for estimating optic disc size and should be taken into
consideration when comparing disc size measurements from patient populations [202, 214] or
for the same individual obtained using different techniques as optic disc parameters influence
glaucoma diagnosis. More specifically, in addition to the optic disc CDR, consideration of the
disc size is relevant in improving the sensitivity of the technique in identifying those with the
condition. Each method for measuring disc size has specific strengths and limitations that may
vary depending on the objective of the measurement. Additionally, for a given
technique/method there are other variables such as the skill of the clinician involved in
measurements that play a role as the skill required to obtain good quality information can vary
from person to person. Apart from techniques, it is also necessary to look at the cut-off range.
Most of the imaging modalities have a proprietary normative database and have different
analysis methods, which are not interchangeable. Several studies are available discussing the

difference between measurements of optic disc topography and RNFL parameters [190, 215-
227]. There is no common agreement between imaging modalities which are attributed because
of factors which influence these measurements and measurement techniques [228-232].
1.7 Detection of glaucoma: Role of RNFL optical coherence tomography
Factors affect RNFL analysis
To optimize the detection of glaucomatous RNFL thinning, it is important to account for factors
that can affect the measured RNFL thickness and allow for them by adjusting the RNFL thickness
value or diagnostic threshold. So far, the following factors have been identified:
1. Demographic factors such as age, [233-235] race and ethnicity [32, 236-241].
2. Larger optic disc size (diameter or area) was associated with thicker RNFL [241-244].
3. RNFL thickness decreases further away from the optic disc margin [149, 245-248].
4. Longer axial eye length and myopia were associated with thinner RNFL [239, 249-253].
1.7.1.1 Age
Estimating the RNFL loss over and above the age-related loss is important for a diagnosis of
glaucoma. Jones et al. (2001) using OCT found maximum RNFL thickness in the superior quadrant
and minimum RNFL thickness in the temporal quadrant with a mean age of 30 ± 10 years of age
[234]. Using OCT, Alamouti and Funk (2003) [235] reported a regression slope of -0.44 µm/year
(R2 = 0.94), Poinoosawmy et al. (1997) [254] reported a slope of -0.38 µm/year, Parikh et al.
(2007) [233] reported linear decrease of average RNFL thickness with age, with a negative slope

of 0.16 µm/year and Chi et al. (1995) [255] reported this as -0.23 µm/year using scanning laser
polarimetry.
1.7.1.2 Ethnicity
Peripapillary RNFL thickness appears to vary between different ethnic groups [238-240, 254,
256, 257]. Studies that used OCT generally reported thicker RNFL measures in adult Caucasians,
[258, 259] than in Asians [239, 240, 257]. However, these differences may also have resulted
due to the use of different instruments. In comparison, Girkin et al. (2011) [237] compared six
different groups with the same instrument as a part of a multicentre trial and found that
Hispanics and African descent individuals had the greatest overall RNFL measurements.
Variation in regional RNFL thickness across racial strata was found, with Hispanics and Indian
individuals having greater RNFL thickness superiorly and inferiorly and African descent and
Indians having a significantly less RNFL thickness in the temporal corresponding to the
papillomacular bundle. Similar results were found from the multicentre African Descent and
Glaucoma Evaluation Study [236].
In another study of 6 and 12-year-old Australian children, Samarawickrama et al. (2010) found
that the RNFL was thicker in East Asian children compared with European Caucasian children
across both age groups, by 3.2 to 12.1% [260]. Similar findings amongst quadrant-specific RNFL
thickness differences were demonstrated in American ethnic groups as well, El-Dairi et al (2009)
found that superior quadrant and average RNFL thickness were significantly greater in black
children compared with white children [261].

1.7.1.3 Disc size
Controversy exists on whether there is a positive correlation between disc size and the number
of retinal nerve fibres. Two studies evaluated the relationship between RNFL thickness and ONH
size and produced divergent results. In agreement with previous Time-domain optical
coherence tomography (TDOCT) data [242], Bendschneider et al. (2010) [244] detected a
positive correlation, as larger discs showed thicker RNFL values. Bendschneider et al. (2010) used
the Spectralis to measure RNFL thickness and the Heidelberg Retinal Tomography to measure
the optic disc area. Such a correlation is likely to depend on the distance between the fixed
diameter OCT circular scan and the ONH margin. Histological studies have shown that the RNFL
thickness decreases at increasing distances from the ONH [149]. In the presence of a large ONH,
the distance between the scan and the ONH margin is reduced and measurements are
performed closer to the optic disc edge; such an artefact leads to an overestimation of RNFL
thickness in patients with large ONH.
1.7.1.4 Axial length
Hoh et al. (2006) used OCT to investigate the relationship of refractive error and axial length
with RNFL [262]. They found that mean RNFL measured did not differ with a myopic refractive
error or axial length. The OCT instrument utilized by this study applied a Littman-based formula
to adjust for different scan sizes due to magnification.
Using Stratus OCT, Budenz et al. (2007) reported that RNFL thickness decreased approximately
by 2.2 µm (95% CI, 1.1–3.4) for every 1mm increase in axial length [241]. Similarly, El Dairi et al.
(2009) reported a 2.6 µm reduction in RNFL for every 1mm increase in axial length in white

children [261]. With the Cirrus HD OCT, Wang et al. (2011) reported a negative correlation
between average RNFL thickness and axial length (r= -0.322, p<0.001) [263]. Bendschneider et
al. (2010) used the Spectralis HRA + OCT and found that a decrease in total RNFL thickness of
4.79 µm per every 1 mm increase in axial length [244].
Recent SDOCT studies have found no relationship between RNFL and axial length. Hirasawa et
al. (2010) using the Topcon 3D OCT-1000 did not find a significant correlation between axial
length and average RNFL thickness after adjusting for age, gender and disc area [264]. The
reason for this discrepancy is due to non-accountability of axial length related ocular
magnification by time-domain OCT and the magnification correction performed by the Topcon
3D OCT-1000. The former statement is supported by the study done by Savini et al. (2012) who
measured RNFL with Cirrus HD OCT and found that after applying the Littman correction for
magnification the relationship of RNFL with axial length disappeared [228]. As axial length
increases the scanning circle projected onto the fundus is larger, therefore sampling the RNFL
further from the disc margin (assuming similar disc sizes in these larger eyes) and Hirasawa et
al. (2010) have shown that larger scanning circles measure thinner RNFL [264]. In summary,
adjustment of measured RNFL thickness by axial length, in addition to age, may lead to a tighter
normative range and improve the detection of RNFL thinning due to glaucoma.
1.7.1.5 Repeatability and reproducibility
Repeatability is a mandatory prerequisite that needs be assessed before any new device can be
accepted for use in clinical practice. Lee et al. (2010) reported high intra-session repeatability of
the SDOCT for RNFL measurements in normal and glaucomatous eyes [265]. Other authors for
the RTVue™ described similar results [266, 267].

Leung et al. (2009) investigated the repeatability and reproducibility of SDOCT in addition to its
diagnostic capabilities [268]. To assess reproducibility, 31 eyes with no evidence of glaucoma
underwent RNFL analysis by both SDOCT and TDOCT in two separate examination sessions
within 1 month. Inter visit variability was lower with SDOCT than TDOCT at the one, three, four,
and 8 to 11 –o’ clock segments of the RNFL map. The intervisit reproducibility of SDOCT ranged
from 4.31 to 22.01 µm. Schuman et al. (1996) also compared the reproducibility of SDOCT RNFL
thickness measurements with 3 different circle diameters and found that the inter-subject
standard deviation was approximately constant among the control subjects but showed a
tendency to drop with diameter among the subjects with glaucoma [269].
1.7.1.6 Quality of scans
For the data constructed by SDOCT to be clinically useful, image quality needs to be adequate.
SDOCT instrument produced by different manufacturers measured signal quality using a
different scoring system. Balasubramanian et al. (2009) conducted a study investigating the
effect of image quality on RNFL thickness measurements obtained with SDOCT [270]. After an
initial set of scans, +2 diopter defocus was induced to artificially degrade image quality. This
introduction of 2 diopter of optical defocus artificially decreased RNFL thickness measurements
by 10 µm for Cirrus SDOCT, artificially increased thickness measurements for Spectralis OCT by
20 to 40 µm and had no appreciable effect on images obtained by RTVue™. However, when
image quality remained within the range specified as acceptable by each of the SDOCT
manufacturers, there was no significant effect on RNFL thickness measurements. Mwanza et al.
(2011) investigated the effect of cataract and its removal on signal strength and RNFL
measurements using Stratus OCT. The investigators found that an overall improvement in signal
strength after cataract surgery led to a 9.3% increase in mean average RNFL thickness [271]. Rao
et al. (2011) looked at the predictors of normal ONH, RNFL and macular parameters and found
that signal strength, optic disc size, and axial length had a significant effect on ONH
measurements, whereas age had a significant effect on macular measurements. None of the
predictors evaluated influenced the RNFL measurements [229].
1.7.1.7 Scan position
Scan location varies from scan to scan due to manual placement of the scanning circle position
and/or sampling points can be scattered along 3.4mm diameter circle due to eye motion during
scanning. Chung et al., (2011) studied the calculation circle location in 69 myopic eyes and found
that myopic tilted disc, RNFL thickness measurements along the calculation circle based on the
contours of the neural canal opening were seen to be more comparable to the normative
database of the SDOCT than did the automatically determined scan position [253].
Diagnostic ability
A considerable number of studies regarding the glaucoma diagnostic capability of SDOCT RNFL
measurements have been published [211, 268, 272-280]. Most of the studies compared the
diagnostic capability of SDOCT RNFL measurements with those of TDOCT [268, 273-277, 279,
280]. Several publications have investigated the diagnostic capability of SDOCT RNFL thickness
measurements using an area under the receiver operating characteristic curve (AUROC) for
discrimination between healthy and glaucomatous eyes [211, 268, 275-280]. All these studies
consistently showed no statistically significant differences in glaucoma diagnostic capability
between SDOCT and TDOCT [268, 275-277, 279, 280]. A summary of studies about the diagnostic
ability of OCT are shown in Table 1.3

Table 1.3: Summary of studies about the diagnostic ability of OCT
OCT device (company) and

Authors
Study design Main findings
Leung et al. Cirrus OCT (Carl Zeiss •The AUROC was 0.962 for SD- and
(2009) [268] Meditec) Vs TDOCT (Stratus) 0.956 for TD-OCT
•No significant difference was detected
between the TD- and SD-OCT
Park et al. (2009) Cirrus OCT (Carl Zeiss •The AUROC was 0.962 for SD- and
[275] Meditec) Vs TDOCT (Stratus) 0.956 for TDOCT
•SDOCT showed a better glaucoma
discrimination capability than TDOCT in
the early stages of glaucoma
Moreno- Cirrus OCT (Carl Zeiss •The AUROC was 0.837 for SDOCT and
Montanes et al. Meditec) Vs TDOCT (Stratus) 0.829 for TDOCT
(2010) [276] •The sensitivity and specificity, and
AUROCs were similar between TDOCT
and SDOCT
Cho et al. (2011) SD-SLO/OCT (OTI) Vs TDOCT •The AUROC was 0.969 for SDOCT and
[277] (Stratus) 0.959 for TDOCT
Li et al. (2010) RTVue OCT (Optovue) Vs •The AUROC for RNFL thickness was
[278] RNFL and ONH parameters 0.816 and for the cup-disc vertical ratio
0.782
Sehi et al. (2009) RTVue OCT (Optovue) Vs •The AUROC was 0.88 for SDOCT and
[279] TDOCT (Stratus) 0.87 for TDOCT
•No significant difference was detected
between the TDOCT and SDOCT

Leung et al. Spectralis OCT (Heidelberg •SDOCT RNFL measurement attained a
(2010) [211] Engineering) Vs HRT higher sensitivity (AUROC; 0.978) than
(Heidelberg Engineering) HRT optic disc measurement (0.905)
Jeoung et al. Cirrus OCT (Carl Zeiss •No significant differences between the
(2010) [280] Meditec) Vs TDOCT (Stratus) AUROCs for SDOCT (0.728) and TDOCT
(0.760) in discriminating preperimetric
glaucoma
Sung et al. (2009) Cirrus OCT (Carl Zeiss •SDOCT demonstrated a higher
[281] Meditec) Vs TDOCT (Stratus) sensitivity (63.6%) than TDOCT (40.0%)
in the normative classification of mean
RNFL thickness
Vizzeri et al. Cirrus OCT (Carl Zeiss •All three SDOCTs could detect localized
(2009) [272] Meditec) glaucomatous structural damage seen
Spectralis OCT (Heidelberg in stereo photographs
Engineering)
RTVue OCT (Optovue) Vs
Localized RNFL defect
Chang et al. Cirrus OCT (Carl Zeiss •The sensitivity and specificity of
(2009) [274] Meditec) Vs TDOCT (Stratus) various RNFL parameters using the
Cirrus OCT for glaucoma with early to
moderate visual field defects are
excellent and are equivalent to Stratus
OCT

1.7.2.1 Glaucoma diagnosis with optical coherence tomography
Spectral-domain OCT has replaced TDOCT to assist clinicians in glaucoma detection because of
its smaller test-retest variability [268] and higher specificity and sensitivity [282, 283]. In addition
to RNFL measurement, SDOCT is used to measure the ONH parameters. Mwanza et al. (2011)
compared the discriminating ability of circumpapillary RNFL thickness and ONH parameters
between normal and glaucomatous eyes with SDOCT. Seventy-three glaucoma patients and 146
age-matched normal subjects were included in that study. The AUROC for the best ONH
parameter was vertical rim thickness (AUROC=0.963), which was comparable to average RNFL
thickness (AUROC=0.950) in discriminating glaucoma from normal subjects independent of the
severity of glaucoma [284]. In the study by Sung et al., (2012) they imaged 229 glaucomatous
patients, 405 pre-perimetric glaucoma patients, and 109 healthy individuals with SDOCT. The
AUROC was higher for average RNFL thickness than for rim area (0.957 vs. 0.871, P<0.001).
Combining RNFL thickness and rim area has been shown to improve the diagnostic ability for
detection of glaucoma [285].
The macula has the highest concentration of retinal ganglion cells in the retina (approximately
50% of the ganglion cells of the entire retina). The loss of retinal ganglion cells in glaucoma can
thus be detected in this area [286]. With TDOCT, it has been shown that total macular thickness
measured has the inferior diagnostic performance of glaucoma detection compared with
circumpapillary RNFL thickness [287]. The macular ganglion cell-inner plexiform layer measured
by Cirrus™ SDOCT has high measurement reproducibility with an intra-class correlation
coefficient (ICC) ranging from 92.5% to 99.9% and coefficient of variation (CV) ranged from
0.41% to 2.24% [288]. Kim et al. (2014) showed that the diagnostic ability of macular ganglion
cell inner plexiform layer parameters was comparable to that of circumpapillary RNFL and ONH
parameters for detection of pre-perimetric glaucoma [289]. Macular ganglion cell inner

plexiform layer combined with other ONH parameters would improve the diagnostic ability for
discrimination between glaucoma and normal subjects [290].
1.8 Determination of retinal image size
An accurate method for determining true retinal image size is by histo-morphometry but this
method has a major disadvantage that it cannot be performed in-vivo. The next best methods
are planimetry and imaging modalities like OCT and HRT. Even for these methods, one should
consider the magnification factor of the eye as well magnification factor of the camera [291].
The magnification of a camera is determined by the optics inside the camera and is usually fixed.
While considering the magnification factor of the eye, we need to focus on two aspects. One is
refractive error and the second is the axial length of the eye. The eye is considered as a complex
optical system with different refractive surfaces and refractive medium. As the refractive
properties of the system changes, the image magnification also changes. Hence, considering the
refractive status of the eye while calculating image magnification is important [292, 293]. The
second magnification factor we need to consider is the axial length of the eye. As the axial length
of the eye changes the angular magnification of the eye changes and hence, there is a need to
consider axial length while considering optic disc morphometry [292, 294].
The traditional method to calculate the real size of the object on a fundus camera was first
developed and described by the German physicist Hans Littmann [291]. According to Littmann
(1982) the true size of an object on the fundus of the living eye obtained by the telecentric
fundus camera is based on the angular diameter of the image. Littman’s retinal size calculations
are based mainly on trigonometric graphs. The true size or diameter of the retinal object (t)
equals the multiplication of the measurement of an image on a photographic film or observed

dimension (s) with the magnification factor of the camera (p) and with the magnification factor
caused by the ammetropia of the eye (q).
Equation 1: Littmann formula to calculate true retinal size

𝑡 = 𝑠×𝑝×𝑞
We apply the above formula extensively to calculate the real size of a retinal feature. The
limitations of Littman’s method was that it assumed the fundus camera was telecentric, with
ammetropia ranging from +15 Dioptres to -15 Dioptres and the parameters used to derive the
equation were based on Gullstrand’s schematic eye [291]. Bengtsson et al. (1992) extensively
discussed all the potential limitations of Littman’s method and also simplified the equation
[210]. Bennett et al. (1994) made improvements to Littman’s method. They concluded that
calculations are closest to accurate based on a ray tracing technique [295]. Later Garway-Heath
et al. (1998) compared most of the methods available by that time and discussed the sources of
error by each method [170]. They also proposed a new method which simplified calculating true
retinal size if we have at least axial length of the eye photographed and proved that
measurements are correlated well with the traditional methods.
One can calculate the magnification factor of eye provided the optical system used to
photograph the eye is telecentric. An optical system is considered telecentric when the optical
axis of the eye being photographed is in collation with the optical path of the imaging system
[170]. Which means the value of p in equation-1 must be constant with varying ammetropia.
Details about the telecentric optical system and other features of a fundus camera are well
described by Bengtsson and Krakau (1977) [296]. The telecentric optical systems provide a
constant magnification of the objects, regardless of the working distance, which allows
measurements of the structures, without distortion of the images and regardless of the working
distance. Therefore, it reduces the variability of the measurements. Not all the fundus cameras

available in the market are telecentric. A study done by Rudnicka et al. (1998) compared 14
different cameras available in the market by the year 1998 including stereo fundus camera, a
Rodenstock scanning laser ophthalmoscope, the Heidelberg Laser Tomographic Scanner, and
the HRT[297]. They concluded that the degree of variation in camera magnification with
ammetropia for the non-telecentric camera differs particularly for high refractive errors. They
also found that out of 14 cameras tested eight of them proved telecentric and the rest of them
did not have a constant relationship of camera magnification with varying degree of
ammetropia.
Littman (1982) calculated his formulae based on nomogram or network chart, Gullstrand’s
schematic eye values as standard and assuming axial ammetropia as norm [291]. Alternate
methods have been suggested by Bennett et al. (1994) and made modifications to Littman’s
calculations [295]. Later Coleman et al. (1996) found the per cent bias for the measurement
made when corneal parameters were presumed for axial length ranged from 15.5% to 29.7%
[298]. Hence, to obtain true retinal dimensions one should also consider the axial length values.
1.9 Rationale for research
The main difficulties in the clinical assessment of the ONH are as fellows
a) Inherent subjectivity and variability in assessment between clinicians
b) The overlapping spectrum of optic disc appearance between normal to physiological to
glaucomatous
c) The large diversity in the appearance of the normal and diseased optic disc
d) Understanding of normal appearance of the ONH
e) Training and clinical experience

To diagnose glaucoma, imaging modalities such as fundus photographs can be used as a quick,
simple, inexpensive, specific, sensitive and most important objective method of ONH analysis
provided there is database about optic disc size and its parameters. It is known from studies of
disc photographs [167] and image analysis [147, 201] that CDR increases with an increase in the
size of the disc. Several studies, using image analysis, have demonstrated a linear relationship
between cup size and disc size [166, 299, 300]. Neuroretinal rim area also increases with
increasing optic disc size [149, 201, 299-301]. However, the contour of the cup may influence
this correlation. For example, cups with flat temporal slopes will have a greater increase in rim
area for a given increase in disc area than those discs with steep circular cups [302]. Inter-eye
correlation of disc parameters has also been reported. Cup size has been shown to have a high
degree of symmetry [303-306]. There is also high inter-ocular symmetry for the CDR. Armaly et
al. (1967) reported asymmetry of more than 0.2 occurring in only 1% of the normal
population[303].
In addition to studies that have looked at the total area of the disc, cup, and rim, some studies
have divided the disc head into sectors and reported on sectoral areas [307]. Jonas et al. (1993)
reported that neuroretinal rim area changes in size according to the disc sector[150]. They
observed that the rim was largest in the inferotemporal sector, followed by the supero-temporal
sector, nasal, with the temporal sector being the smallest. This regional distribution of rim area
is correlated with visibility of RNFL bundles (usually better detected in the inferotemporal region
than the supero-temporal), diameter of the retinal vessels (larger in the inferotemporal arcade
than supero-temporal) and the location of the fovea which is situated approximately 0.5mm
inferior to the midpoint of the optic disc [308].
Knowledge of the patient’s disc area is of relevance when screening for glaucoma, as the vertical
CDR depends on the disc area [149]. If one uses the same planimetric method to determine the

disc area and rim area, linear regression can be used to determine how deviant the rim area and
sectoral rim/disc ratio is in comparison with a general population. Till date, there is no standard
normative database of ONH planimetry parameters through which we can delineate normal
ONH to glaucomatous.
Apart from the ONH, OCT is the imaging methodology that samples most axons from retinal
ganglion cells in the circumpapillary RNFL scan. The B-scan analysed is typically a 12-degree
circular scan centred on the optic nerve, with a nominal scan circumference of 10.87 mm. This
specific scan path is used by many clinical OCT systems as it has the largest dynamic range with
the smallest intra-subject variability in both normal and glaucomatous eyes [309]. RNFL
thickness measures in normal eyes with smaller axial lengths are usually larger than for longer
or myopic eyes [228, 241, 249]. This relationship between axial length and RNFL thickness is a
direct reflection of scan path on thickness measures. Specifically, for a fixed 12-degree diameter
scan, the scan path would be further from the rim margin in longer eyes, where the RNFL is also
thinner [245, 310]. Similarly, the proximity of the scan path to the ONH rim for anatomically
large nerves may explain the positive correlation of RNFL thickness with nerve size [228, 242,
310]. The clinical standard for circumpapillary RNFL thickness measurement with OCT is with a
circular scan of 3.4 mm scanning diameter centred on ONH, regardless of ONH size. Hence, the
distance between the scan and the ONH margin will be reduced in the presence of a large ONH,
which would lead to overestimation of RNFL in patients with large ONH, as the measurement
would be made closer to the optic disc edge. Hence RNFL parameters need adjustment
according to optic disc size.

