Title Page VALIDATING the ABILITY of a VISION TECHNICIAN IN

Title Page

VALIDATING THE ABILITY OF A VISION TECHNICIAN IN

DETECTING GLAUCOMA IN A SOUTH INDIAN RURAL

POPULATION

A thesis submitted in fulfilment of the requirements for the degree of

Doctor of Philosophy

Uday Kumar Addepalli, B. Optom

L V Prasad Eye Institute, Hyderabad, India

Brien Holden Vision Institute, Sydney, Australia

Vision Cooperative Research Centre, Sydney, Australia

School of Optometry and Vision Science, Sydney, Australia

University of New South Wales

January 2018

Uday Kumar Addepalli_Final_Thesis_2018 PLEASE TYPE THE UNIVERSITY OF NEW SOUTH WALES Thesis/Dissertation Sheet

name:ADDEPALLI Surname or Family name:UDAY First Other name/s:

Abbreviation for degree as given in the University calendar:PhD School of Optometry and Vision Science Faculty of Science School Faculty Title:Validating the ability of a vision technician in detecting glaucoma South Indian rural population in

Abstract 350 words maximum: (PLEASE TYPE)

This thesis describes the selection of a reference standard study optometrist for glaucoma diagnosis in the community and evaluated the ability of a vision technician to detect glaucoma in a South Indian rural population.

A sample 3833 subjects and 16 vision technicians were selected, who were also part of major population based study, the L V Prasad Eye Institute-Glaucoma Epidemiology and Molecular Genetics Study (LVPEI-GLEAMS). Eight VTs were involved for clinical examination on-site and 8 VTs involved in glaucoma detection based on various paradigms.

Both the study VTs and the optometrists performed a comprehensive eye examination, including undilated direct ophthalmoscopy for fundus examination, slit-lampbiomicroscopy with photographs, mydriatic and non-mydriatic fundus photographs(MFP/NMFP), applanation tonometry, gonioscopy and frequency doubling technology(FDT) for perimetry. Taking the group of VTs as a whole, sensitivities for detecting glaucoma were 18%(range 14-22) when based on IOP, 61% (57-70) for CDR by direct ophthalmoscopy,64% (58-70) for clinical diagnosis, 60% (55-65) for gonioscopy using the ISGEOclassification and 73% (69-78) if a referral criterion of a positive result on any clinical test was used. Specificities were for all above 90%, except for the referral criterion (80%). Similarly, group of VTs as a whole, sensitivities for detecting glaucoma were 18% (10-28) when based on FDT, 64% (34-85) for NMFP, 77% (72-82) for clinical in combination with NMFP, 97% (89-100) for clinical along with FDT and 29% (17-42) for FDT with NMFP. Specificities were for all above 70%. Likelihood ratios showed a large post-test probability of glaucoma diagnosis for CDR,gonioscopy and clinical diagnosis whereas the effects for all the screening paradigms other than clinical examination were moderate.

This study showed that a trained VT can detect glaucoma based on clinical examination. An improvement in I performance accrues with the addition of information derived from NMFP and FDT, either individually or when combined with clinical examination. This study indicates that glaucoma detection by a VT is possible both clinically and with technology additives. Declaration relating to disposition of project thesis/dissertation

I hereby grant to the University of New South Wales or its agents the right to archive and to make available my thesis or dissertation in whole or 1n part in the University libraries 1n all forms of media, now or here after known, subject to the provisions of the Copyright Act 1968. I retain all property rights, such as patent rights. I also retain the right to use in future works (such as articles or books) all or part of this thesis or d1ssertat1on.

s to use the 350 word abstract of my thesis in DissertationAbstracts International (this is applicable to doctoral

nises that th may be exceptional circumstances requiring restrictions on copying or conditions on use. Requests for rio of up to 2 years must be made in writing. Requests for a longer period of restriction may be considered in exceptional re ire the a roval of the Dean of Graduate Research.

I FOR OFFICE USE ONLY Date of completion of requirements for Award.

ORIGINALITY STATEMENT

‘I hereby declare that this submission is my own work and to the best of my knowledge it contains no materials previously published or written by another person, or substantial proportions of material which have been accepted for the award of any other degree or diploma at UNSW or any other educational institution, except where due acknowledgement is made in the thesis. Any contribution made to the research by others, with whom I have worked at UNSW or elsewhere, is explicitly acknowledged in the thesis. I also declare that the intellectual content of this thesis is the product of my own work, except to the extent that assistance from others in the project's design and conception or in style, presentation and linguistic expression is acknowledged.’

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‘I hereby grant the University of New South Wales or its agents the right to archive and to make available my thesis or dissertation in whole or part in the University libraries in all forms of media, now or here after known, subject to the provisions of the Copyright Act 1968. I retain all proprietary rights, such as patent rights. I also retain the right to use in future works (such as articles or books) all or part of this thesis or dissertation. I also authorise University Microfilms to use the 350 word abstract of my thesis in Dissertation Abstract International (this is applicable to doctoral theses only). I have either used no substantial portions of copyright material in my thesis or I have obtained permission to use copyright material; where permission has not been granted I have applied/will apply for a partial restriction of the digital copy of my thesis or dissertation.'

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Abstract

This thesis describes the selection of a reference standard study optometrist for glaucoma diagnosis in the community and evaluation of the ability of a trained vision technician to detect glaucoma in a South Indian rural population. The ability to utilise personnel with relatively short training would be expected to increase the numbers of those diagnosed with glaucoma during community screening programs.

A sample of 3833 subjects and 16 vision technicians (VT) were selected, who were also part of major population-based study, the L V Prasad Eye Institute-

Glaucoma Epidemiology and Molecular Genetics Study (LVPEI-GLEAMS).

Eight VTs were involved for clinical examination on-site and 8 VTs involved in glaucoma detection based on various paradigms.

Both the study VTs and the optometrist performed a comprehensive eye examination, including undilated direct ophthalmoscopy for fundus examination, slit-lamp biomicroscopy with photographs, mydriatic and non-mydriatic fundus photographs (MFP/NMFP), applanation tonometry, gonioscopy and frequency doubling technology (FDT) for perimetry.

Taking the group of VTs as a whole, sensitivities for detecting glaucoma were

18% (range 14-22) when based on IOP, 61% (95%CI; 57-70) for CDR by direct ophthalmoscopy, 64% (58-70) for clinical diagnosis, 60% (95%CI; 55-65) for gonioscopy using the ISGEO classification and 73% (95%CI; 69-78) if a referral criterion of a positive result on any clinical test was used. Specificities were all above 90%, except for the referral criterion which was 80%. 4

When considering the value of additional diagnostic techniques, sensitivities for detecting glaucoma were 18% (95%CI;10-28) when based on FDT, 64%

(95%CI; 35-84) for NMFP, 77% (95%CI; 72-82) for clinical in combination with

NMFP, 97% (95%CI; 89-100) for clinical along with FDT and 29% (95%CI;17-

42) for FDT with NMFP. Specificities were all above 70%.

Likelihood ratios showed a large post-test probability of glaucoma diagnosis for

CDR, gonioscopy and clinical diagnosis, whereas the effects for all the screening paradigms other than clinical examination were moderate.

This study showed that a trained VT can detect the majority of cases of glaucoma based on clinical examination. An improvement in performance accrues with the addition of information derived from NMFP and FDT to that from clinical examination.

Contents

Title Page ...... 1

Originality Statement ...... 2

Abstract ...... 3

Acknowledgements ...... 11

Dedication...... 12

List of Abbreviations ...... 13

Publications...... 17

Chapter 1: Introduction ...... 23

1.1 Background and Rationale: ...... 23

1.2 Glaucoma ...... 27

1.2.1 Definition and Classification: ...... 27

1.2.2 Prevalence: ...... 31

1.2.3 Mechanism of glaucoma: ...... 34

1.2.4 Risk factors of glaucoma: ...... 36

1.3 Glaucoma detection ...... 39

1.3.1 Need for Early detection: ...... 39

1.3.2 Screening and Referrals by optometrists: ...... 40

1.4 Primary health care ...... 44 6

1.4.1 Primary care centres: ...... 44

1.4.2 LVPEI’s pyramidal model: ...... 45

1.5 Vision technicians: ...... 49

1.6 Summary: ...... 53

1.7 Aims and objectives: ...... 55

Chapter 2: Materials and Methods ...... 56

2.1 Methods and Approval: ...... 57

2.2 Methodology for the baseline study: ...... 58

2.2.1 Study protocol: ...... 58

2.3 Reference standard optometrist for the current study: ...... 60

2.3.1 Patient allocation: ...... 62

2.3.2 Categorization of gonioscopy and optic disc findings:...... 62

2.4 LVPEI-GLEAMS: ...... 63

2.4.1 Study design and Sample size ...... 63

2.4.2 Sampling method ...... 64

2.4.3 Study location and selection of subjects: ...... 65

2.4.4 Eligibility and Exclusion Criteria ...... 66

2.5 Training of vision technicians (VT’s): ...... 67

2.5.1 Assessments at the community level ...... 68 7

2.5.2 Assessments at the vision centre ...... 69

2.5.3 Documentation of findings by vision technicians: ...... 72

2.6 Diagnostic definitions and classification of glaucoma: ...... 73

2.7 Instruments used in glaucoma detection: ...... 76

2.7.1 Diagnostic ability of instruments: ...... 76

2.7.2 Measures of diagnostic ability: ...... 77

2.8 Instruments used in the current study ...... 81

2.8.1 Frequency doubling technique (FDT): ...... 81

2.8.2 Non mydriatic fundus camera: ...... 85

2.8.3 Instruments in clinical examination ...... 87

2.9 Image grading procedure: ...... 93

2.9.1 Grading doubling technique (criterion of non mydriatic fundus pictures

(NMFP) and frequency FDT): ...... 93

2.9.2 Grading by reference standard optometrist: ...... 94

2.9.3 Grading by vision technicians (VT’s): ...... 95

Chapter 3: Evaluating the ability of vision technicians in detecting ocular pathologies – A baseline study ...... 96

3.1 Introduction: ...... 96

3.2 Methods: ...... 97 8

3.2.1 Definition of disease:...... 97

3.3 Statistical analysis: ...... 99

3.4 Results: ...... 99

3.4.1 Disease detection: ...... 99

3.4.2 Agreement for screening ocular pathology: ...... 100

3.5 Discussion: ...... 101

Chapter 4: Establishing a reference standard ...... 103

4.1 Introduction: ...... 103

4.2 Methods: ...... 105

4.3 Results - Agreement between glaucoma specialist ophthalmologists and two study optometrists: ...... 106

4.3.1 Gonioscopy: ...... 106

4.3.2 Optic disc evaluation: ...... 107

4.4 Diagnostic accuracy between glaucoma specialist ophthalmologists and two study optometrists: ...... 108

4.4.1 Gonioscopy: ...... 108

4.4.2 Optic disc evaluation: ...... 109

4.5 Agreement of frequency doubling technology (FDT) criteria in detecting glaucoma: ...... 110

4.6 Discussion ...... 112 9

4.6.1 Study findings: ...... 112

4.6.2 Trained glaucoma optometrists as reference standard: ...... 114

Chapter 5: Evaluating the ability of vision technicians glaucoma detection with individual tests ...... 116

5.1 Introduction: ...... 116

5.2 Methods: ...... 117

5.2.1 NMFP Image Quality ...... 119

5.2.2 Data Treatment ...... 119

5.3 Results ...... 120

5.3.1 Diagnostic accuracy of vision technicians using clinical tests: ...... 120

5.3.2 Diagnostic accuracy of vision technicians with Additional Tests: .... 128

5.3.3 Based on frequency doubling technology (FDT): ...... 130

5.4 Discussion ...... 131

5.4.1 Study findings: ...... 131

5.4.2 Glaucoma detection by vision technicians: ...... 132

Chapter 6: Evaluating the ability of vision technicians – Combined tests in glaucoma detection ...... 136

6.1 Introduction: ...... 136

6.2 Results - Diagnostic ability of each VT in different screening paradigm:

...... 138 10

6.2.1: Diagnostic accuracy of VT 1 ...... 138

6.2.2 Diagnostic ability of VT2 ...... 139

6.2.3: Diagnostic accuracy of VT3 ...... 140

6.2.4 Diagnostic ability of VT4 ...... 141

6.2.5 Diagnostic ability of VT5: ...... 142

6.2.6 Diagnostic ability of VT6: ...... 143

6.2.7 Diagnostic ability of VT7: ...... 144

6.2.8 Diagnostic ability of VT8: ...... 145

6.4 Discussion: ...... 146

6.5 Summary: ...... 147

Chapter 7: Conclusion ...... 149

7.1 Introduction: ...... 149

7.2 Study findings: ...... 151

7.3 Limitations: ...... 154

References...... 157

Glossary ...... 167

Acknowledgements

I would like to express my sincere appreciation and gratitude to my supervisors

Professor Eric B Papas, Dr Rohit C Khanna, Prof Jill Keeffe, Dr Subhabrata

Chakrabarti and Dr G Chandrasekhar for their high level support, constructive feedback, consistent encouragement and guidance during my entire PhD candidacy. All of them had been great mentors helping me design this project and I thank them for their availability every moment whenever I needed them as the best resource and Dr Thomas Naduvilath and Dr Harsha L Rao for the statistical advice.

My heartfelt thanks to L V Prasad Eye Institute, Brien Holden Vision Institute and Vision CRC for the continuous support and encouragement during the last few years.

This journey wouldn’t have been completed without the kind support of LVPEI-

GLEAMS team and participants, our librarian, Ms S Banu, my colleagues across the LVPEI network who had let me work and created that environment to keep up with my thesis and my family members.

Dedication

This thesis is dedicated to my mentor Dr Garudadri Chandrashekar who has been a constant source of support and encouragement during the challenges of my thesis and life. I am thankful for having you in my life.

This work is also dedicated to my parents, Addepalli Venkata Rama Sarma and

Santha Kumari, who have always loved me unconditionally and whose good examples have taught me to work hard for the things that I aspire to achieve, to my beloved wife Swathi and dearest son Kriss for the unconditional love and support throughout my hard times, my father-in-law Kanduri Ramachary and

Mother-in-law Bhagya Rekha, who had been guiding me, supporting me throughout this journey and helped me take care of son to let me work on my thesis. I could have never achieved this work without the constant unconditional love and support of all the above mentioned.

List of Abbreviations

ACES – The Aravind Comprehensive Eye Survey

ACG- Angle closure glaucoma

AP – Andhra Pradesh

APEDS – The Andhra Pradesh Eye Disease Study

AS-OCT – Anterior segment optical coherence tomography

AUC – Area under the curve

CCT- Central corneal thickness

CDR – Cup disc ratio

CGS – The Chennai Glaucoma Study

CI –Confidence intervals

DDLS – Disc damage likelihood scale

DR –Diabetic retinopathy

FDT – Frequency doubling technique

FDP – Frequency doubling perimeter

FN – False negative

FP – False positive 14

GAT- Goldman applanation tonometer

GDx VCC – Scanning laser polarimetry

GLEAMS – Glaucoma epidemiology and molecular genetics study

HDOCT – High definition optical coherence tomography

HRT – Heidelberg retinal tomography

HVF- Humphrey visual fields

IOP – Intra-ocular pressure

ISEGO – International Society of Geographical and Epidemiological

Ophthalmology k – Kappa

LCD – Limbal chamber depth

LLR – Likelihood ratios

LVPEI – L V Prasad Eye Institute

NMFC – Non Mydriatic fundus camera

NMFP – Non mydriatic fundus photographs

Non-OSI – no specialist interest in Glaucoma

NPV – Negative predictive values

NRR- Neuro-retinal rim

OAG – Open angle glaucoma 15

OCT – Optical coherence tomography

OHT – Ocular hypertension

ONH – Optic nerve head

OSI –Specialist interest in Glaucoma

PAC – Primary angle closure

PACG – Primary closed angle glaucoma

PACS – Primary angle closure suspect

POAG – Primary open angle glaucoma

PPV – Positive predictive values

RNFL – Retinal nerve fibre layer

ROC – Receiver operating characteristics curve

SAP – Standard automated perimetry

Sn – Sensitivity

Sp – Specificity

SPAC – Scanning peripheral anterior chamber depth analyzer

TN – True negative

TP – True positive

UK – United Kingdom 16

UNSW – University of New South Wales

VA- Visual acuity

VC – Vision centre

VES – Vellore Eye Study

VF – Visual Field

VI – Visual Impairment

Vision CRC – Vision Co-operative research service

VT’s – Vision technicians

WBGS –West Bengal Eye Study

WHO – World health organization

Publications

1. Agreement of Glaucoma specialists and optometrists in gonioscopy and optic

disc evaluation. Addepalli U K, Babu J G, Garudadri C S, Senthil S, Eric B

Papas, Padmaja Sankaridurg, Rao H L, Rohit C Khanna. J Optom. 2013

Oct; 6(4): 212–218. Published online 2013 Oct

17. doi: 10.1016/j.optom.2013.09.002

2. Accuracy of Vision Technicians in Screening Ocular Pathology at Rural Vision

Centres of Southern India. Vasantha S, Addepalli U K, Krishnaiah S, Vilas K,

Rohit CK. Clin Exp Optom. 2016; 99: 183- 187

3. LV Prasad Eye Institute Glaucoma Epidemiology and Molecular Genetic Study

(LVPEI- GLEAMS). Report 1: study design and research methodology.

Addepalli U K, Jonnadula GB, Garudari CS, Rao HL, Rani PK, Chakrabarti S,

Papas EB, Sankaridurg P, Khanna RC. Ophthalmic Epidemiol. 2013 Jun;

20(3):188-95. doi: 10.3109/09286586.2013.792938.

List of Figures

Figure 1: LVPEI eye care network...... 50

Figure 2: The multi-tiered eye health delivery model of the L V Prasad Eye institute...... 51

Figure 3 – Flowchart of studies discussed in the current thesis…………….…60

Figure 4: Sequence of examinations at the vision Centre and time taken……74

Figure 5: Sequence of the analysis to evaluate the diagnostic accuracies of VTs in glaucoma detection...... 123

List of Tables

Table 1.1 - International Society of Geographical and Epidemiological

Ophthalmology (ISGEO) criteria for primary angle closure glaucoma [14] ...... 32

Table 1.2 - International Society of Geographical and Epidemiological

Ophthalmology (ISGEO) criteria for primary angle closure glaucoma [14] …….33

Table 1.3 -Summary of glaucoma prevalence reported by various studies conducted in rural and urban populations in India [8-14, 43, 44]...... 36

Table 1.4 - Summary of studies in which supplementary equipment was used to aid disease detection by different eye care personnel’s [94, 99, 105, 128, 129] …...... 55

Table 2.1-Subject recruitment by village ...... 69

Table 2.2- Criteria for classification of glaucoma established for the current study ...... 75

Table 2.3- Definitions of glaucoma used in community and population based studies worldwide [8-13, 16, 43, 44, 99, 134-136]...... 78

Table 2.4 - Sensitivity and specificity of various diagnostic instruments [14] …80

Table 2.5 - 2 x 2 table of possible diagnostic outcomes for a given test, relative to the gold standard reference.[138] ...... 81 20

Table 3.1 - Ocular pathology in the study population as determined by the vision technicians and the ophthalmologist...... 103

Table 3.2 - Agreement between vision technicians (VT’s) and ophthalmologist in screening ocular pathologies ...... 104

Table 4.1– Demographic details of the subjects ……………………………….110

Table 4.2- Agreement between glaucoma specialist ophthalmologists and two study optometrists in interpretation of gonioscopy ...... 111

Table 4.3 - Agreement between glaucoma specialist ophthalmologists and two study optometrists in interpretation of optic disc examination ……………….. 112

Table 4.4- The diagnostic accuracies of optometrists in interpretation of gonioscopy ...... 113

Table 4.5- The diagnostic accuracy of optometrists in interpretation of the optic disc ...... 114

Table 4.6- The agreement between the study optometrist and glaucoma specialist ophthalmologist for FDT...... 115

Table 5.1- Diagnostic accuracy of Vision Technicians based on a criterion of

Intra Ocular Pressure >16 mm Hg criteria ...... 125 21

Table 5.2 - Diagnostic performance of Vision Technicians in glaucoma detection based on cup to disc ratio (CDR) ≥0.6:1...... 127

Table 5.3 - Diagnostic accuracy of VTs in glaucoma detection based on

Gonioscopy according to ISGEO classification ……………………………….. 129

Table 5.4 - Diagnostic accuracy of VT based on referral criterion: Refer IF IOP >

16mmHg AND/OR CDR ≥0.6:1 AND/OR Gonio occludable AND/OR A diagnosis of Glaucoma ...... 130

Table 5.5 -Diagnostic accuracy of vision technicians based on the clinical diagnosis of glaucoma...... 132

Table 5.6-Mean Diagnostic accuracy of VTs in grading Non mydriatic fundus pictures (NMFPs) as compared with the reference standard optometrist in patients with NORMAL VISION (n = 4,592) ……………………………..…...... 133

Table 5.7 – FDT interpretation for each vision technician in detecting glaucoma...... 134

Table 6.1 - Diagnostic ability in different screening paradigms – VT 1 ...... 142

Table 6.2 - Diagnostic ability in different screening paradigms – VT 2 ...... 143

Table 6.3 - Diagnostic ability in different screening paradigms – VT 3 ...... 144 22

Table 6.4 - Diagnostic ability in different screening paradigms – VT 4 ...... 145

Table 6.5 - Diagnostic ability in different screening paradigms – VT 5 ...... 146

Table 6.6 – Diagnostic ability in different screening paradigms – VT 6 ...... 147

Table 6.7- Diagnostic ability in different screening paradigms – VT 7 ...... 148

Table 6.8 - Diagnostic ability in different screening paradigms – VT 8 ...... 149

Chapter 1: Introduction

1.1 Background and Rationale:

Visual impairment (VI) has become one of the major challenges in public health care and the burden of sight threatening, ocular conditions is significantly increasing in the developed countries, [1] with a sharp incline in the prevalence being noted in the last two decades.[2] Blindness and visual impairment is an additional burden on public health care. According to the World Health

Organization (WHO), worldwide there are about 235 million people who are impaired visually, with 39 million of these being blind. India accounts for 8 million people in this figure. [3] India has disproportionate levels of blindness, relative to the rest of the world, with uncorrected refractive error and cataract representing the major causes.[4]

Globally, age related macular degeneration and glaucoma stand as the 3rd and

4th leading causes of blindness respectively, after cataract and uncorrected refractive errors.[5, 6]

Leaving aside those conditions for which correction is possible, glaucoma stands as the commonest cause of irreversible vision loss worldwide. In the year 2010, blindness owing to glaucoma was estimated to affect 2.1 million people with 4.2 million being visually impaired. The total number of people with glaucoma related blindness or visual impairment increased by 0.8 million and

2.3 million [7] respectively from 1990 to 2010, indicating an inclination in the global burden of this disease. Various studies [8-13] have noted a regional difference in the prevalence of primary open angle (POAG) and primary angle 24

closure glaucoma (PACG) in the rural and urban populations of India. Bilateral blindness due to PACG was two times greater than with POAG.[14]

The threat posed by glaucoma is heightened because it is asymptomatic. It is therefore challenging to diagnose and leads to irreversible blindness if not detected early. Glaucoma screening is essential therefore and successful early detection reduces the incidence of blindness and visual impairment, thereby reducing health care expenditure and improving the quality of life for those affected. [15] These benefits can be achieved only by implementing proper screening models in the community that accurately identify individuals with glaucoma.

To ensure that accuracy in disease detection is optimal, the parameters used when screening for glaucoma, should be similar to those of an ophthalmologist during their investigation.[15] An examination with a standard protocol including measurement of intra ocular pressures (IOP), optic disc examination, observation of retinal nerve fibre layer (RNFL) appearance and assessment of visual fields (VF), should thus be emphasized in glaucoma detection. For these methods to be effective at the community level, appropriate equipment, with good diagnostic accuracy, has to be made available.

When considering which tests to include, several possibilities are evident. For example, while Goldman applanation tonometry stands as the gold standard in measuring IOP, IOP itself lacks sensitivity for diagnosing glaucoma and so cannot be considered in isolation.[16, 17] Accordingly, structural changes at the optic disc also need to be carefully examined. For this purpose, direct ophthalmoscopy can be helpful in a community vision screening, as it is 25

inexpensive and portable. However due to a small field of view of 15 degrees, difficulty in performing with an undilated pupil and the fact that it requires expertise to appreciate even the slightest structural change clinically, it is a difficult glaucoma detection tool for those, like the vision technicians, who are not skilled in its use. Recently, non mydriatic fundus cameras have been used to overcome the drawbacks of a handheld direct ophthalmoscopy for examining the posterior pole, with satisfactory results.[18] This technology has been mastered by technicians[19] trained to take images, which are transferred to an ophthalmologist for interpretation.[20]

Glaucoma affects the visual field and so perimetry is an important means of disease monitoring. Standard automated perimetry (SAP) is the gold standard for assessing visual fields defects; however frequency doubling technology

(FDT) has been shown to be a viable screening technique that is effective at a community level.[21, 22]

While the methods and techniques mentioned above are known to be valuable, they are typically used by skilled and highly trained individuals such as ophthalmologists or optometrist. Given that the numbers of such professionals available during community level screening programs are limited, it would be highly desirable to understand if these methods can be equally effective when operated by personnel with different levels of training. In recognition to this, several screening methods and referral studies have been conducted using different instruments in rural and remote populations worldwide with the intention of benefitting people locally and thereby reducing the burden of glaucoma on society. 26

In the main, rural cohorts suffer the most problems because of the tendency to be unaware of, or ignore vision loss, due to lack of primary eye health services.

Even in countries, such as India, where such services are provided, they may well be poorly utilized. [23-25] As many cases go undiagnosed, the real challenge lies in detection of the disease, with treatment being a secondary issue. Most eye care professionals practice in urban areas; hence there is a need for trained personnel to serve rural and remote populations. In view of this, VISION 2020, a global initiative implemented to eliminate avoidable blindness, [26] advocates the training of ophthalmic technicians and assistants as a means of achieving the target. L V Prasad Eye Institute was one of the organizations supporting this initiative with the introduction of their vision centre (VC) model.[27] These vision centres are run by vision technicians (VTs), who are initially trained at the tertiary centre for a period of 1 year so that they can perform initial assessments, to identify and refer complicated cases to the secondary centres.

The primary focus in training the vision technicians lies in teaching them to provide an accurate spectacle prescription followed by the ability to detect sight threatening conditions. A screening in the community by the vision technicians may thus help to reduce the impact of sight threatening conditions by correcting refractive error, recognizing the presence of sight threatening conditions and initiating referral for confirmation and treatment.

This model can work as expected only if VTs can effectively acquire and utilize the necessary skills. Previous studies [28, 29] on VT performance in these circumstances, indicate that they are competent enough in detecting refractive errors and anterior segment pathologies but are less adept at spotting posterior pole diseases like glaucoma. Nevertheless, using VT type personnel in the 27

context of large scale health delivery models, such as the L V Prasad Eye institute pyramidal approach, remains attractive due to the known challenges posed by the limited availability of glaucoma specialist ophthalmologists at the community level. The intention of the present work therefore, was to revisit the question of VT performance in the task of glaucoma detection. In this case, VT personnel underwent formal training in the various key techniques prior to assessment and their behaviour was monitored and validated by glaucoma trained optometrist at the community level. Throughout, the emphasis was on glaucoma detection both clinically and with the addition of information derived from FDT and NMFP.

1.2 Glaucoma

1.2.1 Definition and Classification:

Glaucoma is a chronic, progressive, neuro-degenerative disease characterized by structural changes in the optic nerve head (ONH) and retinal nerve fibre layer(RNFL), accompanied by irreversible visual loss. The chronic and insidious nature of the disease has contributed to glaucoma becoming the third leading cause of blindness globally.[30, 31] The two major categories of glaucoma include primary open angle glaucoma (POAG) and primary angle closure disease

(PACD). PACD includes different stages such as primary angle closure suspect

(PACS), primary angle closure (PAC) and primary angle closure glaucoma

(PACG), all of which can also present as secondary conditions. POAG or PACD are idiopathic in nature whereas secondary forms are usually associated with other detectable ocular co- morbidities such as pseudo-exfoliation, rubeosis 28

iridis, uveitis, ocular surgery, retinal detachments, vascular occlusion or even diabetes. Glaucoma is classified into open angle and angle closure based on the anterior chamber angle structures as detected clinically on a comprehensive eye examination. Normal clinical appearance of the angles indicates an open angle whereas a physical tissue obstruction restricting the aqueous outflow indicates an angle closure. Even when the angle is open, the aqueous outflow can be restricted, as in steroid induced glaucoma, resulting in open angle glaucoma.[32] In this study, for all the clinical diagnosis analysis we have used on site cut-offs of clinical parameters such as an IOP of >21mm Hg, a CDR of

>0.5:1, gonioscopy showing ≤180 degrees or two quadrants of posterior trabecular meshwork seen and a clinical diagnosis of glaucoma which also includes the non-clinical parameters such as the family history of glaucoma or a suspicion of glaucoma in the past or a history of using anti-glaucoma medication. Based on these cut-offs a referral criteria was designed confirms the presence of glaucoma if the subject has an IOP of >21 mm Hg and/or a

CDR of >0.6:1 and/or gonioscopy showing ≤180 degrees or two quadrants of posterior trabecular meshwork seen and/or a positive clinical diagnosis for glaucoma.

A lack of agreement exists on the universal definition for the diagnosis of glaucoma. Elevated IOP, angle closure on gonioscopy, high cup to disc ratio

(CDR), thin neuro-retinal rim (NRR) width, splinter haemorrhage, notch and abnormal visual fields are all possible factors contributing to the diagnosis but there is no single parameter that confirms the disease. In an effort to address this problem and set standard criteria for uniformity in reporting disease prevalence[9, 33], the International Society of Geographical and Epidemiological 29

Ophthalmology (ISGEO) has proposed a set of criteria for classifying glaucoma as shown in Table 1.1

Table 1.1 - International Society of Geographical and Epidemiological Ophthalmology (ISGEO) criteria for primary angle closure glaucoma [14]

Type Criteria

Primary angle closure Appositional closure contact between peripheral iris and suspect (PACS) posterior trabecular meshwork (TM) (pigmented TM not seen >180 or 270 degrees

PACS together along with features indicating that TM Primary angle closure obstruction by peripheral iris (peripheral anterior (PAC) synechiae, elevated IOP, iris whorling, glaucomflecken, lens opacities or extensive TM pigmentation

Primary angle closure PAC together with evidence of glaucoma (as defined glaucoma (PACG) below)

Table 1.2 - International Society of Geographical and Epidemiological Ophthalmology (ISGEO) criteria for primary angle closure glaucoma[14]

Intra ocular Category Visual pressure (IOP) Optic disc Field defect Acuity and Treatment - - Category 1: Cup disc ratio (CDR) or Defect Structural and CDR asymmetry consistent with functional >0.97.5th percentile for glaucoma evidence the normal population. NRR reduced width to <0.1 CDR (Superior 11-1 o’clock and Inferior 5-7 o’clock)

Category 2: CDR or CDR asymmetry Subjects who Advanced - - >0.97.5th percentile for have not structural the normal population. completed damage with Neuro-retinal rim (NRR) visual fields unproved field reduced width to <0.1 (VF). defect CDR (Superior 11-1 o’clock and Inferior 5-7 o’clock)

Category 3: <3/60 Intraocular pressure (IOP) >99.5th percentile or <3/60 optic disc not VF test not seen done.

Evidence of glaucoma filtration surgery or using anti- glaucoma medication (AGM) 31

1.2.2 Prevalence:

Around 10% of all blindness worldwide arises from glaucoma and Asia alone accounts for 60% of this number. [15, 34] It is predicted that due to the changing demographics and increased life expectancy there will be a significant increase in the number of glaucoma patients worldwide. Estimates report that the glaucoma population will increase from 60.5 million in 2010 to 80 million people in 2020 [35] and to approximately 111.8 million by the year 2040.[36] Globally, the prevalence of primary glaucoma is higher than secondary and about two thirds of the population are affected with open angle glaucoma.[36, 37] Overall, glaucoma prevalence is closely related to the increasing age of the population and not associated with any specific sex.[38] Studies conducted in rural areas that lack eye care access show that the prevalence of PACG is relatively high.

A large cross-sectional population based study in rural district of Myanmar (n =

2076) showed 2.5% prevalence for PACG and 2% for POAG, and also indicated that PACG accounted for 84% of total blindness.[39] Another study conducted in northern Mongolia (n=942) showed that the prevalence of gonioscopically occludable angles was 6.4% (n=64; including glaucoma).

Prevalence of blindness was 1.2% (n=12) in which primary glaucoma accounted for one third of cases (n=4).[40]”Interestingly, though primary open angle glaucoma is more common worldwide, the incidence of blindness is higher with angle closure glaucoma (ACG).[41] ACG is more prevalent among Asians, with the Chinese population accounting for almost half of the glaucomatous cases, about three fold more than open angle glaucoma (OAG).[42] [43] Global estimates report that the prevalence of POAG will increase to 58.6 million by the year

2020 and 5.3 million individuals would suffer bilateral blindness due to PACG.[44] 32

The prevalence of undetected glaucoma in the developed world is around 50% and that in the developing world is even higher.[35] The impact of this situation can be seen from the results of work such the Vellore Eye Study[45] which was the first population based study to highlight the prevalence of angle closure disease in an urban cohort, in this case residing at Vellore, Tamil Nadu. Other population based studies since then include the Andhra Pradesh Eye Diseases

Study (APEDS)[8-10], Aravind Comprehensive Eye Survey (ACES)[11], Chennai

Glaucoma Study (CGS)[12, 13] and West Bengal Glaucoma Study (WBGS)[46] conducted in north and southern India.[47] All these studies followed the ISGEO criteria but two studies, CGS and WBGS, made minor modifications to the criteria. The results of these studies are summarized in Table 1.3.

It was evident from the ACES that the prevalence of secondary glaucoma was in the range 0.08% to 1.39%. However, since three fourths of individuals above

40 years of age required eye care services but a third had never undergone an ocular examination, it is likely the true prevalence is higher than this.[48]

Additionally to the estimations of blindness rates, around 28.1million people have ocular hypertension (OHT), primary angle closure and primary angle closure suspect.[49]

Some of the population based studies in India considered the prevalence of glaucoma nationwide based on work conducted in rural and urban settings, as mentioned in Table 1.3

Table 1.3 -Summary of glaucoma prevalence reported by various studies

conducted in rural and urban populations in India [8-14, 45, 46]

Study Population Reported Prevalence POAG PACG PACS

Vellore Eye Study Urban 0.41 4.32 Not Reported (VES)

The Andhra Urban (n= 934) 2.56 1.08 2.21 Pradesh Eye Disease Study (APEDS)

Rural (n= 5150) 1.7 0.5 Not Reported The Aravind Comprehensive Eye Survey (ACES)

Rural (n= 1296) 2.99 Not Reported 6.27 and 7.24 West Bengal Glaucoma Study (WBGS)

Rural (n= 3924) 1.62 and 3.51 0.71 and 2.75 Not Reported The Chennai and Urban (n= Glaucoma Study 3850) (CGS) PACG: Primary angle closure glaucoma, POAG: Primary open angle glaucoma; PACS: Primary angle closure suspect

1.2.3 Mechanism of glaucoma:

Though the pathogenesis of glaucoma is multi-factorial, IOP is a major risk factor for injury to the optic nerve head.[50] The pressure gradient between the intraocular pressure and the cerebro-spinal fluid at the lamina cribrosa plays a main role in maintaining the blood flow in the optic nerve head. If the pressure gradient increases, the axonal transport is disrupted, leading to retinal ganglion cell death. In cases of POAG and normal tension glaucoma (NTG), there seems to be low blood flow in the optic nerve head and retina leading to reduced ocular perfusion. Reduced ocular perfusion occurs due to low blood pressure typically observed in open angle and normal tension glaucoma [51, 52]. Different gene mutations and risk alleles for causing glaucoma have been studied. POAG is due to mutations in myocilin (MYOC), where abnormal myocilin proteins retained in the trabecular meshwork prevent normal aqueous flow, resulting in elevation of intraocular pressure and glaucoma. Optineurin (OPTN) is another gene mutation found in some populations of NTG, but is not usually associated with elevated pressures in POAG. [53]

Even though an exact aetiology and mechanism of glaucoma has not yet been explained, several studies have proposed possible mechanism of the disease.

For example, Kumar Parida[54] proposed that in POAG, micro-perforations occur in the anterior hyaloid face as a result of elevated intra-ocular pressures.

Aqueous enters into the vitreous chamber through these pores, exerting pressure on the capillaries, thereby occluding blood flow and causing damage to the optic nerve fibres and ganglion cells at the macula.

Another possible pathogenesis involves an increased pressure differential between the cerebro-spinal fluid and intra-ocular contents at the lamina cribrosa 35

which disrupts axonal transport and causes retinal ganglion cell death.[55, 56] The mechanism may also involve ischemic hypoxia which is known to be associated with ganglion cell death. [57, 58] Glutamate is a known transmitter in the central nervous system and is released by retinal cells in response to hypoxia. Mouse studies have shown that higher concentrations of glutamate results in toxicity[59] and can eventually lead to destruction of retinal ganglion cells.[60]

Yet another possibility that may relate to those with axial myopia, is that the associated elongation of the globe causes stress at the lamina cribrosa which is accentuated by scleral weakness at the optic nerve. Resulting defects in the lamina cribrosa may thus contribute to the glaucomatous damage[61] 36

1.2.4 Risk factors of glaucoma:

Studies reveal that a detailed patient’s history is critical to the identification of risk factors associated with glaucoma. The following are identified as the risk factors of glaucoma:

Family history: Individuals with a strong family history of glaucoma are at a greater risk of developing the disease. It was found that, where glaucoma runs in families, relatives are 10 times more at risk compared to the normal cohort.[62]

There is a strong association between open angle glaucoma and family history, especially between siblings. In short, the risk of open angle glaucoma is three to six times more in close relatives with family history, in comparison to the general population.[63]

Age: Advancing age is considered a primary risk factor for developing glaucoma. The prevalence was found to be 0.3% in individuals aged 40 years but this increased to 3.3% in older individuals, aged 70 years. [64]

Ethnicity: The prevalence of glaucoma varies with ethnicity, with non-

Caucasians being at greater risk. [65] A difference in the types of glaucoma between ethnicities is also evident. For example, the prevalence of open angle glaucoma is greater among those of American, Hispanic and African descent[66,

67] and lowest in East and South Asians[68] , whereas angle closure is highly prevalent in Asia, especially among the Chinese population.[69]

Intra-ocular pressure: IOP varies constantly over the 24 hour day but pressure spikes on top of this diurnal variation, or constantly raised IOP, impact the posterior structures of the eye affecting the optic nerve, lamina cribrosa and adjacent tissues. As the lamina is the weakest point, compression and 37

deformation is most likely to manifest at this location. [70] Thus, intra ocular pressure spikes are always a significant risk factor for all forms of glaucoma and 21mmHg is seen[71] as the upper limit.

There is always a fluctuation in the intraocular pressure of the human eye.

Though this has not been explored completely, it has been noted that the fluctuation occurs more in open and angle closure glaucoma than in normals; primary angle closure glaucoma having the highest diurnal fluctuation. One study indicated that individuals presenting with IOPs of 20mmHg to 23mmHg were four times more at risk of developing glaucoma than those below

16mmHg.[66]

OHT may progress to glaucoma and in advancing glaucomatous cases there is a 10% increase risk for every 1mmHg rise in IOP levels.[67]

Myopia: Literature on the association between myopia and glaucoma has been known for several decades.[72-74] Myopia is strongly related to glaucoma with studies showing a two to three fold increased risk, compared to Emmetropes and 14 fold risk of visual field defects.[75]

High myopes with defects at the lamina are likely to go on to develop glaucoma.

Previous studies have reported an association of axial myopia greater than -

1.00DSph with POAG.[76] The Rotterdam eye study [77] reported that myopia > -

4.00DSph was associated with visual field loss and that the risk of glaucomatous damage increased with refractive errors exceeding -6.00Dsph.[78]

Defects at lamina cribrosa which cannot be found through clinical examination can be detected on standard automated perimetry (SAP) or optical coherence 38

tomography (OCT) which might help in early detection of glaucomatous damage. [61]

Long term intake of Corticosteroids: Drug induced glaucoma is said to be caused by long term intake of corticosteroids.[79, 80] A case study reported that a patient developed steroid induced glaucoma within a few weeks of steroid treatment approximately at 1 month of follow up.[81] Studies [75, 82] identified that inhaled steroids can also be a significant factor pertaining to development of glaucoma.Prolonged doses of inhaled steroids can increase the risk of open angle glaucoma, however, overall these drugs were not found to be strongly associated with the disease [83]

Ocular trauma: Several risk factors are associated with post traumatic glaucoma in open and closed globe injuries.[84] Unusual unilateral pigment dispersion without angle recession due to blunt trauma and elevated IOP has been documented in a case study.[81] Trauma to the eye causing an angle recession can be considered as a risk factor. [85-87] It has been shown that about

6-7% of angle recessions turn to glaucoma as a late complication after 10 years.[88] Other risk factors pertaining to post-traumatic glaucoma can be pigment accumulation in the trabecular meshwork, lens dislocation, hyphema,

[89] corneal injury, traumatic cataract , advancing age, poor VA, intra ocular inflammation, long standing vitreous haemorrhage and coagulated blood components. The prevalence of raised IOP was about 17% in cases of open globe injuries.[90]

Systemic diseases: An equivocal literature on the association between diabetes and POAG exists. The diabetic population is at 1.4 fold higher risk of 39

developing POAG in comparison to a normal cohort.[91] Neuronal injury occurs due to stress, as a consequence of the long standing hyperglycaemic levels and lipid anomalies in diabetes. While some studies [92, 93] have proposed a direct relationship between development of open angle glaucoma and diabetes, controversy exists in this area. [94, 95] Several population based studies [92, 93] have reported a positive association between diabetes and glaucoma. On the contrary, studies such as the Ocular Hypertension Treatment Study (OHTS), indicate that diabetes is not a risk factor of glaucoma and may even be considered protective for the disease. Understanding of the complex relationship between systemic hypertension duration and patient’s age in relation to development of glaucoma remains incomplete.[96]

1.3 Glaucoma detection

1.3.1 Need for Early detection:

Due to its insidious nature, combined with the increasing prevalence of the chronic disease, glaucoma has become a major public health problem. The disease is asymptomatic until the advanced stages and to reduce the burden of increasing prevalence, early detection and treatment of glaucoma are essential.[31] Early manifestations can be missed in up to half of the cases if the individuals do not undergo a comprehensive eye examination or consult an optometrist or ophthalmologist for regular eye examinations.[97] As glaucomatous damage is often already evident in subjects who present later on, these cases usually suffer from moderate to advanced visual loss. [98] About

50% of glaucoma cases go undiagnosed and almost 60% of those in 40

developing countries are unaware[15] of the sight threatening condition.[38] Thus, early detection aids in early diagnosis, which in turn minimizes vision loss.