1.10 Thesis aims
The objective of this thesis was to evaluate the influence of ONH parameters on detection
of glaucoma
The specific aims considered in the following chapters are:
• To develop using the planimetric technique, a normative database of ONH parameters
from a population-based cohort aged 40 years and above. (Chapter 3)
• To determine if planimetric assessments of optic disc parameters improve the
diagnostic ability in differentiating normal versus glaucomatous eyes compared to
subjective assessment of CDR. (Chapter 3)
• To determine the distribution of RNFL thickness along a 3.4mm circum papillary scan
from a normal population-based cohort. (Chapter 4)
• To determine if there is an influence of the disc size on the RNFL thickness measurement
conducted using a 3.4mm circumpapillary scan. (Chapter 4)

1.11 Thesis hypotheses
Hypothesis I
Consideration of ONH parameters such as cup area, neuroretinal rim area, especially when
adjusted for disc area will improve the accuracy of glaucoma diagnosis over clinical assessment
of CDR.
Hypothesis II
Utility of RNFL thickness in detection of glaucoma can be improved when the RNFL thickness
measured at a circumpapillary scan circle of 3.4mm is adjusted for disc size.
1.12 Thesis overview
At the completion of this thesis, this study will produce normative data of the general
characteristics of ONH and will help determine if assessment of disc area, other ONH
parameters will improve the accuracy of detection of glaucoma. Additionally, the study will
also determine if consideration of the nerve fibre layer thickness using the standard 3.4mm
scan circle varies when disc size is considered.

CHAPTER 2: METHODS
2 MATERIALS AND METHODS
2.1 Introduction
The present study was undertaken as part of the larger population-based study L V Prasad Eye
Institute-Glaucoma Epidemiology And Molecular-genetics (LVPEI-GLEAM) study. The LVPEI-
GLEAM study was designed with the aim to estimate the prevalence of glaucoma in a rural
population from the state of Andhra Pradesh, India and to determine ocular, systemic and
genetic risk factors associated with glaucoma. Three thousand eight hundred thirty-three
permanent residents aged 40 years or above were enumerated. Stereo optic disc photographs
were obtained from 3,448 participants, visual fields were obtained from 3,632 participants and
OCT were obtained from 3,510 participants. A summary of sample size collection, description of
procedures used in LVPEI-GLEAM study and determining the size of retinal features on fundus
photographs and its calculations will be described in this chapter.
2.2 Data collection
To evaluate the aims listed in Chapter 1, data were collected from the LVPEI-GLEAM study. The
study commenced in September 2011 and was completed in September 2013. A total of 3833
participants underwent a comprehensive eye examination. All the participants had stereo
photographs of the optic disc as well as OCT examination of the posterior segment.

CHAPTER 2: METHODS
2.3 Glaucoma Epidemiology and Molecular Genetics Study
The LVPEI-GLEAM study was conducted in a rural population of a southern Indian state of
Andhra Pradesh and was designed to determine the prevalence rates of glaucoma as well as to
determine ocular, genetic and systemic risk factors. The protocol of the study has been reported
previously [311] but described briefly in the following sections.
Sample size
The geographic area for the study sample included 16 villages (sub-district-Pedanandipadu
Mandal) of Guntur district in the state of Andhra Pradesh, Southern India (Figure 2.1). As per the
2002 census of India, this study area had a total population of 44,042 people with 22% being
greater than or equal to 40 years of age with a population growth rate of 1.3% per annum,
10,606 participants aged 40 years and above were expected to reside in this area in 2009.
Figure 2.1: Map showing the study area as published in Addepalli et al., 2013

CHAPTER 2: METHODS
For a survey design based on a cluster random sample, the sample size required was calculated
according to the formula.[312]
𝑡 2 𝑋 𝑝(1−𝑝)
Formula: 𝑛= 𝑚2
Description: n = required sample size
t = confidence level at 95% (standard value of 1.96)
p = estimated prevalence of Glaucoma in the project area
m = margin of error at 10%
Estimating that the prevalence of glaucoma (POAG and PACG) is at 5% (ranging from 4-6%, 95%
confidence interval) in those aged 40 years and above, and derived based on the APEDS[313,
314] and CGS[315, 316] studies, a population of 1825 participants were needed to be screened.
To correct for the difference in design, the sample size was multiplied by the design effect (De).
The design effect is generally assumed to be 2 for eye health surveys using cluster-sampling
methodology.
Sample size = 1825 * 2
= 3650
The sample was further increased by 5% to account for contingencies such as non-response or
recording error.
Sample size = 3650 + (5% of 3650)
= 3833
Thus 3833 participants greater than 40 years of age were required to be enrolled in the study.
Ethics
The ethics committee of the L.V. Prasad Eye Institute approved the study (LEC 08131) and the
study was conducted according to the tenets of the Declaration of Helsinki for experimentation

CHAPTER 2: METHODS
on humans. Informed consent was obtained from all the participants and the data were
collected prospectively using a standardised examination procedure.
Project staff
Two principal investigators (GCS and RCK) had the overall scientific and administrative
responsibility for the study. Two co-investigators (JGB, AUK) were responsible for the scientific
and administrative aspects of the study, coordinating all the procedures of the study, work of
the staff, management of data, quality control and diagnosis of glaucoma. Two ophthalmic
Vision technicians (VTs) with at least 1-year experience were responsible for visual acuity
assessment, refraction, conducting external and anterior segment examination, gonioscopy,
visual fields charting, anterior and posterior segment photography and imaging. 3 vision
guardians (VGs) would facilitate subject recruitment and interview. A housekeeping staff, a
driver for transporting participants to and fro from the study site in a van and a security guard
for the study site would complete the team. Briefly, the study was carried out at a vision centre
that was staffed by VTs who were the first point of contact for patients during the screening
process. Strict quality control measures were taken for proper data management and onsite
routine monitoring was conducted by the project coordinators and the study optometrists.
Examination procedures
The sequence of examination followed is detailed in Figure 2.2.

CHAPTER 2: METHODS
Figure 2.2: Flowchart of examination procedures as published in Addepalli et al., 2013

(n=3,833)
•Vision Assessment
•Informed Consent
VG
•Registration
•History taking
•Vision Recording
VT1 •Subjective and Objective refraction

•Slit lamp examination
•Slit lamp photos

•Non-mydriatic fundus photographs
•Frequency doubling technology Matrix
VT2 •ASOCT
•Intraocular pressure recording

•Gonioscopy
VT1
•Gonioscopy
•Humphrey visual field
•Dilated Slitlamp photographs
Optom •Fundus Photographs

•PSOCT
•Height, Weight, Blood pressure, HbA1c, Central corneal thickness, Axial length,
Lens thickness and anterior chamber depth measurement
VT2
[VG – Vision Guardian; VT – Vision Technician; Optom – Gold standard glaucoma trained optometrist]

CHAPTER 2: METHODS
All the participants screened by the VGs in their village, all the participants who satisfy the
inclusion criteria of LVPEI-GLEAM study were mobilized to the vision centre after taking the
informed consent, where, two trained VTs and a glaucoma specialist performed a complete
evaluation. Then they will proceed through various ophthalmic examinations and diagnostic
investigations which are listed below.
a) Ocular, medical and systemic history
b) Lensometry if needed
c) Presenting vision, Refraction and best corrected visual acuity
d) Slit-lamp examination with photography
e) Frequency-doubling perimetry (30-2-1 screening program)
f) Fundus photography with a non-mydriatic camera
g) Examination of the posterior pole with Direct Ophthalmoscope
h) Anterior segment imaging with Visante™
i) Applanation tonometry
j) Gonioscopy with 4-mirror Susman lens
k) Central corneal thickness measurement
l) Posterior segment imaging with Cirrus™
m) Posterior segment examination with an indirect lens
n) Humphrey visual fields 24-2 program if Frequency-doubling perimetry screening report
is abnormal
All the procedures will be done according to the standard protocol described in the literature.
The sequence of examination with vision technician, trained vision technician and the gold
standard are shown in the flowchart.

CHAPTER 2: METHODS
Stereo optic disc photography and grading
Following dilatation of the pupils, sequential stereoscopic optic disc photographs were obtained
for all participants enrolled in The LVPEI-GLEAM study except those who were diagnosed to have
primary angle closure disease. All photographs were obtained with a Topcon Non-mydriatic
retinal camera, TRC-NW8 (Topcon, Bauer Drive, Oakland, NJ). All photographic evaluations were
performed by two experienced optometrists (JGB and AUK), on a large screen liquid crystal
display monitor with a stereoscopic viewer (Screen-Vu stereo viewer; Berezin stereo
photography products, Mission Viejo, CA). The graders were masked to patient identification,
diagnosis, and visual field status. They independently reviewed each photograph and classified
as ‘Normal’ or ‘Glaucoma’. Quality assessments of each image pair were recorded separately
for clarity as ‘Good’, ‘Gradable’ or ‘Not-Gradable’ and for stereopsis as ‘Good’, ‘Moderate-
Stereo’ or ‘No-Stereo’. Discrepancies between the two readers were solved by a third
experienced fellowship-trained glaucoma subspecialist. The final decision of ‘Normal’ or
‘Glaucoma’ was based on “majority wins” manner (e.g., if two graders voted as normal and one
voted as glaucoma, the image is labelled as normal). Using this method, we attempted to
exclude glaucoma suspects and minimize the subjectivity of glaucoma diagnosis based on stereo
disc photographs.
Spectral-domain optical coherence tomography
Spectral-domain optical coherence tomography was performed using Cirrus™ SDOCT (software
version 4.0, Carl Zeiss Meditec Inc., Dublin, CA). The technical feature of the instrument was
described briefly in Chapter 1. The optic disc cube 200 x 200 protocols were used for all the
participants enrolled in LVPEI-GLEAM study except those that were diagnosed to have primary
angle closure disease during their test visit. The optic disc cube protocol was a tridimensional

CHAPTER 2: METHODS
scan of a 6x6 mm2 area centred on the optic disc and information from a 1024 x 200 x 200 point
collected. The Cirrus SDOCT software analyzed the data points and based on the segmentation
algorithm the software automatically detected the borders of the internal limiting membrane
and outer RNFL of each b-scan image. Then the software automatically constructed a RNFL map
combining the 200 b-scans data. Cirrus™ SDOCT software extracts a 3.46 mm diameter
peripapillary circle of data points coinciding the centre of the optic disc to the centre of the
circle.
2.4 Overall characteristics of the study sample
In the LVPEI-GLEAM study, 3,833 participants aged 40 years or older underwent a complete eye
examination. The mean age of the study population was 54 ± 9 years (range: 40 to 90). The
distribution and demographics of the study population is shown in Table 2.1 and Table 2.2. There
were more women than men among the participants (female: male ratio 2166/1667 P < 0.001,
Chi-square test). The age range (40 – 90 years) of the participants in the LVPEI-GLEAM study was
representative to that of the population (44,000), however, the response rate for inclusion was
more in females than males (M-43% Vs F-57%).
Table 2.1: Demographic distribution of participants in LVPEI-GLEAM study population
(n=3,833)
Variable Mean Standard Deviation Range
Age (years) 54 9 40 to 90
Visual Acuity (LogMAR) 0.15 0.40 0 to NPL
Spherical Equavalent (Diopters) -0.12 1.63 -11.00 to +14.00

CHAPTER 2: METHODS
Table 2.2: Age and gender distribution of the study population (n=3,833)
Age Total Males Females
40-44 611 176 435
45-49 703 244 459
50-54 700 291 409
55-59 533 259 274
60-64 572 283 289
65-69 350 190 160
70-74 226 129 97
75-79 86 57 29
80-84 43 31 12
85-90 9 7 2
Grand Total 3833 1667 2166
2.5 Determining the size of retinal features
Both the camera optics and the ametropia of the given eye influence the magnification of a
fundus photograph[210, 295]. Hence, mathematical equations are needed to determine the size
of retinal features. Over twenty years ago, Bennett et al. (1994) published their formula for
calculating the true size of a retinal feature from fundus photographs taken with a telecentric

CHAPTER 2: METHODS
fundus camera. In their article, Bennett et al. (1994) noted the fact that all formulas have
experimental and inherent errors, and that their formula is not an exception.
The formula of Bennett et al. (1994) applies to fundus photographs taken with the telecentric
Zeiss fundus camera. The magnification characteristics of the Zeiss fundus camera have
previously been presented in detail[296, 297]. However, such specific information is not
available on all cameras used for fundus photography. When a fundus photograph of unknown
magnification has been taken, it is necessary to rely on other ways to determine the size of the
object of interest. Different means have been invented in order to investigate the magnification
characteristics of the Topcon fundus camera[317, 318].
The Zeiss fundus camera
The Zeiss fundus camera designed by Littmann was presented to the German Ophthalmological
Society in 1955. Behrendt & Doyle (1965) found that errors of exposure, camera positioning, and
changes in focusing did not affect the quantitative measurements carried out on fundus
photographs taken with the Zeiss fundus camera[319]. However, large defocusing did make
measurements uncertain due to the blurring of the margins of the structures in question.
Differences in the centring of the image on the negative resulted in errors of up to 10 %.
The findings of Pach et al. (1989) were that varying the distance between the eye and the camera
had no notable effect on the size of an optic disc image in an emmetropic eye[292]. On the
contrary, in high ametropia, the magnification of the Zeiss fundus camera depends on the
camera-to-eye distance according to Lotmar (1984)[320]. In his work, Lotmar (1984) presented
an example of an eye with ametropia of + 16 diopter. Change in the magnification was 1.6 % per
one mm of variation in the camera-to-eye distance. He discusses the fact that magnification
CHAPTER 2: METHODS
differences of several percents can occur in cases of high ametropia because a ±2 mm difference
in the camera-to-eye distance does not affect image quality considerably. In addition, according
to Lotmar (1984) changing the camera´s diopter range scales for ammetropia also has an impact
on the magnification of approximately 5 %. Arnold et al. (1993) reported a change in the
magnification from -4.5 % to +6.8 % in myopic conditions, and from -5.6% to +4.6 % in hyperopic
conditions, when the camera-to-eye distance was changed by +/- 5 mm[293]. Their study was
conducted using a model eye.
The essential features of the telecentric principle of the Zeiss fundus camera have been
thoroughly explained in the work of Bengtsson & Krakau (1977) and in the works of Bennett et
al. (1994) and Rudnicka et al. (1998)[295-297]. The following is a summary of the basic features
illustrated in Figure 2.3 adapted from Rudnicka et al. (1998):
Figure 2.3: Ray tracing diagram of an eye in front of a fundus camera. The camera
components of a telecentric imaging system nearest the subject´s eye is represented
as a thick lens and its anterior and posterior principal points denoted with P c and Pc’
respectively. Figure adapted from Rudnicka et al., 1998

CHAPTER 2: METHODS
In Figure 2.3, the two principal points of the eye are marked with P and P´. A1 indicates the
corneal vertex. The distance from P to the eye´s far point plane MR is marked with k and k´ is the
distance from P´ to the retina. The anterior focal length of the camera is fc. Q represents a point
on the retina and gives rise to the ray QP´. The distance between Q and M is t. The camera´s
optical components nearest the subject´s eye are illustrated here with a single thick lens with its
anterior and posterior principal points with Pc and Pc´, respectively. The camera´s anterior
principal focus Fc and the eye´s anterior principal point P are made coincident. The refracted ray
PE is derived from QP´ and forms the angle U with the optical axis. After refraction by the
camera´s imaging system, the refracted ray PE becomes parallel with the optical axis, and the
ray EG will emerge. The distance PcE is equal to y. In a telecentric fundus camera, the image size
on the camera film or image sensor plane is directly proportional to y over a wide range of
ammetropia. The distance y is determined by the angle U, which in turn is proportional to U´.
On refraction, by the eye itself, an image Q1´ will be formed on the eye´s far point plane MR, in
myopia MR is in the front of the eye and in hyperopia behind the retina. Q1´ is located on the
path of the refracted ray PE. It follows that Q1’ will then become an object for the camera´s
imaging system and a second image Q2´ will be formed. Its location can be found as follows: A
ray form NL will be refracted to Fc´, i.e., the posterior focal point of the camera´s imaging system.
The place where this ray crosses the emergent ray EG designates the location of Q2´. Ray EG is
parallel to the optical axis and continues its way to the camera´s film or image sensor plane.
The Topcon fundus camera
Meyer and Howland (2001) found that the results of mean optic disc areas of different racial
groups analyzed with various machines including the Topcon fundus camera differed compared
to those taken with the Zeiss fundus camera[317]. They then calculated a multiplier which was
CHAPTER 2: METHODS
called a normalizing factor for the Topcon and found it to be 1.04 compared to the Zeiss fundus
camera. The normalizing factor for the Zeiss fundus camera was 1.
Quigley and Dubé (2003) introduced a method for estimating the true size of a retinal object
from a fundus photograph taken with two different Topcon fundus cameras (TRC-50F and TRC-
50X; Topcon American Corp)[318]. The distance of the objective lens from the film plane is
altered to bring the image into focus with a focusing knob. The position of the knob was
registered against a fixed point on the camera body with a 180-degree protractor or by a
photocopy of a 150 mm ruler attached on the knob. Their results showed that the position of
the knob correlated highly with the refractive error of the given eye. Thus, an additional step
where the refractive error of the eye is determined by other means was no longer needed.
However, in this method, the eye-camera magnification still needs to be calculated with a proper
formula based on the refractive error of the given eye.
Determining the size of a retinal feature by fundus photography
The magnification of a camera is determined by the optics inside the camera and is usually fixed
for the telecentric camera[213]. While considering the magnification factor of the eye, we need
to focus on two aspects. One is refractive error and the second is the axial length of the eye.
According to Littmann (1982) the true size of an object on the fundus of the living eye obtained
by the telecentric fundus camera is based on the angular diameter of the image [291]. The true
size or diameter of the retinal object (t) equals the multiplication of the measurement of an
image on a photographic film or observed dimension (s) with the magnification factor of the
camera (p) and with the magnification factor caused by the ammetropia of the eye (q) as
described in section 1.9.
𝑡 =𝑝 ∗𝑞∗𝑠
CHAPTER 2: METHODS
This formula is used for determining the true size of a retinal feature from a fundus photograph
taken with the telecentric Zeiss fundus camera[291]. Here t stands for the true size of a retinal
feature, the constant 1.37 (°/mm over the range of ammetropia from -16 to + 17 diopter) applies
to the telecentric Zeiss fundus camera used by Littmann, q (mm/°) is determined by the optical
dimensions of the given eye, and s equals the size of a retinal feature on the camera film. The
quotient q (mm/°) can be determined from nomograms published by Littmann (1982).
𝑡 = 1.37 ∗ 𝑞 ∗ 𝑠
Bennett et al. (1994) further developed the formula of Littmann (1982) into the form of:
𝑡 = 0.01306 ∗ (𝑥 − 1.82) ∗ 1.37 ∗ 𝑠
In the formula of Bennett et al. (1994) Littmann´s q is replaced by 0.01306 ∙ (x - 1.82).
This is derived from the following:
𝑈´ = 𝑡 / 𝑘´
When t is very small (Figure 2.3).
Furthermore, according to small-angle approximation
𝑈´ = 𝑈 / 𝑛
Where n = 1.336 and represents the refractive index of the final ocular medium.
Hence, the size of a given object t on the retina can be expressed by
𝑡 = 𝑘´ ∙ 𝑈´ = 𝑘´ ∙ 𝑈 / 𝑛
From the relationship between degrees and radians it follows
𝑈´° / 360° = 𝑡 / (2 ∙ 𝜋 ∙ 𝑘´)

CHAPTER 2: METHODS
and
𝑡 = (2 ∙ 𝜋 ∙ 𝑘´) ∙ 𝑈´° / 360° = 𝑘´ ∙ 𝑈´° ∙ (𝜋 / 180°) = 𝑘´ ∙ 𝑈° / 𝑛 ∙ (1 / 57.296°)
where n = 1.336.
Thus,
𝑡 = 𝑘´ ∙ 𝑈° / 76.547° = 0.01306 / ° ∙ 𝑘´ ∙ 𝑈°
According to the telecentric system
𝑠 = 𝑈° / 𝑝
where U° is expressed in degrees and p is a constant for the fundus camera used.
Thus,
𝑡 = 0.01306 ∙ 𝑘´ ∙ 𝑠 ∙ 𝑝
Equation 10 corresponds to Littmann´s original formula t = 1.37 ∙ q ∙ s [291]. The constant p
equals 1.37 (°/mm) and is specific to the Zeiss fundus camera used by Littmann. Littmann´s q is
replaced by 0.01306 ∙ k´ in the formula of Bennett et al. (1994).
According to Bennett et al. (1994), even though k´ cannot be determined directly, it can be
closely approximated. This can be done by subtracting the mathematical location of the second
principal point P´ from the apex of the cornea, i.e., by subtracting 1.82 mm from axial length x.
This leads to the final form of the formula
𝑡 = 0.01306 ∗ (𝑥 − 1.82) ∗ 1.37 ∗ 𝑠
The mathematical location of the second principal point P´ of a given eye is subject to varying
forces depending on the power and the location of the crystalline lens and the cornea. Hence,
the constant 1.82 is different between individuals and could be subject to change[295].