At a global level, various screening strategies have been proposed and implemented to assist early detection and management of the disease.

Bokman[99] and colleagues conducted a study among Haitians to identify individuals suspicious for glaucoma who had not undergone any ocular examination for ten years or more. About 21% of suspects were younger than

40 years of age. Another community based study,[100] conducted to identify the detection rate of glaucoma in Philadelphia, reported about 39.1% with a glaucoma related diagnosis with open and closed angle glaucoma rates being

9% and 1% respectively. Alternative technology additives in mass screening, conducted using an FDT in the general population detected 83.3% and 100% of early and advanced glaucomatous cases respectively.[101]

1.3.2 Screening and Referrals by optometrists:

Due to the estimates indicating that prevalence rates of glaucoma globally are high, screening is indicated as a means of detecting those at risk. [102] Due to the chronic, asymptomatic nature of the disease there is a strong argument for screening in the community to promote early detection and prevent significant vision loss.

Glaucoma screening has historically been quite challenging, as there is no single parameter or test with high sensitivity and specificity. [103] For example, a study [104] conducted in a Latino population, above the age of 40 years, to determine the efficacy of screening tests in isolation and combination to detect glaucoma, found that clinical examination incorporating IOP and CDR 41

(horizontal and vertical), along with Humphrey visual field (HVF) imaging, provided a high yield in screening the disease. They also reported that measuring IOP alone for glaucoma detection yields poor sensitivity with high specificity. FDT had fair sensitivity of 0.71 (using CART analysis) and specificity of 0.69 for high risk population. In support to this, another study which reviewed all studies has reported that IOP in isolation had overall poor sensitivity of 46%

(95% CI of 22-71) whereas the performance of FDT was promising with sensitivity of 92% (95% CI of 65-99)[105]

Another report coming from the United Kingdom based on a small sample, shows that clinical examination including visual acuity (VA), intra ocular pressure (IOP), contrast sensitivity and color differentiation did not obtain acceptable results in the detection of glaucoma but on the addition of IOP, HVF and optic disc assessment, sensitivity improved to >90%[106]

An ideal screening should be cost effective, inexpensive to perform in large communities, less time consuming and have high sensitivity and specificity rates.[107] As there is no single, safe precise and validated “diagnostic test” for glaucoma, as defined by the UK national screening committee in 1988,[108] screening methods must currently involve a comprehensive eye examination incorporating several required components as part of the investigation.

Typically, individuals identified as normal during screening, are advised to return annually for regular eye examination. Subjects with elevated IOP, abnormal disc findings, unreliable VF or family history of glaucoma, are referred to an ophthalmologist for more detailed evaluation. An important metric of the screening process is the referral rate, or the number of referrals made as a proportion of all those examined. Reports on the current standards of screening 42

show poor sensitivity and specificity for IOP and visual fields in isolation, misdiagnosis of the glaucoma and even optic disc evaluation by the trainers is ineffective due to lack of proper training.[14, 15].

Referrals:

Screening methods and referral criteria for glaucoma vary widely among practitioners [109]. The burden on the hospitals is twofold. One is the initial appointment following referral, which involves many baseline investigations but result in many patients being discharged with no abnormality found. The second is the long-term follow-up of patients with ocular hypertension (OHT), glaucoma suspects (GS) and low-risk glaucoma, all of which require a considerable commitment of hospital resources to maintain. The impact can be reduced by relocating care visits into the local community using community specialist optometrist.[110] At present, glaucoma is diagnosed mostly in the hospital setting where most referrals come from optometrists[111] or opticians in the community. Referral rates by the optometrists to the hospitals for further evaluation and investigations are approximately 15-20% of all the patients and by the end of 2020 it is estimated to increase to 35%. In the UK, almost 90% of

POAG suspect referrals are initiated by optometrists. The false positive rate in referral ranges from 29 to 68% and in an effort to reduce this a number of referral schemes have been proposed and conducted in different communities of different regions. [112-116] The Peterborough scheme for community specialist optometrist in glaucoma study indicated that there is potential for a significant increase in the role of primary care optometry in glaucoma management of patients referred with stable disease. [110] Another study reported on the referral accuracy between optometrists with no specialist interest in glaucoma (non- 43

OSI) and those with specialist interest in glaucoma (OSI). About 20% of the glaucoma suspect’s referrals were sent to the tertiary centres by optometrists with no specialist interest in glaucoma, compared with the OSI group, a difference that was statistically significant. Further, the OSI outcomes were a closer match with those of the ophthalmologist, suggesting that OSI training can decrease the false positive rate of referrals to the eye hospital.[114]

Currently, in UK about 60,000 individuals per year are referred with a diagnosis of suspect glaucoma by an optometrist Other studies has shown that the accuracy of these referrals may vary from 32% and 72% [117, 118] A retrospective analysis carried out to study the referral accuracy by optometrist for a period of

5 years from 1988 to 1993 showed a decline in the true positive rate from referrals and mild increase in false positives over the period of observation.[119]

The authors suggest that this was due to optometrists starting to perform VF prior to examining the optic disc. Thus, a positive VF might prompt a referral, irrespective of disc appearance.

Screening programs naturally come with significant costs attached. For example, one glaucoma study estimated that about 5.1million Euros are required to screen a population of 1 million people, while finding 4,715 new cases of glaucoma. In practice, the costs of screening for glaucoma depend significantly on the targeted population and the personnel utilized during the screening process. [120] Nevertheless, as impaired vision worsens the quality of life for those affected and causes a considerable economic impact on society, it is reasonable to expect that the costs of conducting screening programs that result in early intervention will be offset by reductions in the social burden of disease and improvements in individual wellbeing for those with VI or Blindness. 44

In summary, the referral studies mentioned above were mainly aimed at assessing how the quality of referrals might be improved by accurately detecting the disease. Some benefits of referral schemes were reported including faster assessment with a complete examination and ancillary investigations in a single day and reducing the false positive rates for detection of the disease by an optometrist. Unfortunately, no such studies were conducted in developing countries so the diagnostic ability of eye care personnel in glaucoma detection relative to that of glaucoma specialist ophthalmologists under local, social, economic and geographical circumstance remains unknown. Hence the utility of such personnel as a means of glaucoma detection in a community based setting is poorly defined.

1.4 Primary health care

1.4.1 Primary care centres:

Glaucoma has also become one of the major public health concerns[121] worldwide and providing universal and affordable access to health care is the main goal of the primary health systems. There above mentioned community glaucoma screening programs aimed at early diagnosis and prevention of further visual loss. Among the major issues identified are several that particularly affect developing countries including the shortage of trained human resources, especially in rural areas, [122-124] political, infrastructural and financial constraints on national health systems and access to affordable eye care services is [125] Other work, such as the Philadelphia glaucoma detection and treatment project, was conducted to study glaucoma among in the local 45

underserved population and identified a number of additional barriers to accessing care including insufficient knowledge of glaucoma and its progression, lack of awareness about eye care services, language barriers, difficulty in obtaining transportation, the high number of follow up’s and the cost of treatment[100]

The rate of reduction in blindness is also lower in developing countries than developed countries.[126] Shortage of trained human resources in developing nations, especially in rural areas, is considered to be one of the major hindrances. The issue is worsened by political, infrastructural and financial constraints in the national health systems of developing countries.[122-124] In such a scenario, a shared care between different ophthalmic professions is expected to bring about a synergistic effect on augmented delivery of eye care.[127]

With that idea, the L V Prasad Eye Institute (LVPEI) initiated its vision centre model to target and eliminate avoidable blindness, providing equitable eye care.

1.4.2 LVPEI’s pyramidal model:

The L V Prasad Eye Institute has implemented many innovative strategies at tertiary, secondary and primary levels in Andhra Pradesh, creating a wide network. The initiation of the vision centres [27, 128] in rural towns and villages was a unique strategy developed and practiced by L V Prasad Eye Institute to eliminate avoidable blindness by providing primary health services to remote and underserved populations. Individuals with vision problems at rural level

[25] ignore eye care due to affordability issues. Hence, the main objective of the 46

vision centres was to provide easy access and affordability to health care services.

Around 50,000 individuals were chosen as a population unit for each vision centre and a service centre covers around 10 such vision centres in nearby districts. These primary care centres are staffed by vision technicians (VT) who have a minimum education requirement of a high school diploma and have the potential to serve the community. A VT undergoes one year training at LVPEI and is certified to perform history taking, visual acuity assessment, refraction, slit-lamp examination, applanation tonometry, undilated fundus examination, and to prescribe glasses. Patients seek eye care at vision centres and after evaluation by the VT; those requiring further evaluation are referred to the ophthalmologist at a secondary service centre.[128, 129] Vision technicians are intensely trained for a period of 1 year, focusing on the three primary eye care functions of detecting eye problems, accurate spectacle prescription and referral. Simultaneously they engage in mass screenings in communities and schools.

VT’s are capable enough to detect, diagnose and refer cases of visual impairment for further referrals,[28] yet many issues occur at the primary- secondary interface include decisions to refer, appropriateness of referrals, variation in referral rates, outcome of referrals, and communication.[130, 131] 47

Figure 1: LVPEI eye care network

The vision and secondary care centres described above, fit into the Eye Health

Pyramid of the LV Prasad Eye Institute and together with recent advances in glaucoma diagnosis, offer a potential solution to the problem of glaucoma detection at an early stage in the community.

The pyramidal model was based on analysis by LVPEI and developed for eye care delivery.[128] It has a five tiered structure where each level of the pyramid has appropriately trained manpower and appropriate infrastructure. Glaucoma detection and treatment are integral parts of the upper 3 tiers of the pyramid. 48

There is however, potential for detection at the first two levels of care, within the community.

It is hypothesized that glaucoma detection at community eye care and primary care centres can be incorporated within this model to reduce the burden of blindness. To accomplish this, the lower two tiers of the pyramid must involve efficient screening and detection of glaucoma at the community level.

1 Figure 1 Multitiered interlinked eye-care delivery model

1 for 50,000,000 population

1 for 5,000,000 population

1 for 5,00,000 to 1,000,000 population

1 for 50,000 population

Community; self care

Figure 2: The multi-tiered eye health delivery model of the L V Prasad Eye institute

This need fits into the eye care delivery model, whereby a detailed eye examination is conducted close to the residence of the individuals. This 49

procedure also results in the identification of suspected pathology and an efficient referral process is initiated to provide for confirmation of the diagnosis and administration of appropriate treatment within a reasonable time frame. [132]

The primary activity takes place at the vision centre which is manned by a vision technician and clearly, the accuracy of the referral event depends on the skills and knowledge of this individual. It is therefore important to understand how good such individuals are at making such decisions, given their relative lack of training.

1.5 Vision technicians:

Very few studies have been published about the performance of community level ophthalmic personnel in the detection of glaucoma. The first of those studies aimed to evaluate the effectiveness of screening for glaucoma by ophthalmic assistants, who had been trained for 2 years in refraction and diagnosis of major ocular disease and who received 3 days further training, including the use of FDT, in glaucoma detection. A complete examination was conducted by both the ophthalmologist and the ophthalmic assistant including diagnostic tests such as visual fields (VF) using FDT perimetry and a dilated fundus examination. This study was conducted both in a hospital and a community based setting. [133]

There was good agreement between the ophthalmic assistants and ophthalmologist in diagnosing glaucoma suspects in the hospital (kappa value of 0.74), however only moderate agreement (kappa = 0.50) was found in the community environment. For the assistants in the hospital setting, sensitivity in 50

diagnosing suspects was higher at 95.2% with CI of (91.4-97.7) vs 82.9% (69.7-

91.7) in the community, which might have been due to the presence of more advanced cases of glaucoma. The lower specificity of 71.4% (60-78.7) in the hospital vs community setting 76.8% (72.7-79.5) may reflect over caution in diagnosis among ophthalmic assistants. This result indicates an encouraging and a substantial agreement between the ophthalmic assistants and the ophthalmologists in the diagnosis of glaucoma suspects and offers the possibility that, with further clinical experience, the diagnostic performance might improve.[133]

Thomas et al [1] determined the performance of a vision technician in detecting ocular disease using FDT and also assessed if the detection rate in the community could be improved with the use of FDT perimetry. The vision technician performed a comprehensive eye examination which included best corrected visual acuity with refraction, applanation tonometry, slit lamp biomicroscopy, undilated direct ophthalmoscopy along with 20-1 FDT. Of the

1764 subjects who participated, 360 (20.4%) cases of significant ocular disease were detected by the ophthalmologist, whereas the VT detected 245 (13.2%).

Using FDT increased the rate of disease detection by vision technicians to

17.9%, as 71 out of 115 missed cases were revealed by FDT. Hence technological support in the form of FDT was effective for posterior segment pathologies, although false positives are expected to be high.[116]

Suram et al also reported the accuracy of seven primary care vision technicians in detecting ocular pathologies in a south Indian population. These VTs were trained for 1 year and certified as being competent to perform the initial assessments, which included visual acuity, refraction, slit lamp biomicroscopy 51

and intraocular pressure measurements with an applanation tonometer. In this study, the reference standard was a trained glaucoma fellow, who was a consultant at the secondary centre. Both the VTs and reference standard ophthalmologist performed all the tests, along with the dilated fundus examination. An excellent agreement was found in detecting anterior segment pathologies including cataract (0.97), refractive errors (0.98), corneal pathology

(1), and other anterior segment pathologies (0.95). A fair to moderate agreement was found in detecting glaucoma (0.43) and retinal pathologies

(0.39). [29] The authors suggested that the addition of imaging techniques such as FDT or NMFP might improve the diagnostic accuracies of the VTs in posterior segment disease.

Table 1.4 - Summary of studies in which supplementary equipment was used to aid disease detection by different eye care personnel’s [99, 104, 110, 134, 135]

Study (n) Equipment used Assessment done by

The Peterborough GAT, Handheld Specialist optometrists in Scheme For Pachymeter, HVF and glaucoma (SOG’s) Community Specialist ONH evaluation through in Glaucoma (n = 1184) Slit lamp biomicroscopy.

The Los Angles Latino GAT, Ultrasonic Ophthalmic technicians Eye Study pachymeter, HVF, FDT (LALES) (n=7789) and Optic disc photographs

The Philadelphia GAT, Gonio, Pachymeter Initial examination - Glaucoma Detection and HVF. Ophthalmic technician and And Treatment Project dilated examination - (n = 1649) Ophthalmologist

Glaucoma Screening Tonopen, Pachymeter, Glaucoma fellows and In Haiti Population (n NMFC, FDT, and Direct Medical students =750) Ophthalmoscope

Eye care Quality and GAT, Gonio and SD OCT Primary care Optometrist in Accessibility Improved VC In The Community For Adults At Risk For Glaucoma (EQUALITY) 53

GAT: Goldmann applanation tonometer, ONH: Optic nerve head, HVF: Humphrey visual fields, FDT: Frequency doubling technology, NMFC: Non mydriatic fundus camera, SD-OCT: Spectral domain optical coherence tomography, VC: Vision centre

1.6 Summary:

The foregoing discussion has highlighted the wide prevalence and debilitating nature of glaucoma as a cause of blindness and visual impairment across the globe. Reducing the impact of this disease clearly requires that it is detected at an early stage and doing that effectively means screening the population at a local level. A lack of resources, particularly in terms of numbers of suitably trained eye care professionals (ophthalmologists and optometrist) has generally hampered this effort.

In India, community level eye examination is being conducted within the framework of the LVPEI pyramid model, which uses vision technicians, rather than ophthalmologists or optometrists, to reach the large numbers of people who need to be examined. While some work has indicated the value of such relatively untrained personnel in successfully detecting ocular pathology, little is known about how they perform in the context of a community level environment.

The present study seeks to address this knowledge gap

Considering the burden of glaucoma [7], initially studies reported the increasing prevalence of glaucoma globally and different studies have looked at the prevalence at urban and rural population [8-13]. Later studies [110] [114] have implemented screening strategies and referrals to detect and diagnose glaucoma through optometrists, ophthalmologists and other trained technicians.

Suspects detected in these studies were further referred to a glaucoma specialist ophthalmologist. The referral accuracy of the optometrists was also 54

quantified in one of the studies [117, 118]. In other scenario where the rural population lacks eye care facilities, L V Prasad Eye institute has introduced vision centres [27, 128] staffed with vision technicians to serve the individuals at the remote and rural communities. Two studies [1] [29] have determined the clinical capabilities of the vision technicians in detecting major eye diseases.

Though they reported a good agreement against the ophthalmologists in detecting anterior segment pathologies but a low agreement was found in detecting posterior segment pathologies. It was also found earlier that the vision technician disease detection rate improved with the use of FDT, it was suggested that with training and use of other additive technologies, the sensitivity in posterior disease detection might improve. As there lies a gap in the literature in detecting an insidious disease like glaucoma at the rural population utilizing vision technicians, this study focused at glaucoma detection through vision technician’s abilities.

The current study utilizes vision technicians to detect glaucoma in a south

Indian rural population determining the diagnostic accuracy in disease detection.

1.7 Aims and objectives:

The main aim of the present study is to evaluate the ability of a vision technician to detect glaucoma in a south Indian rural population.

The objectives of the current study are to:

1. Evaluate the agreement between trained optometrists and glaucoma

specialist ophthalmologists

2. Validate the ability of vision technicians to detect glaucoma, based on

available clinical examination, in a South Indian rural population,

3. To evaluate the diagnostic yield of glaucoma detection by a vision

technician when clinical information is combined with frequency doubling

perimetry and non-mydriatic fundus photography.

Chapter 2: Materials and Methods

Overview

Based on the current literature this study was designed such a way that the data can be collected as part of a major population based study, L V Prasad

Eye Institute - Glaucoma Epidemiology and Molecular Genetics Study (LVPEI-

GLEAMS) [136]

The LVPEI-GLEAMS was designed to determine the prevalence rates of glaucoma along with clinical, genetic and systemic risk factors conducted in a rural population of a southern Indian state of Andhra Pradesh. The study was carried out at a vision centre that is staffed by vision technicians and who become the first point of contact for patients during the screening process.

Subjects included in the study were from 16 villages of Pendanandipadu sub- district in Guntur district of Andhra Pradesh state. The study team comprised 2 study optometrists, 8 trained vision technicians, 2 vision guardians and a field coordinator. The vision technicians were trained clinically, handling diagnostic procedures and reading the reports of NMFP and FDT using different teaching sessions in view of carrying out effective assessments.

Strict quality control measures were taken for proper data management and onsite routine monitoring was done by the project coordinators and the study optometrists.

2.1 Methods and Approval:

This ethics committee of the L.V. Prasad Eye Institute approved the study (LEC

08131and was conducted according to the tenets of the Declaration of Helsinki).

Informed consent was obtained from all the participants and the data were collected prospectively following the standard proforma of patient examination.

The below flow chart briefs on the two sub studies carried out to achieve the aim. The methods for all these studies have been explained in detail in further sections after the flow chart Figure 3

Baseline study – Agreement of screening ocular pathology between vision technicians and ophthalmologist

Establishing reference standard to train and evaluate vision technician’s diagnostic ability

Validating the ability of vision technician in

detecting glaucoma at a rural population

Figure 3 – Flowchart of studies discussed in the current thesis 58

Based on a study conducted to have an insight of VT’s ability in screening for potentially blinding diseases at a vision centre as assessed by an ophthalmologist, with a small sample size at 7 vision centres. Based on a kappa agreement and detection rates, further study was planned to establish a reference standard through study optometrists followed by short duration of training in glaucoma detection and evaluation of the diagnostic ability.

2.2 Methodology for the baseline study:

A baseline study was conducted at 7 vision centres in 7 villages of the LVPEI network in Southern India and all the patients attending the VC during the study duration were enrolled after an informed consent. The vision technicians were compared to a gold standard who is an ophthalmologist and fellowship trained specialist in glaucoma.

Assuming that the vision technicians would be able to detect 60% ocular diseases and with ophthalmologists increase the detection of abnormalities by further 20%, the sample size required was 279 subjects (with an alpha error of

5%)

2.2.1 Study protocol:

Every week the ophthalmologist visited a particular vision centre and during that period the patients attending the VC consecutively were enrolled. The ophthalmologist conducted a dilated examination for providing a diagnosis which is considered as “reference standard”. Each and every subject’s demographics were entered and the clinical examination was initially carried out 59

by the vision technician. All subjects underwent clinical history taking, visual acuity, subjective and objective refraction, torch light examination, slit lamp evaluation, intraocular pressure measurement (IOP) and direct ophthalmoscopy. Every individual’s findings were recorded in a data collection sheet separately which had self-coded questions. The quality control checks were done every day to ensure the completion of data forms by the vision technicians.

Referral criteria: Any patient whose visual acuity did not improve even after spectacle correction (distance VA of at least 6/18 and N6 for near acuity); shallow or narrow anterior chamber angles; raised IOP (20mmHg or more); any presence of anterior/posterior segment abnormalities; ocular trauma; any active infection or un explained vision loss.

After the data collection an agreement was evaluated between the vision technicians and the ophthalmologists. Based on this, it was decided to have study optometrist as reference standard in training the vision technicians in glaucoma detection followed by evaluating their diagnostic accuracy.

In the main study, study optometrists were established as a reference standard for glaucoma detection, a set of two vision technicians (at least 1 year of experience but not more than 3 years), of which one VT performed the clinical examination which included history taking, visual acuity assessment, refraction, external and anterior segment examination, gonioscopy and undilated disc examination with a direct ophthalmoscope. The second VT performed the slit lamp photography, non-mydriatic fundus photography, frequency doubling technology (FDT). Finally, the results obtained through the vision technicians 60

are compared with the reference standard study optometrist, who also examined all the patients.

The two reference standard optometrists were also responsible for the scientific and administrative aspects of the study, co-ordinating all the procedures of the study, work of the staff, management of data, quality control and diagnosis of glaucoma.

2.3 Reference standard optometrist for the current study:

Primarily, a reference standard optometrist was established whose agreement with the specialists in glaucoma diagnosis at a tertiary centre had been evaluated. The study proceeded by evaluating the ability of the vision technicians to diagnose glaucoma, compared with the standard optometrist, as a part of LVPEI- GLEAMS study.

For the above mentioned reference standard, the study was conducted in the outpatient department of the L.V. Prasad Eye Institute, Hyderabad, India. The L

V Prasad Eye Institute, being a centre of excellence in eye care delivery pyramidal model,[129] most of the patients come with complex eye problems.

Each and every patient who reports at the front desk is directed to the outpatient department for a comprehensive eye examination by both the optometrist and ophthalmologist. Referral to the subspecialty clinic follows depending on the necessity. A standard training protocol is followed by every optometrist at LVPEI.

In determining the reference standard for the current study, three glaucoma specialists with experience ranging from 8 through 23 years and 2 study 61

optometrists who had been working with the same specialists for over 7 years in the glaucoma department of a tertiary eye care centre took part in this work. In this period well over 5000 glaucoma patients were examined and managed by the ophthalmologists. As both the study optometrists performed gonioscopy and optic disc assessment on over 2000 patients, they gained good experience in the assessment and management of glaucoma patients in collaboration with the same glaucoma specialist ophthalmologists.

A standard proforma was followed for the examination procedures. For every patient, gonioscopy was performed pre dilated with a Sussman 4 mirror gonio lens (Volk Optical Inc., Mentor, Ohio, USA) and a post dilated evaluation of optic disc and fundus was done with a 90.00 D (Volk Optical Inc, Mentor, Ohio,

USA) lens. Disc cupping and appearance were documented by drawing important features such as the cup-disc ratio (CDR), neuro-retinal rim (NRR), asymmetry, peripapillary atrophy (PPA), retinal nerve fibre layer defects

(RNFL), disc haemorrhages and collateral vessels.

The findings were documented in handwritten notes which concluded with a summary “impression” of the clinical state including information on whether discs, fields and intra ocular pressure’s (IOPs) were stable or progressive. In this study, all the findings remained masked to the observers, as all examiners retained their own gonioscopic and optic disc assessment information in a separate log book. No other clinical data was available to the observers.

2.3.1 Patient allocation:

New patients attending the comprehensive outpatient department at LVPEI were recruited for the study. After the initial work-up by the general optometrists, each of the two experienced optometrists and the glaucoma specialist ophthalmologist carried out gonioscopy and documented their findings in their respective log book in masked fashion. These procedures continued until the glaucoma specialist had recorded a total of 150 eyes including 25 with occludable angles only, 25 with occludable angles and synechiae and 100 eyes with open angles without any other abnormality. Gonioscopy was done after

IOP recording and the category of the angle was entered in a separate log book as 0 (open) or 1 (suspect) or 2 (closed). Similarly, post dilated optic disc examination was conducted for all the new patients, by each of the experienced optometrists followed by the glaucoma specialist in a masked fashion. Again details of the results were masked between the clinicians and the process continued until the glaucoma specialist had recorded a total number of 200 eyes, 30 with suspect discs, 30 with glaucomatous discs and the rest normal and graded as 0 (Normal) or 1(Disc Suspect) or 2 (Glaucomatous). Patients with a history of any ocular surgery or with dense media opacities which would affect the fundus examination and disc assessment were excluded.

2.3.2 Categorization of gonioscopy and optic disc findings:

For the current study, as mentioned in the above section, the gonioscopic findings for open angle, primary angle closure suspect (PACS) and primary angle closure (PAC) were categorised as 0, 1 & 2 respectively and optic disc findings as 0, 1 & 2 for normal, disc suspect and glaucomatous respectively. A 63

classification of the optic disc as normal, suspect or glaucomatous was entirely based on its appearance. For gonioscopic criteria the ISGEO classification was used.[33]

2.4 LVPEI-GLEAMS:

2.4.1 Study design and Sample size

This was a population based cross-sectional study. For a survey design based on a cluster random sample, the sample size required can be calculated according to the following formula.[137]

Formula:

Description:

Estimating a prevalence of glaucoma (POAG and PACG) to be 5% in those aged 40 years and above, based on the APEDS[8, 10] and CGS,[12, 13] with the estimate ranging from 4-6% (with 95% confidence), a sample of 1825 subjects needed to be screened.

To correct the difference in design (for extrapolating to population), the sample size is multiplied by the design effect (D).

The design effect is generally assumed to be 2 for eye health surveys using cluster-sampling methodology.[138] 64

N= n*2

Sample size = 1825 * 2 = 3650

The sample was further increased by 5% to account for contingencies such as non-response or recording error.

N = n + 5%

= n * 1.05

= 3833

Thus, 3833 subjects greater than 40 years of age needed to be enrolled in the study

2.4.2 Sampling method

The study area comprises a total population of 44,000 people residing in 16 villages spread over Pedanandipadu mandal of Guntur district. Twenty three percent (23%) of the population was greater than 40 years of age as per the

2002 census of India report. With the same age distribution 9,890 subjects aged above 40 years are expected in this area and 3,833 people from this defined population were recruited.

The sample from each village was selected by probability proportionate to size.

2.4.3 Study location and selection of subjects:

The study areas of 16 villages from Pedanandipadu mandal were on average within 25 km from the vision centre and 30 km from the service centre.There was no ethnic difference found in any villages. The order of the village was selected randomly by drawing a chit from 16 chits. Once, a village is selected that chit was removed from the draw.

The selection of subjects from each village was as follows:

Village (cluster) for the subject recruitment was identified.

Map of the village was taken and divided into 3 equal parts and were labelled as

A, B, C, etc; so that the cluster within each village was identified by drawing lots.

If within that segment the desired number of subjects was not reached then another chit was picked by the vision guardian and subject enumeration was done in that segment of the village. The vision guardian conducted a door-to- door survey by the above mentioned procedure and carried out a torch light examination to rule out any anterior segment abnormality and motivate the subjects to undergo the complete examination. The number of subjects to be enrolled from each village are listed in the below Table 2.1

Table 2.1 -Subject recruitment by village

S.No. Village Name Persons Age >40 Yrs Subjects recruited

1 Abbineniguntapaelm 2500 575 218

2 Annaparru 2000 460 174

3 Annavaram 2600 598 226

4 Gogulmudi 3000 690 261

5 Gorijavoluguntapalem 1200 276 105

6 Katrapadu 2000 460 174

7 Koparru 3000 690 261

8 Nagulapadu 2600 598 226

9 Palaparru 3500 805 305

10 Pamidivaripalem 1500 345 131

11 Pedanadipadu 6000 1380 523

12 Pusuluru 3200 736 279

13 Rajupalem 900 207 78

14 Ravipadu 1500 345 131

15 Uppalapadu 4500 1035 392

16 Varagani 4000 920 348

2.4.4 Eligibility and Exclusion Criteria

Individuals aged 40 years and above, or those turning 40 in the current calendar year and who were resident at the target household for a minimum period of 6 months and willing to participate were eligible for inclusion. People staying at the target household for a period of less than 6 months, residents who died after 67

enumeration but prior to examination and eligible residents who could not be contacted after 3 attempts were excluded as were very old persons who could not be transported to the vision centre.

A refusal was recorded when the residents did not provide household information or answer general questions on history of eye diseases or turned down compliance with examination after repeated requests. There was no monetary benefit offered for participation in the study but the subjects were offered free treatment under the L V Prasad Eye Institute eye health pyramid, based on the eye condition detected and the level of care and attention necessary.

2.5 Training of vision technicians (VT’s):

The vision technicians were trained to perform visual acuity, refraction, slit lamp examination and intraocular pressure measurement with Goldmann applanation tonometry (GAT) but were additionally trained to perform the following evaluations: Gonioscopy and undilated disc examination by direct ophthalmoscopy, non-mydriatic fundus photography, anterior segment imaging of the angle with Cirrus HD-OCT, Humphrey visual field analyzer, FDT perimetry and posterior segment imaging with Cirrus HD-OCT.

The training comprised of 2 parts: a) theoretical modules involving study of videos of gonioscopy, pictures of angle structures, and series of optic nerve images of different grades of glaucomatous damage and suspected cases with small, medium and large size discs and b) field training involving evaluation of 68

ocular characteristics of patients attending a vision centre over a period of 2 weeks under the supervision of the reference standard optometrist.

2.5.1 Assessments at the community level

The project coordinator and the vision guardians carried out the field operations.

The vision guardian conducted a door-to-door survey of all the households in the study area and collected details regarding the number of families in the area, total number of members and eligible members in each family. Members living on the same premises and sharing a common kitchen are defined as one household. All the subjects above or equal to 40 years of age were recruited from the community by the vision guardian. During the door-to-door survey the vision guardian went to each house, introduced themselves and met the head of the household. Then the vision guardian collected all the details of the household and explained the study purpose and the logistics. When the eligible candidate in the household agreed to participate in the study then he/she signed the informed consent. Informed consent was available in all the three languages (Telugu, Hindi and English), for those who could not read, the vision guardian read the document for them in the presence of either a relative or attendant. The vision guardian then registered the subject for the study by assigning an ID number. The vision guardian then recorded the visual acuity and performed a torch light examination on the eligible candidate and noted down his findings. The vision guardian then motivated the eligible members to undergo the clinical examination the next day. On the day of the examination, the vision guardian accompanied the subjects in the project vehicle. Once the comprehensive evaluation was over, the subjects were transported back to their residence. 69

2.5.2 Assessments at the vision centre

All the subjects screened by the vision guardian were mobilized to the vision centre where two trained VTs and a study optometrist performed the complete evaluation. On arrival at the vision centre, the registered subjects ID number was noted in the case report form (CRF). Then they were taken through various ophthalmic examinations and diagnostic investigations in the following order:

 Ocular, medical and systemic history

 Lensometry (only if required)

 Presenting vision, refraction and best corrected visual acuity

 External examination with a torch light

 Slit-lamp examination with photography

 Frequency-doubling perimetry (30-2-1 screening program)

 Fundus photography with a non-mydriatic fundus camera (Topcon non-

mydriatic retinal camera, TRC-NW8 - Topcon, Bauer Drive, Oakland,

NJ).

 Examination of the posterior pole with Direct Ophthalmoscope in

undilated pupils

 Anterior segment imaging with Cirrus™ ( Anterior Segment Cube

512 × 128 and Anterior Segment 5 line raster in all four quadrants)

 Applanation tonometry 70

 Gonioscopy

 Central corneal thickness measurement (AL-1000 ultrasonic

pachymeter - ultrasonic velocity is set to 1640m/s for central

corneal thickness measurements)

 Posterior segment imaging with Cirrus™

 Posterior segment examination with an indirect lens

 Humphrey visual fields (24-2 Swedish interactive threshold algorithm

– standard)

All the procedures were conducted according to the standard protocol described in the GLEAMS [136] literature. The sequence of examination with the trained vision technician and the reference standard, along with the time taken at each level, are shown in Figure 4

Diagnosis was made by each of the examiners in their case report form (CRF).

The vision technician performing the imaging marked a check in the place provided in case report form, once each investigation is done.

Figure 4: Sequence of examinations at the vision Centre and time taken

2.5.3 Documentation of findings by vision technicians:

Training was given for the VTs in identifying optic disc changes for small, average and large disc size for both > 50% damage and < 50% damage from glaucomatous change, as well as normal.

Table 2.2 - Criteria for classification of glaucoma established for the current study

Classification of glaucoma

Normal No definite features of glaucoma

Damage > 50% indicates definite notch with significant neuro- Disease retinal rim loss in either one or both quadrants of the disc.

Damage < 50% damage indicates no significant neuro-retinal

damage, with or without notch.

All the abnormal discs along with discs which didn’t fall below 50% Suspects damage were considered as suspects.

The remaining discs which did not fall within one of the 3 groups in table 2.2 were considered as “others”. If the trained vision technician could make a classification, this was documented in the CRF and those discs he/she could not identify were labelled as unclassified and referred to the secondary centre for further evaluation.

2.6 Diagnostic definitions and classification of glaucoma:

The definitions of POAG and angle closure disease (ACD) were based on

ISGEO classification as described in the previous chapter 1.2.1. ISGEO classification[14] uses the 99.5 and 97.5 percentiles of the IOP and CDR of the normal population. The data from all subjects with a normal and reliable FDT will be used to calculate the 99.5 and 97.5 percentiles of the IOP and CDR at later stages.

Glaucoma was classified according to 3 levels of evidence. In category 1, diagnosis would be based on structural and functional evidence. It requires

CDR asymmetry  97.5th percentile of the normal population, or NRR width narrowed to 0.1 cup disc ratio (between 10- and 1-o’clock or 5- and 7-o’clock) with definite VF defects consistent with glaucoma.

Category 2 consists of advanced structural damage with unproven field loss.

This would comprise those subjects in whom visual fields could not be determined or were unreliable, neuroretinal rim (NRR) width reduced to 0.1

CDR (between 10- and 1-o’clock or 5- and 7-o’clock) or CDR asymmetry 

99.5th percentile of the normal population.

Lastly, category 3 consists of persons with an IOP  99.5th (21mmHg) percentile of the normal population, whose optic discs could not be examined because of media opacities.

Further, glaucoma cases would also be classified as mild, moderate and severe based on the visual field data, according to the classification by Hodapp,

Anderson and Parisch[139]. However, the analysis is not part of this thesis. 74

The diagnosis of glaucoma doesn’t depend on IOP measurements alone but takes into account the evaluation of optic disc excavation and RNFL defects that usually correlate with the visual field defects. Most studies relying on diagnostic criteria for glaucoma use the definitions from the ISGEO classification, though alternatives exist because any positive clinical sign for glaucoma is sufficient to escalate the patient for treatment and monitoring.

Table 2.3 - Definitions of glaucoma used in community and population based studies worldwide [8-13, 16, 45, 46, 104, 140-142]

Study Definition for glaucoma diagnosis

BES VA: <20/30 in either eye, IOP >21mmHg, CDR= >0.7, NRR = <0.15 width

LALES Used CART analysis with cut offs – Criteria of any defect on FDT, IOP > 21mmHg, CCT > 504 and CDR > 0.8

Singapore Chinese ISEGO criteria Eye Study

The Blue Mountains Glaucomatous defects on 30-2 correlated with optic disc Eye Study changes regardless of the intra ocular pressure

APEDS ISEGO criteria

VES ISEGO criteria

ACES ISEGO criteria

WBGS ISEGO criteria

CGS ISEGO criteria

GLEAMS Positive clinical signs in angle and fundus for glaucoma and ISEGO criteria BES: The Baltimore Eye Study, LALES: The Los Angles Latino Eye Study, APEDS: The Andhra Pradesh Eye Disease Study, VES: Vellore Eye Study, ACES: The Aravind Comprehensive Eye Survey, WBGS: West Bengal Glaucoma Study, CGS: The Chennai Glaucoma Study GLEAMS: Glaucoma Epidemiology and Molecular Genetic Study. 76

2.7 Instruments used in glaucoma detection:

2.7.1 Diagnostic ability of instruments:

The developing world has moved into the digital age where high resolution photographs can be taken in remote areas and stored or transferred easily for review by an expert. Disease detection such as glaucoma, diabetic retinopathy and macula related pathologies can be conducted by imaging techniques and importantly these instruments needs to have good diagnostic ability.[143] A number of studies have aimed to screen glaucoma with aid of instruments such as frequency doubling technique (FDT), Non mydriatic fundus camera (NMFC),

Humphrey visual field (HVF) analyzer, Optical coherence tomography (Time

Domain-OCT and Spectral Domain -OCT).

The important metrics for evaluation of these various instruments include diagnostic accuracy, sensitivity, specificity, predictive values, likelihood ratios

(LR), receiver operating characteristics (ROC) and area under the curve. A full description of these measures is given below.

Table 2.4 - Sensitivity and specificity of various diagnostic instruments to detect appropriate diseases states [14]

Test Sensitivity (%) Specificity (%)

Tonometry (cut off IOP 25.1% - 47.1% 92.4% - 95.3% >21mmHg)

Optic disc (CDR > 0.5) 59% 73%

Automated perimetry 97% 84%

FDT 90 -94% 91 – 96%

Stereo photographs 94% 87%

HRT II 73%, 83% 77%, 90%

OCT 3, RNFL 86%, 82% 84%

GDx VCC 84% 84%

Oblique flash light 80-86% 69 – 70% technique

Van Herick grading 62 - 80% 89.3 – 92%

AS- OCT 94.1% 55.3%

SPAC 84.9% 73.1%

IOP: Intraocular pressure, CDR: Cup-disc ratio, FDT: Frequency doubling technology, OCT: Optical retinal tomography, RNFL: Retinal nerve fibre layer, HRT: Heidelberg retinal tomography, AS-OCT: Anterior segment optical retinal tomography, SPAC: Scanning peripheral anterior chamber

2.7.2 Measures of diagnostic ability:

As the disease is asymptomatic until the advanced stages, detection of early damage in the healthy population is challenging, even with sophisticated imaging equipment, because of the wide variability in examination methods and 78

lack of standard references in glaucoma diagnosis. When presented with a range of tests for glaucoma it is useful to be able to compare them in terms of their ability to produce a correct diagnosis. Diagnostic accuracy is the ability of a test to correctly differentiate between the diseased and healthy states. A disease is indicated when the test results are above a certain cut off value while outcomes below this usually exclude the disease. Assuming that some definitive means of diagnosis is available as the “gold standard” the cut off divides the examined cases into four sub groups: true positive (TP), true negative (TN), false positive (FP) and false negative (TN) as shown in table 2.5. These help in the assessment of diagnostic ability[144] as they permit calculation of other measures of quantification including sensitivity (Sn), specificity (Sp), positive predictive values (PPV), negative predictive values (NPV), likelihood ratios

(LLR) and receiving operator characteristics curve (ROC). Definitions for these terms follow below.

Table 2.5 - 2 x 2 table of possible diagnostic outcomes for a given test, relative to the gold standard reference.[144]

Subjects with the disease Subjects without the disease

Positive True positive (TP) False positive (FP)

Negative False negative (FN) True negative (TN)

DEFINITIONS: [144]

Sensitivity (Sn): Sensitivity is defined as “The proportion of true positive subjects with the disease in a total group of subjects with the disease

(TP/TP+FN)”

Specificity (Sp): Specificity is defined as “A proportion of subjects without the disease with negative test results in total of subjects without disease

(TN/TN+FP)

Predictive values: Predictive values are of two types:

Positive predictive value (PPV): “The probability of having the state/disease of interest in a subject with positive result. Therefore PPV represents a proportion of patients with positive test result in total of subjects with positive result

(TP/TP/FP)”

Negative predictive Value (NPV): “Negative predictive value (NPV) describes the probability of not having a disease in a subject with a negative test result.

NPV is defined as a proportion of subjects without the disease with a negative test result in total of subjects with negative test results (TN/TN+FN).”(Unlike sensitivity and specificity, predictive values are influenced by the prevalence of the disease. PPV’s tend to increase as prevalence increases, while the reverse is true for NPV’s.

In this study, as the analysis involves 8 different study VTs, the prevalence of glaucoma may not be same in all the groups examined. Because of the fact that the predictive values largely depend on the prevalence of the condition, significant fluctuations may be expected as a result. Thus , predictive values 80

can be considered only when a single test is evaluated but not in combination.[145]

Likelihood ratios (LLR): Likelihood ratio (LR) is the probability of a given test result in those with the condition, divided by the probability of the same test result in those without the condition. The LR for a given test result indicates how much that result will raise or lower the probability of disease. LR tells us how many times more (or less) often a test result is seen among those with the disease as compared to those without the disease.

LR+ = sensitivity/ (1-specificity): Likelihood ratio for positive test results (LR+) tells us how much more likely the positive test result is to occur in subjects with the disease compared to those without the disease.

LR - = (1- sensitivity) / specificity : Likelihood ratio for negative test result (LR-) represents the ratio of the probability that a negative result will occur in subjects with the disease to the probability that the same result will occur in subjects without the disease.

Interpretation of LR[146]:

 LRs of >10 or <0.1 generate substantial changes from pre- to post-test

probability, so much so that the next step is clear.

 LRs of 5–10 and 0.1–0.2 generate moderate and usually conclusive

changes from pre- to post-test probability.