CHAPTER 2: METHODS
The reliability of the formula compared to other methods for

calculating the true size of a retinal feature
Bennett et al. (1994) postulated that individual variations in P´ are unlikely to exceed +/- 0.55
mm. This would result in the following change in the formula:
𝑡 = 0.01306 ∙ (𝑥 − 1.82 +/− 0.55) ∙ 1.37 ∙ 𝑠
In total this would result in a maximum error of only
0.01306 ∙ (+/− 0.55) = +/− 0.007
in q.
Garway-Heath et al. (1998) compared different methods of evaluating the size of a retinal
feature. In addition, they identified their sources of error. The method that uses the most
biometric data, namely information concerning axial length, anterior chamber depth, crystalline
lens thickness, keratometry, and ametropia, also presented by Bennett et al. (1994), was the
benchmark. All other methods, including the formula of Bennett et al. (1994) where 1.82 mm is
accepted as the general value of P´, were compared to this method. The other methods
evaluated, and which are presented by different authors, all use various biometric data:
ametropia and keratometry only, axial length and ametropia only [210, 291, 295, 321]. In
addition to these, a new method was presented and evaluated by Garway-Heath et al. (1998) as
well as a method that uses Heidelberg retina tomography. Both methods use biometric
information concerning keratometry and ametropia.
The results of Garway-Heath et al. (1998) showed that when the axial length is known the
formula of Bennett et al. (1994) gives results that are close to the method that uses most

CHAPTER 2: METHODS
biometric data. It is superior in accuracy compared to the methods that use information based
on keratometry and ametropia alone. Hence, if the axial length is known, Garway-Heath et al.
(1998) recommend the use of the formula of Bennett et al. (1994) instead of those methods.
They also discussed the various sources of error of the different methods. All the methods rely
on biometric data derived from measurements carried out to determine the different optical
components of the eye. Therefore, they all are subject to measurement error regardless of the
accuracy of the theoretical basis of the methods themselves[170].
Determining the magnification of fundus photographs taken with the

fundus camera
A checkerboard pattern of a 1-millimetre square is printed on the back surface of the model as
known retinal surface. This model eye (Figure 2.4) was placed in front of the Topcon fundus
camera and was photographed. The true size of one millimetre of the photographed millimetre
square on film was determined by attaching another piece of millimetre paper on the bottom
corner of the film and by taking a photograph of the film with a digital camera and a slide
duplicator.
By this means, a digital image of the film with an image of the original millimetre paper taken
with the Topcon fundus camera and another piece of millimetre paper attached to it was
obtained. This obtained image was then magnified on a 21-inch computer screen. The ratio of
one mm of the photographed millimetre paper on the film and one mm of the millimetre paper
attached to it was then calculated. The result was 0.43388. By this means, the true size of one
mm of the millimetre paper originally photographed with the Topcon fundus camera was

CHAPTER 2: METHODS
obtained. From this digital image of the original millimetre paper photographed with the Topcon
fundus camera the size of one mm of the photographed millimetre paper in pixels was
calculated.
23.05 pixels = 1 digital mm
With the help of the knowledge of the true size of one mm of the millimetre paper on film (one
photographed mm on film was 0.43388 mm), the ratio of one pixel/mm was calculated.
23.05 pixels/0.43388 mm = 53.13 pixel/mm
In this way, the size of one mm of the millimetre paper on film converted to a digital photograph
could be measured in pixels and then calculated in true mm on film.
Figure 2.4: Model Eye used to calculate the size of the object of interest measured in
pixels from a digital photograph.
A, B & D are the width of the corneal, retinal

and lens of the model eye.
C-Cornea
L-Base of the cornea
P-Pupil
V-Vitreous
R-Retina
CL-Distance from the cornea to the lens
LP-Corneal sagittal distance
PV- Distance from pupil to vitreous base
VR-Distance from vitreous base to retina

apex

CHAPTER 2: METHODS
2.6 Summary
To evaluate the aims listed in section 1.10, all the participants from LVPEI-GLEAM study was
evaluated. This chapter summarizes the overall methodology used in this study. Methods
specific to individual chapter are found in the same chapters. This chapter also describes the
method to calculate the actual retinal size using Topcon TRC NW8 camera and its magnification
factors.

CHAPTER 3: PLANIMETRY AND DISC SIZE
3 OPTIC NERVE HEAD PARAMETERS- NORMATIVE VALUES AND

DETECTION OF GLAUCOMA
3.1 Background
As discussed in Chapter 1, most commonly, clinicians rely on a subjective estimate of vertical
CDR as a marker for glaucoma. Although simple in its assessment, it is not an accurate or reliable
diagnostic parameter as it is not objective, varies between examiners and nor does it take into
consideration, for example, the size of the disc versus cup or the area devoted to neuroretinal
rim area particularly any asymmetrical rim narrowing. For example, it is well known that it is
clinically difficult to distinguish physiologic cupping from glaucomatous changes [322, 323] and
at times, glaucomatous change is misdiagnosed as a large CDR. This can be prevented if disc size
is measured because we know that large discs generally have a larger CDR [147, 201, 324] and
therefore can differentiate glaucomatous to physiological cupping with greater confidence.
The importance of disc size in determining disc parameters such as CDR in relation to disc size
was highlighted in a number of recent publications [201, 226, 301, 325, 326]. Budde et al. (2000)
showed that the CDR for disc size has the highest diagnostic power compared to other optic disc
parameters for separating normal participants from pre-perimetric glaucoma patients [325]. The
shape of the neuroretinal rim, the area of neuroretinal rim and cup area relative to disc area are
likely to be more meaningful in discriminating normal versus glaucomatous eyes. Furthermore,
in large scale epidemiological studies as in the present case, a more objective assessment was
important to determine the normal range and values for parameters of the ONH to establish the
normative values for the general population.

The normative values will help establish the threshold or cut-off values for detection of
glaucomatous eyes.
This chapter describes the distribution and determinants of various measures of optic disc
morphology from a normal (non-glaucomatous population) with emphasis on clinically relevant
measures. Additionally, the chapter also explores the diagnostic ability of the optic disc
parameters for diagnosing glaucomatous eyes from normal eyes.
3.2 Aims
1. To develop using the planimetric technique, a normative database of optic disc
parameters from a population-based cohort aged 40 years and above.
2. To determine if planimetric assessments of optic disc parameters improve the
diagnostic ability in differentiating normal versus glaucomatous eyes compared to
subjective assessment of CDR.

3.3 Methods
Participants
The population was 7,666 eyes of 3,833 participants enrolled in the study. A pair of sequential
ONH photographs (parallax of approximately 80) for both eyes were obtained with a digital non-
mydriatic fundus camera, TRC-NW8 (Topcon). However, stereo photographs could not be
obtained for 944 eyes (12.3%) of 559 participants (14.5%) due to dense cataract, corneal opacity,
large pterygium, pupils unable to be dilated due to narrow angles and eyes that needed laser
Iridotomy. Of the 6,722 (87.6%) - optic disc stereo pair images that were obtained, the following
were excluded: 45 (0.7%) stereo pairs were unusable due to poor image quality, 33 (0.5%)
stereo pairs did not have good appreciable stereo depth, 671 (10.0%) images were from
pseudophakic eyes and 35 (0.5%) images were from aphakic eyes [327]. Of the remaining 5,938
(88.3%)-optic disc stereo pairs, images from a further 170 (2.5%) eyes were excluded as they
had features of glaucomatous damage (e.g. rim thinning, rim notch, diffuse or slit retinal nerve
fibre defect or presence of optic disc haemorrhage) and a further 4 images of 4 (0.1%) eyes that
were ocular hypertensive (IOP>21 mm Hg plus normal Humphrey 24-2 visual field) were also
excluded. Additionally, 3,577 (53.2%) eyes were excluded as either the Humphrey 24-2 visual
field was unreliable, or glaucoma hemifield test was flagged as “Outside Normal Limits”. Of the
remaining 2,187 (32.5%)-optic disc stereo pair images, 1,263 (36.6%) participants had only one
eye eligible and 462 (13.4%) participants had both eyes eligible of which one eye was randomly
selected. From the 2187 (32.5%) images, a sample of 150 (6.9%) optic disc stereo pairs that
were age and gender-matched to the glaucoma sample (explained below) was derived randomly
to form test sample-I. Randomization was done using the ‘sample’ command in the base package
of the R-programming without replacement[328]. After deriving the 150 (2.2%) eyes test
sample-I from the 2,187 (32.5%) normal stereo pair optic disc photographs, there were 1,650
(24.5%) participants remaining. One eye from the 1,650 (24.5%) participants optic disc stereo
photographs was used as the sample for normative database.
Considering the 170 (2.5%) stereo pair images that had features of glaucomatous damage, only
125 (1.9%) had reliable field damage correlating with the ONH damage. However, 35 (0.5%)
eyes had visual field glaucoma hemifield test result other than “Outside normal limits” and
therefore were excluded. Of the remaining 90 (1.3%) eyes, had only one eye eligible and 15
(0.4%) participants had both eyes eligible of which one eye was randomly selected. Finally, 75
(1.1%) eyes of the 75 participants were considered as glaucoma test sample-II.
The details of normative and test sample derivation are illustrated in the flowchart of Figure 3.1.

Figure 3.1: Flowchart demonstrating derivation of normal, test samples – I and II

Definitions
Normal : Included both the sample populations of Normative database sample and Test Sample-
I. The population consisted of healthy participants with IOP not higher than 21 mmHg, normal
ONH appearance based on stereoscopic optic disc photographs viewed on stereoscopic viewing,
and a reliable normal visual field result. For the purposes of this analysis, a normal ONH
appearance was defined as a symmetric CDR of less than or equal to 0.6 with an uniform
neuroretinal rim. A “reliable” visual field was a visual field report wherein all reliability
parameters were less than or equal to 33%. A visual field was defined as normal whereinthe
message on the Glaucoma Hemifield Test was flagged as "Within Normal Limits" or "Borderline"
or "General Reduction of Sensitivity" or "Borderline and General Reduction of Sensitivity".
Glaucomatous – Included population from Test Sample-II wherein the ONH demonstrated a
either a loss or thinning of neuroretinal rim, notching, or excavation with an associated visual
field defect in the corresponding location. A glaucomatous visual field defect had three or more
significant (P<0.05) non-edge contiguous points with at least one at the p<0.01 level on the same
side of the horizontal meridian in the pattern deviation plot and graded outside normal limits in
the Glaucoma Hemifield Test.
Procedures
The ONH photographs were assessed using planimetric techniques. Planimetry was conducted
using a custom built software for the 1,650, 150 and 75 stereo optic disc photographs from the
normative, test I and test II samples respectively. The custom software was developed using
MATLAB version 8 (Mathworks Inc., MA). Stereo pairs of ONH photographs from each eye were
displayed together on a 21” LED monitor with an IPS panel. The “Screenscope” (Berezin Stereo
Photography products, Mission Viejo, CA, USA) stereo viewer that permits the use of digital
stereo photographs on a computer screen was used. All markings were made on the right side
of the photograph, under direct stereo-viewing conditions. A screenshot of the custom software
is shown in figure 3.2.
While stereoscopically viewing the optic disc, the disc contour, defined as the boundary of the
parapapillary scleral ring, was determined by a series of 14 points joined with spline
interpolation and the cup contour, defined as the point of change of slope from the cup wall to
the neural rim, was determined as a closed curve by an unlimited number of points placed on
the computer monitor using a computer mouse. The disc centre was automatically calculated as
the centre of the disc area. The central point served as the centre of a circle that was divided
into 12 radial segments each measuring 30o. The ONH was divided into 12 sectors corresponding
to clock hours of SDOCT ONH and RNFL scan analysis protocols. From the disc centre, 12 radial
lines are drawn with 30o apart bisecting the horizontal and vertical raphe as shown in Figure 3.3.
A single observer (glaucoma trained optometrist with 12 years’ experience) made the
measurements.

Figure 3.2: Snapshot of the customized MATLAB Software for planimetry
Figure 3.3: Sketch showing the description of ONH parameters.

3.4 Statistical analysis
Following the marking of the optic disc and rim anchor points, the custom software calculated
and outputs 46 parameters marked which were grouped as a) area & dimensions of ONH; b)
optic disc area for each clock hour(1-12), rim area for each clock hour (1-12); and; c) ratio of rim
to disc area for each clock hour (1-12).
The parameters are as illustrated in Figure 3.3. To commence with, all the 46 parameters were
considered, but thereafter, only those parameters that were found to be correlated with optic
disc area (statistically significant with linear regression analysis) were considered for further
comparison and analysis with the test samples.
Additionally, the optic disc area was considered as a continuous measure and classified into
small, medium and large disc sizes based on the disc area. The optic disc area that was below
mean disc area minus one standard deviation was considered as small disc size. Similarly, the
disc area above the mean disc area plus standard deviation was categorised as large disc size.
All disc size within mean ± standard deviation was considered as medium disc size.
Pearson’s correlation was used to determine the association between continuous variables. For
associations between measures of the same variable on two different procedures (validation of
planimetry software), the intra-class correlation was used. The t-test was used to compare the
means of two continuous variables. The associations between categorical variables were
explored using the Chi-square test. To determine if the ONH parameters were related to disc
size, regression analysis was performed between the optic disc area (as an independent variable)
and each of the parameters (as dependent variables) from the data derived from the normal

control participants. A significant relationship was taken to be one in which p≤0.05 and r2 was
greater than or equal to 0.1.
Assessment of ONH parameters that did not consider or factor in the area of the optic disc were
termed as “Unadjusted”. The unadjusted indices were computed for each of the planimetry
variable on a continuous scale and the Receiver operated characteristic (ROC) curve generated
using a binary categorization of normal versus glaucoma as the outcome variable. The ROC curve
for each planimetry parameter was then used to estimate its sensitivity at 95% specificity. For
those parameters found to vary with disc size, the normal ranges for each parameter were
defined by the 95th percentile prediction intervals from the quantile regression analysis. The
95th percentile prediction interval was chosen for us to develop an analysis method that is of
the greatest use clinically for the detection of glaucoma cases compared to linear
regression[329]. To calculate the 95th percentile predicted values we have adopted the standard
method used in a package “quantreg” with ‘tau’ value of 0.95 from the open-source statistical
programming environment R[330]. The normal ranges were calculated from the normative
database sample described earlier in the methods section 3.3. for each ONH parameter
corresponding to the disc area. The 95th percentile predicted values derived from the normative
database is compared with the test sample I & II actual value, the difference between predicted
to actual values is considered as a new continuous variable. The new parameter generated from
the difference between actual to predicted is computed for each planimetry variable on a
continuous scale and generating the ROC curve using the binary gold standard decision (normal
and glaucoma) as the outcome variable. The ROC curve for each planimetry parameter was then
used to estimate the sensitivity at 95% specificity. When adjusted for disc size, the parameters
were termed as “Adjusted”.

The AUROC was used to describe the ability of each parameter to discriminate glaucoma
subjects from normal subjects. The method of Robin Xavier et al. (2011) was used to compare
the AUROCs of different parameters[331]. Sensitivity for detection of glaucomatous eyes was
determined by obtaining the highest sensitivity values with target specificity set at ≥95%. To
calculate p-values between two AUROCs values DeLong method was used[332]. To calculate the
confidence intervals for AUROC the simple asymptotic method was used [333]. Confidence
intervals are an excellent way of understanding the role of sampling error in the averages and
percentages that are ubiquitous in user research. According to Newcombe (1998) [333], ‘The
usual two-sided confidence interval is thus simply interpreted as a margin of error about a point
estimate’. In setting a confidence interval for a single proportion, the familiar, asymptotic
Gaussian approximation is often used, and for computation simplicity, this approach has the
apparent advantage of producing intervals centred on the point estimate, thus resembling those
for the mean of a continuous normal variate. To assess the agreement between OCT cup area
and rim area with planimetry derived cup area and rim area Bland-Altman plot was done. All
statistical analysis was performed using the R Statistical Software[328]. A p-value of p≤0.001 was
considered a significant difference.
Reproducibility of measurements
Two glaucoma-trained optometrists (JGB, AC) independently traced each image of 50 eyes (50
participants) that were randomly selected on two separate occasions. The images were
presented to the optometrists randomly and they were masked. Intra-class correlation (ICC)
coefficients were computed for the optic disc morphology parameters obtained by the stereo
photographs to investigate the reproducibility of the custom software.

The mean difference between the two optometrists for the vertical ONH diameter was 0.005 ±
0.004 mm, ICC coefficient 0.99; for horizontal ONH diameter, it was 0.004 ± 0.004 mm, ICC
coefficient 0.99 and for area measurements, it was 0.011 ± 0.03 mm2 with ICC coefficient 0.99.

3.5 Results
The demographic and clinical characteristics for the 1650 participants from the normative
database are summarized in Table 3.1.
Table 3.1: Normative database: Demographic and clinical characteristics of
participants (n=1,650)
Standard
Variable Mean Range
deviation
Age (years) 52 9 40 to 85
Gender – Female, count(%) 935 (56.67%)
Gender – Male, count(%) 715 (43.33%)
Visual acuity (LogMAR) 0.08 0.16 0.00 to 1.00
Spherical equivalent (Dioptres) -0.07 1.25 -6.00 to +6.00
Intraocular pressure (mm Hg) 12.5 2.4 5.0 to 21.0
Axial length (mm) 22.65 0.76 20.19 to 30.46
Mean deviation (dB) -3.01 1.91 -5.79 to 2.13
Pattern standard deviation (dB) 1.94 0.65 0.91 to 4.44
Visual field index (%) 97 2 80 to 100
Disc area, mm2 1.90 0.35 1.06 to 3.37
Cup area, mm2 0.66 0.25 0.16 to 1.78
Cup height, mm 0.79 0.15 0.40 to 1.37
Cup width, mm 0.77 0.15 0.38 to 1.37
Rim area, mm2 1.24 0.23 0.61 to 2.28
Cup disc area ratio 0.34 0.09 0.11 to 0.65

As shown in Table 3.1, the study population were adults ranging in age from 40 to 85 years with
the majority of them being females (56.67%). The mean LogMAR visual acuity was 0.08 and
ranged from 0.0 to 1.0. The visual acuity was poor for 4 participants because of early cataract.
The normative database participants included a range of refractive error from +6 dioptres to -6
dioptres and axial lengths 20.19 mm to 30.46 mm with a mean of 22.65 mm. All of them had
normal IOP and was in the range of 5 to 21 with mean 12.5 mm Hg. The mean visual field global
indices were normal but the lower range of mean deviation, pattern standard deviation and
visual field index is again because of 4 patients have an early cataract. The mean disc area was
1.90 mm2 with a mean CDR of 0.34. The mean cup area was 0.66 mm2 and was approximately
half of the mean rim area (1.24 mm2) indicating that most of the normative database
participants had significant rim tissue.
Table 3.2 presents the comparison between the sample from the normative database and test
sample I.
Table 3.2: Demographic and clinical characteristics of participants in test sample I &
normative database sample
Normative database Test sample I
sample (n= 1,650) (n=150)

Variable p-value
mean (S.D.), mean (S.D.),
median [IQR] median [IQR]
Age (years) 52 (8.8), 54 (9.5),

0.0002
50 [45, 58] 54 [47, 61]
Gender – Female, count(%) 935 (56.67%) 75 (50%)

0.1363
Gender – Male, count(%) 715 (43.33%) 75 (50%)
Visual acuity (LogMAR) 0.08 (0.16), 0.08 (0.16),

0.5005
0.00 [0.00, 0.10] 0.00 [0.00, 0.10]

Spherical equivalent -0.07 (1.25), -0.26 (1.54),

0.0951
(Diopters) 0.00 [-0.25, 0.50] 0.00 [-0.69, 0.50]
Intraocular pressure 12.5 (2.4), 12.6 (2.3),

0.7504
(mm Hg) 12.0 [10.0, 14.0] 12.0 [10.0, 14.0]
Axial length (mm) 22.65 (0.76), 22.72 (0.79),

0.3399
22.62 [22.19, 23.09] 22.62 [22.20, 23.23]
Mean deviation (dB) -3.01 (1.91), -2.95 (1.74),

0.7093
-2.88 [-4.06, -1.68] -2.75 [-3.92, -1.61]
Pattern standard 1.94 (0.65), 1.85 (0.58),

0.0999
deviation (dB) 1.79 [1.51, 2.19] 1.73 [1.47, 2.06]
Visual field index (%) 97 (2), 97 (1),

0.1402
98 [96, 99] 98 [97, 99]
Disc area, mm2 1.90 (0.35), 1.90 (0.35),

0.9908
1.85 [1.65, 2.11] 1.84 [1.66, 2.08]
Cup area, mm2 0.66 (0.25), 0.66 (0.26),

0.9035
0.62 [0.48, 0.80] 0.61 [0.48, 0.78]
Cup height, mm 0.79 (0.15), 0.80 (0.16),

0.8183
0.78 [0.68, 0.90] 0.78 [0.69, 0.89]
Cup width, mm 0.77 (0.15), 0.76 (0.15),

0.4744
0.76 [0.67, 0.86] 0.75 [0.66, 0.85]
Rim area, mm2 1.24 (0.23), 1.24 (0.21),

0.8833
1.21 [1.07, 1.37] 1.21 [1.12, 1.34]
Cup disc area ratio 0.34 (0.09), 0.34 (0.09),

0.6421
0.34 [0.27, 0.41] 0.33 [0.28, 0.39]

As observed from Table 3.2, there were no significant differences between eyes from the
normative database and test sample- I for any of the variables except for age. Although the age
differences between the two groups were statistically significant with the test sample I
presenting with a slightly greater age, the difference between the groups was less than few years
and based on the evidence for differences in optic disc parameters versus age it was not
considered to be relevant. The mean disc area, rim area, cup area and cup disc ratio were similar
between the groups.
Figure 3.4 presents the distribution of the ONH area from the normative database participants
and Table 3.3 presents the morphometric characteristics of the same.
Figure 3.4: Frequency distribution of optic disc area in mm2 (n=1,650)
250
210
198 200
200
167
Number of eyes
150 137
131 130
101 102
100
60
50 43 40
31
24 21 17
9 6 7 6
4 2 3 1
0
1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 1.9 2.0 2.1 2.2 2.3 2.4 2.5 2.6 2.7 2.8 2.9 3.0 3.1 3.2 3.3
Disc area in mm2

Table 3.3: Morphometric parameters of optic disc data (n=1,650)
Mean
5th to 95th
Variable (Standard Range Median
percentile
deviation)
Optic disc
Disc area, mm2 1.90 (0.35) 1.06 to 3.37 1.85 1.40 to 2.54
Cup area, mm2 0.66 (0.25) 0.16 to 1.78 0.62 0.32 to 1.13
Rim area, mm2 1.24 (0.23) 0.61 to 2.28 1.21 0.91 to 1.66
Cup disc area ratio 0.34 (0.09) 0.11 to 0.65 0.34 0.20 to 0.49
Disc height, mm 1.40 (0.14) 0.99 to 1.91 1.40 1.19 to 1.65
Cup height, mm 0.79 (0.15) 0.40 to 1.37 0.78 0.56 to 1.07
Cup disc height ratio 0.56 (0.08) 0.32 to 0.82 0.56 0.43 to 0.69
Disc width, mm 1.29 (0.13) 0.92 to 1.85 1.29 1.10 to 1.51
Cup width, mm 0.77 (0.15) 0.38 to 1.37 0.76 0.54 to 1.04
Cup disc width ratio 0.59 (0.08) 0.33 to 0.80 0.60 0.46 to 0.72
Cup disc average ratio 0.58 (0.08) 0.34 to 0.80 0.58 0.45 to 0.70
Rim area clock hour wise
Rim area @ 1, mm2 0.12 (0.03) 0.05 to 0.24 0.12 0.08 to 0.16
Rim area @ 2, mm2 0.11 (0.02) 0.03 to 0.20 0.11 0.07 to 0.15
Rim area @ 3, mm2 0.10 (0.02) 0.03 to 0.20 0.09 0.07 to 0.13
Rim area @ 4, mm2 0.09 (0.02) 0.04 to 0.21 0.09 0.06 to 0.13
Rim area @ 5, mm2 0.10 (0.02) 0.04 to 0.21 0.10 0.07 to 0.15
Rim area @ 6, mm2 0.11 (0.03) 0.05 to 0.24 0.11 0.07 to 0.16
Rim area @ 7, mm2 0.10 (0.02) 0.03 to 0.23 0.10 0.07 to 0.15

Rim area @ 8, mm2 0.09 (0.02) 0.04 to 0.22 0.09 0.06 to 0.13
Rim area @ 9, mm2 0.09 (0.02) 0.03 to 0.19 0.09 0.06 to 0.13
Rim area @ 10, mm2 0.10 (0.02) 0.04 to 0.17 0.09 0.06 to 0.13
Rim area @ 11, mm2 0.11 (0.02) 0.05 to 0.22 0.11 0.08 to 0.15
Rim area @ 12, mm2 0.12 (0.03) 0.05 to 0.26 0.11 0.08 to 0.16
Disc area clock hour wise
Disc area @ 1, mm2 0.17 (0.03) 0.08 to 0.35 0.17 0.12 to 0.23
Disc area @ 2, mm2 0.16 (0.03) 0.08 to 0.30 0.15 0.11 to 0.21
Disc area @ 3, mm2 0.14 (0.03) 0.07 to 0.30 0.14 0.10 to 0.20
Disc area @ 4, mm2 0.15 (0.03) 0.07 to 0.32 0.14 0.10 to 0.20
Disc area @ 5, mm2 0.16 (0.03) 0.08 to 0.30 0.15 0.11 to 0.22
Disc area @ 6, mm2 0.17 (0.03) 0.08 to 0.36 0.17 0.12 to 0.23
Disc area @ 7, mm2 0.17 (0.03) 0.08 to 0.32 0.16 0.12 to 0.23
Disc area @ 8, mm2 0.15 (0.03) 0.07 to 0.29 0.15 0.11 to 0.21
Disc area @ 9, mm2 0.14 (0.03) 0.06 to 0.29 0.14 0.10 to 0.20
Disc area @ 10, mm2 0.15 (0.03) 0.07 to 0.29 0.14 0.11 to 0.20
Disc area @ 11, mm2 0.16 (0.03) 0.08 to 0.31 0.16 0.12 to 0.22
Disc area @ 12, mm2 0.17 (0.04) 0.08 to 0.31 0.16 0.12 to 0.23
Rim-to-disc area ratio clock hour wise
Rim disc area ratio @ 1 0.69 (0.10) 0.33 to 0.94 0.70 0.53 to 0.84
Rim disc area ratio @2 0.69 (0.10) 0.34 to 0.97 0.70 0.52 to 0.85

As seen from Table 3.3, the average ONH area is 1.9 ± 0.35 mm2 (range 1.06 mm2 to 3.37 mm2)
and the most frequently seen optic disc areas were in the range of 1.6 mm2 to 1.8 mm2 with a
median value of 1.84 mm2. The distribution of optic disc area is shown in Figure 3.4. The per
cent of the population in the dataset that had small disc areas (1.0 mm2 - 1.5 mm2) was 14%.
Similarly, the per cent of the population that had large disc areas (2.24 mm2 – 3.3 mm2) was 15%.
With respect to the optic disc cup, the mean area was 0.65 ± 0.24 mm2 and the mean CDR was
0.34 ± 0.08 mm2(range of 0.11 to 0.65 mm2). Considering the rim area clock hour wise, clock
hours 1, 6, 7, 11 and 12 had greater areas compared to the rest indicating a vertically oval disc.
Similarly, the cup area was greater in 1, 2, 6, 7, 11 and 12 clock hour meridians (i.e. superior and
inferior meridians) indicating that the cup was also vertically oval. Overall, the cup to disc area
ratio was greater in 1, 2, 3, 11 and 12 clock hour meridians indicating that the cup occupied more
of the disc area in these meridians compared to the rest.

Figure 3.5: Plot between disc area in mm2 versus cup disc area ratio, cup area, cup
height and cup width parameters (n=1,650)
---- Top dashed line represents 95th percentile

Bottom dashed line represents 5th percentile

Figure 3.6: Plot between disc area versus rim area from 7,8,10 and 11 clock hours
(n=1,650)
---- Top dashed line represents 95th percentile

Bottom dashed line represents 5th percentile

Figure 3.5(A to D) are scatterplots showing the relationship of optic disc area with cup disc area
ratio, global cup area, cup width and cup height. All the 4 parameters show moderate correlation
with disc area. Figure 3.6 (A to D) are scatterplots showing the relationship of the optic disc area
with rim area at 7,8,10 and 11 o’ clock hours respectively. Generally, the scatterplots show a
relation with an increase in disc area associated with an increase in cup disc area ratio, cup area,
cup height, cup width and individual rim areas.
Table 3.4: Linear regression intercept, slope coefficient, standard error of slope, p-
values and r-squared value of optic disc parameters with optic disc area
Standar
Slope p-
Variable Intercept d error R-squared
coefficient value
of slope
Optic disc
Cup area, mm2 -0.335 0.524 0.011 <0.001 0.564
Rim area, mm2 0.335 -0.524 0.011 <0.001 0.564
Cup disc area ratio 0.176 0.088 0.006 <0.001 0.123
Cup height, mm 0.198 0.314 0.008 <0.001 0.511
Cup width, mm 0.205 0.298 0.007 <0.001 0.505
Cup disc height ratio 0.426 0.073 0.005 <0.001 0.102
Cup disc width ratio 0.453 0.073 0.005 <0.001 0.104
Cup disc average ratio 0.439 0.073 0.005 <0.001 0.112
Rim area @ 1, mm2 0.029 0.047 0.001 <0.001 0.432
Rim area @ 2, mm2 0.028 0.042 0.001 <0.001 0.436

Rim area @ 3, mm2 0.026 0.037 0.001 <0.001 0.386
Rim area @ 4, mm2 0.024 0.037 0.001 <0.001 0.362
Rim area @ 5, mm2 0.023 0.041 0.001 <0.001 0.373
Rim area @ 6, mm2 0.025 0.046 0.001 <0.001 0.383
Rim area @ 7, mm2 0.031 0.039 0.001 <0.001 0.311
Rim area @ 8, mm2 0.032 0.032 0.001 <0.001 0.265
Rim area @ 9, mm2 0.028 0.033 0.001 <0.001 0.300
Rim area @ 10, mm2 0.029 0.035 0.001 <0.001 0.341
Rim area @ 11, mm2 0.033 0.041 0.001 <0.001 0.391
Rim area @ 12, mm2 0.027 0.047 0.001 <0.001 0.428
Rim disc area ratio @ 1 0.863 -0.089 0.006 <0.001 0.105
Rim disc area ratio @2 0.861 -0.090 0.007 <0.001 0.102

Linear regression of the optic disc area with parameters such as cup area, rim area and rim disc
area ratio are shown in Table 3.4. It is seen that the optic disc area is significantly correlated with
cup area, cup height and cup width and moderately correlated with rim areas. There is a poor
correlation with a rim-to-disc area ratio which indicates that the rim-to-disc area ratio is
independent of disc size, i.e. for a given disc area, the rim to disc area ratio can vary.

3.6 Diagnostic ability of the predictive normative database
Table 3.5 details the demographic parameters for test samples - I and II. The mean age of the
population from test sample-II was higher, mean visual acuity was 1 line worse and intra ocular
pressure was higher. Furthermore, the visual field parameters such as the mean deviation,
pattern standard deviation and visual field index were significantly different between groups.
This is expected as test sample II were diagnosed to be glaucomatous.
Table 3.5: Demographic and clinical characteristics of participants from the test
sample I & II
Test sample I (n=150) Test sample II (n=75)
Variable mean (S.D.), mean (S.D.), p-value
median [IQR] median [IQR]
Age (years) 54 (9.5), 57 (10.7), 0.0813
54 [47, 61] 58 [48, 64]
Gender – Female, count(%) 75 (50%) 39 (52%) 0.8875
Gender – Male, count(%) 75 (50%) 36 (48%)
Visual acuity (LogMAR) 0.08 (0.16), 0.15 (0.22),

0.0147
0.00 [0.00, 0.10] 0.00 [0.00, 0.20]
Spherical equivalent -0.26 (1.54), -0.27 (1.82),

0.7586
(Diopters) 0.00 [-0.69, 0.50] 0.00 [-1.00, 0.50]
Intraocular pressure 12.6 (2.3), 13.8 (3.5),

0.0031
(mm Hg) 12 [10.00, 14.00] 13 [11, 16]
Axial length (mm) 22.72 (0.79), 22.64 (0.83),

0.4738
22.62 [22.20, 23.23] 22.70 [22.40, 23.16]

Mean deviation (dB) -2.95 (1.74), -10.57 (7.52), <0.0001
-2.75 [-3.92, -1.61] -8.02 [-12.56, -5.26]
Pattern standard 1.85 (0.58), 6.41 (3.40), <0.0001
deviation (dB) 1.73 [1.47, 2.06] 5.70 [3.16, 9.62]
Visual field index (%) 97 (1), 74 (25), <0.0001
98 [97, 99] 85 [70, 90]
Disc area, mm2 1.90 (0.35), 1.92 (0.43), 0.6275
1.84 [1.66, 2.08] 1.92 [1.64, 2.14]
Cup area, mm2 0.66 (0.26), 1.07 (0.35), <0.0001
0.61 [0.48, 0.78] 1.07 [0.85, 1.27]
1.07 (0.16), 0.80 (0.16), <0.0001

Cup height, mm
1.08 [0.97, 1.18] 0.78 [0.69, 0.89]
1.07 (0.17), 0.76 (0.15), <0.0001

Cup width, mm
1.08 [0.96, 1.18] 0.75 [0.66, 0.85]
Rim area, mm2 1.24 (0.21), 0.85 (0.21), <0.0001
1.21 [1.12, 1.34] 0.84 [0.69, 0.96]
Cup disc area ratio 0.34 (0.09), 0.55 (0.10), <0.0001
0.33 [0.28, 0.39] 0.55 [0.49, 0.61]

versus 95% predicted intervals of ONH parameters after adjusting for disc size
AUR Unadjusted Adjusted

OC sensitivity at sensitivity at
Variable Unadjusted Adjusted p- 95% 95%
AUROC AUROC valu specificity specificity
(CI) (CI) e# (CI $) (CI $)
Optic cup-disc ratio 0.830 0.319
(Clinical) (0.773-0.888) (0.244-0.394)
Cup disc area ratio 0.943 0.965 0.740 0.820

0.011
(0.912-0.974) (0.943-0.987) (0.670-0.810) (0.759-0.881)
Cup disc height ratio 0.962 0.970 0.807 0.860

0.103
(0.936-0.988) (0.950-0.991) (0.743-0.870) (0.804-0.916)
0.836 0.967 0.273 0.853

Cup area, mm2 0.000
(0.779-0.893) (0.946-0.988) (0.202-0.345) (0.797-0.910)
Cup height, mm 0.885 0.963 0.638 0.800

0.000
(0.839-0.931) (0.941-0.985) (0.561-0.715) (0.736-0.864)
Cup width, mm 0.906 0.982 0.678 0.880

0.000
(0.864-0.948) (0.968-0.997) (0.604-0.753) (0.828-0.932)
Rim area @ 7 clock 0.929 0.923 0.687 0.653

0.782
hour, mm2 (0.895-0.962) (0.886-0.960) (0.612-0.761) (0.577-0.729)
Rim area @ 8 clock 0.893 0.925 0.433 0.700

0.246
hour, mm2 (0.845-0.942) (0.891-0.958) (0.354-0.513) (0.627-0.773)
Rim area @ 10 clock 0.844 0.854 0.333 0.467

0.778
hour, mm2 (0.790-0.899) (0.804-0.903) (0.258-0.409) (0.387-0.547)
Rim area @ 11 clock 0.876 0.869 0.373 0.400

0.850
hour, mm2 (0.825-0.927) (0.818-0.920) (0.296-0.451) (0.322-0.478)
AUROC- Area under the receiver operating characteristics curve, CI - Confidence interval,
# - Delong method, $ - Asymptotic method

Table 3.6 compares the diagnostic ability of the parameters such as clinical optic CDR, cup-disc
height ratio, cup area, cup height and cup width unadjusted for disc size compared to those
adjusted for disc size for discriminating between normal versus glaucomatous eyes (binary
classification). The AUROC for all the 46 planimetry parameters were measured for both
unadjusted and adjusted for disc area are shown in Appendix-A of chapter 7 but for those
parameters that were found correlated with the disc, size is presented in Tables 3.6 to 3.9.
Further classifying disc area range into small medium and large, AUROC of optic nerve
parameters for discriminating between normal versus glaucomatous eyes were considered.
Both unadjusted and parameters adjusted for optic disc size were considered. Tables 3.7 to 3.9
shows the diagnostic ability of adjusted versus unadjusted disc areas for small, medium and
large disc size respectively.

versus 95% predicted intervals of ONH parameters after adjusting for disc size in small disc
size cohort

AUROC AUROC value specificity specificity
(CI) (CI) # (CI $) (CI $)
(Clinical) (0.742-0.955) (0.202-0.345)

0.179
(0.852-0.999) (0.892-0.998) (0.747-0.872) (0.747-0.872)
0.855 0.960 0.476 0.786

Cup area, mm2 0.017
(0.751-0.959) (0.920-1.000) (0.396-0.556) (0.720-0.851)
Cup height, mm 0.923 0.973 0.550 0.881

0.099
(0.842-1.000) (0.942-1.000) (0.470-0.630) (0.829-0.933)
Cup width, mm 0.939 0.989 0.624 0.952

0.117
(0.869-1.000) (0.970-1.000) (0.546-0.701) (0.918-0.986)
Rim area @ 7 clock 0.961 0.930 0.786 0.762

0.373
hour, mm2 (0.911-1.000) (0.846-1.000) (0.720-0.851) (0.694-0.830)
Rim area @ 8 clock 0.963 0.942 0.881 0.762

0.326
hour, mm2 (0.917-1.000) (0.890-0.993) (0.829-0.933) (0.694-0.830)
Rim area @ 10 clock 0.880 0.817 0.643 0.619

0.023
hour, mm2 (0.795-0.965) (0.713-0.922) (0.566-0.720) (0.541-0.697)
Rim area @ 11 clock 0.926 0.821 0.667 0.476

0.015
hour, mm2 (0.861-0.992) (0.709-0.934) (0.591-0.742) (0.396-0.556)

size cohort

(CI) (CI) # (CI $) (CI $)
(Clinical) (0.796-0.965) (0.283-0.437)

0.726
(0.983-1.000) (0.982-1.000) (0.926-0.990) (0.926-0.990)
0.986 0.991 0.903 0.931

Cup area, mm2 0.403
(0.970-1.000) (0.980-1.000) (0.855-0.950) (0.890-0.971)
Cup height, mm 0.985 0.986 0.903 0.889

0.967
(0.970-1.000) (0.970-1.000) (0.855-0.950) (0.839-0.939)
Cup width, mm 0.991 0.992 0.931 0.958

0.784
(0.980-1.000) (0.981-1.000) (0.890-0.971) (0.926-0.990)
Rim area @ 7 clock 0.951 0.961 0.792 0.819

0.314
hour, mm2 (0.912-0.989) (0.929-0.994) (0.727-0.857) (0.758-0.881)
Rim area @ 8 clock 0.974 0.978 0.889 0.861

0.693
hour, mm2 (0.941-1.000) (0.954-1.000) (0.839-0.939) (0.806-0.916)
Rim area @ 10 clock 0.915 0.931 0.778 0.778

0.269
hour, mm2 (0.861-0.969) (0.885-0.977) (0.711-0.844) (0.711-0.844)
Rim area @ 11 clock 0.935 0.948 0.750 0.708

0.353
hour, mm2 (0.889-0.981) (0.906-0.990) (0.681-0.819) (0.636-0.781)

cohort

OC sensitivity sensitivity at
Variable Unadjusted Adjusted p- at 95% 95%
(CI) (CI) # (CI $) (CI $)
(Clinical) (0.608-0.863) (0.191-0.331)

0.184
(0.837-0.990) (0.871-0.995) (0.420-0.580) (0.504-0.662)
0.851 0.939 0.361 0.611

Cup area, mm2 0.006
(0.752-0.949) (0.880-0.997) (0.284-0.438) (0.533-0.689)
Cup height, mm 0.873 0.911 0.472 0.667

0.177
(0.777-0.968) (0.838-0.983) (0.392-0.552) (0.591-0.742)
Cup width, mm 0.923 0.958 0.644 0.722

0.155
(0.852-0.994) (0.912-1.000) (0.568-0.721) (0.651-0.794)
Rim area @ 7 clock 0.916 0.928 0.833 0.778

0.612
hour, mm2 (0.839-0.992) (0.860-0.997) (0.774-0.893) (0.711-0.844)
Rim area @ 8 clock 0.830 0.860 0.361 0.667

0.512
hour, mm2 (0.720-0.940) (0.767-0.953) (0.284-0.438) (0.591-0.742)
Rim area @ 10 clock 0.854 0.836 0.611 0.500

0.670
hour, mm2 (0.758-0.950) (0.735-0.937) (0.533-0.689) (0.420-0.580)
Rim area @ 11 clock 0.885 0.880 0.556 0.583

0.894
hour, mm2 (0.800-0.969) (0.793-0.967) (0.476-0.635) (0.504-0.662)

Considering table 3.6, it is seen that the clinical evaluation of the cup-to-disc ratio was 0.85. In
comparison, all parameters as obtained with planimetry, i.e. cup area,cup-disc height ratio, cup
width and height and rim areas 7,8, 10 and 11, except for cup area and rim area for 10’0 clock
hour had higher detection accuracy for discriminating normal versus glaucomatous discs
(AUROC of all were 0.87 and above). When adjusted for disc area, the AUROC for all except rim
area 10 improved. When adjusted for disc size, cup width (horizontal) had the highest detection
accuracy.
When consideration was given to disc size (tables 3.7 to 3.9), clinical evaluation of CDR had the
poorest detection accuracy for large discs. When adjusted for disc size, cup width showed the
highest detection accuracy followed by cup area and cup height. Although significant rim areas
10 and 11 had the least AUROC in terms of detection accuracy.