 LRs of 2–5 and 0.5–0.2 generate small but rarely important changes

from pre- to post-test probability. 81

 LRs of 1–2 and 0.5–1 generate practically no important changes from

pre- to post-test probability.

Receiver operator characteristic curve (ROC) and Area under the curve

(AUC): ROC and AUC are two important measures that help estimate how high the discriminating power of the test is. The shape of the ROC curve indicates the accuracy of the test. The closer curve towards the upper-left hand corner and large area under the curve helps in discriminating correctly between the diseased and normal. The value ranges from 0 to 1, higher the value better the performance of the diagnostic test.

2.8 Instruments used in the current study

2.8.1 Frequency doubling technique (FDT):

Based on the location of glaucomatous damage to the retinal ganglion cells and their axons, VF defects occur in distinctive patterns. VF loss in earlier stages of glaucoma is generally confined to the superior hemi field with inferior losses following later. The introduction of imaging technology has provided greater sensitivity in detection and aids in monitoring the progression of the disease.

Among the techniques used in testing the visual field, static perimetry is widely used to assess glaucomatous visual loss. Standard automated perimetry (SAP) remains the reference standard in assessing the visual field damage as it is more sensitive in detecting the defect. Testing with SAP takes a long time and learning effects and non-portability issues are inherent problems.

FDT has been introduced to address the problem with SAP and has improved the diagnosis and is accepted as alternative to monitor progression. There are 82

four different screening modes used in FDT: C-20-1, C-20-5, N-30-1, N-30-5.

The C-20 mode tests only 20 degree field where as C-30 mode tests 20 degrees in addition to 10 degrees nasal field. The 1st generation FDT perimeter uses two types of testing procedures: C-20 and N-30 testing patterns. It is based on 10° x 10° sinusoidal gratings (0.25cycles/degree) which tests about

17 to 19 locations within 20-30° along with a smaller central target about 5° at the macular region to test contrast sensitivity. [147, 148] Studies indicate that FDT1 perimetry has reasonable performance in detecting VF defects in early to advanced glaucomatous cases.[149, 150] Though FDT1 perimetry is relatively inexpensive and faster than SAP (less than 1minute for screening and 5 minutes for full threshold), it still has some limitations. For example: As FDT1 tests only about 17 to 19 test locations, it becomes difficult to detect minor visual field changes or small localized defects. Another problem is that of differing performance between the eyes during examination. During mass screening for glaucoma using the C- 20-1 algorithm, version 2.6, Tatemichi et al found a disparity in the performance of the FDT between the eyes along with frequent artefacts in the left eye.[151] The specificity was lower in the left eye

(44.6% vs 53.3%), but sensitivity (90.5% and 91.2%) was close to equal. The false positive rate was also 1.5 fold higher for left eye when compared to the right. Delayed adaptation, dichoptic adaptation, fatigue and physiological effects were reported as the cause.

The performance of FDT1 perimetry in glaucoma screening was reported in several population based studies. In the Tajimi study, FDT1 perimetry diagnostic performance was evaluated using C-20-1 method.[152] A total of 2892 individuals participated and a diagnosis of glaucoma was made by the 83

glaucoma specialist using 30-2 results of SAP and optic disc stereo photographs. The sensitivity and specificity of FDT was reported to be 55.6% and 92.7% respectively but the sensitivity increased to 73.7% when glaucoma was diagnosed using SAP. Another community based study used FDT1 perimetry as a screening tool in detection of glaucoma and reported the positive predictive values ranged from 33% to 45%.[101] Yamanda et al[153] have also used FDT1 perimetry in public glaucoma screening. A total of 151 subjects and

26 definite glaucoma subjects were recruited. It was reported that the sensitivity and specificity of FDT1 was 92% and 93% (high) when only one sector was required to define as abnormal result on FDT. With this it was evident that FDT1 perimetry did not have high diagnostic performance in detecting early glaucomatous cases but was high only in case of established glaucomatous cases.

The second generation FDT perimetry, Matrix FDT (Carl Zeiss Meditec) uses smaller stimulus size with 5º x 5º squares with a higher spatial frequency of

0.5cycles/degree when compared to the first generation.[154] A total of 5 threshold testing’s are provided in Matrix FDT perimetry which includes N-30-F,

24-2, 30-2, 10-2 and macular. The N-30-F generally tests at 19 locations similar to FDT1 but to reduce the duration time only two reversals modified binary search algorithm (MOBS) strategy is followed in the FDT2 perimetry.[155] The

24-2 tests at 55 locations and 30-2 tests at 69 locations which is comparable to

SAP as a similar algorithm is used in SAP. When compared to other tests, the

10-2 and macular in Matrix FDT uses a smaller stimulus size of 2º which helps in detecting central visual field loss and in patients with severe glaucomatous damage with residual central field.[156] 84

It is found from the literature that the spatial resolution used in the 24-2 testing pattern in FDT2 was similar to standard automated perimetry (SAP).[157] In a study conducted by Kim et al, FDT2 perimetry was compared to SAP after

RNFL measurements were obtained using optical coherence tomography

(OCT) to define glaucoma.[158] A few cases in which SAP showed normal results, FDT2 showed abnormal fields. Finally it was concluded that the abnormal fields on FDT2 perimetry matched with abnormal RNFL indicating that

Matrix FDT can detect early visual field defects earlier than SAP.[159] A similar study which compared the diagnostic performance of FDT2 with FDT1 perimetry and SAP, found that Matrix FDT was better than SAP.[160, 161] Spry et al have investigated the diagnostic performance of full threshold Matrix FDT perimetry with SAP and did not find much difference between the two testing perimetry and was close to similar.[162] In contrast, a study reported that Matrix

FDT failed to detect 36% visual field defects which were abnormal on SAP indicating a lower sensitivity value. [163] Though the comparison of defects on

FDT and SAP is difficult, Matrix FDT enables a proper visual field examination and can be closely compared to SAP which adds the advantages of early detection of glaucoma. With the evident literature FDT Matrix can be a useful tool in glaucoma detection but the higher diagnostic accuracy comparing SAP remains unclear. As compared to those strategies used in the above discussed studies, no study had actually reported the diagnostic accuracy of the strategy used in the current study, 24-2-1 screening of the FDT Matrix which takes not more than 2 minutes per eye.

Humphrey Matrix visual field FDT screening tests are all supra-threshold tests, which mean that they test specific age-corrected contrast values based on the 85

normative database probability levels. Probability levels are selected based on the population to be screened. For general clinical use to maximize sensitivity (-

5 is used, which uses the 5% probability level) or for population based screening to maximize specificity (-1 is used, which uses the 1% probability level). The screening test results consist of probability plots of the tested locations for each eye and the overall reliability measures along with patient and test information. Test locations indicate the different probability levels with different patterns, increasing in darkness with decreasing probability level.

In this study the FDT Matrix (Welch Allyn, Skaneateles, N.Y., and Carl Zeiss

Meditec, Dublin, California) perimetry, 24-2-1 screening strategy was used in testing the visual fields defects. The 24-2-5 (or 24-2-1) FDT screening test is a screening version of the 24-2 full threshold test. Each test location is assigned one of two probability levels, depending on the test selected (-1 for the current study). Each visual field location is tested at a single probability level (pass/fail).

Each visual field location is tested until the patient responds or the location is tested twice at the initial probability level to complete the screening.[164]

2.8.2 Non mydriatic fundus camera:

The use of non mydriatic fundus (NMF) camera in detection of glaucoma was reported even earlier than the 20th century. [165, 166] The resulting images can be scrutinized either on site or at a later opportunity and action taken when problems are detected, thereby improving quality care and reduce vision loss.

Several studies [165, 166] have attempted to evaluate the utility of using NMF cameras in glaucoma management. 86

The Philadelphia glaucoma detection study has reported the reproducibility of optic disc grading from hand-held, monoscopic, non-mydriatic fundus camera photographs.[167] Cup disc ratio (CDR) and disc damage likelihood scale (DDLS) were graded and concluded that there was a moderate agreement between the readers and a fair agreement in differentiating normal from the diseased. In a study designed to evaluate the diagnostic accuracy of a non-mydriatic fundus camera in detecting diabetic retinopathy and glaucoma in diabetic individuals, a trained nurse took the pictures and two observers, who were glaucoma specialist and masked to the patients’ details, graded the images. Overall the sensitivity of NMF was 79.83% and specificity of 80% in a diabetic group. The main drawback of this study was its small sample size.

Tuulonen et al [168] reported that the non mydriatic fundus camera was a useful tool in detecting glaucoma in 183 first degree relatives of glaucoma patients.

Success rate of photographs defined in terms of quality was reported to be

92%. The study used black and white photographs taken from a Canon CR3

NMF camera performed in dim illumination with 4 mm minimum pupil size. A total of 366 images were gradable. They reported that 31 individuals were sent for further referral, 6 new glaucoma cases diagnosed and another 12 had glaucomatous changes like retinal nerve fibre layer (RNFL) defects and splinter haemorrhages. Later, a follow up study was conducted for patients with glaucoma by repeating the same photographic screening and concluded that

NMF camera was capable of detecting the progressive glaucomatous changes correctly identifying the disease.[169]

A similar investigation involved ocular photographs being taken by nurse practitioners which were then evaluated, within 24 hours, by an ophthalmologist 87

[170]. As direct ophthalmoscopy needs expertise and pharmacological mydriasis may be difficult, especially during emergency cases, a study was conducted to evaluate the feasibility of NMF camera.[170] This study reported about 83% had good quality images. Hence, several studies have demonstrated the utility of

NMF camera in detection of glaucoma[168] providing accuracy figures in different conditions.

The NMF camera proves to be a useful screening tool in detecting posterior segment pathologies and can be used by trained technicians or primary care practitioners.

2.8.3 Instruments in clinical examination

The clinical examination forms an important part of the overall assessment of any individual during the process of screening for glaucoma. In the context of the present investigation the procedure included a range of standard tests as well as several requiring more sophisticated equipment. Reduced visual acuity, for example, can be disease related, particularly if it persists after the best attempts at refractive correction have been made.

The current study was carried out in a primary care centre termed as a vision centre where a vision technician is the primary eye care provider and performs initial assessments. The complete clinical evaluation along with the instruments used for the current study is discussed below:

A) Detailed clinical procedures:

i) Medical and systemic history: 88

Complete history including duration of spectacle wear if any, present or past ocular or systemic ailments, details of medical, surgical, or laser treatment and also use of steroids in any form and family history of glaucoma. ii) Visual acuity, Lensometry, Refraction and external examination

Distance and near visual acuity, measured with the participant's habitual correction (aided or unaided) using Log MAR charts. If the participant wears spectacles, these are measured with a lensometer and the power is noted.

Following this, objective and subjective refraction, external eye examination, pupil reactions, slit lamp examination with peripheral anterior chamber depth

(assessed by Van Herrick’s technique) are performed.[171] iii) Non-mydriatic fundus photography

A single color photograph of the retina with macula in the centre was taken for both eyes of each participant using a Topcon non-mydriatic retinal camera,

TRC-NW8 (Topcon, Bauer Drive, Oakland, NJ).

iv) Undilated Direct ophthalmoscopy

The fundus was examined with a direct ophthalmoscope (Heine, Beta 200,

Germany), and all findings recorded.

v) Anterior segment optical coherence tomography (ASOCT) 89

Anterior segment angle imaging performed using Cirrus HD-OCT (Carl Zeiss

Meditec. Inc, Dublin, California, USA). The anterior segment scans are acquired by two protocols i.e. Anterior segment cube 512 X 128 and anterior segment 5 line raster in all four quadrants.[172] vi) Intraocular pressure (IOP)

Intraocular pressure is measured using Goldmann applanation tonometry

(Haag-streit AT 900, Haag-streit AG, Switzerland) 0.5% proparacaine drop

(Para Cain, Sunways (I.) P. Ltd., Mumbai, India) is used to anaesthetize the cornea and a 2% fluorescein strip moistened with lubricating drop ex: aurosol to stain the tear film. vii) Gonioscopy

Careful examination of the angles permits detection of angle closure, or individuals at risk for glaucoma. The standard way of assessing the drainage angle is through gonioscopy, however as many Asian ophthalmologists do not have access to this equipment, or lack expertise in its use, angle estimation by observing limbal chamber depth (LCD) is considered a safe and non- invasive alternative. Although not yet seen as a standard test, the performance of the

LCD estimation in detecting the angle closures has been reasonably good and it has been suggested that the method has value in large populations where gonioscopy is too time consuming. Due to the higher prevalence of angle closure among East Asians however, gonioscopy was considered an essential procedure for all those attending the ocular examination during the current activity. [173] 90

Both eyes of each participant are anaesthetized by instilling a 0.5% proparacaine drop (Para Cain, Sunways (I.) P. Ltd., Mumbai, India) into the lower fornix. Gonioscopy with a Sussman four mirror gonioscope (Volk Optical

Inc, Mentor, Ohio, USA) is performed under standard conditions with the participant looking straight in primary gaze with dim room illumination and the smallest convenient slit beam, ensuring that the beam does not fall in the pupillary area. Structures visible in all the four quadrants are documented.

Subsequently indentation is performed to note the angle opening, blotchy pigments and synechiae.[174] About 2% Gonioscopy was ‘not possible’ in participants who were non-compliant for this technique.

viii) Dilated slit lamp photographs

Diffuse anterior segment, Van-Herrick’s anterior chamber depth, optic section and retro illumination of crystalline lens photographs are taken for each eye of each participant using a Topcon DC3 slit lamp camera (Topcon, Bauer Drive,

Oakland, NJ). All participants are dilated with 5% phenylephrine and 0.8% tropicamide drops (Itrop Plus, Cipla limited, India).

ix) Grading of lens opacities

Grading of lens opacities is performed using the Lens Opacities Classification

System (LOCS III).[175] Nuclear color, nuclear opalescence, cortical and posterior sub-capsular opacities are graded separately. Participants with 91

significant cataracts are offered cataract surgery with intra ocular lens implantation at a secondary centre.

x) Dilated fundus examination

Dilated fundus examination is performed on all participants except those who are diagnosed with PACD (primary angle closure disease). A +90D lens (Volk

Optical Inc., Mentor, Ohio, USA) is used and the procedure carried out by the optometrist.

xi) Humphrey visual fields (HVF)

All participants undergo a Standard automated perimetry (SAP) with 24-2

Swedish Interactive Threshold Algorithm – Standard (SITA; Carl Zeiss Meditec

Inc. Dublin, CA) prior to any invasive procedure. Fields with fixation losses of

>20% or false-positive or false-negative response rates of >33% are considered unreliable and repeated a maximum of three times to get a reliable result. The instructions for undergoing this test are reinforced at regular intervals and between the tests to ensure reliable performance by the participant.

xii) Frequency doubling technology matrix (FDT Matrix)

FDT Matrix (Welch Allyn, Skaneateles, N.Y., and Carl Zeiss Meditec, Dublin,

California) is done on all the participants before or after HVF. All the 92

participants undergo screening with the 24-2-1 program. If the test is unreliable, it is repeated three times, with a break of at least 5 minutes between the tests.

The instructions for undergoing this test are reinforced at regular intervals and between the tests to ensure reliable performance by the participant. A test is defined as unreliable if the fixation error or false positive error exceeds 30%.

xiii) Posterior segment optical coherence tomography

The Cirrus HD-OCT (Carl Zeiss Meditec. Inc., Dublin, CA, USA) offers 5 different scan protocols for posterior segment imaging: a 200 X 200 macular cube scan, a 512 X 128 macular cube scan, 200 X 200 optic disc cube scan, 5 line raster and a high definition-5 line raster. All the scan protocols were used, except the 5 line raster and HD-5 line raster as they do not offer automated thickness measurements of the retinal and optic disc parameters. The details of these scan protocols are described elsewhere.[176-178]

xiv) Dilated fundus photographs

Full field color, red free and four filed dilated fundus photographs are acquired for each eye of each participant using Topcon non-mydriatic retinal camera,

TRC-NW8 (Topcon, Bauer Drive, Oakland, NJ).

xv) Pachymetry and Biometry 93

Central corneal thickness, axial length, lens thickness and anterior chamber depth measurements were made with AL-1000 (Tomey Corporation,

Noritakeshinmachi, Nishi-Ku, Nagoya) ultrasonic pachymeter. The ultrasonic velocity is set to 1640 m/s for the CCT (central corneal thickness) measurements. Both the eyes are anaesthetized by instilling 0.5% proparacaine drop (Para Cain, Sunways (I.) P. Ltd., Mumbai, India) into the lower fornix and the CCT measurement are taken by placing the probe perpendicular to the corneal surface on the centre of the cornea. One measurement is taken for each eye. This single measurement mode calculates the average of 10 sets of pulses and provides the mean and the standard deviation. If the standard deviation is more than 5μm, the measurement is repeated. Similar procedure is followed for measuring axial length, lens thickness and anterior chamber depth but only 5 sets of pulses are taken.

2.9 Image grading procedure:

2.9.1 Grading doubling technique (criterion of non mydriatic fundus pictures (NMFP) and frequency FDT):

Because the defects shown on an FDT report are not disease specific and visual field defects related to glaucoma occur in a distinctive pattern, typically affecting the superior hemi field in early stages of the disease with the inferior field becoming involved later on, a criterion was designed for diagnosing glaucoma using FDT. This is set out below.

Similarly, a criterion was designed for NMF pictures again listed below.

The quality of NMF pictures was considered gradable if the grader could identify any of the above mentioned glaucoma specific findings. 94

The established criteria for glaucoma during NMFP and FDT grading were strictly followed in making the diagnosis and categorizing the cases. The procedure of grading by reference standard optometrist was followed by vision technicians. Initially, the reference standard graded all the non mydriatic fundus pictures and FDT reports thereby classifying them as normals and glaucomatous based on the criteria designed. For the current study, to evaluate the ability of the vision technicians in detecting glaucoma, results were compared against the reference standard study optometrists’ findings.

Criteria for Glaucoma Diagnosis based on NMFP:

 Presence or suspicion of all or any one of the glaucomatous optic

nerve damage, retinal nerve fibre layer defect, notch, rim thinning,

splinter haemorrhage, cup-disc ratio of ≥ 0.6:1 and asymmetric

cupping of >0.2:1.

Criteria for Glaucoma Diagnosis based on FDT:

 More than 2 non edge points depressed at p<1% in arcuate

region, with or without involving the central point and not

continuous with the blind spot.

2.9.2 Grading by reference standard optometrist:

In the current study, all the NMF pictures were graded by the glaucoma trained study optometrist. Study optometrist was considered as reference standard for glaucoma diagnosis after an agreement in glaucoma detection based on optic disc examination and gonioscopic evaluation against glaucoma specialist 95

ophthalmologists. Clinical examination, FDT reports, NMF pictures and other eye examination results were all graded in a masked fashion. The reference standard optometrist classified the optic discs into glaucomatous and control groups based on the presence or absence of characteristic glaucomatous optic disc changes (RNFL visibility, focal or diffuse neuro-retinal rim thinning, localized notching or nerve fibre layer defects and splinter haemorrhages).

Eyes, where a classification to either glaucoma or control group was not possible were labelled as “suspects” and were pooled in the disease group for analysis.

2.9.3 Grading by vision technicians (VT’s):

All the study VTs were trained by the study optometrist for a period of one week in grading NMFPs and classifying FDT reports as per the above mentioned criteria. For grading of NMFP, 8 sets of 500 non mydriatic fundus images from the 6043 pictures that were acquired from the participants of LVPEI-GLEAMS were allocated to 8 different vision technician graders. A set of 500 subjects’

NMFPs and FDT reports were given to each vision technician for grading. The vision technicians graded the images based on the criteria mentioned above, where quality and RNFL visibility is also being taken into consideration for glaucoma detection. The same procedure was followed for all the 8 vision technicians. Similarly, FDT reports were graded following the similar steps.

Finally, the results of the vision technicians were compared to those of the study optometrist, first of all based on clinical examination only and then with the addition of NMFP and FDT results both separately and in combinations. These results show the ability of the vision technicians in glaucoma detection based on clinical and imaging information both in isolation and in combination. 96

Chapter 3: Evaluating the ability of vision technicians in detecting ocular pathologies – A baseline study

3.1 Introduction:

As discussed in chapter 1.4.2, the VT’s are exposed to a one year training programme before heading on to the vision centres and are certified to conduct history taking, visual acuity assessment, refraction, slit lamp examination, applanation tonometry, undilated fundus examination and to prescribe glasses.

After this preliminary examination, patients deemed to be abnormal are referred to the secondary centre for further evaluations by the ophthalmologists.[28] The interface between the primary and secondary levels of care raises several issues including appropriateness of referrals, decision making of referrals, referral outcomes and communication. [130, 131]

Fundamental to understanding these questions and indeed the use of VTs as a diagnostic resource in general, is how well their diagnostic abilities replicate those of the more highly trained personnel. So, to get an insight into this situation, the current study investigated the ability of the VTs to detect ocular diseases clinically against an ophthalmologist. The VTs in this part of the 97

investigation had undergone the standard one year training program but no specialist instruction in glaucoma.

In explanation of the accuracy of the screening, this chapter additionally provides information to determine any disagreements between the VT’s and ophthalmologist and also further plan for training requirements.

Hence the aim of this study was to determine the diagnostic ability of the vision technicians in detecting potentially blinding disease along with their referral agreement, in both cases compared to an ophthalmologist.