3.7 Discussion
This chapter examines in detail the morphometric characteristics of the optic disc and its
constituent parts, the neuroretinal rim and the optic cup in a relatively large normal population-
based sample of south Indian state using planimetric techniques. Furthermore, the data was
utilised to determine the predictive accuracy of various ONH parameters in being able to
discriminate between normal versus glaucomatous eyes. Our data suggest that of all the ONH
parameters, optic cup width had the highest diagnostic accuracy followed by cup area and cup
height.
Optic nerve head parameters
It has been said that there is racial variation in the size of the ONH. In our sample of 1,650 eyes
aged above 40 years and above using planimetric techniques, the ONH measured 1.90 ± 0.35
mm2 in area and ranged from 1.06 to 3.37mm2. Although the Vellore eye study used stereo
photographs, disc margins were identified by outlining on paper and additionally the sample size
of the study was quite small and may explain the large variability between eyes as found in that
study[203]. In the APEDS, conducted on a larger sample size than the Vellore Eye Study, and in
the same state as the current study, the ONH dimensions were much larger at 3.37 ± 0.68 mm2
[197]. Although that study also used planimetric assessment of the ONH dimensions and
corrected for the magnification factor, the different methodology was adopted and the ONH
constructed as a series of polygons. Furthermore, the smaller sample sizes of the previous
studies would have precluded measurement of sufficient numbers of small and larger disc areas.
Additionally, the CGS reported the ONH area to be 2.82 ± 0.52mm2 and was significantly larger
compared to the previous studies[204]. Although not of the same ethnicity, the measurement

of ONH area from the current study is more in agreement with (disc area 1.77 ± 0.34 mm2) recent
studies, wherein the disc was photographed using OCT and the disc margin detected as the area
where Bruch’s membrane terminates [334]. Further comparisons of ONH analysis using similar
techniques and other Indian populations would be useful to determine if our measurements are
comparable or if indeed significant variability exists between individuals of the same population.
However, our data represents one of the largest normative data sets exploring ONH parameters
from a South Indian population. It should also be noted that the Cirrus™ OCT also has inbuilt
software and algorithms to detect disc margin and cup margin and compute disc area, cup area
and neuro-retinal rim area. However, in the present study we chose to use planimetric
techniques rather than the inbuilt software as: a) the process for identification of ONH margin
and cup margin is not well- defined and b) expensive equipment such as OCT are not used in all
practices and the planimetric techniques lend themselves to be used with any good quality
fundus photograph. As is seen from Figure 3.10, when the cup area as determined by the inbuilt-
algorithm of OCT was compared to the planimetric assessment, when OCT cup area was lower
than that measured by planimetry, there was an underestimation and when the OCT cup area
was larger than the planimetric assessment it appeared to have overestimated the cup area.
This suggests that the identification of the disc margin in OCT uses a different
technique/algorithm. No such differences were seen for cup area.

Table 3.10: Bland-Altman plot between A) OCT and planimetry cup area in mm2 B) OCT
and planimetry rim area in mm2 C) OCT and planimetry disc area in mm2
1.5
Difference between OCT cup area and planimetry cup
+1.96 SD: 0.42

0.5
area in mm2
Mean - 0.01
0
-1.96 SD: -0.40
-0.5
-1
0 0.5 1 1.5 2 2.5
Avarage between OCT cup area and planimetry cup area in mm2
1
Difference between OCT rim area and planimetry rim
0.8
+1.96 SD: 0.54
0.6
0.4
0.2 Mean - 0.12

area in mm2
-0.2 -1.96 SD: -0.29
-0.4
-0.6
-0.8
-1
0.5 0.7 0.9 1.1 1.3 1.5 1.7 1.9 2.1 2.3 2.5
Avarage between OCT rim area and planimetry rim area in mm2

1.5
Difference between OCT disc area and Planimetry disc 1
1.96 SD, 0.52

0.5
Mean, 0.14
area in mm2
-1.96 SD, -0.23

-0.5
-1
-1.5
1 1.5 2 2.5 3 3.5 4
Average between OCT disc area and Planimetry disc area in mm2
As shown in previous studies, the disc area was positively correlated to the neuro-retinal rim
area (1.24 ± 0.23 mm2) and the cup area (0.66 ± 0.25 mm2) respectively [12, 203, 204, 335]. The
relationship is quite significant and indicates that as the disc area increases, both the
neuroretinal and the cup area increase or in other words, there is a near constant relation
between the cup to disc area ratio irrespective of the disc size in normal population. Based on
the planimetry data, this was 0.34 ± 0.09 and ranged from 0.11 to 0.65. Interestingly, although
the optic disc area varied between the various studies described previously, the CDR is similar
between the studies. The CGS measured mean CDR at 0.36 ± 0.18 and was slightly higher in the
Vellore study as 0.37 ± 0.08[203, 204]. Our data demonstrate the horizontal cup width is slightly
larger than the vertical cup width and therefore, the ONH is one where the optic disc is vertically
oval with a horizontally oval optic cup. This relation has been previously reported from other
populations [202, 300].

The CDR is the most commonly used clinical metric to detect glaucoma, but the ratio measured
in the clinic is relative to the size of the disc and is assessed using various means such as a slit-
lamp biomicroscopy with the help of an indirect lens (60D, 78D or 90D) corrected for
magnification factor of lens. But given the variability within a population, a large optic disc can
have a large cup and still be physiological whereas in small optic discs, where the cup should be
smaller a CDR of for example 0.5 can be abnormal. Thus given the variability in optic disc size in
vertical and horizontal dimensions, the variability of optic cup in vertical and horizontal
dimensions, the large variability as demonstrated within and in between populations,
consideration of a single parameter such as a subjective assessment of the cup to disc area can
have low detection accuracy for glaucoma and can be increased by consideration of the disc
size/area.
Apart from CDR we also measured the horizontal and vertical measures of the cup. The mean
cup disc area ratio, cup height to disc height ratio and cup width to disc width ratio is 0.34 ±
0.09, 0.56 ± 0.08 and 0.59 ± 0.08 respectively. The cup disc ratio estimates found in our study
were close to estimates found by Varma et al. (1994) [202], Nangia et al. (2008) for Central India
eye and medical study[335], Chennai Glaucoma study[204] and Tanjong Pagar study[207]. The
mean cup height to disc height ratio in this study was smaller than the mean cup width to disc
width ratio. This change is in slight variation with other studies published[177, 187, 203, 204,
207, 335], which is because of different methods used to measure the ONH parameters.
Additionally, we reported the sectoral neuro-retinal rim area in 30-degree equivalents (or one
clock hour). Previously, planimetry software such as the Discam and scanning laser
ophthalmoscope (HRT) divided the ONH parameters into different sectors ranging from 60
degrees to 30 degrees[218]. Since it has been well characterised that glaucomatous changes
commonly affect the inferior and/or superior poles of the ONH, we chose to divide the ONH and
its constituent regions i.e the neuroretinal rim area and the cup areas into 30 degree equivalents
to be able to examine the relationship between the optic disc area and the neuroretinal rim area
and help improve the predictive accuracy of either the neuroretinal rim area or the disc area in
differentiating glaucomatous versus non-glaucomatous eyes. To the best of our knowledge, a
division of the ONH parameters, i.e. the neuro-retinal rim area and the rim to disc area ratio in
clock hour equivalents has not been previously reported.
The neuroretinal rim was largest in the superior and inferior portions of the optic disc and
followed the previously reported rule wherein neuroretinal rim was considered to be broadest
in the inferior and superior regions. More importantly, our data show that the rim area was
broadest in the superior rather than the inferior rim regions. Linear regression analysis showed
that there is a weak correlation between Disc area and Rim area in clock hour wise. This could
be because the range of possible values is small when the rim area itself is divided into 12
sectors, hence, we anticipated that the rim area will not show much of change with respect to
disc area. In contrary neither CDR nor rim disc area ratio clock hour wise did show any correlation
with disc size and this was expected as the ratio includes the parameter of change itself, hence,
cup-to-disc or rim-to-disc ratio can be considered independent of disc size for an average disc
size.
Diagnostic accuracy of ONH parameters in diagnosing glaucomatous

eyes
Table 3.5 details the ONH parameters between normal and glaucomatous eyes and although the
disc size was similar between the populations, there were significant differences between the
two groups for cup area, cup height and width, rim area and cup-to-disc area ratio. The AUROC
of clinical assessment of CDR as well as the ONH parameters found to be significant such as cup-
to-disc height ratio, cup area, cup width and height, rim area and cup-to-disc area ratio for
discriminating between normal and glaucomatous eyes were calculated. Specifically, rim areas
7, 8, 10 and 11 were found to have a significant correlation with disc size and therefore were
considered in the analysis. The AUROC of the above-mentioned parameters were considered
without relevance to disc size, i.e. as an independent variable and as well as when adjusted for
disc size. The disc size was further categorised as small, medium and large. Tables 3.7 to 3.9
provide the results of the analysis. The best variable to separate between normals and glaucoma
are cup disc ratio, cup area, cup height and cup width.
With regard to a clinical assessment of cup-to-disc ratio, the AUROC of the parameter for
discriminating between normal and glaucomatous eyes was 0.83 (95% CI: 0.77-0.88) but was
poor 0.32 when it was considered at sensitivity with 95% specificity. The results that the AUROC
improves significantly for all ONH parameters calculated using planimetry. Significantly, an
assessment of the cup to disc area ratio improves AUROC to 0.94 (95% CI: 0.91-0.97) and
improves further to 0.97 (95% CI: 0.94-0.98) when adjusted for disc size. Although all the ONH
parameters (i.e. the cup area, cup height and cup width, neuroretinal rim areas 8,9, 10 and 11)
improved the AUROC, cup width (horizontal cup diameter) was the parameter that seemingly
outperformed the other ONH parameters when unadjusted as well as adjusted for disc size.
When the optic disc was further sub-divided into small, medium and large disc sizes and the
AUROCs to discriminate between normal versus glaucoma eyes was considered, AUROCs of all
ONH parameters as measured by planimetry were superior to a clinical assessment of CDR.
Considering the AUROC of the clinical assessment of cup-to-disc ratio, it was 0.85, 0.88 and 0.73
for small, medium and large discs indicating poor discriminatory and detection ability for large
cups. The ability of ONH parameters as measured by planimetry was superior to the clinical
assessment for all ONH parameters that were considered. Especially considering small disc sizes,
rim areas 7 and 8 were superior over others when adjusted for disc size but when adjusted for
disc size, cup width had the highest AUROC. For medium disc sizes, cup-to-disc area ratio and
cup width had the highest discriminatory ability. For large disc sizes, again cup-to-disc area ratio
and cup-width had the highest AUROC over other parameters. Interestingly, at sensitivity with
95% specificity, rim area 7 had the highest AUROC. In our cohort definition for glaucoma was
both disc damage and visual field with three or more significant (P<0.05) non-edge contiguous
points with at least one at the p<0.01 level on the same side of the horizontal meridian in the
pattern deviation plot and graded outside normal limits in the Glaucoma Hemifield Test were
considered as glaucomatous not just large cup-disc ratio hence sensitivity did not change much
after adjusting. Any large cup with normal visual field and no glaucomatous disc damage is
considered as normal. Moreover, in our cohort more than 50% patients have torsional tilt
(macula either superiorly or inferiorly) probably because there was some head tilt during fundus
photo image capturing. Else there is no probable reason why cup width should be a better
discriminator than cup-disc area ratio. These results indicate the poor discriminatory ability of
clinical cup- to disc assessment especially for large discs and planimetric assessment of cup
width and cup-to-disc area ratio both unadjusted and adjusted for disc size had the highest
discriminatory ability. This indicates that considering rim area in isolation without consideration
to the disc size may lead to errors in diagnosing glaucoma. A smaller rim area is considered to
be pathognomonic for glaucoma and in smaller discs, if the disc size is not taken into
consideration then there is an increased risk of misdiagnosis. Differences in reported estimates
of the discriminating ability between instruments may be due to differences in the
characteristics and severity of glaucoma in the study population. Not all the variation in
sensitivities and specificities can, however, be attributed to differences in the severity of
glaucoma in the patients studied. This difference of our diagnostic ability to what reported by
Morgan et al. (2005) may be due to the magnification correction factor which was based on
keratometry and refractive error, a different definition of cup margin and divided neuroretinal
rim by horizontal and vertical raphe[336]. Our results of cup width and cup-to-disc area ratio are
aligned with previous studies that reported cup-to-disc area ratio and rim areas as a good
discriminant [12, 203, 204, 335], but is the first study to report the high discriminatory ability of
cup width both adjusted and unadjusted for disc size and across different disc sizes. Interestingly
our results are somewhat different from those reported by Jonas et al. (2000) and other
previous studies that reported that vertical cup-to-disc ratio had the highest discriminatory
ability[146, 337]. However, there is overlap between the two studies as both reported that when
adjusted for disc size, parameters related to cup versus disc rather than neuroretinal rim area
had a higher discriminatory ability.
Limitations
The patient population for the analysis included residents of Pedanandipadu sub-district.
Although the results based on analysis of the ONH parameters indicate that the population is
similar to other populations from the sub-continent[197, 203, 204], clearly further work needs
to be conducted to determine if the data can be generalisable to the population at large.
In the present study, we took stereo disc photographs and since it does not allow for automated
analysis of the ONH parameters, we had to undertake manual identification of the disc and cup
margins and thereafter analyse it using a software. The process was labour intensive. The
manual and semi-automated nature of the process suggests that it is prone to errors and delays.
Furthermore, the identification of the disc and cup margins does not allow for more in-depth
identification such as the deepest point of the cup. Furthermore, all identification and analysis
of all the planimetry measurements were conducted by a single observer (JGB). Although utmost
care was taken while marking the stereo ONH images viewing stereoscopically, it is also likely
that error with the identification of the disc and cup margins were possible. Automated analysis
of the disc margin is likely to have minimised errors. In this regard, if the examiner repeatedly
identified points to the inside or the outside of the disc margin as detection of the disc margin
then errors are likely to present in a systematic manner, but however, if their errors were few
and random, then such identification errors are likely to minimised due to large sample size of
the the study. Furthermore, although conducted on sample size, the gradings were conducted
by two independent observers and found to be highly correlated. The normative limits for IOP
measurements in GLEAM study were 7.7 to 17.3 mm Hg, this therefore resulted in a few of the
Ocular hypoertensive subjects (n=4) erroneously graded as ‘Normal’. These Ocular
hypertensives were excluded from all, i.e. Normative, Test sample I and Test sample II.
Interestingly, the data also shows that the IOP in the glaucomatous group (Test sample II) was
on an average 13.8 mm Hg and highlights the poor value of utilising intra-ocular pressure
measurements as a diagnostic indicator for glaucoma.
Additionally, the sample used to discriminate the ability between normal and glaucomatous
population was a small sample of 150 eyes and 75 eyes respectively and therefore we were
unable to further subdivide the glaucomatous eyes into mild, moderate and severe glaucoma.
The ability of the ONH parameters to aid in discriminations of the stages of glaucoma would be
quite useful and especially relevant for milder stages of glaucoma where misdiagnosis is more
likely to happen. The highly correlated parameters with disc area did not improve AUROC, the
reason why AUROC did not change as the AUROC will show how the change in disc size the
tradeoff between the sensitivity and specificity.
In summary, our results for ONH parameters are the largest to date from Indian ethnicity. The
data shows differences and variability between previously reported studies in terms of disc area
and may be related to differences in techniques used to calculate the parameters as well as the
high inter-individual variability in the parameters of the ONH. Significantly, the disc area was
related to the cup area and the neuroretinal rim area. We also found that the clinical assessment
of CDR had the poor discriminatory ability for differentiating between normal versus
glaucomatous eyes over planimetric assessment of ONH and this was especially true for large
optic discs. More importantly, planimetric assessments of various ONH parameters, i.e. the cup-
to-disc area ratio, cup area, cup height and cup width as well as rim area assessments were
superior to clinical assessment of CDR for discriminating between normal and glaucomatous
eyes and improved in accuracy when adjusted for disc size. Of all the parameters, cup-to-disc
area ratio and cup width had the highest discriminatory ability and this was true for all disc sizes,
i.e., small, medium and large discs.
CHAPTER 4: RNFL AND DISC SIZE
4 OPTICAL COHERENCE TOMOGRAPHY RETINAL NERVE FIBRE

LAYER PARAMETERS
4.1 Background
Since the 1990's, there have been significant advances in the technology especially with the
introduction of OCT[212] with the ability to scan anterior and posterior segments of the eye.
More specifically, OCT has emerged to be the instrument of choice for characterising and
analysing changes in the RNFL in the para/circum papillary area. There now exists considerable
evidence in the literature on the utilisation of OCT for measurement of RNFL thickness in
detection, diagnosis and progression of glaucoma[213]. Mostly, measurement of the RNFL layer
is based on the utilisation of a circular, circumpapillary scan with a diameter of 3.4mm[309],
which is later segmented by the OCT software to provide a measurement of the RNFL layer
along the 3.4mm circle. Detection, diagnosis or progression of glaucoma is made on the basis of
the comparison of the RNFL measurements made along the 3.4mm circle scan to a normative
database and thereafter classified as “within normal limits”, “borderline” and “outside normal
limits” respectively. Other circum papillary scan diameters that were considered were 2.9mm
and 4.5mm [269]. For example, larger diameter circles may theoretically sample RNFL areas that
are less affected by blood vessel variation and irregularity because large blood vessels branch
into more evenly distributed smaller vessels further from the optic disc. In addition, larger
diameter circles may avoid areas of parapapillary atrophy, which result in RNFL segmentation
errors[338]. In addition, certain studies also considered RNFL thickness measurements along the
entire volume of the scan circle.
Figure 4.1: Sketch showing the gap between disc margin to scan circle in large disc size
and small disc size
However, there has been little work so far that considered the relevance of disc size to
measurements along a 3.4-mm circum papillary scan circle. From Figure 4.1, it can be
appreciated that the distance between disc margin to scan circle is greater with a small disc
compared to a larger disc. For example, with a small disc, a 3.4mm circum papillary scan circle
theoretically samples area further away from the centre of the disc and therefore may sample
RNFL area that is less affected by blood vessel variation similar to that seen with the use of a
large scan circle. Furthermore, as there is variation in RNFL thickness depending on the distance
from the disc margin there may be spurious influences on the results of the RNFL thickness based
on the scan circle, which theoretically assumes a fixed distance from the disc margin. Therefore,
in this chapter, we explored the influence of disc size on RNFL measurements conducted using
a 3.4 mm circum papillary scan and to determine if there is a significant variation in RNFL
measurements along the 3.4mm circumpapillary scan in normal eyes with varying disc sizes.
4.2 Aims
• To determine the distribution of RNFL thickness along a 3.4 mm circumpapillary scan
from a normal population-based cohort.
• To determine if there is an influence of the disc size on the RNFL thickness measurement
conducted using a 3.4 mm circumpapillary scan.
4.3 Methods
Participants
The participants were as described in section 3.3.1. Of the 6,722 (n= 3,448 participants) eyes
for which optic disc stereo pair images were captured, the following were excluded: 45 (0.66%)
stereo pairs were unusable due to poor image quality, 33 (0.49%) stereo pairs did not have good
appreciable stereo depth. Of the remaining 6,644-optic disc stereo pairs (3,433 participants),
the following were excluded: 2,315 eyes (n= 1,630 participants) had unreliable visual fields and
243 (n=159 participants) could not undergo vidual fields testing either due to poor best
corrected visual acuity (worse than 20/600) or could not cooperate with testing. Of the 4,086-
optic disc stereo pair images with reliable visual fields, 1,201 eyes of 852 participants had
spectral-domain OCT scan signal strength less than 6 and were excluded and another 327 eyes
of 252 participants were excluded either because spectral domain OCT scanning could not be
performed (because of cataract, pupil not dilated or participants did not co-operate for SDOCT
scanning) or the results were not optimal due to issues such as eye blink or eye movements
during the scan . A further 91 eyes were excluded as they had the features of glaucomatous
damage (e.g. rim thinning, rim notch, diffuse or slit retinal nerve fibre defect or presence of optic
disc haemorrhage). Additionally, 994 eyes were excluded if the Humphrey 24-2 visual field
glaucoma hemifield test was flagged as “Outside Normal Limits”. Of the remaining 1,478 eyes
(n= 1,062 participants) 5 eyes were diagnosed to have either ocular hypertension or high
refractive error and were excluded and resulted in 1,473 eyes of 1,058 participants (Normative
database sample-II). Details of the normative and test sample derivation are illustrated in Figure
4.2.
Figure 4.2: Flowchart showing the selection of eyes from LVPEI-GLEAM study
4.4 Statistical analysis
RNFL data was exported from OCT version 6.0.2 CIRRUS review software™ to Microsoft Excel.
RNFL data was presented as sample means and standard deviation with 5th and 95th percentile
values. Regression analysis was performed with the optic disc area as the independent variable
and RNFL thickness measurement in each clock hour as well as in 4-quadrants as dependent
variables. Bland-Altman plot was done to assess the agreement between disc area measure with
OCT to disc area measured with planimetry.
4.5 Results
The demographic and clinical characteristics for the 1,473 eyes of 1,058 participants that were
considered for the normative database are summarized in Table 4.1.
Table 4.1: Demographic and clinical characteristics of normative database sample
(n=1,473)
Variable Mean Standard Deviation Range
Age (years) 49.0 7.7 40.0 to 85.0
Gender – Female, count(%) 871 (59.1%)
Gender – Male, count(%) 602 (40.9%)
Visual acuity (LogMAR) 0.04 0.10 0.00 to 1.00
Spherical equivalent (Dioptres) 0.02 0.93 -6.00 to 3.25
Intraocular pressure (mm Hg) 12.0 2.4 5.0 to 21.0
Axial length (mm) 22.62 0.71 20.01 to 25.91
Mean deviation (dB) -2.72 1.78 -11.79 to 2.13
Pattern standard deviation (dB) 1.89 0.60 0.94 to 5.99
Visual field index (%) 97 2 81 to 100
The sample size considered in Table 4.1 is from the LVPEI-GLEAM study cohort. The normative
database consist of normal appearance of ONH, reliable visual fields with glaucoma hemifield
test flagged as “Within Normal Limits”, OCToptic disc cube scans with signal strength of more
than 5 and free from motion artifacts. To get wide range of disc area we have included both eyes
of participants which is a subset of the sample considered previously in Chapter 3(Table 3.1) as
well as the other eye of participants which satisfied the inclusion criteria and therefore the
sample varied slightly. The mean age of the population in Table 4.1 at 49.0 ± 7.7 was slightly
younger compared to the mean age of the larger normative dataset considered in Table 3.1
(mean age 52.0 ± 8.8). Also, the mean spherical equivalent refractive error was more hyperopic
(0.02 ± 0.3D versus -0.07 ± 1.25D). The mean axial length of normative database sample was
22.62 ± 0.71 mm (range 20.01 to 25.91). The mean IOP for the normative database was 12 ± 2.4
mm Hg (range 5 to 21 mm Hg) and was normal. Table 4.2 presents the distribution of RNFL and
ONH parameters for this population.
Table 4.2: Distribution of RNFL and ONH parameters (n=1,473).
Mean
5th to 95th
Variable (Standard Range Median
percentile
deviation)
RNFL (microns)
Average RNFL 94 (9) 62 to 124 94 79 to 109
Quadrant Temporal 58 (9) 34 to 105 58 44 to 74
Quadrant Superior 121 (16) 61 to 175 120 96 to 149
Quadrant Nasal 74 (11) 44 to 131 73 57 to 93
Quadrant Inferior 122 (16) 65 to 178 123 97 to 148
Clock hour 1 114 (23) 46 to 207 112 81 to 155
Clock hour 2 92 (17) 47 to 171 90 66 to 123
Clock hour 3 63 (11) 35 to 106 62 46 to 82
Clock hour 4 68 (13) 37 to 123 67 49 to 91
Clock hour 5 103 (22) 42 to 193 101 70 to 142
Clock hour 6 140 (25) 57 to 233 140 99 to 180
Clock hour 7 125 (23) 49 to 198 124 88 to 162
Clock hour 8 60 (13) 30 to 120 59 42 to 83
Clock hour 9 47 (9) 30 to 112 46 34 to 62
Clock hour 10 68 (12) 31 to 153 67 50 to 88
Clock hour 11 117 (23) 53 to 190 117 80 to 154
Clock hour 12 132 (25) 44 to 213 132 92 to 173
Optic disc
Rim area (mm2) 1.35 (0.22) 0.70 to 2.46 1.32 1.03 to 1.73
Disc area (mm2) 1.99 (0.36) 1.13 to 3.46 1.94 1.48 to 2.63
Cup disc area ratio 0.53 (0.15) 0.06 to 0.84 0.56 0.23 to 0.71
Vertical cup disc ratio 0.50 (0.14) 0.05 to 0.83 0.53 0.22 to 0.68
Cup volume (mm3) 0.19 (0.16) 0.00 to 1.02 0.15 0.01 to 0.50
As seen from Table 4.2, the average RNFL at the 3.4 circumpapillary scan was 94 ± 9 µm.
Considering the RNFL thickness, quadrant wise, the inferior and superior quadrants were thicker
at 122 ± 16 µm and 121 ± 16 µm, respectively. The nasal and temporal RNFL was thinner at 74 ±
11 µm and 58 ± 9 µm, respectively. The differences in thickness between the quadrants were
statistically significant (all p<0.0001). Considering the RNFL thickness, clock hour wise, thickness
was greatest at 6 (inferior) 12 (superior), 3 (nasal) and 9 (temporal) clock hours.
The disc area was 1.99 ± 0.36 mm2 and the rim area was 1.35 ± 0.22 mm2. The cup disc area
ratio was 0.53 ± 0.15 and ranged from 0.05 to 0.83. The optic disc area was divided into small
(1.13 to 1.53 mm2), medium (1.54 to 2.21 mm2) and large (2.22 to 3.46 mm2) disc areas similar
to the method described in section 3.4.
Table 4.3: Comparison of mean RNFL thickness in optic disc size groups
Disc size
All Large Medium Small
Variable
(n=1,473) (n=228) (n=1,042) (n=203) p-value
RNFL (microns)
Mean (S.D.), mean (S.D.), mean (S.D.), mean (S.D.),
[range] [range] [range] [range]
94 (9), 91 (10), 94 (9), 96 (9),

Average RNFL <0.0001
[62, 124] [64, 124] [62, 122] [73, 119]
Quadrant 58 (9), 56 (9), 59 (9), 60 (10),

<0.0001
Temporal [34, 105] [34, 85] [35, 104] [36, 105]
Quadrant 121 (16), 118 (16), 121 (15), 123 (16),

0.0036
Nasal [61, 175] [76, 172] [61, 175] [87, 173]
Quadrant 74 (11), 72 (11), 74 (11), 75 (10),

0.0240
Superior [44, 131] [44, 111] [45, 131] [52, 110]
Quadrant 122 (16), 119 (17), 123 (15), 124 (16),

0.0013
Inferior [65, 178] [77, 172] [65, 178] [72, 174]
114 (23), 113 (22), 114 (23), 114 (22),

Clock hour 1 0.9597
[46, 207] [46, 186] [47, 207] [62, 189]
92 (17), 90 (18), 92 (17), 91 (16),

Clock hour 2 0.2963
[47, 171] [51, 135] [47, 171] [53, 134]
63 (11), 62 (11), 63 (11), 64 (11),

Clock hour 3 0.1385
[35, 106] [37, 99] [35, 106] [38, 98]
68 (13), 65 (13), 68 (13), 69 (13),

Clock hour 4 0.0006
[37, 123] [38, 108] [37, 123] [40, 102]
103 (22), 101 (24), 103 (22), 103 (22),

Clock hour 5 0.2054
[42, 193] [53, 193] [42, 186] [55, 167]
140 (25), 136 (26), 140 (25), 142 (25),

Clock hour 6 0.0449
[57, 233] [74, 204] [57, 233] [78, 218]
125 (23), 121 (23), 125 (22), 128 (24),

Clock hour 7 0.0018
[49, 198] [49, 189] [56, 198] [69, 184]
60 (13), 58 (12), 61 (13), 62 (14),

Clock hour 8 0.0011
[30, 120] [30, 92] [33, 120] [32, 107]
47 (9), 45 (9), 47 (9), 48 (10),

Clock hour 9 0.0028
[30, 112] [30, 108] [30, 103] [30, 112]
68 (12), 65 (12), 68 (12), 70 (12),

Clock hour 10 <0.0001
[31, 153] [37, 128] [31, 153] [37, 106]
117 (23), 111 (23), 118 (22), 120 (23),

Clock hour 11 <0.0001
[53, 190] [53, 177] [54, 190] [68, 183]
132 (25), 130 (24), 133 (25), 133 (26),

Clock hour 12 0.2139
[44, 213] [60, 199] [44, 213] [71, 196]
From Table 4.3, considering the RNFL thickness across different disc sizes, although the
differences were found to be statistically significant for many of the quadrants/clock hours, the
differences in thickness between the groups were less than 10 µm. The largest difference of 9
µm between large and small discs was found at 11’0 clock followed by 7 0’ clock hour at 7 µm.
Irrespective of the percentile cut-off, the differences in RNFL thickness at the 3.4mm
circumpapillary scan circle for small, medium or large discs were minimal and insignificant.
Table 4.4: Table showing 95th, 5th and 1st percentiles of all(n=1,473), small(n=228),
medium(n=1,042), and large(n=203) RNFL thickness parameters.
Optic disc size

Variable All Small Medium Large
RNFL (microns)
95% 5% 1% 95% 5% 1% 95% 5% 1% 95% 5% 1%
Average RNFL 109 79 73 106 75 71 109 80 75 112 80 75
Quadrant
74 44 40 71 42 39 74 45 40 79 44 39
Temporal
Quadrant Nasal 149 96 84 144 90 84 149 98 84 150 96 90
Quadrant
93 57 51 91 55 49 93 57 51 92 60 53
Superior
Quadrant
148 97 85 144 90 83 149 99 86 152 98 92
Inferior
Clock hour 1 155 81 67 150 82 65 156 81 67 154 80 73
Clock hour 2 123 66 56 120 65 56 123 66 56 123 67 56
Clock hour 3 82 46 40 82 45 38 82 46 40 82 49 43
Clock hour 4 91 49 41 87 46 40 92 49 41 92 50 48
Clock hour 5 142 70 60 141 68 58 144 70 60 139 67 60
Clock hour 6 180 99 81 178 94 80 181 100 81 181 102 81
Clock hour 7 162 88 73 161 81 70 160 89 74 167 91 76
Clock hour 8 83 42 37 79 40 35 83 43 37 87 42 35
Clock hour 9 62 34 31 61 33 31 61 34 31 67 35 32
Clock hour 10 88 50 42 87 47 41 87 51 42 93 52 41
Clock hour 11 154 80 69 149 74 63 154 80 71 159 85 71
Clock hour 12 173 92 77 166 91 78 173 93 76 178 90 77
Figure 4.3: Plot showing the difference in RNFL thickness between small(n=228),
medium(n=1,042), and large(n=203) 95th, 5th and 1st percentiles measured on 3.4 mm
circle diameter
13 12
11
RNFL thickness (microns)
11 10 10
9
9 8 88 8 8 8 8 8
Difference in
7 6 666 6 6 6 6
5 5 5 5 5
5 4 4 4 4 4
3 3
3 2
1
2 2
1
2 2
1
1 0 0 0 0 0
-1
-1 -1-1
-3 -2 -2
-5
Quadrant Clock hour

Large-Small 95th Large-Small 5th Large-Small 1st
13
11
9
Difference in
7 7
6 6 6 6 6
7 5 55 5
4
5 3 3 3 33
2 2 22
3 1 1 1 11 1 1
00 0 0 0 0 0 0 0 0
1
-1
-1-1 -1 -1 -1 -1 -1
-3 -2 -2 -2
-3 -3
-5
-5
Quadrant Clock hour

Large-Medium 95th Large-Medium 5th Large-Medium 1st
13
11 9
9 8 8 8
Difference in
7
7 6 6 6
5 5 5 5 5
5 4 4 4 4
3 33 3 3 3 3 3 3
3 222 2 2 22 2 2
1 1 1 1 1 1 1
1 0 0 0 0 0 0
-1
-1 -1
-3 -2
-5
Quadrant Clock hour

Medium-Small 95th Medium-Small 5th Medium-Small 1st
Figure 4.4: Scatterplot showing Disc area in mm2 and average RNFL thickness
between small, medium and large disc sizes
Scatterplot showing disc area in mm2 and average RNFL

thickness in small disc size
130
Average RNFL thickness
120
110
in microns
100
90
80
70
60
50
1 1.1 1.2 1.3 1.4 1.5 1.6 1.7
Disc area in mm2

thickness in medium disc size
130
120
110
in microns
100
90
80
70
60
50
1.6 1.7 1.8 1.9 2 2.1 2.2 2.3 2.4
Disc area in mm2

thickness in large disc size
130
120
110
in microns
100
90
80
70
60
50
2.3 2.4 2.5 2.6 2.7 2.8 2.9 3
Disc area in mm2
Table 4.4 and Figure 4.3 show the 95th,5th and 1st percentile of RNFL thickness for small, medium
and large disc sizes and its differences between groups similar to the normative database cut-
offs in the OCT software RNFL analysis. By this, we want to represent the same cutoff which OCT
instrument uses but for different disc size. With respect to both large and small discs, the
difference for 95th percentile was greatest for clock hour 11 and 12 and the difference between
5th percentile values was greatest for clock hour 7. Figure 4.4 are scatter plots illustrating the
correlations between average RNFL thickness and ONH area in small, medium and large disc
area respectively. Comparing the scatterplot between small, medium and large disc size small
disc with low disc area showed thinner average RNFL (7.45 microns thinner on average) whereas
there was no significant difference between in average RNFL thickness between medium and
large disc size. This is precisely the areas where there is a maximum number of nerve fibres
converge. Similarly, between Inferior quadrant and superior quadrant, the difference between
all percentiles is high in Inferior to superior(9 µm for inferior and 6 µm for superior). Comparing
the large disc size to medium disc size for clock hour 7 has a difference of 7 µm for 95th followed
by clock hour 10 and clock hour 4 for 1st percentile. When comparing medium disc size group to
small disc size group there is a difference of 9 µm for inferior quadrant and 8 µm difference for
superior and clock hour 7 in the 5th percentile cutoffs. Similarly, there is a difference of 7 to 8
µm for clock hour 12 and clock hour 11 with 1st and 95th percentile cutoffs respectively.
Table 4.5: Correlation of optic disc parameters, age, gender, axial length and RNFL
parameters with optic disc area
Standard
Slope
Variable Intercept error of p-value R-squared
coefficient
slope
Optic disc
1.026 0.171 0.017 <0.001 0.064

Rim area, mm2
Average cup disc ratio 0.135 0.213 0.010 <0.001 0.224
Vertical cup disc ratio 0.115 0.207 0.010 <0.001 0.236
Cup volume, mm3 -0.271 0.247 0.011 <0.001 0.262
RNFL (microns)
86.998 3.765 0.718 <0.001 0.018

Average RNFL
Quadrant Temporal 51.305 3.835 0.712 <0.001 0.019
Quadrant Nasal 112.618 4.489 1.229 <0.001 0.009
Quadrant Superior 70.502 1.954 0.868 0.024 0.003
Quadrant Inferior 113.906 4.568 1.233 <0.001 0.009
Clock hour 1 113.831 -0.074 1.800 0.967 0.000
Clock hour 2 90.402 0.729 1.368 0.594 0.000
Clock hour 3 59.695 1.611 0.867 0.063 0.002
Clock hour 4 61.322 3.559 1.025 0.001 0.008
Clock hour 5 100.947 1.072 1.743 0.538 0.000
Clock hour 6 129.302 5.499 1.963 0.005 0.005
Clock hour 7 111.300 7.220 1.770 <0.001 0.011
Clock hour 8 53.112 3.883 0.991 <0.001 0.010
Clock hour 9 41.982 2.661 0.732 <0.001 0.009
Clock hour 10 58.881 4.921 0.947 <0.001 0.018
Clock hour 11 96.219 11.120 1.780 <0.001 0.026
Clock hour 12 127.939 2.365 1.952 0.226 0.001
Table 4.5 shows that the optic disc area is moderately correlated with the average cup-to-disc
ratio, vertical cup-to-disc ratio and cup volume and poorly correlated with RNFL thickness.
Figure 4.5 presents the Bland-Altman plot comparing the disc area measured with OCT versus
planimetric assessment of fundus photographs and the results indicate that the disc area as
measured by OCT was slightly greater at an average of 0.13 mm 2 compared to the disc area
measured using planimetry techniques.
Figure 4.5: Bland-Altman plot between disc area measured by OCT and planimetry
0.8
Difference between OCT disc area and
0.6 +1.96 SD: 0.48

Planimetry disc area in mm2
0.4
0.2
Mean: 0.13
0
-1.96 SD: -0.22
-0.2
-0.4
-0.6
-0.8
-1
0 0.5 1 1.5 2 2.5 3 3.5 4
Avarage between OCT disc area and planimetry disc area in mm2
4.6 Discussion
To our knowledge, our results of parapapillary nerve fibre layer thickness from a South India
cohort is the largest to date. The data indicates that the average nerve fibre layer thickness
along a 3.4mm circumpapillary scan for an adult South Indian population was 94 ± 9µm.
Comparing these results to an earlier assessment we conducted on a small population of 201
eyes aged 33 ± 20 years using a 3.4 scan circle on Stratus OCT, the average thickness of RNFL
was 97 ± 11 µm[233]. It has been well established that RNFL shows a decrease in thickness in
age due to age-related loss of the nerve fibre layers and thus for a comparative age group of >
50 years, the mean RNFL thickness in the previous study was 92 ± 10 µm and is comparable to
the data obtained from the current study. In comparison, in a small sample of adults from
Hyderabad aged 36 ± 14 years, the mean RNFL thickness as measured with a Cirrus OCT was
approximately 108 µm and decreased with age[339].
As previously reported, our results also confirm the regional variation of the retinal fibre layer
thickness, also referred to as “double-hump” configuration wherein maximal thickness was
found in the vertical meridian at the opposite poles of superior and inferior quadrants and
minimal thickness in the temporal quadrant. Is there truly a regional variation in RNFL thickness
across the various quadrants? Considering the thickness clock hour wise it is seen that the
maximal thickness was at 12 and 6 o’clock hours and thinnest temporally at 9 0’ clock followed
by 3 0’ clock. Thus it possible the the double hump configuration is artefact induced by using a
circular scan diameter over a vertically oval optic disc and is best determined by applying and
estimating the thickness along a circum papillary oval ring which ensures that the measurement
point is equidistant from the disc margin across all meridians. Although histological
measurements revealed a thinner RNFL in the temporal quadrant the differences between
superior, inferior and nasal quadrants were less exaggerated in comparison to the data obtained
from the current study and other studies that used an OCT to measure the RNFL[238, 257, 340-
345].
In addition to the application of a circular scan, a further consideration is the impact of the size
of the optic disc on the measurements along the circumpapillary scan. In the event of a smaller
optic disc, the distance from the optic disc margin to the point along the 3.4mm scan would be
greater than if the disc were larger.
RNFL thickness at 3.4mm circumpapillary scan circle and influence of