3.2 Methods:

The sampling procedure and study protocol have been widely elucidated in chapter 2 Methods and Materials (see section 2.2) A sample of 279 patients was enrolled in this baseline study. The study team comprised of 7 vision technicians and one ophthalmologist. The entire vision technician’s and the ophthalmologist’s findings were masked to each other to avoid bias. The VT’s as well as the ophthalmologists examined the patients, documented the findings and identified disease based on the definitions given below. In addition a referral decision was made in each case. The ophthalmologist findings were final and considered as the “gold standard” against which the VTs findings were compared.

3.2.1 Definition of disease:

The following disease definitions were used during the study: 98

Cataract: Cataract was defined as visible opacity in pupillary area impairing vision and partly or complete obscuration of red reflex on distant direct ophthalmoscopy.[179]

Corneal opacity: Macular, leucomatous or nebular opacity on the corneal surface involving the pupillary axis, causing diminished visual acuity and/or symptoms.

Glaucoma suspect: Based on intraocular pressure (IOP) and anterior chamber depth based on the Van Herrick’s' technique.[171] If media are clear, it is based on the abnormal appearance of the optic disc which includes vertical cup: disc ratio of 0.65 or more; disc notch, haemorrhage or nerve fibre layer (NFL) defect; neuroretinal rim <0.2 in any quadrant; disc asymmetry ≥ 0.2 and IOP ≥ 20 mm of Hg.

Other posterior segment disease: Either the presence of hard or soft drusen; retinal pigment epithelium changes; micro aneurysms; haemorrhages; hard or soft exudates; venous beading; intraretinal microvascular abnormalities; new vessels elsewhere (NVE); geographic atrophy; choroidal neovascular membranes (CNVM); disciform scar; macular edema; epiretinal membranes

(ERM);vascular occlusions; degenerations, non-glaucomatous optic atrophy etc.

Subjects who did not fit into any of the above mentioned descriptions were classified as others (ex: atrophic bulbi, phthisis etc.).

3.3 Statistical analysis:

For all the normal distributed variables; descriptive statistics, which included mean, standard deviation (SD) and range, were calculated. The weighted kappa statistic [180] was used in determining an agreement between the vision technician and the ophthalmologist. Statistical analyses were performed using commercial software (Stata version 11; StataCorp, College Station, TX). A p value of <0.05 was considered to be statistically significant.

3.4 Results:

3.4.1 Disease detection:

Overall, 279 patients were screened at 7 vision centres (VC’s) with mean age of

32.9 years (SD = ± 21.8 years). There were 128 males and 151 females in this baseline study.

An agreement was evaluated after each patient had been examined by a vision technician as well as the ophthalmologist. A total of 250 ocular diseases were detected by the vision technicians and around 283 ocular pathologies were diagnosed by the ophthalmologists. Table 3.1 illustrates the ocular pathologies detected by the VT’s and ophthalmologists.

Table 3.1 - Ocular pathology in the study population as determined by the vision technicians and the ophthalmologist

Diagnosis Ophthalmologist Vision Technician

N (%) N (%) 100

Refractive error 107 (37.8) 110(44)

Cataract 54 (19.1) 55 (22)

Corneal pathology 21 (7.4) 21 (8.4)

Glaucoma suspect 45 (15.9) 22 (8.8)

Retinal pathology 19 (6.7) 6 (2.4)

Others 37 (13.1) 36 (14.4)

Total 283 (100) 250 (100)

The number of refractive errors detected by the vision technicians was higher in number than any other ocular pathology and only 7 cases were missed when compared to the ophthalmologists. Good detection rates were found among the vision technicians for anterior segment evaluation.

For glaucoma suspects, almost half of the cases were missed and the same trend was evident for retinal pathologies.

3.4.2 Agreement for screening ocular pathology:

The sensitivity and specificity rates with 95% confidence intervals (CI) for all the ocular pathologies were determined and is shown in Table 3.2

Table 3.2 - Agreement between vision technicians (VT’s) and ophthalmologist in screening ocular pathologies

Sensitivity Specificity Kappa Diagnosis (95% CI) (95% CI) (95% CI)

Refractive 100 98.9 0.98

error (RE) (0.96-1.0) (96.6-100) (96.8-99.8) Anterior segment 98.1 99.4 0.97 pathologies Cataract (97.8-99.9 (0.93-1.0) (90.1-100) 101

Corneal 100 100 1.0 pathology (83.9-100) (99-100) (1.0-1.0)

Glaucoma 35.6 98.2 0.43

suspects (21.9-51.2) (96.1-99.3) (0.28-0.59) Posterior segment Retinal 26.3 99.7 0.39 pathologies pathology (0.14-0.63) (9.2-51.2) (98.4-100)

CI; Confidence intervals

The results indicate good agreement for anterior segment examination which included refractive error, cataract and corneal pathologies. An excellent kappa value was found in this category, along with overall sensitivity of 94.6 to 100%.

However, there was only moderate to fair agreement between the vision technicians and the ophthalmologists for glaucoma suspects and retinal pathologies. The overall kappa (κ) agreement for referral between the VTs and ophthalmologist was 0.79 (95% CI; 0.74-0.84).

3.5 Discussion:

This was a baseline study prior to conducting the main investigations. The main purpose of the study was to determine the inter observer agreement and diagnostic accuracy of screening ocular pathologies when VT’s are compared against ophthalmologist. This also signifies the abilities of the vision technicians and their performance in disease detection of various sight threatening conditions after their one year course without additional training.

Detecting all forms of sight threatening ocular conditions and referring them to the secondary centre is the most expected from vision technicians. Based on 102

the training they undergo at the tertiary level, the vision technicians mostly deal with the anterior segment and are not allowed to dilate to examine the posterior segment. This background is reflected by the results outlined above which show that the vision technicians had excellent agreement in detecting the anterior segment pathologies. This supports work published by Paudel and colleagues

[28] where the vision technicians had an overall sensitivity of 18.3% in detecting the posterior segment pathologies (includes all retinal disease detection). The present study did not consider posterior segment disease like diabetic retinopathy or maculopathy separately. Though Paudel et al [28] reported high accuracy referral rates of 87.5% for glaucoma suspects; there existed low sensitivity rates along with the referral criteria.

Based on the above results and in view of VT’s low detection rates in the posterior segment category, the question arose of whether giving additional training to the vision technicians would improve their performance and if so, by how much. Thus, the evaluations described in subsequent chapters utilised VTs who had received such training.

The main aim of the study was to evaluate the accuracy of VT’s in glaucoma detection. This requires a large sample and evaluate vision technician and ideally would require several specialist ophthalmologists to serve as “gold standard” references. As mentioned previously, there was a general lack of available ophthalmologists to support the study. Hence, the following chapter describes the process of establishing an alternative reference standard by using study optometrist.

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Chapter 4: Establishing a reference standard

4.1 Introduction:

Overall results of the current study are divided into two chapters. The first of these shows how agreement between the two study optometrists and the glaucoma specialist ophthalmologist was established so that the former could serve as the reference standard in the main study. The subsequent chapter discusses the use of this standard in the evaluation of diagnostic ability for the vision technicians in detecting glaucoma.

The obvious choice of reference standard would be an ophthalmologist specialized in glaucoma detection and several studies conducted in developed countries have used the findings of an ophthalmologist as the “gold standard” where the diagnostic capabilities of optometrists and other trained technicians were being evaluated. [181-183] . This was not feasible for the current study because for remote and rural communities, providing glaucoma specialist ophthalmologists for the assessment of ocular conditions is quite difficult and challenging due to the following reasons:

1. Employing an ophthalmologist in rural setting is not feasible due to high

expenses.[184]

2. Currently, the ratio of ophthalmologist to rural population in India is dismal

1:219,000; availability becomes a concern to provide a glaucoma specialist

ophthalmologist at a rural setting.[116]

3. Even if available, glaucoma specialists are not many. 104

Hence based on the above reasons, a substitute had to be deployed who could act as a reference standard for evaluating the abilities of the vision technicians.

The next most appealing alternative was an experienced glaucoma trained optometrist who was termed as a “study optometrist” in the current study.

Optometrists present a possible alternative as the standard, since their role in the elimination of visual impairment due to potentially sight threatening conditions has been acknowledged by the WHO.[184] In the GLEAMS study, optometrist work very closely with glaucoma specialist ophthalmologists and duplicate many of their activities. In the community setting they are therefore frequently the primary source of diagnosis for those with glaucoma. With this as a platform, it was necessary to confirm that the diagnostic abilities of these study optometrists were sufficiently similar to those of the glaucoma specialist, that they could be substituted to serve as a surrogate standard.

This chapter describes an evaluation of two study optometrists in terms of their ability to replicate the findings of a glaucoma specialist ophthalmologist when examining the eyes of individuals with and without glaucoma. The investigation was based on gonioscopy and optic disc assessment as described in chapter 2 sections 2.2.1 and 2.2.2.

Ultimately, the study sought to answer the question; can the study optometrists be utilized as an alternative standard to the glaucoma specialist ophthalmologists in deciding if a study participant has glaucoma based on gonioscopy or optic disc examination? 105

4.2 Methods:

Initially, the two optometrists performed all the clinical examination, as part of the standard clinical protocol followed at the LVPEI, along with pre-dilated gonioscopy and optic disc assessment documentation after dilation. Pre-dilated gonioscopy and post-dilated optic disc assessment were then replicated by the ophthalmologist. All the findings were documented as described earlier. The glaucoma specialist ophthalmologist’s diagnosis was taken as final and stood as the gold standard. Study optometrists and glaucoma experts were masked from the findings documented by each of them to prevent bias in the diagnosis.

Agreement was evaluated individually for the two study optometrist’s responses.

Weighted kappa statistics were estimated, assigning linear weights to disagreements among the above categories.[185-187] To evaluate the diagnostic accuracy of gonioscopy and optic disc evaluation, individual responses of both the study optometrists were used to calculate the sensitivity, specificity, predictive values and likelihood ratios against the gold standard. Statistical analyses were performed using commercial software (Stata ver. 10.0;

StataCorp, College Station, TX).

The criteria for qualification as a reference standard were that the optometrists were required to achieve ‘strong’ agreement with the gold standard, achieving a weighted kappa of greater than or equal to 0.80, and diagnostic accuracy above

80% in diagnosing glaucoma, based on gonioscopy and optic disc examination with a 90D lens. 106

Separate cohorts of subjects were evaluated by each optometrist for agreement in gonioscopy and optic disc interpretation. The age and sex details of the patient are given in the Table 4.1

Table 4.1– Demographic details of the subjects

Optometrist 1 Optometrist 2

Mean Age (± Mean Age (± M:F n* M:F n* SD) SD)

Gonioscopic examination 41: 31 53 ± 12 years 72 46: 31 50 ± 18 years 77

Optic disc evaluation 59:35 48 ± 15 years 94 60: 40 48 ± 15 years 100

* Total number of subjects but whose only one eye was examined (randomly selected); sd= standard deviation

4.3 Results - Agreement between glaucoma specialist ophthalmologists and two study optometrists:

4.3.1 Gonioscopy:

The kappa (κ) was 0.92 (SE 0.12) for agreement between the ophthalmologists and optometrist 1, and 0.84 (0.10) for agreement between the ophthalmologists and optometrist 2 in the interpretation of gonioscopy (Table 4.2). On this basis, both the study optometrists had met the criteria of attaining a ‘strong’ agreement against the gold standard findings in performing gonioscopy.

107

Table 4.2- Agreement between glaucoma specialist ophthalmologists and two study optometrists in interpretation of gonioscopy

Optometrist 1 Optometrist 2

Open PACS PAC Open PACS PAC

Open 53 2 1 52 0 0

PACS 0 4 0 1 7 3 Ophthalmologist PAC 0 1 11 1 3 10

Weighted 96.5%; κ=0.92; SE=0.12 94.2%; κ=0.84; SE=0.10 agreement

PACS: Primary angle closure suspect, PAC: Primary angle closure, κ: Kappa, SE: Standard error

4.3.2 Optic disc evaluation:

Table 4.3 shows the kappa (κ) was 0.90 (0.12) for agreement between ophthalmologists and optometrist 1 and 0.89 (0.10) for optometrist 2 in the interpretation of the optic disc. Both the study optometrists met the criteria of attaining ‘strong’ agreement against the gold standard in interpretation of optic discs.

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Table 4.3 - Agreement between glaucoma specialist ophthalmologists and two study optometrists in interpretation of optic disc examination

Optometrist 1 Optometrist 2

Normal Suspect Glaucoma Normal Suspect Glaucoma

Normal 64 3 0 71 0 0

Ophthalmologist Suspect 2 13 1 4 9 0

Glaucoma 0 0 11 1 1 14

Weighted 96.8%; κ=0.90; SE=0.09. 96.5%; κ=0.89; SE=0.09. agreement

κ: Kappa, SE: Standard error

4.4 Diagnostic accuracy between glaucoma specialist ophthalmologists

and two study optometrists:

4.4.1 Gonioscopy:

The diagnostic accuracy of each optometrist for gonioscopy is shown in Table

4.4. Both showed sensitivities and specificities above 90% when discriminating

open from occludable angles by gonioscopy. Positive and negative likelihood

ratios had large effects on the post-test probability of having occludable angles.

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Table 4.4 - The diagnostic accuracies of optometrists in interpretation of gonioscopy

Optometrist 1 Optometrist 2

(95%CI) (95%CI)

Sensitivity 100% (79.4 to 100) 92% (74 to 99)

Specificity 94.6% (85.1 to 98.9) 100% (93.2 to 100)

PPV 84.2% (60.4 to 96.6) 100% (85.2 to 100)

NPV 100% (93.3 to 100) 96.3% (87.3 to 99.5)

ROC 1 (0.8 – 1) 1 ( 0.8 – 1)

PLR 18.7 (6.21 to 56.1) ∞

NLR 0 0.08 (0.02 to 0.30)

PPV: Positive predictive values, NPV: Negative predictive values, PLR: Positive likelihood ratios, NLR: Negative likelihood ratios CI: Confidence intervals

4.4.2 Optic disc evaluation:

Table 4.5 shows the optic disc findings for each optometrist. Specificities were greater than 95% to discriminate normal from glaucomatous discs in both cases, while the sensitivities were 83% and 93%. Positive and negative likelihood ratios had large effects on the post-test probability of having abnormal optic discs.

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Table 4.5 - The diagnostic accuracy of optometrists in interpretation of the optic disc

Optometrist 1 Optometrist 2

(95%CI) (95%CI) 92.6% 82.8% Sensitivity (75.7 to 99.1) (64.2 to 94.2) 95.2% 100% Specificity (87.5 to 99.1) (94.9 to 100) 89.3% 100% PPV (71.8 to 97.7) (85.8 to 100) 97% 93.4% NPV (89.5 to 99.6) (85.3 to 97.8) 0.9 0.9 ROC (0.8 – 0.1) (0.8 – 1) 20.7 PLR ∞ (6.81 to 62.8) 0.08 0.17 NLR (0.02 to 0.30) (0.08 to 0.38) PPV: Positive predictive values, NPV: Negative predictive values, PLR: Positive likelihood ratios, NLR: Negative likelihood ratios CI: Confidence intervals

4.5 Agreement of frequency doubling technology (FDT) criteria in detecting glaucoma:

A criteria for the FDT Matrix screening 24-2-1 strategy was used, as mentioned in the methodology chapter (section 2.9.1). The criterion used was reported be having a sensitivity and specificity of 91.2% and 84.8% respectively with area under ROC of 0.88 (95% CI: 0.80-0.95) for diagnosing glaucoma, as reported by Noro et al[188] The agreement was evaluated for the criteria used in making a decision on referral with 100 randomly selected reports that were graded by the study optometrist 1 and a glaucoma specialist ophthalmologist. One FDT report 111

had to be excluded due to poor reliability parameters. Using the criteria, an

excellent agreement (κ) of 0.9 was found with sensitivity of 94% and specificity

of 96%. Positive and negative likelihood ratios had a large effect on the post-

test probability of having glaucoma based on the criteria.

Table 4.6 - The agreement between the study optometrist and glaucoma specialist ophthalmologist for FDT

Agreement of FDT Criteria in detecting Glaucoma (Optom Vs Opthal.) (n = 99)

Sensitivity Specificity PPV NPV ROC PLR NLR Kappa

Criteria 94 96 96 94 0.9 24 0 0.9

(0.8- 95% CI (83-99) (87-100) (87-99) (84-99) (0.9-1) (6-α) (0-0.1) 0.9)

FDT: Frequency doubling technology, PPV: Positive predictive values, NPV: Negative

predictive values, ROC: Receiver operating characteristics, PLR: Positive likelihood

ratios, NLR: Negative likelihood ratios CI: Confidence intervals

112

4.6 Discussion

4.6.1 Study findings:

The uniqueness of the current study lies in the involvement of gonioscopy, as listed in the UK NICE guidelines, April 2009 as an essential competence for those providing glaucoma care.[189] The technique of gonioscopy [190]for optometrists has been elucidated earlier but no studies have reported the diagnostic accuracy of optometrists using this method. Previous studies [112, 191,

192] investigated the agreement of ophthalmologists and optometrists in detecting glaucoma on the basis of individual features like optic disc assessments, suspect referrals and decision making in management of glaucoma, but this is the first study to evaluate the diagnostic ability of vision technicians in detecting glaucoma by establishing reference standard study optometrists in a community based set up.

The findings of this study indicate a high level of agreement between the glaucoma specialist’s ophthalmologists and study optometrists which is reflected in all parameters considered, such as interpretation of gonioscopy, optic disc assessment and FDT evaluation.

A reliable and accurate assessment of optic disc evaluation plays a key role in glaucoma detection. It has been suggested that morphological changes of the optic disc appearance are the best reference standard for early glaucoma diagnosis and so understanding how well these modifications can be detected by screening personnel is an important factor in establishing their utility.[193]

There are studies [185, 187, 194] providing evidence of agreement between optometrists and ophthalmologists in assessing optic nerve head appearance 113

through stereo disc photography, but little is known about how they compare during clinical evaluation of this parameter. In most previously published agreement studies, stereo photographs, non-stereo optic disc photographs or direct ophthalmoscopic assessments were shown to ophthalmologist or optometrist observers, who had varying levels of experience. The results demonstrated a poor to moderate intra-observer and inter-observer reliability.[37,

195]

One study reported the clinical documentation of the optic discs through dilated pupils using a stereoscopic viewing system and this method showed improved intra-observer agreement.[195]. Despite this however, the inter-observer agreement using this parameter was quite poor. This contrasts with the current results, possibly due to the fact that both optometrists had quite long experience working with the glaucoma specialist ophthalmologists. Comparing to a study done in selection of standard optometrist in evaluating other eye care personnel’s based on clinical refraction and disease diagnosis both the optometrist had a good agreement of kappa value 0.80 and 1.00 respectively in glaucoma detection.[184] Another study reported a substantial agreement of 89% with kappa value of 0.7 between accredited glaucoma optometrist and consultant ophthalmologist in diagnosing glaucoma.[196] In both of the studies no specific parameters were assessed individually for glaucoma detection.

Various publications support the utility of optometrist in the community [112, 192,

195] in detecting glaucoma, but this study importantly assessed the utility of the optometrists as potential standard for identifying the presence of glaucoma based on clinical evaluation and to evaluate the vision technicians in their abilities to detect glaucoma. 114

In this study, the study optometrists were assessed as the potential standards for identifying glaucoma based on gonioscopy and optic disc assessment. Study optometrists also trained the VTs to acquire good quality imaging. On site presence of the study optometrist will also take care of the underperformance of appropriate examination techniques by the VTs in the community level, as compared with the standards of Preferred Practice Patterns were the major concerns.[184, 197]

4.6.2 Trained glaucoma optometrists as reference standard:

Globally, depending on the economic health of the particular nation, optometrists and/or vision technicians are the primary eye care providers, and are the first point of contact in the community prior to an ophthalmologist.

Historically, optometrists were limited to conducting a preliminary examination of the eye and initiating referral when necessary, but in the recent years, they have been used to detect potential sight threatening conditions such as glaucoma in many community screening programs. There are several advantages to this direction, including easy access of eye care facilities through optometrists, reducing the shortage of trained eye care personnel’ available to the rural population,[184] community recognition as a health care professional, professional independence,[198] a viable alternative for ophthalmologist and also in assessing the performance of vision technicians. If the use of optometrists is to expand for these purposes, those involved will need to improve their skills in glaucoma detection so that they can be confidently used as a reference standard at a community level. The question of how closely the performance of a cohort of optometrists with such training matches that of the specialist 115

ophthalmologist is a critical one to answer if such services are to be widely trusted.

In this study, agreement between the trained optometrists and the glaucoma specialist ophthalmologists for parameters used in glaucoma detection was evaluated.

It was found that the study optometrists had met the criteria for being considered as a reference standard with a ‘strong’ agreement of greater than or equal to 0.80 for weighted kappa and diagnostic accuracy of above 80% in detecting glaucoma based on gonioscopy and optic disc assessment as compared to the gold standard ophthalmologist. One reason for this high level of agreement might be that both the optometrists were trained in glaucoma while working with the same glaucoma specialists over a period of 7 years and so it would not be entirely surprising to find that the behaviour of the students mimicked that of their teacher. Possibly, a better design would have been to include other glaucoma ophthalmologists as it will be interesting to see if the results remain the same. Nevertheless, the results do indicate the success of the training program and if it can be assumed that the behaviour of the specialist is at an acceptably high standard clinically, it would be reasonable to conclude from this set of studies that the optometrists can be considered to have acquired a similar level of skill. Thus, replacing glaucoma specialists with properly trained study optometrists appears to be an acceptable option for community based glaucoma screening programs and can also be used as the reference standard to evaluate the performance of the vision technicians subsequently.