disc area on RNFL thickness
To optimize the detection of abnormal thinning in the circumpapillary area and therefore
possible glaucomatous changes, it is important to account for factors that can affect the
measured RNFL thickness at the circum papillary area. It is well established that there is a
decrease in the circum papillary RNFL thickness with age with certain studies also reporting a
quadrant specific decrease in RNFL thickness with age[346]. Additionally, eye length or spherical
equivalent refractive error also found to have an effect. Eyes with longer axial length or more
myopic refractive error were said to have less RNFL. It is well known that OCT is a telecentric
camera mounted on a slitlamp but also gets affected by the magnification factor of the eye[228,
241]. Both TD-OCT and SD-OCT operates with a default axial length of 24.56 mm and refractive
error of 0 Diopters. As the axial length of the eye changes the resultant magnification effect of
eye changes and hence the resultant scan circle diameter is affected. Huynh et al. (2006) showed
with the difference in axial length the scan circle would also have magnification effect and the
resultant would be scanning at a different distance apart from proposed 3.4mm diameter[347].
Budenz et al. (2007) showed that there is a possibility that OCT measurements are affected
optically by greater axial length and higher myopia, producing apparently thinner RNFL as an
artifact[241]. An opposite counteracting effect might occur simultaneously, if the greater axial
length would affect OCT measurements optically with an increasing scan circle in a larger eye,
measuring RNFL in a greater distance from the optic disc margin. In conclusion, when the optic
disc area is of importance for the predictive power of the OCT, axial length or refractive error
should be considered. In the present study, we simply used the OCT data and as the RNFL
thickness is associated with biometry, we assume that the resultant RNFL thickness was
corrected for axial length .
Althought refractive error is a corollary of eye length, a number of factors limit the direct
application of spherical equivalent refractive error to correct for any magnification changes. For
example, a myopic shift in refraction might be induced by nuclear sclerosis/ developing cataract
and it might therefore not always be related to the size of the eye. In clinical settings, refractive
error as a substitute for axial length can only be applied to phakic patients.
In addition to these previously reported findings, we hypothesised that the disc size also has an
influence on the RNFL thickness at 3.4mm circumpapillary circle. Indeed, hiistological studies
showed that the RNFL thickness increases with increasing distance from the disc margin,
however, the sample size was small[245].
In the present study, the disc area for small to large discs ranged as follows: small at 1.13 to 1.53
mm2, medium 1.54 to 2.21 mm2 and large 2.22 to 3.46 mm2 disc areas. In a previous study
conducted by Budenz et al. (2007) the range of disc area was from 0.85 to 4.06 mm2, whereas
in our study the range of disc area as measured by OCT and ranging from 1.13 to 3.46 mm2 was
smaller and importantly a majority of the eyes i.e. nearly 71% had medium sized discs and
therefore, the sample size for small and large discs was limited.
Budenz et al. (2007) showed from Stratus OCT™ that with every unit increase in mm2 of disc area
there is a change of 3.3 µm increase in average RNFL thickness[241]. In contrast, in the present
study, there was no significant change in in RNFL thickness with an increase in disc size. Our
results are similar to those by Mansoori et al.(2010) who had reported RNFL thickness for a
population from Hyderabad city[348]. It should be noted that the sample size of Budenz and
Mansoori were quite small and in addition, the age range in Budenz study was quite large at 18
to 85 years. Furthermore, the population was signficiantly Caucasian at 63% followed by
Hispanics at 24%. In contrast, although the age range of our current population was still quite
wide and ranged from 40 to 85 years they were all adults and therefore subjected to lesser
variability than in the Budenz study. Given that, although the sample size for small and large
discs was smaller, it was substantially large enough to provide confidence that there was no
signficant change in the RNFL thickness across the various disc sizes.
Furthermore, in the current study, there was no correlations between ONH size versus
segmented RNFL thickness (i.e. quadrant and clock hour wise). Previous studies have found that
RNFL thickness measured at a fixed diameter was positively correlated with the optic disc
area[242, 243]. In a study by Kaushik et al.(2009), the peripapillary RNFL of 32 normal eyes was
scanned with the fast-scanning protocol at a diameter of 3.4 mm using Stratus OCT and disc area
did not affect RNFL thickness measurement. They found the similar results and suggested that
RNFL thickness is dependent on the distance from the centre of the optic disc rather than the
point of exit from the scleral canal and that RNFL thickness should be measured at similar
distances from centre of the optic disc, regardless of the size of scleral canal[349]. The
implication was that the number of nerve fibres in the RNFL depends on the disc area, and it
might be possible to reduce the variation in the measured RNFL thickness if the scan diameter
was adjusted according to disc diameter. In our study, the correlation between the RNFL
thickness and apparent disc area could be explained by the image magnification variation due
to the variation of the axial length of the eye. Different investigators have proposed performing
OCT scans at either fixed distance from the optic disc margin[243, 246] or perform OCT scanning
at a fixed diameter, and then perform adjustment for optic disc size using a mathematical
formula. Budenz et al. (2007) corrected the magnification differences between fundus cameras
but did not account for the magnification variation due to axial length variation[241]. Thus, the
link between RNFL thickness and apparent disc size that was found by Savini et al. (2007) and
Budenz et al. (2007) was probably due to the magnification artifact rather than a true anatomic
correlation[241, 310].
In addition to RNFL thickness when considering the optic disc margin segmentation with OCT to
test whether OCT can replace the digital planimetry as a gold standard for measuring the ONH
parameters in a clinical setting. We showed that when compared with OCT, digital planimetry
showed smaller measures of ONH size. This is because retinal pigment epithelium is referred to
as the edge of disc margin for OCT measurements, while the inner border of Elschnig’s ring is
used for planimetry. Peripapillary atrophy may additionally limit the use of the OCT method for
determining the optic disc border in glaucoma patients based on retinal pigment epithelium.
While this effect is known to cause significant discrepancies in some patients, it does not occur
in all and seems to not generally impair the results in glaucoma patients.
Limitations
It is a limitation that the current study was cross sectional in nature and thus longitudinal
differences in age and relation with growth patterns could not be explored in detail.
Furthermore, although the sample was quite large it was limited to adult individuals only. It has
been said previously that there exists a decay of approximately 1.5 to 2 µm RNFL thickness per
every year, and although this change may be small and insignificant for differentiating between
normal versus glaucomatous eyes, it still is important to consider and account for age in models
that use RNFL thickness to different between normal versus glaucomatous eyes. A further
limitation is that the refractive error of range ± 6.00 Diopter range of our study is limited as it
does not take into consideration, for example, high myopia. In this regard, while some studies
demonstrated an increase in thickness with high myopia,[249, 350, 351] other studies
demonstrated no influence of myopia on RNFL[262]. Additionally, although it is advisable to
correct for magnification factor of the eye while evaluating the RNFL thickness, such correction
factors were not applied in the study as we assumed that entering the values in the software
would take care of magnification factor as reported by Huynh et al. (2006) [347]. The ideal scan
radius of the peripapillary RNFL thickness has not investigated fully.
With consideration to disc size, it is seen that a majority of eyes in the present study fell into the
medium category with only approximately 15% of eyes having small or large discs respectively.
Although the large sample size meant that we still had couple of hundred of small and large discs
that were included in the analysis, it is a short coming of the current study that the sample size
was unequal and therefore may have implications for our conclusion that there was no effect of
disc size on the RNFL thickness. In addition, other patient related factors such as correlations
between right and left eyes, influence of gender were considered as they were not found to
associated with RNFL thickness previously. Furthermore the data was also not adjusted for
diurnal variations in the status of RNFL thickness.
In summary, we present the RNFL thickness at a circumpapillary scan diameter of 3.4mm for a
large, normal adult cohort from South India. The data serves as a reference for detection of
abnormal RNFL changes and especially useful for detection of glaucomatous changes. Although
it was hypothesised that the disc area could potentially influence the measurements of RNFL
thickness at a fixed scan circle diameter of 3.4mm, our data from this large cohort failed to reveal
any relation with respect to disc area and RNFL thickness at the 3.4mm scan circle. Although
there some differences in certain sectoral regions (6,7 and 11 clock hours) for RNFL thickness
between small versus large discs the differences were small. Our results indicate that there is
no adjustment needed for disc size when considering the RNFL thickness at 3.4mm
circumpapillary scan diameter.
CHAPTER 5: CONCLUSION
5 DISCUSSION AND CONCLUSION
5.1 Introduction
Glaucoma is a progressive condition characterised by optic neuropathy and therefore, resulting
in an irreversible loss of visual field and therefore, functional vision. In the year 2040, glaucoma
is estimated to affect approximately 111 million. Early detection of glaucoma is critical to
prevent loss of functional vision. Over the years, evaluation and assessment of ONH for
glaucomatous changes and an assessment of visual field has the cornerstone for detection and
management of glaucoma. As already discussed in section 1.4, testing of the visual field is time-
consuming and standards for mass screening are not clearly defined. However, the introduction
of technology such as OCT that enables a more detailed assessment and measurement of the
retinal layers has revolutionised management of glaucoma and excitingly have provided with
avenues to better detect and manage glaucoma.
With respect to examination of the ONH, combining the advantages of OCT with a more
objective evaluation of the ONH taking into consideration for example the disc area and the
constituent areas such as cup area and neuro retinal rim area with planimetric techniques offers
yet another diagnostic ability and provides improved sensitivities and specificities for diagnosing
glaucoma over traditional techniques alone. Samarawickrama et al. (2009) reported that
planimetry was more sensitive to small ONH size over OCT[352]. This is because the OCT is
unable to differentiate between the portion of the neuroretinal rim occupied by the trunk of the
central retinal vessel to that occupied by the nerve fibre tissue. This would make OCT
overestimate the rim for small or physiological normal ONH, in our study from figure 4.5 we can
see that difference. Apart from glaucoma diagnosis, OCT plays a major role in detecting the
progression of glaucoma as OCT has the advantage of the highest resolution and less intra and
interobserver variability[353].
The objective of this thesis was to study the distribution of optic disc parameters as measured
by digital planimetry and RNFL thickness in a large cohort of normal population. Thereafter I
planned to compared the ONH and RNFL thickness parameters between normal and
glaucomatous eyes and to determine if ability to detect glaucoma can be improved with a)
planimetric assessment of ONH parameters compared to a subjective assessment of CDR as
conducted clinically and b) consideration of disc size in assessment of ONH parameters and
RNFL thickness.
5.2 Population based study and key findings
The aims of the study were systematically addressed as part of a large–scale, population-based
cohort study conducted in South India from 2011-2013. A total of 3833 adult participants, aged
40 to 85 years enrolled, and a complete ocular assessment conducted including posterior
segment OCT. ONH parameters (disc, cup and neuro-retinal rim) were extracted, measured and
analysed using planimetric techniques and custom software. From the OCT images, RNFL data
for the 3.4mm scan circle was extracted. The eyes were divided into 3 sets: normative, test
(normal) and test (glaucomatous) eyes. ONH parameters were categorized using the normative
dataset. Using the test sets, the AUROC for the ONH parameters in detecting glaucoma was
determined and compared against a subjective assessment of CDR. The RNFL measurement and
ONH parameters were adjusted for disc size to determine if the accuracy in diagnosing glaucoma
could be improved.
The key findings of the study with respect to the two main aims are:
a) planimetric assessment versus subjective assessment of the ONH parameters
• The study is the largest to date to consider and report on the normative data
for ONH parameters for a South Indian population The mean optic disc, cup and
rim area for normal eyes were 1.90 ± 0.35, 0.66 ± 0.25 and 1.24 ± 0.23 mm2
respectively and disc area was highly correlated to cup area, rim area, cup height
and width respectively (r2 = 0.564, 0.515, 0.511, 0.505 respectively, p<0.001).
• With respect to detection of glaucoma, ONH parameters namely cup-to-disc
area, cup area, cup width and height and sectoral neuro-retinal rim areas (8, 9,
10 and 11) had a better discriminatory ability (AUROC >0.9) over subjective cup-
to-disc ratio (AUROC 0.83) and improved further when adjusted for disc area.
Our study is the first to date the outlines the importance of cup width in addition
to the previously reported parameters of cup-to-disc area and vertical cup
height.
b) Influence of disc size in the assessment of circumpapillary RNFL thickness
• We measured the circumpapillary RNFL thickness using a 3.4 mm scan circle,
and as with the ONH parameters the report of RNFL thickness in a normal South
Indian population is the largest reported to date. The data indicates that for an
adult, South Indian population, the average RNFL thickness at the 3.4mm scan
circle was 94 ± 9 µm and was thickest in the superior and inferior quadrants and
thinnest in the temporal and nasal meridians. In the present study, the disc area
for small to large discs ranged as follows: small at 1.08 to 1.53 mm2, medium
1.54 to 2.21 mm2 and large 2.22 to 3.26 mm2 disc areas. A majority
(approximately 70%) of the discs were medium in size, approximately 15% were
small and the remaining 15% were large. The data indicated that the disc area
(or the size of the disc) was not correlated to RNFL thickness. Therefore
clinically, an output of the RNFL thickness at the circumpapillary scan circle of
3.4mm is enough to consider if the values were suggestive of glaucoma or
attributed to normal physiology without needing to consider the influence of
disc area.
This study has several strengths with the sample size for the cross-sectional population-based
of age group 40 years and above being one of the largest considered to date. Additionally, the
study had a high response rate for sampling the population, had a standardised examination
protocol with rigorous methods applied to measurement of variables from the population.
With respect to the specific aims of the study, namely ONH parameters, we had considered and
applied parameters to adjusted for the magnification of eye. Furthermore, all planimetric
assessments (after appropriate inter observer correlation was performed) were performed by a
single masked observer and therefore the risk of inter-observer variation and observer bias were
minimised.
The study also suffered from several limitations. Although the planimetry technique for
assessment of ONH parameters had its advantages, the process was laborious, time intensive
and the semi-automated nature involving single observer indicates it is prone to bias and errors.
Also, the planimetric technique is limited in its ability to identify important landmarks of the
ONH. Whilst the normative dataset was large, the sample used to discriminate the ability
between normal and glaucomatous population was small at 150 eyes and 75 eyes respectively
and therefore we were unable to further subdivide the glaucomatous eyes into mild, moderate
and severe glaucoma. Similarly, when considering the influence of disc size, the sample size for
small and large discs was small in proportion to the number of eyes with medium sized disc.
Although the results from the study based on analysis of the ONH parameters and RNFL
thickness indicate that the population is similar to other populations from the sub-
continent[197, 203, 204], clearly further work needs to be conducted to determine if the data
can be generalisable to the population at large.
Based on the key findings, strengths and limitations of the study, I believe that the future
research should consider the following points
• Improve the generalisability of the current data to population at large by considering an
expanded sample size of normal versus glaucomatous eyes for evaluation of the
sensitivity and specificity of planimetric assessment of ONH parameters in detection of
glaucoma over subjective clinical assessment of CDR. Furthermore, inclusion of
glaucomatous eyes at various stages of the disease, i.e. mild, moderate and severe will
improve the sensitivity of the technique in detecting glaucoma.
• With respect to RNFL thickness at the circumpapillary scan circle, consideration needs
to be given to age and the data adjusted appropriately. Furthermore, the data needs to
be corrected for the eye length. Additionally, it is of interest to determine if the RNFL
thickness were likely to change if an oval circle that is equidistant from the disc margin
would produce RNFL thickness like those obtained with a circular scan circle. The data
is likely to be strengthened by addition of a greater number of eyes with small and large
disc areas.
• Since the data acquisition processes and analysis processes differ between the various
OCT systems, it needs to be determined if data from one system can be generalised to
populations measured using different OCT systems.
• Expansion of the sample to include a cohort from other locations or ethnicities to
determine if data and results are localised to particular populations or can be
generalised to the population at large.
In summary, this thesis has provided estimates of ONH parameters and RNFL thickness from a
large population-based cohort and therefore the data can be applied with confidence especially
to South Indian population. The study indicated that assessment of ONH parameters especially
cup-to-disc area ratio and cup width when adjusted for disc area was superior to subjective
assessment of cup-to-disc ratio in detecting glaucoma. Finally the study also found the disc size
has no influence on RNFL thickness as measured at a circumpapillary scan circle of 3.4mm and
thus reduces the need and complexity involved in considering the influence of disc size in RNFL
measurements for both normal and glaucomatous eyes.
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APPENDIX
7 APPENDIX
APPENDIX
Appendix – A
Table 7.1: Comparison of the diagnostic ability of the ONH parameters unadjusted for
disc size versus 95% predicted intervals of ONH parameters after adjusting for disc
size- with all parameters
Unadjusted Adjusted
Unadjusted Adjusted AUROC sensitivity at sensitivity at
Variable AUROC AUROC p-value 95% 95%
(CI) (CI) # specificity specificity
(CI $) (CI $)
Optic cup-disc 0.830 0.319
ratio
(Clinical) (0.773-0.888) (0.244-0.394)
Cup area, mm2 0.836 0.967 0.000 0.273 0.853
(0.779-0.893) (0.946-0.988) (0.202-0.345) (0.797-0.910)
Cup disc area 0.943 0.965 0.011 0.740 0.820
ratio (0.912-0.974) (0.943-0.987) (0.670-0.810) (0.759-0.881)
Rim area, mm2 0.912 0.912 0.998 0.400 0.627
(0.869-0.956) (0.874-0.950) (0.322-0.478) (0.549-0.704)
Rim disc area 0.943 0.958 0.002 0.740 0.793
ratio (0.912-0.974) (0.932-0.983) (0.670-0.810) (0.729-0.858)
Disc height, mm 0.527 0.512 0.480 0.040 0.047
(0.445-0.609) (0.431-0.594) (0.009-0.071) (0.013-0.080)
Cup height, mm 0.885 0.963 0.000 0.638 0.800
(0.839-0.931) (0.941-0.985) (0.561-0.715) (0.736-0.864)
Disc width, mm 0.554 0.578 0.557 0.000 0.087
(0.468-0.640) (0.497-0.659) (0.000-0.000) (0.042-0.132)
Cup width, mm 0.906 0.982 0.000 0.678 0.880
(0.864-0.948) (0.968-0.997) (0.604-0.753) (0.828-0.932)
Cup disc height 0.962 0.970 0.103 0.807 0.860
ratio (0.936-0.988) (0.950-0.991) (0.743-0.870) (0.804-0.916)
APPENDIX
Cup disc width 0.969 0.974 0.395 0.773 0.827
ratio (0.950-0.988) (0.955-0.992) (0.706-0.840) (0.766-0.887)
Cup disc 0.971 0.978 0.271 0.833 0.840
average ratio (0.952-0.991) (0.962-0.994) (0.774-0.893) (0.781-0.899)
Rim area @ 1, 0.856 0.844 0.722 0.292 0.447
mm2 (0.802-0.911) (0.791-0.898) (0.219-0.364) (0.367-0.526)
Rim area @ 2, 0.797 0.799 0.942 0.153 0.220
mm2 (0.730-0.864) (0.736-0.863) (0.096-0.211) (0.154-0.286)
Rim area @ 3, 0.764 0.783 0.609 0.153 0.273
mm2 (0.693-0.836) (0.718-0.847) (0.096-0.211) (0.202-0.345)
Rim area @ 4, 0.838 0.845 0.834 0.360 0.340
mm2 (0.781-0.895) (0.790-0.899) (0.283-0.437) (0.264-0.416)
Rim area @ 5, 0.909 0.892 0.479 0.433 0.440
mm2 (0.864-0.953) (0.847-0.937) (0.354-0.513) (0.361-0.519)
Rim area @ 6, 0.917 0.902 0.502 0.500 0.507
mm2 (0.877-0.958) (0.857-0.947) (0.420-0.580) (0.427-0.587)
Rim area @ 7, 0.929 0.923 0.782 0.687 0.653
mm2 (0.895-0.962) (0.886-0.960) (0.612-0.761) (0.577-0.729)
Rim area @ 8, 0.893 0.925 0.246 0.433 0.700
mm2 (0.845-0.942) (0.891-0.958) (0.354-0.513) (0.627-0.773)
Rim area @ 9, 0.838 0.857 0.572 0.260 0.560
mm2 (0.779-0.897) (0.809-0.905) (0.190-0.330) (0.481-0.639)
Rim area @ 10, 0.844 0.854 0.778 0.333 0.467
mm2 (0.790-0.899) (0.804-0.903) (0.258-0.409) (0.387-0.547)
APPENDIX
Rim area @ 11, 0.876 0.869 0.850 0.373 0.400
mm2 (0.825-0.927) (0.818-0.920) (0.296-0.451) (0.322-0.478)
Rim area @ 12, 0.864 0.860 0.910 0.307 0.393
mm2 (0.811-0.917) (0.808-0.913) (0.233-0.380) (0.315-0.472)
Rim disc area 0.897 0.914 0.017 0.600 0.500
ratio @ 1 (0.852-0.941) (0.872-0.955) (0.522-0.678) (0.420-0.580)
Rim disc area 0.840 0.859 0.015 0.373 0.473
ratio @2 (0.784-0.896) (0.807-0.912) (0.296-0.451) (0.393-0.553)
Rim disc area 0.826 0.837 0.132 0.347 0.380
ratio @3 (0.768-0.885) (0.781-0.893) (0.271-0.423) (0.302-0.458)
Rim disc area 0.864 0.873 0.027 0.400 0.393
ratio @4 (0.811-0.917) (0.822-0.924) (0.322-0.478) (0.315-0.472)
Rim disc area 0.919 0.923 0.049 0.520 0.540
ratio @5 (0.876-0.961) (0.882-0.965) (0.440-0.600) (0.460-0.620)
Rim disc area 0.939 0.942 0.137 0.613 0.607
ratio @6 (0.901-0.976) (0.906-0.978) (0.535-0.691) (0.528-0.685)
Rim disc area 0.957 0.960 0.145 0.767 0.767
ratio @7 (0.930-0.984) (0.936-0.985) (0.699-0.834) (0.699-0.834)
Rim disc area 0.955 0.959 0.105 0.767 0.793
ratio @8 (0.928-0.981) (0.935-0.984) (0.699-0.834) (0.729-0.858)
Rim disc area 0.901 0.913 0.060 0.467 0.560
ratio @9 (0.859-0.942) (0.877-0.950) (0.387-0.547) (0.481-0.639)
Rim disc area 0.889 0.907 0.015 0.513 0.627
ratio @10 (0.845-0.933) (0.868-0.945) (0.433-0.593) (0.549-0.704)
APPENDIX
Rim disc area 0.911 0.928 0.011 0.620 0.673
ratio @11 (0.874-0.949) (0.896-0.960) (0.542-0.698) (0.598-0.748)
Rim disc area 0.915 0.930 0.051 0.607 0.713

ratio @12
(0.878-0.952) (0.897-0.962) (0.528-0.685) (0.641-0.786)
AUROC- Area under receiver operating characteristics curve, CI - Confidence Interval,

# - Delong Method, $ - Asymptotic Method
Figure 7.1: Plot showing the ROC curve of all disc size A. Cup-disc ratio in the clinic by
an optometrist, B. Average cup-disc ratio of the horizontal and vertical disc and cup
diameter measured by planimetry, C. Cup-disc ratio of disc and cup area measured by
planimetry, D. Cup-disc ratio of disc and cup area measured by planimetry
APPENDIX
Figure 7.2: Plot showing the ROC curve of all disc size A. Rim area at 6 o clock hour
measured by planimetry, B. Rim-disc area ratio at 6 o clock hour measured by
planimetry, C. Rim area at 12 o clock hour measured by planimetry, D. Rim-disc area
ratio at 12 o clock hour measured by planimetry
APPENDIX
Table 7.2: Comparison of the diagnostic ability of the ONH parameters unadjusted
for disc size versus 95% predicted intervals of ONH parameters after adjusting for
disc size in small disc size cohort- with all parameters
Unadjusted Adjusted
(CI $) (CI $)
ratio
(Clinical) (0.742-0.955) (0.202-0.345)
Cup area, mm2 0.855 0.960 0.017 0.476 0.786
(0.751-0.959) (0.920-1.000) (0.396-0.556) (0.720-0.851)
Cup disc area 0.925 0.945 0.179 0.810 0.810
ratio (0.852-0.999) (0.892-0.998) (0.747-0.872) (0.747-0.872)
Rim area, mm2 0.966 0.915 0.129 0.857 0.833
(0.929-1.000) (0.839-0.990) (0.801-0.913) (0.774-0.893)
Rim disc area 0.925 0.936 0.178 0.810 0.810
ratio (0.852-0.999) (0.873-1.000) (0.747-0.872) (0.747-0.872)
Disc height, mm 0.576 0.610 0.006 0.095 0.143
(0.421-0.731) (0.465-0.756) (0.048-0.142) (0.087-0.199)
Cup height, mm 0.923 0.973 0.099 0.550 0.881
(0.842-1.000) (0.942-1.000) (0.470-0.630) (0.829-0.933)
Disc width, mm 0.673 0.598 0.224 0.214 0.167
(0.535-0.811) (0.455-0.742) (0.149-0.280) (0.107-0.226)
Cup width, mm 0.939 0.989 0.117 0.624 0.952
(0.869-1.000) (0.970-1.000) (0.546-0.701) (0.918-0.986)
Cup disc height 0.962 0.969 0.262 0.857 0.833
ratio (0.908-1.000) (0.923-1.000) (0.801-0.913) (0.774-0.893)
Cup disc width 0.983 0.987 0.275 0.881 0.952
ratio (0.960-1.000) (0.968-1.000) (0.829-0.933) (0.918-0.986)
APPENDIX
Cup disc average 0.977 0.986 0.266 0.929 0.905
ratio (0.944-1.000) (0.965-1.000) (0.887-0.970) (0.858-0.952)
Rim area @ 1, 0.929 0.835 0.034 0.738 0.524
mm2 (0.868-0.989) (0.729-0.942) (0.668-0.808) (0.444-0.604)
Rim area @ 2, 0.873 0.761 0.009 0.571 0.357
mm2 (0.788-0.958) (0.637-0.884) (0.492-0.651) (0.280-0.434)
Rim area @ 3, 0.874 0.779 0.015 0.452 0.286
mm2 (0.785-0.964) (0.658-0.901) (0.373-0.532) (0.213-0.358)
Rim area @ 4, 0.907 0.831 0.028 0.381 0.333
mm2 (0.818-0.995) (0.722-0.940) (0.303-0.459) (0.258-0.409)
Rim area @ 5, 0.930 0.879 0.123 0.690 0.381
mm2 (0.864-0.996) (0.784-0.973) (0.616-0.764) (0.303-0.459)
Rim area @ 6, 0.933 0.894 0.205 0.524 0.476
mm2 (0.863-1.000) (0.792-0.996) (0.444-0.604) (0.396-0.556)
Rim area @ 7, 0.961 0.930 0.373 0.786 0.762
mm2 (0.911-1.000) (0.846-1.000) (0.720-0.851) (0.694-0.830)
Rim area @ 8, 0.963 0.942 0.326 0.881 0.762
mm2 (0.917-1.000) (0.890-0.993) (0.829-0.933) (0.694-0.830)
Rim area @ 9, 0.902 0.851 0.081 0.571 0.619
mm2 (0.822-0.981) (0.760-0.942) (0.492-0.651) (0.541-0.697)
Rim area @ 10, 0.880 0.817 0.023 0.643 0.619
mm2 (0.795-0.965) (0.713-0.922) (0.566-0.720) (0.541-0.697)
Rim area @ 11, 0.926 0.821 0.015 0.667 0.476
mm2 (0.861-0.992) (0.709-0.934) (0.591-0.742) (0.396-0.556)
APPENDIX
Rim area @ 12, 0.927 0.830 0.024 0.619 0.405
mm2 (0.860-0.995) (0.719-0.941) (0.541-0.697) (0.326-0.483)
Rim disc area 0.879 0.894 0.035 0.524 0.548
ratio @ 1 (0.779-0.979) (0.802-0.986) (0.444-0.604) (0.468-0.627)
Rim disc area 0.803 0.824 0.015 0.452 0.548
ratio @2 (0.683-0.923) (0.709-0.938) (0.373-0.532) (0.468-0.627)
Rim disc area 0.790 0.810 0.014 0.310 0.357
ratio @3 (0.663-0.917) (0.688-0.931) (0.236-0.384) (0.280-0.434)
Rim disc area 0.806 0.818 0.047 0.381 0.405
ratio @4 (0.680-0.933) (0.695-0.941) (0.303-0.459) (0.326-0.483)
Rim disc area 0.877 0.880 0.204 0.548 0.548
ratio @5 (0.772-0.981) (0.776-0.984) (0.468-0.627) (0.468-0.627)
Rim disc area 0.918 0.922 0.234 0.667 0.690
ratio @6 (0.823-1.000) (0.828-1.000) (0.591-0.742) (0.616-0.764)
Rim disc area 0.948 0.950 0.699 0.714 0.667
ratio @7 (0.886-1.000) (0.893-1.000) (0.642-0.787) (0.591-0.742)
Rim disc area 0.934 0.938 0.365 0.643 0.690
ratio @8 (0.872-0.996) (0.877-1.000) (0.566-0.720) (0.616-0.764)
Rim disc area 0.866 0.877 0.135 0.595 0.595
ratio @9 (0.776-0.955) (0.792-0.961) (0.517-0.674) (0.517-0.674)
Rim disc area 0.847 0.865 0.033 0.476 0.595
ratio @10 (0.751-0.944) (0.775-0.954) (0.396-0.556) (0.517-0.674)
Rim disc area 0.898 0.916 0.076 0.762 0.738
ratio @11 (0.822-0.975) (0.850-0.982) (0.694-0.830) (0.668-0.808)
APPENDIX
Rim disc area 0.920 0.937 0.192 0.786 0.786
ratio @12 (0.852-0.987) (0.883-0.991) (0.720-0.851) (0.720-0.851)

Figure 7.3: Plot showing the ROC curve of small disc size A. Cup-disc ratio in the clinic
by an optometrist, B. Average cup-disc ratio of the horizontal and vertical disc and cup
APPENDIX
Figure 7.4: Plot showing the ROC curve of small disc size A. Rim area at 6 o clock hour
APPENDIX
disc size versus 95% predicted intervals of ONH parameters after adjusting for disc size
in medium disc size cohort- with all parameters
Unadjusted Adjusted
(CI $) (CI $)
ratio
(Clinical) (0.796-0.965) (0.283-0.437)
Cup area, mm2 0.986 0.991 0.403 0.903 0.931
(0.970-1.000) (0.980-1.000) (0.855-0.950) (0.890-0.971)
Cup disc area 0.993 0.992 0.726 0.958 0.958
ratio (0.983-1.000) (0.982-1.000) (0.926-0.990) (0.926-0.990)
Rim area, mm2 0.985 0.991 0.404 0.903 0.931
(0.964-1.000) (0.981-1.000) (0.855-0.950) (0.890-0.971)
Rim disc area 0.993 0.993 1.000 0.958 0.958
ratio (0.983-1.000) (0.983-1.000) (0.926-0.990) (0.926-0.990)
Disc height, mm 0.600 0.520 0.008 0.096 0.028
(0.482-0.718) (0.392-0.648) (0.049-0.143) (0.001-0.054)
Cup height, mm 0.985 0.986 0.967 0.903 0.889
(0.970-1.000) (0.970-1.000) (0.855-0.950) (0.839-0.939)
Disc width, mm 0.688 0.620 0.060 0.153 0.083
(0.569-0.806) (0.493-0.747) (0.095-0.210) (0.039-0.128)
Cup width, mm 0.991 0.992 0.784 0.931 0.958
(0.980-1.000) (0.981-1.000) (0.890-0.971) (0.926-0.990)
Cup disc height 0.989 0.988 0.480 0.903 0.903
ratio (0.974-1.000) (0.974-1.000) (0.855-0.950) (0.855-0.950)
Cup disc width 0.991 0.991 1.000 0.917 0.917
ratio (0.979-1.000) (0.979-1.000) (0.872-0.961) (0.872-0.961)
APPENDIX
Cup disc average 0.993 0.991 0.414 0.958 0.903
ratio (0.984-1.000) (0.980-1.000) (0.926-0.990) (0.855-0.950)
Rim area @ 1, 0.906 0.941 0.057 0.569 0.792
mm2 (0.847-0.966) (0.899-0.982) (0.490-0.649) (0.727-0.857)
Rim area @ 2, 0.852 0.898 0.018 0.264 0.389
mm2 (0.760-0.943) (0.826-0.971) (0.193-0.334) (0.311-0.467)
Rim area @ 3, 0.820 0.864 0.034 0.389 0.500
mm2 (0.725-0.914) (0.784-0.945) (0.311-0.467) (0.420-0.580)
Rim area @ 4, 0.889 0.938 0.009 0.375 0.667
mm2 (0.813-0.966) (0.889-0.986) (0.298-0.452) (0.591-0.742)
Rim area @ 5, 0.934 0.959 0.124 0.472 0.736
mm2 (0.871-0.998) (0.922-0.997) (0.392-0.552) (0.666-0.807)
Rim area @ 6, 0.926 0.944 0.177 0.514 0.653
mm2 (0.860-0.992) (0.896-0.992) (0.434-0.594) (0.577-0.729)
Rim area @ 7, 0.951 0.961 0.314 0.792 0.819
mm2 (0.912-0.989) (0.929-0.994) (0.727-0.857) (0.758-0.881)
Rim area @ 8, 0.974 0.978 0.693 0.889 0.861
mm2 (0.941-1.000) (0.954-1.000) (0.839-0.939) (0.806-0.916)
Rim area @ 9, 0.945 0.952 0.601 0.667 0.750
mm2 (0.901-0.989) (0.916-0.989) (0.591-0.742) (0.681-0.819)
Rim area @ 10, 0.915 0.931 0.269 0.778 0.778
mm2 (0.861-0.969) (0.885-0.977) (0.711-0.844) (0.711-0.844)
Rim area @ 11, 0.935 0.948 0.353 0.750 0.708
mm2 (0.889-0.981) (0.906-0.990) (0.681-0.819) (0.636-0.781)
APPENDIX
Rim area @ 12, 0.914 0.930 0.289 0.722 0.736
mm2 (0.860-0.968) (0.877-0.982) (0.651-0.794) (0.666-0.807)
Rim disc area 0.970 0.970 0.852 0.889 0.903
ratio @ 1 (0.941-0.998) (0.942-0.998) (0.839-0.939) (0.855-0.950)
Rim disc area 0.934 0.931 0.453 0.653 0.639
ratio @2 (0.887-0.981) (0.882-0.981) (0.577-0.729) (0.562-0.716)
Rim disc area 0.902 0.897 0.291 0.542 0.556
ratio @3 (0.838-0.965) (0.831-0.963) (0.462-0.621) (0.476-0.635)
Rim disc area 0.931 0.929 0.598 0.667 0.667
ratio @4 (0.878-0.983) (0.875-0.983) (0.591-0.742) (0.591-0.742)
Rim disc area 0.952 0.950 0.342 0.653 0.639
ratio @5 (0.903-1.000) (0.898-1.000) (0.577-0.729) (0.562-0.716)
Rim disc area 0.950 0.948 0.539 0.625 0.639
ratio @6 (0.903-0.997) (0.899-0.998) (0.548-0.702) (0.562-0.716)
Rim disc area 0.974 0.972 0.278 0.861 0.819
ratio @7 (0.950-0.998) (0.947-0.998) (0.806-0.916) (0.758-0.881)
Rim disc area 0.990 0.990 1.000 0.944 0.931
ratio @8 (0.979-1.000) (0.979-1.000) (0.908-0.981) (0.890-0.971)
Rim disc area 0.972 0.972 0.833 0.861 0.861
ratio @9 (0.947-0.997) (0.946-0.998) (0.806-0.916) (0.806-0.916)
Rim disc area 0.954 0.954 0.881 0.861 0.861
ratio @10 (0.918-0.990) (0.917-0.991) (0.806-0.916) (0.806-0.916)
Rim disc area 0.970 0.966 0.271 0.847 0.847
ratio @11 (0.942-0.998) (0.937-0.996) (0.790-0.905) (0.790-0.905)
APPENDIX
Rim disc area 0.970 0.970 0.869 0.861 0.861
ratio @12 (0.943-0.997) (0.943-0.997) (0.806-0.916) (0.806-0.916)

Figure 7.5: Plot showing the ROC curve of medium disc size A. Cup-disc ratio in the
clinic by an optometrist, B. Average cup-disc ratio of the horizontal and vertical disc
and cup diameter measured by planimetry, C. Cup-disc ratio of disc and cup area
measured by planimetry, D. Cup-disc ratio of disc and cup area measured by
planimetry
APPENDIX
Figure 7.6: Plot showing the ROC curve of medium disc size A. Rim area at 6 o clock
hour measured by planimetry, B. Rim-disc area ratio at 6 o clock hour measured by
APPENDIX
disc size versus 95% predicted intervals of ONH parameters after adjusting for disc size
in large disc size cohort- with all parameters
Unadjusted Adjusted
(CI $) (CI $)
ratio
(Clinical) (0.608-0.863) (0.191-0.331)
Cup area, mm2 0.851 0.939 0.006 0.361 0.611
(0.752-0.949) (0.880-0.997) (0.284-0.438) (0.533-0.689)
Cup disc area 0.913 0.933 0.184 0.500 0.583
ratio (0.837-0.990) (0.871-0.995) (0.420-0.580) (0.504-0.662)
Rim area, mm2 0.917 0.902 0.716 0.667 0.500
(0.845-0.988) (0.821-0.982) (0.591-0.742) (0.420-0.580)
Rim disc area 0.913 0.932 0.079 0.500 0.583
ratio (0.837-0.990) (0.867-0.996) (0.420-0.580) (0.504-0.662)
Disc height, mm 0.587 0.618 0.752 0.083 0.083
(0.436-0.737) (0.470-0.766) (0.039-0.128) (0.039-0.128)
Cup height, mm 0.873 0.911 0.177 0.472 0.667
(0.777-0.968) (0.838-0.983) (0.392-0.552) (0.591-0.742)
Disc width, mm 0.580 0.704 0.100 0.028 0.194
(0.426-0.734) (0.562-0.845) (0.001-0.054) (0.131-0.258)
Cup width, mm 0.923 0.958 0.155 0.644 0.722
(0.852-0.994) (0.912-1.000) (0.568-0.721) (0.651-0.794)
Cup disc height 0.931 0.946 0.267 0.722 0.806
ratio (0.863-0.998) (0.891-1.000) (0.651-0.794) (0.742-0.869)
Cup disc width 0.926 0.927 0.935 0.472 0.583
ratio (0.853-0.999) (0.858-0.997) (0.392-0.552) (0.504-0.662)
APPENDIX
Cup disc average 0.938 0.943 0.668 0.583 0.639
ratio (0.872-1.000) (0.886-1.000) (0.504-0.662) (0.562-0.716)
Rim area @ 1, 0.865 0.832 0.389 0.500 0.361
mm2 (0.770-0.959) (0.721-0.943) (0.420-0.580) (0.284-0.438)
Rim area @ 2, 0.767 0.764 0.938 0.144 0.111
mm2 (0.639-0.895) (0.630-0.898) (0.088-0.201) (0.061-0.161)
Rim area @ 3, 0.735 0.740 0.918 0.111 0.139
mm2 (0.596-0.874) (0.599-0.880) (0.061-0.161) (0.084-0.194)
Rim area @ 4, 0.834 0.814 0.552 0.500 0.389
mm2 (0.729-0.939) (0.697-0.930) (0.420-0.580) (0.311-0.467)
Rim area @ 5, 0.900 0.894 0.750 0.472 0.500
mm2 (0.814-0.987) (0.806-0.981) (0.392-0.552) (0.420-0.580)
Rim area @ 6, 0.927 0.933 0.822 0.778 0.750
mm2 (0.855-0.999) (0.869-0.997) (0.711-0.844) (0.681-0.819)
Rim area @ 7, 0.916 0.928 0.612 0.833 0.778
mm2 (0.839-0.992) (0.860-0.997) (0.774-0.893) (0.711-0.844)
Rim area @ 8, 0.830 0.860 0.512 0.361 0.667
mm2 (0.720-0.940) (0.767-0.953) (0.284-0.438) (0.591-0.742)
Rim area @ 9, 0.760 0.748 0.806 0.194 0.278
mm2 (0.633-0.888) (0.623-0.872) (0.131-0.258) (0.206-0.349)
Rim area @ 10, 0.854 0.836 0.670 0.611 0.500
mm2 (0.758-0.950) (0.735-0.937) (0.533-0.689) (0.420-0.580)
Rim area @ 11, 0.885 0.880 0.894 0.556 0.583
mm2 (0.800-0.969) (0.793-0.967) (0.476-0.635) (0.504-0.662)
APPENDIX
Rim area @ 12, 0.880 0.859 0.516 0.611 0.528
mm2 (0.796-0.964) (0.763-0.955) (0.533-0.689) (0.448-0.608)
Rim disc area 0.854 0.860 0.489 0.278 0.361
ratio @ 1 (0.749-0.959) (0.759-0.961) (0.206-0.349) (0.284-0.438)
Rim disc area 0.784 0.793 0.473 0.194 0.194
ratio @2 (0.655-0.913) (0.670-0.916) (0.131-0.258) (0.131-0.258)
Rim disc area 0.784 0.787 0.787 0.250 0.306
ratio @3 (0.659-0.908) (0.666-0.908) (0.181-0.319) (0.232-0.379)
Rim disc area 0.850 0.856 0.293 0.389 0.417
ratio @4 (0.749-0.950) (0.758-0.955) (0.311-0.467) (0.338-0.496)
Rim disc area 0.933 0.934 0.727 0.694 0.694
ratio @5 (0.868-0.998) (0.869-0.999) (0.621-0.768) (0.621-0.768)
Rim disc area 0.946 0.946 1.000 0.889 0.861
ratio @6 (0.884-1.000) (0.883-1.000) (0.839-0.939) (0.806-0.916)
Rim disc area 0.942 0.943 0.882 0.889 0.889
ratio @7 (0.876-1.000) (0.881-1.000) (0.839-0.939) (0.839-0.939)
Rim disc area 0.933 0.934 0.806 0.667 0.722
ratio @8 (0.873-0.993) (0.875-0.993) (0.591-0.742) (0.651-0.794)
Rim disc area 0.846 0.854 0.502 0.611 0.583
ratio @9 (0.750-0.942) (0.762-0.946) (0.533-0.689) (0.504-0.662)
Rim disc area 0.868 0.875 0.570 0.528 0.556
ratio @10 (0.779-0.957) (0.789-0.961) (0.448-0.608) (0.476-0.635)
Rim disc area 0.863 0.876 0.254 0.417 0.472
ratio @11 (0.771-0.956) (0.791-0.962) (0.338-0.496) (0.392-0.552)
APPENDIX
Rim disc area 0.855 0.854 0.915 0.333 0.361
ratio @12 (0.756-0.954) (0.757-0.951) (0.258-0.409) (0.284-0.438)

Figure 7.7: Plot showing the ROC curve of large disc size A. Cup-disc ratio in the clinic
by an optometrist, B. Average cup-disc ratio of the horizontal and vertical disc and cup
APPENDIX
Figure 7.8: Plot showing the ROC curve of large disc size A. Rim area at 6 o clock hour

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Optic nerve head parameters and their relevance in glaucoma

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Jonnadula Ganesh Babu

A thesis in fulfilment of the requirements for the degree of

School of Optometry and Vision Science, Sydney, Australia

Brien Holden Vision Institute, Sydney, Australia

The University of New South Wales

OPTIC NERVE HEAD PARAMETERS AND THEIR RELEVANCE IN GLAUCOMA DIAGNOSIS ii

Inclusion of Publications Statement

OPTIC NERVE HEAD PARAMETERS AND THEIR RELEVANCE IN GLAUCOMA DIAGNOSIS iv

Copyright and Authenticity statement

OPTIC NERVE HEAD PARAMETERS AND THEIR RELEVANCE IN GLAUCOMA DIAGNOSIS v

Thesis/Dissertation Sheet .............................................................................................................. ii

Originality statement .................................................................................................................... iii

Inclusion of Publications Statement ............................................................................................. iv

Copyright and Authenticity statement .......................................................................................... v

LIST OF FIGURES ............................................................................................................................ ix

LIST OF TABLES .............................................................................................................................. xi

LIST OF SYMBOLS AND ABBREVIATIONS ..................................................................................... xiii

ACKNOWLEDGEMENTS ............................................................................................................... xiv

Template of circles ....................................................................................... 27

2.1 Introduction ............................................................................................................ 45

3.1 Background ............................................................................................................. 64

4.1 Background ........................................................................................................... 107

5.1 Introduction .......................................................................................................... 131

7 APPENDIX ........................................................................................................................ 167

Appendix – A ................................................................................................................... 168

Figure 2.2: Flowchart of examination procedures as published in Addepalli et al., 2013

Figure 3.3: Sketch showing the description of ONH parameters. .............................................. 71

OPTIC NERVE HEAD PARAMETERS AND THEIR RELEVANCE IN GLAUCOMA DIAGNOSIS ix

OPTIC NERVE HEAD PARAMETERS AND THEIR RELEVANCE IN GLAUCOMA DIAGNOSIS x

Table 1.1: The prevalence of glaucoma in population-based studies .......................................... 4

Table 2.1: Demographic distribution of participants in LVPEI-GLEAM study population

Table 3.1: Normative database: Demographic and clinical characteristics of participants

Table 3.3: Morphometric parameters of optic disc data (n=1,650) ........................................... 80

OPTIC NERVE HEAD PARAMETERS AND THEIR RELEVANCE IN GLAUCOMA DIAGNOSIS xi

LIST OF SYMBOLS AND ABBREVIATIONS

OCT : Optical coherence tomography

teach me statistics, R-Programme, building model eye, verifying magnification correction of

planimetry software, correcting the results and providing valuable support.

duration of the Study.

funding to conduct L V Prasad Eye Institute-Glaucoma Epidemiology And Molecular Genetic

love and for having made me what I am.

OPTIC NERVE HEAD PARAMETERS AND THEIR RELEVANCE IN GLAUCOMA DIAGNOSIS xv

compared to subjective assessment and b) consideration of disc size in assessment of ONH

parameters and RNFL thickness.

Methods: In a population-based study conducted in South India (2011-2013), 3,833 participants

on the RNFL thickness.

ratio in detecting glaucoma.

an international consensus panel published a definition of glaucoma that is now widely

presentations. Glaucoma leads to distinctive changes in the shape or morphology of the

OPTIC NERVE HEAD PARAMETERS AND THEIR RELEVANCE IN GLAUCOMA DIAGNOSIS 1

OPTIC NERVE HEAD PARAMETERS AND THEIR RELEVANCE IN GLAUCOMA DIAGNOSIS 2

prevalence of glaucoma as reported in these studies is summarized in Table 1.1

OPTIC NERVE HEAD PARAMETERS AND THEIR RELEVANCE IN GLAUCOMA DIAGNOSIS 3

Table 1.1: The prevalence of glaucoma in population-based studies

Welsh glaucoma survey White Wales 40+ 0.4 0.1

Rotterdam eye study White Netherlands 55+ 1.1 0

Roscommon eye study White Ireland 50+ 1.9 0.1