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Chapter 5: Evaluating the ability of vision technicians glaucoma detection with individual tests

5.1 Introduction:

The main purpose of establishing the study optometrist as reference standard for glaucoma diagnosis is to permit their use in the validation of the diagnostic abilities of vision technicians (VT’s) at a vision centre level. Understanding whether a VT is able to detect glaucoma and make a referral to the secondary centre for further management by an ophthalmologist is a necessary step in constructing an effective program in the rural community. Having established in the previous chapter that a trained study optometrist is a reasonable substitute for a specialist ophthalmologist as a standard in the detection of glaucoma, this chapter describes the performance of trained VTs using individual tests utilized in glaucoma detection against this secondary standard.

All the study VTs were trained in glaucoma detection based on gonioscopy, direct ophthalmoscopic optic disc assessment and handling imaging equipment to acquire good quality test reports or photographs, depending on the equipment. This study hypothesized that the vision technician’s sensitivity in glaucoma detection would improve after a short course of training. Further that adding information derived from instrumentation such as fundus cameras and perimetry to the clinical component of examination would further improve diagnostic ability.

This chapter mainly focuses on the individual tests that included gonioscopy, assessment of cup disc ratio on direct ophthalmoscopy, intraocular pressure 117

measurement, overall clinical examination, and a referral criterion of a glaucoma positive result on any one of the individual clinical parameters. In addition, evaluation of non mydriatic fundus photographs and frequency doubling perimetry by the VTs was considered.

5.2 Methods:

A detailed description of the methodology was given in Chapter 2. However, the overall approach was to have a large series of individuals from rural community evaluated both by a VT and a standard optometrist. The examination consisted of a standard set of clinical tests, as described in section 2.7.3, followed at a later stage by grading of the NMFPs and FDT reports.

In order to be able to generalize the outcomes, one VT for every 500 subjects was selected randomly from the LVPEI network, which included 100 VTs in total and approximately 30 with the required experience, i.e. more than one, but less than 3, years. A total of 16 VTs participated in the study. Eight conducted on- site clinical examination and 8 graded NMFPs and FDT reports.

The ability of the vision technicians to detect glaucoma in a rural setting was evaluated based on their performance using clinical procedures, then with additive technologies such as non-mydriatic fundus pictures (NMFPs), and frequency doubling technology (FDT) reports. The full suite of tests applied is listed in Figure 5

As detailed in the previous chapter, two study optometrists, whose abilities in glaucoma detection had been validated against the glaucoma specialist ophthalmologist, served as the reference standards for the study. 118

On-site, a total of 8 study VTs took part in the study. Each VT examined 500 subjects before being replaced. The detailed process involved in the changeover and the protocol followed was described in Chapter 2 (section 2.5).

All examinations were conducted so that both the vision technicians and reference standard examiners were masked from each other’s assessment of the patient outcomes.

After the on-site data collection, 8 sets of data from 500 subjects including non- mydriatic fundus pictures and FDT reports, along with clinical data were separated consecutively and assigned, one for each of the 8 study VTs, selected randomly from the LVPEI network. After each set had been graded by the study VT, the results were compared to those of the reference standard study optometrist and various indicators of their diagnostic ability were calculated. All the VT’s were given prior training by the study optometrist in grading the NMFPs and FDT reports as mentioned in chapter 2, section 2.9.3.

From the total sample size of 3833 study participants, we captured 6,043

NMFPs and 1,479 FDT reports. Corresponding subjects’ clinical data with

NMFPs and FDT reports were divided them into 8 sets containing 500 subjects in each, with last set containing the remaining 333 subject’s data from the entire sample size. Set of clinical data along with corresponding NMFP and FDT reports were presented to each of the VTs in a masked and randomized fashion. Due to delay in delivery of software upgrades from the manufacturer it was not possible to conduct FDT on all participants and NMFPs could not be acquired on all the participants due to technical issues. Hence the available

FDT reports were divided into 3 sets and given to 3 VTs chosen at random from the available cohort with the requisite experience 119

Figure 5: Sequence of the analysis to evaluate the diagnostic accuracies of VTs in glaucoma detection

5.2.1 NMFP Image Quality

Of the total NMFPs, 5340 (88%) images were gradable and 703 (12%) images were of poor quality (non-gradable). All those pictures which allowed the visibility of the presence or suspicion of all or any one of the glaucomatous optic nerve damage, retinal nerve fibre layer defect, notch, rim thinning, splinter haemorrhage, cup-disc ratio of ≥ 0.6:1 and asymmetric cupping of >0.2:1 were diagnosed to have glaucoma by study optometrist and each of the study VTs.

5.2.2 Data Treatment

In evaluating the information presented to them, all participants (VTs and reference standard) recorded the outcome of each test for every patient in a dichotomous fashion, i.e. disease present or disease absent. Contingency 120

tables (2x2) were then used to evaluate the diagnostic accuracy outcomes for each paradigm. Sensitivity, specificity, PPV, NPV, PLR, NLR and ROC with

95% CIs were reported for all the study VTs. Mc Nemars chi square test was used to test the difference between the two proportions (disease positive and negative), in the paired data. This procedure tests whether the over-all distributions of subjects across the dichotomous categories according to the two judges differed from each other or not.

Results were calculated using the statistical analysis software STATA (Stata ver. 10.0; StataCorp, College Station, TX).

5.3 Results

5.3.1 Diagnostic accuracy of vision technicians using clinical tests:

This section deals with the diagnostic performance of VTs in detecting glaucoma by based on the five main clinical procedures. These were:

 Intraocular pressure measurements (IOP) using Goldmann applanation

tonometry (GAT) with a cut-off of 16 mm Hg, which is the 95th percentile

from the current population.

 Gonioscopy according to ISGEO classification

 Cup-disc ratio assessment with a cut-off of ≥0.6:1, which is the 95th

percentile from the current population.

 A referral criterion of a positive result in any one of the above.

 Clinical diagnosis of glaucoma as mentioned in section 1.2.1 121

5.3.1.1 Based on Intraocular pressure measurements (IOP):

Intraocular pressure was measured by the vision technicians in a total of 7,668

eyes. Each vision technician measured approximately 1,000 eyes, except for

the last, who had only 684 eyes.

The diagnostic performance of the vision technicians in detecting glaucoma with

an IOP cut-off of 16 mm Hg, is shown in Table 5.1

Table 5.1 - Diagnostic accuracy of Vision Technicians based on a criterion of Intra Ocular Pressure >16 mm Hg criteria

Diagnostic accuracy of VT Vs Optom in IOP >16 mm Hg criteria

Sensitivity Specificity PPV NPV ROC PLR NLR (95% CI) (95% CI) (95% CI) (95% CI) (95% CI) (95% CI) (95% CI) n 20 95 39 88 0.5 4 0.8 VT1 1000 (14-28) (93-96) (28-51) (85-90) (0.5-0.6) (2-7) (0.8-0.9) 12 95 21 90 0.5 2 0.9 VT2 998 (6-19) (93-96) (12-34) (88-92) (0.5-0.6) (0.9-5) (0.8-1) 16 95 31 90 0.5 3 0.9 VT3 994 (10-24) (94-97) (20-45) (88-92) (0.5-0.6) (2-8) (0.8-1) 18 96 38 90 0.5 5 0.9 VT4 998 (11-26) (95-97) (25-51) (87-91) (0.5-0.6) (2-9) (0.8-0.9) 31 90 20 94 0.6 3 0.8 VT5 998 (21-42) (88-92) (13-29) (92-95) (0.5-0.6) (2-5) (0.6 –0.9) 20 95 29 92 0.5 4 0.8 VT6 998 (13-30) (93-96) (19-42) (90-94) (0.5-0.6) (2-8) (0.7 –0.9) 10 91 11 90 0.5 1 1 VT7 998 (5-17) (89-93) (6-20) (88-92) (0.4-0.5) (0.5–2) (0.9–1) 24 88 13 93 0.5 2 0.9 VT8 684 (13-37) (85-90) (7-22) (91-95) (0.4-0.6) (0.9-4) (0.7-1) PPV: Positive predictive values, NPV: Negative predictive values, ROC: Receiver operating characteristics, PLR: Positive likelihood ratios, NLR: Negative likelihood ratios CI: Confidence intervals

Sensitivity of the IOP criteria with a cut-off of 16 mm Hg ranged from 10% to

31% with good specificity of above 90% for all the VTs except one. Likelihood

ratios for all the VTs showed a low to moderate (2-5) post-test probability of 122

glaucoma based on IOP at a cut-off of 16 mm Hg. Similarly, the mean diagnostic ability of VTs in glaucoma detection based on IOP had a sensitivity of

18% (95%CI; 14-22) with a specificity of above 90% (95%CI; 93-94) and only a moderate post-test probability. From a total of 401 eyes with an IOP of more than 16 mm Hg, 330 eyes were not detected as glaucoma by the VTs, which could be due to the fact that most of the glaucoma patients were reported to be presenting with statistically normal range of IOP.[47] Hence, a false negative rate of 82% is not an acceptable percentage.

5.3.1.2 Based on cup disc ratio (CDR):

Undilated funduscopy with a direct ophthalmoscope was performed to determine the cup disc ratio, which is an essential parameter in detection of the presence of glaucoma. In examining the disc with a CDR ≥0.6:1 was used for diagnosis. The results are shown in Table 5.2

VTs were able to diagnose glaucoma based on the CDR evaluated by a direct ophthalmoscope with sensitivity ranging from 36-70% and specificities of more than 90%.

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Table 5.2 - Diagnostic performance of Vision Technicians in glaucoma detection based on cup to disc ratio (CDR) ≥0.6:1

Diagnostic accuracy of VT Vs Optom in diagnosing glaucoma based on CDR ≥0.6:1 Specificit PPV PLR NLR Sensitivit NPV ROC y (95% (95% (95% (95% y (95% CI) (95% CI) (95% CI) n* CI) CI) CI) CI) 40 98 72 91 0.6 20 0.6 100 VT1 (28-53) (96-99) (55-86) (88-94) (0.6-0.7) (7-53) (0.5-0.8) 0 55 96 67 93 0.7 13 0.5 100 VT2 (46-65) (94-97) (56-76) (91-95) (0.7-0.8) (8-22) (0.4-0.6) 0 45 97 74 90 0.7 15 0.6 100 VT3 (36-54) (96-98) (63-83) (88-92) (0.6-0.7) (9-28) (0.5-0.7) 0 36 96 63 89 0.6 9 0.7 100 VT4 (28-45) (94-97) (51-74) (86-91) (0.6-0.7) (5-15) (0.6-0.8) 0 49 93 54 92 0.70 7 0.5 VT5 998 (40-58) (91-95) (44-63) (89-93) (0.6-0.7) (4-12) (0.4-0.7) 77 94 74 95 0.8 13 0.2 100 VT6 (70-83) (92-96) (67-80) (93-97) (0.8-0.9) (9-21) (0.2-0.3) 0 69 92 63 94 0.8 9 0.3 100 VT7 (61-76) (90-94) (55-70) (92-95) (0.7-0.8) (6-13) (0.3-0.4) 0 77 96 79 96 0.8 19 0.2 VT8 672 (68-85) (94-98) (70-87) (94-97) (0.8-0.9) (11-43) (0.2-0.3) * Number of eyes; VT: Vision technician, PPV: Positive predictive values, NPV:

Negative predictive values, ROC: Receiver operating characteristics, PLR: Positive likelihood ratios, NLR: Negative likelihood ratios CI: Confidence intervals

For VTs using a criterion of CDR ≥0.6, sensitivity ranged from 36% to 77% with good specificity of above 90% in all cases. Likelihood ratios showed a large (7-

20) post-test probability of having glaucoma. Taking the group as a whole, the mean diagnostic ability of VTs had a sensitivity of 61% (95% CI; 57-64) with a specificity of 95% (95% CI; 94-95) with high post-test probability. For the 995 eyes found to have a CDR of more than 0.5 according to the reference standard, the false negative rate among VTs was 35% (348 eyes). Which mean 124

that the presence of glaucoma might have been in the remaining 647 eyes, if a criterion only on CDR of ≥0.6:1is considered.

5.3.1.3 Based on Gonioscopy:

The results are shown in Table 5.3, from which it can be seen that VTs were able to identify occludable angles using gonioscopy with sensitivity ranging from

47% to 70% with good specificity rates of above 90% in all cases. Overall, likelihood ratios showed a moderate to large (8-64) post-test probability of having angle closure based on gonioscopy. Similarly, the mean diagnostic ability of VTs in detecting angle closure had a sensitivity of 64% (95%CI; 58-70) with a specificity of 98% (95% CI; 97-98) and had a high post-test probability of having an occludable angle. Of the 264 eyes found with occludable angles by the reference standard using the ISGEO criteria as mentioned in section 1.2.1,

76% of those with occludable angles were correctly identified by the VTs, which is an important observation as in Indian and Chinese population the number of people with ACG are more that POAG and the only way to suspect an occludable angle is by proper gonioscopy.[47]

125

Table 5.3 - Diagnostic accuracy of VTs in glaucoma detection based on Gonioscopy according to ISGEO classification

Diagnostic accuracy of VT Vs Optom based on GONIOSCOPY Sensitivity Specificity PPV NPV ROC PLR NLR n* (95% CI) (95% CI) (95% CI) (95% CI) (95% CI) (95% CI) (95% CI) 57 93 38 97 0.7 8 0.5 VT1 1000 (44-68) (91-95) (29-48) (95-98) (0.6-0.8) (5-14) (0.3-0.6) 86 98 69 99 0.9 43 0.1 VT2 1000 (71-95) (97-99) (55-81) (98-100) (0.8-0.9) (24-95) (0-0.3) 60 97 56 97 0.7 20 0.4 VT3 988 (46-72) (96-98) (42-68) (96-98) (0.7-0.8) (12-36) (0.3-0.6) 71 97 63 97 0.8 24 0.3 VT4 984 (59-80) (95-98) (52-73) (96-98) (0.7-0.8) (12-40) (0.2-0.4) 47 97 39 98 0.7 16 0.5 VT5 998 (31-64) (96-98) (25-55) (97-99) (0.6-0.8) (8-36) (0.4-0.7) 87 100 87 100 0.9 α 0.1 VT6 1000 (66-97) (99-100) (66-97) (99-100) (0.8-1) (66-α) (0-0.3) 64 99 68 99 0.7 64 0.4 VT7 1000 (45-80) (98-100) (49-83) (98-99) (0.7-0.8) (23-α) (0.2-0.6) 58 99 78 99 0.8 58 0.4 VT8 672 (37-78) (98-100) (52-94) (98-99) (0.7-0.9) (19-α) (0.2-0.6) * Number of eyes; VT: Vision technician, PPV: Positive predictive values, NPV: Negative predictive values, ROC: Receiver operating characteristics, PLR: Positive likelihood ratios, NLR: Negative likelihood ratios CI: Confidence intervals

5.3.1.4 Based on referral criteria:

The VTs were given a referral criterion based on the set of clinical findings for

each subject. Thus, any subject with a positive finding in any one of the

evaluation procedures mentioned above was to be considered potentially

glaucoma positive and referred for further evaluation. Using the same criterion

for the standard optometrist generated the data in Table 5.4 126

Table 5.4 - Diagnostic accuracy of VT based on referral criterion: Refer IF IOP > 16mmHg AND/OR CDR ≥0.6:1 AND/OR Gonio occludable AND/OR A diagnosis of Glaucoma

Diagnostic accuracy of VT Vs Optom based on REFERRAL CRITERIA PPV PLR Sensitivity Specificity NPV ROC NLR (95% (95% (95% CI) (95% CI) (95% CI) (95% CI) (95% CI) n* CI) CI) 55 90 40 95 0.7 6 0.5 VT1 1000 (45-65) (88-92) (32-48) (93-96) (0.6-0.7) (4-8) (0.4-0.6) 65 88 30 97 0.7 5 0.4 VT2 1000 (53-76) (86-90) (23-38) (96-98) (0.7-0.8) (4-8) (0.3-0.5) 78 89 36 98 0.8 7 0.2 VT3 1000 (67-86) (87-91) (29-44) (97-99) (0.7-0.8) (5-10) (0.2-0.4) 61 90 39 95 0.7 6 0.4 VT4 1000 (50-70) (88-92) (31-47) (94-97) (0.7-0.8) (4-8) (0.3-0.6) 63 87 27 97 0.7 5 0.4 VT5 998 (50-74) (85-89) (20-35) (95-98) (0.6-0.8) (3-7) (0.3-0.6) 81 84 18 99 0.8 5 0.2 VT6 1000 (67-92) (81-86) (13-25) (98-100) (0.7-0.8) (4-7) (0-0.4) 69 82 15 98 0.7 4 0.4 VT7 1000 (53-82) (79-84) (10-21) (97-99) (0.6-0.8) (3-5) (0.2-0.6) 70 86 13 99 0.7 5 0.3 VT8 672 (46-88) (83-88) (7-21) (98-100) (0.6-0.8) (3-7) (0.1-0.7) * total number of eyes; VT: Vision technician, PPV: Positive predictive values, NPV:

Negative predictive values, ROC: Receiver operating characteristics, PLR: Positive likelihood ratios, NLR: Negative likelihood ratios CI: Confidence intervals

VTs were able to detect glaucoma with sensitivities ranging from 55% to 81%

with good specificity of above 80% in all cases. Likelihood ratios of the group

showed a moderate (4-7) post-test probability of detecting glaucoma based on

the referral criteria. The mean diagnostic ability of VTs had a sensitivity of 73%

(69-78) with a specificity of 80% (79-81) and had a moderate post-test

probability. Of the total 401 eyes satisfying the referral criteria according to the 127

reference standard107 eyes were missed by the VTs, which means that a false negative rate of 27%.

5.3.1.5 The clinical diagnosis of glaucoma:

The diagnostic accuracy of vision technicians in making a diagnosis of glaucoma based on the clinical examination is given in the Table 5.5. VTs were able to detect glaucoma with sensitivity ranging from 47% to 70% with good specificity of above 90% for all the groups. Likelihood ratios of all the VTs showed a large (8-27) post-test probability of having glaucoma based on the clinical diagnosis. The mean diagnostic ability of VTs had a sensitivity of 60%

(95%CI; 55-65) with a specificity of 95% (95%CI; 95-96) and a large post-test probability of having glaucoma. Of the 401 true positives according to the reference standard, 160 eyes were not identified by the VTs, a false negative rate of 40%.

128

Table 5.5 -Diagnostic accuracy of vision technicians based on the clinical diagnosis of glaucoma

Diagnostic accuracy of VT Vs Optom in diagnosis of glaucoma

PPV NPV Sensitivity Specificity ROC PLR NLR (95% (95% (95% CI) (95% CI) (95% CI) (95% CI) (95% CI) n* CI) CI) 47 96 62 93 0.7 12 0.6 VT 1 901 (37-57) (95-97) (50-72) (91-95) (0.6-0.7) (7-19) (0.4-0.7) 66 96 59 97 0.8 17 0.4 VT 2 891 (53-77) (95-97) (47-70) (96-98) (0.7-0.8) (11-26) (0.2-0.5) 70 93 45 97 0.8 10 0.3 VT 3 927 (58-80) (91-95) (37-57) (96-98) (0.7-0.8) (6-16) (0.2-0.5) 56 96 64 95 0.7 14 0.5 VT 4 916 (45-66) (95-97) (53-74) (93-96) (0.7-0.8) (9-22) (0.4-0.6) 54 98 70 96 0.7 27 0.5 VT 5 927 (42-66) (97-99) (56-82) (95-97) (0.7-0.8) (14-66) (0.3-0.6) 67 95 41 98 0.8 13 0.3 VT 6 886 (51-81) (93-96) (29-53) (97-99) (0.7-0.8) (7-20) (0.2-0.5) 49 94 29 97 0.7 8 0.5 VT 7 906 (34-64) (92-95) (19-40) (96-98) (0.6-0.7) (4-13) (0.4-0.7) 55 96 31 98 0.7 14 0.5 VT 8 594 (32-77) (94-97) (17-49) (97-99) (0.6-0.8) (5-26) (0.2-0.7) * Number of eyes; VT: Vision technician, PPV: Positive predictive values, NPV: Negative predictive values, ROC: Receiver operating characteristics, PLR: Positive likelihood ratios, NLR: Negative likelihood ratios CI: Confidence intervals

5.3.2 Diagnostic accuracy of vision technicians with Additional Tests:

Further evaluation was conducted for imaging techniques individually and in

combination with clinical findings. Subjects with bad NMFPs were excluded and

in those cases the diagnostic accuracy of VTs was based on clinical

examination alone and with a criteria of visual acuity worse than 6/18 and also

with a criteria of visual acuity better than or equal to 6/18 (normal vision). Those

with visual acuity worse than 6/18 are referred anyways, however the VTs

diagnostic accuracy in glaucoma detection for this specific group was also

evaluated. 129

5.3.2.1 Based on non-mydriatic fundus pictures:

Study VTs were masked from the results of the clinical diagnosis made by the

study optometrist to avoid bias while grading the images. Image grading data

were recorded in an Excel sheet (MS Office Enterprise 2007) both by the study

optometrists and the study VTs as mentioned in section 5.2.1. Diagnostic

accuracies for grading NMFPs were calculated. The diagnostic accuracy for

each of the VT’s is presented in Table 5.6. The diagnostic accuracy of the VTs

in detecting glaucoma based on NMFP had ranged from 25 to 100% sensitivity

with specificities ranging from 18 to 99%.

Table 5.6 - Mean Diagnostic accuracy of VTs in grading Non mydriatic fundus pictures (NMFPs) as compared with the reference standard optometrist in patients with NORMAL VISION (n = 4,592)

Diagnostic accuracy of VT’s in grading NMFP Sensitivity Specificity ROC PPV NPV PLR NLR VT n (95% CI) (95% CI) (95% CI) (95% CI) (95% CI) (95% CI) (95% CI) 83 59 0.7 3 100 2 0.3 VT1 430 (36-100) (55-64) (0.5-0.8) (1-6) (98-100) (0.8-3) (0-1) 80 75 0.7 9 100 3 0.3 VT2 833 (44-97) (71-78) (0.64-0.90) (2-7) (99-100) (2-4) (0-0.8) 91 83 0.8 7 100 5 0.1 VT3 759 (59-100) (80-86) (0.7-0.9) (4-13) (99-100) (3-7) (0-0.5) 47 89 0.6 7 99 8 0 VT4 852 (21-73) (87-91) (0.5-0.8) (3-14) (98-100) (2-9) (0.3-1) 100 18 0.5 2 100 1 0 VT5 709 (70-100) (15-21) (0.5-0.6) (1-3) (97-100) (0.8-1) (0-2) 51 94 0.7 23 98 9 0.5 VT6 971 (34-68) (92-95) (0.6-0.8) (14-34) (97-100) (4-14) (0.3-0.7) 25 99 0.6 58 98 25 0.8 VT7 844 (11-45) (99-100) (0.5-0.7) (28-85) (96-98) (11-α) (0.6-0.9) 33 99 0.6 20 100 33 0.7 VT8 645 (1-91) (98-100) (0.3-0.4) (1-72) (99-100) (0.5-α) (0-1) 130

5.3.3 Based on frequency doubling technology (FDT):

As mentioned earlier in chapter 2, FDT could not be done for all the study

participants due to technical reasons such as out dated version of the FDT

Matrix being used in the study and also difficulty in upgrading the software by

Carl Zeiss Meditec. Hence, FDT reports interpretation was done only for first 3

vision technicians. Table 5.7 explains the FDT evaluated as an individual test.

Table 5.7 – FDT interpretation for each vision technician in detecting glaucoma

Diagnostic ability of each VT in FDT interpretation

PPV Sensitivity Specificity NPV ROC PLR NLR (95% n (95% CI) (95% CI) (95% CI) (95% CI) (95% CI) (95% CI) CI) 33 60 1 99 0.4 1 1 VT 1 447 (4-78) (55-64) (0-4) (96-100) (0.2-0.6) (0-2) (0.3-1.7)

17 78 6 92 0.4 1 1.1 VT 2 868 (9-28) (75-81) (3-10) (90-94) (0.4-0.5) (0-1) (0.9-1.2)

17 73 2 96 0.4 1 1.1 VT 3 164 (1-64) (66-80) (0.5-12) (91-99) (0.2-0.6) (0-3) (1.5-0.5) *n=number of eyes; VT: Vision technician; FDT: frequency doubling technology; PPV: Positive predictive value; NPV: Negative predictive value; ROC: Receiver operating characteristics; PLR: Positive likelihood ratio: NLR: Negative likelihood ratios;

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5.4 Discussion

5.4.1 Study findings:

The utility of vision technicians to provide primary eye care in rural communities has been implemented in LVPEI vision centres and also is a model adopted by the WHO in order to deliver eye care at a community level in developing countries. Every vision centre in the LVPEI pyramid model is staffed by a vision technician and if these individuals can be trained to a suitable level, they might provide an alternative diagnostic resource in situations where there are not enough ophthalmological or optometric staff available to combat blindness in the rural communities. The purpose of this study was to assess how well such personnel can detect glaucoma in their local community setting.

In situations where no other diagnostic methods can be applied; the criteria with visual acuity worse than or equal to 6/18 plays a major role in referring the patients for further management. On the other hand, when the visual acuity is normal (better than 6/18) but a good quality NMFP could not be acquired due to patient cooperation or skill of the VT or any other reason; it becomes a challenge as the VT’s could miss potential number of glaucoma cases as shown in results However, our referral criteria results have shown good overall diagnostic abilities which help the VT to correctly identify and send the subjects for further management.

The baseline study reported that VTs are capable of detecting and referring the two most common causes of reversible blindness; uncorrected refractive error and cataract with good sensitivities ranging from 72% (95%CI; 64-79) for all cataracts to 100% (95%CI; 97-100) for refractive errors and corneal diseases 132

with specificities above 95%. However, a poor diagnostic ability in glaucoma detection with sensitivity at 36% (95% CI: 15-65) was reported.[28, 29]

The main study showed that the overall diagnostic accuracy of VTs with a referral criteria in clinical examination had a sensitivity of 73% (95% CI: 69-78) with a specificity of 80% (95%CI: 79-81). Using this rate, it is useful to compare the impact of additional training for VTs in glaucoma detection to the baseline results for VTs with standard training. A standard VT could be expected to identify 22 glaucoma suspects over a period of 7 weeks, during which they would typically see a total of 294 people. A specially trained VT, on the other hand, might detect as many as163 glaucoma suspects during the same period and from the same screening cohort.

Considering the rate of detection of glaucoma suspects from the baseline study,

NMFP alone wouldn’t have made any improvement than post training clinical evaluation by VTs. Whereas, with FDT alone, the pick rate for glaucoma suspect would have been as low as 4 subjects of the total number of 294 subjects.

5.4.2 Glaucoma detection by vision technicians:

This is the first study to validate the ability of vision technicians using FDT and

NMFP along with clinical tests in detecting primary glaucoma in a community based set up. Secondary glaucoma’s, such as pseudoexfoliation, are associated with other causes and as these could have affected the accuracy rates in overall glaucoma diagnosis and they were not included for the study analysis.” 133

The novelty of the study lies in using the study optometrists in evaluating the performance of VTs working at a vision centre where availability of an ophthalmologist or a glaucoma specialist is limited. From the reports of Suram et al, [29] who looked at VTs performance in a similar clinical environment, it was evident that the ability of VT’s in detecting anterior segment pathologies and clinical performance was acceptable but had low sensitivity rates in detecting posterior segment diseases. VTs had a fair sensitivity of 35.6% (95% CI, 21.9 –

51.2) in detection of glaucoma. It is important to consider that these particular

VTs were not trained in detecting posterior pole diseases like glaucoma or diabetic retinopathy and so the fact that they were able to pick up over one third of true cases can be seen as reasonable success. However, if trained VTs showed a similar figure it would be considered to represent a “poor sensitivity” figure

In this study, for clinical diagnosis, various clinical procedures were also analysed to see the VTs diagnostic ability in picking up glaucoma based on an

IOP cut off of 16 mm Hg, CDR cut off on ≥0.6:1 by direct ophthalmoscopy, gonioscopy in detecting occludable angles as classified by ISGEO, and a referral criteria as mentioned in section 1.2.1. Cut offs for IOP and CDR were decided based on the 95th percentile obtained from the current population. The overall sensitivity of VT’s based on the referral criteria was 73% (95%CI; 69-78) with a specificity of 80% (95%CI; 79-81). PLR showed a moderate effect on the post-test probability of having glaucoma. However, there was not much of a difference between the clinical diagnosis of glaucoma based on the complete examination and the referral criteria. 134

In clinical evaluation, as shown in previous studies,[16, 17] measurement of IOP in isolation has poor sensitivity and specificity and the current study results are also in agreement with those findings. It was also reported that, having an understanding of the disease classification in primary angle closure and its various forms, slit lamp gonioscopy was assigned the primacy of ‘gold standard’ for diagnosis.[199] Hence, the study reported the diagnostic accuracy of each of the clinical evaluation tests including gonioscopy according to the classification of ISGEO, CDR with direct ophthalmoscope, clinical diagnosis based on the complete examination and a referral criterion as mentioned in the previous chapter. Except for IOP, all other clinical tests showed reasonably good diagnostic accuracy parameters as compared to the baseline study parameters for glaucoma detection. This could be because of the fact that most of those diagnosed with primary glaucoma’s were actually measured to have normal statistical range at presentation.[47] Poor sensitivity also means that true positives can be missed in significant numbers and requires additional tests that were used and proven in this study. Overall, VTs showed an improvement in glaucoma detection with additional training as compared to baseline result.

Imaging techniques (NMFP and FDT):

Glaucoma detection based on the grading of NMFPs by VTs as compared to the reference standard showed a moderate to good diagnostic accuracies. To the best of our knowledge, no literature is available on the performance of VT's in grading NMFPs for glaucoma detection. While the diagnostic accuracies of the VTs in NMFP grading for glaucoma were either highly sensitive with poor 135

specificities or vice-versa making it less worthy as compared to the values obtained from clinical evaluation.

The study results showed that the VT’s glaucoma detection rates considerably improved with a short duration of additional training was given, which could be an excellent model to the rural populations.

In a resource poor situation , clinical examination including gonioscopy and optic disc examination is the only cost-effective method to detect glaucoma, because of the insidious nature of the disease.[199] An internal ocular examination using these relatively inexpensive methods is the primary opportunity to identify those at risk. Once the disease is detected appropriate tests such as SAP can be done to assess the damage and follow up the patient.[200, 201] The clinical examination protocol that was followed in this study gives an opportunity to detect not only glaucoma but also other potentially blinding diseases of the posterior segment. In this study, VTs were trained in direct ophthalmoscopy with more emphasis on detecting earliest morphological changes related to glaucoma, from optic nerve head and peripapillary area.[142,

193] VTs are limited to the undilated examination of a patient because of the lack of supervision by an optometrist or an ophthalmologist, in a routine scenario. In most of the combinations and technological additives the predictive values suffered, which could be due to the fact that the subjects are from a population based study where more number of normal subjects would be present in the sample rather than diseased which reduce the predictive values.[101] VTs diagnosis was validated with the final diagnosis of the study optometrist who conducted the comprehensive dilated stereo fundus examination with slit lamp on every patient. 136

Chapter 6: Evaluating the ability of vision technicians –

Combined tests in glaucoma detection

6.1 Introduction:

This chapter deals with the combination of tests used in glaucoma detection in this study. The sequence of the tests conducted was described in the previous chapter in figure 5. Considering the fact that 50% of glaucoma patients remain undiagnosed in various parts of the world, though reported to be in the United

States and Europe and among the Japanese population those aged above 40 years old and above, about 93.3% of POAG patients were previously undiagnosed, a mass screening method for glaucoma detection is urgently needed.[202] With that background various paradigms for glaucoma detection were evaluated.

The value of different tests used in glaucoma detection should be considered in

4 different contexts. First being the fundamental context of what is addressed, structural or functional? Structural deals with the identification of glaucoma based on the morphological changes and functional deals with the impact on functional life of those affected by glaucoma.[199] The second context being the socioeconomic resources for glaucoma care in terms of equipment, trained personnel, infrastructure and the political will to provide health benefits to the community are mobilized in terms of resource-poor or resource-abundant communities. In resource-poor community, tests that helps detecting the blinding disease at an early stage is important whereas, in resource-abundant community sophisticated tests that helps both in detection and sensitive monitoring of progression and treatment is the need. Third context is to 137

understand the value of understanding the disease stages and the role of ancillary imaging technologies, while fourth being the value of glaucoma tests in the context of time.[199]

The results of the individual results with clinical, NMFP and FDT had already been described in chapter 5. Results obtained from combination of clinical with

FDT, FDT with NMFP and clinical with NMFP are been described in the current chapter.

Clinical evaluation along with non mydriatic fundus camera (NMFC) and frequency doubling technology (FDT) have been combined in different combinations to understand the best possible combination that yields better results in glaucoma detection. All the study VTs were evaluated on the basis of clinical, NMFP and FDT in isolation and in combinations. As previously described, FDT was evaluated only in first three vision technicians and the remaining VT’s had tests in isolation and combinations of clinical and NMFP.

An ideal screening test for glaucoma is not yet established resulting in more than 50% of undiagnosed glaucoma patients in United States and Europe and

75% in Japan. The effectiveness of individual screening tests were reported to be limited.[101]

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6.2 Results - Diagnostic ability of each VT in different screening paradigm:

The study details on individual performance in clinical and imaging technology

when compared in different combinations of tests.

6.2.1: Diagnostic accuracy of VT 1

Table 6.1 shows the performance of VT1 in individual and combined tests. For

the VT1, when Clinical+NMFP+FDT were evaluated in pair-wise combinations,

there seemed to be an excellent sensitivity rate and a good specificity rate. The

receiver operating characteristic (ROC) of 0.8 (95% CI; 0.7-0.9) indicating a

good diagnostic test. However the predictive values are not to be considered in

combinations. All the tests had moderate effect on the post-test probability of

having glaucoma except for clinical alone which had a high effect.

Table 6.1 - Diagnostic ability in different screening paradigms – VT 1

Mode of Sensitivity Specificity PPV NPV ROC PLR NLR n Screening (95% CI) (95% CI) (95% CI) (95% CI) (95% CI) (95% CI) (95% CI)

0.71 12 0.6 47 96 62 93 Clinical (0.6-0.7) (7-19) (0.4 - 0.7) 901 (37-57) (95-97) (50-72) (91-95)

0.8 50 59 2 99 0.5 1 NMFP (0.2-1.8) 430 (12-88) (54-63) (0.5-5) (97-100) (0.3-0.7) (0-2)

1 33 60 1 99 0.4 1 FDT (0.3-1.7) 447 (4-78) (55-64) (0-4) (96-100) (0.2-0.6) (0-2)

Clinical+ 100 68 3 100 0.8 3 0 554 NMFP (54-100) (64-72) (1-7) (92-100) (0.8-0.9) (2-4) (0.7-0)

FDT+ 100 71 3 100 0.8 3 0 388 NMFP (40-100) (66-75) (1-9) (99-100) (0.8-0.9) (1-4) (0.9-0)

Clinical+ 100 62 3 100 0.8 3 0 FDT 472 (54-100) (57-66) (1-7) (99-100) (0.7-0.8) (1-3) (0.8-0)

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NMFP- Non mydriatic fundus pictures, FDT- Frequency doubling technology, PPV- Positive predictive values, NPV- Negative predictive values, ROC- Receiver operating characteristics, PLR- Positive likelihood ratio, NLR- Negative likelihood ratio

6.2.2 Diagnostic ability of VT2

For VT2, Table 6.2 shows that Clinical, NMFP, Clinical+NMFP and

Clinical+FDT yielded good sensitivities and so as with ROC; except for FDT

which either alone or in combination had only a poor sensitivity rate 17% (95%

CI: 09-28) and 22% (95% CI; 12-36) respectively. All the tests had moderate

effect on the post-test probability of having glaucoma except for clinical alone

which had a high effect and FDT either alone or in combination had a low effect

on the post-test probability.

Table 6.2 - Diagnostic ability in different screening paradigms – VT 2

Mode of Sensitivity Specificity PPV NPV ROC PLR NLR N Screening (95% CI) (95% CI) (95% CI) (95% CI) (95% CI) (95% CI) (95% CI) 66 96 59 97 0.80 17 0.4 Clinical 891 (53-77) (95-97) (47-70) (96-98) (0.7-0.8) (11-26) (0.2-0.5) 74 72 14 98 0.7 3 0.4 NMFP 833 (60-85) (69-75) (10-19) (96-99) (0.6-0.8) (2-3) (0.2-0.6) 17 78 6 92 0.4 1 1.1 FDT 868 (9-28) (75-81) (3-10) (90-94) (0.4-0.5) (0-1) (0.9-1.2) Clinical+ 100 72 4 0.8 4 0 0 868 NMFP (93-100) (69-75) (3-4) (0.8-0.9) (3-0) (0.1-1.2) FDT+ 22 73 5 94 0.4 1 1.1 868 NMFP (12-36) (70-76) (2-8) (92-96) (0.4-0.5) (0-2) (0.8-1.3) Clinical+ 100 81 24 100 0.9 5 0 830 FDT (93-100) (78-84) (19-31) (99-100) (0.8-0.9) (4-1) (.1-1.1) NMFP- Non mydriatic fundus pictures, FDT- Frequency doubling technology, PPV- Positive predictive values, NPV- Negative predictive values, ROC- Receiver operating characteristics, PLR- Positive likelihood ratio, NLR- Negative likelihood ratio

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6.2.3: Diagnostic accuracy of VT3

The results for VT3 are detailed in Table 6.3. Clinically, this study VT had

exhibited good sensitivity rate in clinical 70% (95% CI; 58-80) which however

did not had any improvement with other diagnostic additives or in combination

with technology. ROC and likelihood ratios were also best in clinical evaluation

alone.

Table 6.3 - Diagnostic ability in different screening paradigms – VT 3

PLR Mode of Sensitivity Specificity PPV NPV ROC NLR (95% N Screening (95% CI) (95% CI) (95% CI) (95% CI) (95% CI) (95% CI) CI) 70 93 45 97 0.8 10 0.3 (0.5- Clinical 927 (58-80) (91-95) (37-57) (96-98) (0.7-0.8) (6-16) 0.2)

31 83 10 95 0.5 2 0.8 (1- NMFP 759 (18-47) (80-86) (6-17) (93-97) (0.5-0.6) (1-3) 0.6)

17 73 2 96 0.4 1 1.1 FDT 164 (1-64) (66-80) (0.5-12) (91-99) (0.2-0.6) (0-3) (1.5-0.5)

Clinical+ 63 81 17 97 0.7 3 0.5 876 NMFP (48-77) (78-84) (12-23) (96-98) (0.6-0.7) (2-5) (0.7-0.3)

FDT+ 50 76 5 98 0.6 2 0.7 76 NMFP (1-99) (64-85) (0.5-26) (91-100) (0.1-1) (0-7) (1.5-0)

Clinical+ 67 72 8 98 0.6 2 0.5 168 FDT (22-96) (64-78) (2-19) (94-100) (0.4-0.9) (1-4) (1.2-0.1) NMFP- Non mydriatic fundus pictures, FDT- Frequency doubling technology, PPV- Positive predictive values, NPV- Negative predictive values, ROC- Receiver operating characteristics, PLR- Positive likelihood ratio, NLR- Negative likelihood ratio

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6.2.4 Diagnostic ability of VT4

The FDT interpretation wasn’t evaluated from the 4th vision technician through

the 8th VT. Table 6.3 shows that the vision technician was good at detecting

glaucoma through clinical evaluation with a sensitivity of 56% (95% CI; 45-66)

and when clinical was combined with NMFP, sensitivity was similar to the

clinical results 56% (95% CI; 42-69). The similar result was found for specificity

between clinical test in isolation and when combined with NMFP with good

specificities of above 87% in combination to 96% in clinical evaluation. ROC

and likelihood ratio is also found to be good with clinical and in combination with

clinical but not with NMFP alone.

Table 6.4 - Diagnostic ability in different screening paradigms – VT 4

NLR Mode of Sensitivity Specificity PPV NPV ROC PLR (95% n Screening (95% CI) (95% CI) (95% CI) (95% CI) (95% CI) (95% CI) CI)

56 96 64 95 0.75 14 0.5 916 Clinical (45-66) (95-97) (53-74) (93-96) (0.7-0.8) (9-22) (0.6-0.4)

21 90 13 94 0.5 2 0.9 852 NMFP (11-34) (88-92) (7-21) (92-96) (0.5-0.6) (1-4) (1-0.7)

56 87 23 97 0.7 4 0.5 Clinical+ 886 (42-69) (85-89) (16-31) (95-98) (0.6-0.7) (3-6) (0.7-0.3) NMFP NMFP- Non mydriatic fundus pictures, FDT- Frequency doubling technology, PPV- Positive predictive values, NPV- Negative predictive values, ROC- Receiver operating characteristics, PLR- Positive likelihood ratio, NLR- Negative likelihood ratio

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6.2.5 Diagnostic ability of VT5:

Table 6.5 shows that the study VT5 had a sensitivity of 54% (95% CI: 42-66) in

detecting glaucoma with high specificity of 98% (95% CI: 97-99). Both ROC and

likelihood ratios were also found to be high in clinical alone. Sensitivities with

NMFP and in combination with clinical evaluation, though had high sensitivities,

specificities, ROC and likelihood ratios were not significant enough.

Table 6.5 - Diagnostic ability in different screening paradigms – VT 5

PPV NPV PLR Mode of Sensitivity Specificity ROC NLR (95% (95% (95% N Screening (95% CI) (95% CI) (95% CI) (95% CI) CI) CI) CI)

54 98 70 96 0.76 27 0.5 (0- Clinical 927 (42-66) (97-99) (56-82) (95-97) (0.7-0.8) (16-66) 0.6)

94 23 6 99 0.6 1 0.3 (1- NMFP 709 (81-99) (20-27) (4-8) (96-100) (0.5-0.6) (1-1) 0)

Clinical+ 97 18 5 99 0.6 1 0.2 (1- 748 NMFP (84-100) (16-22) (4-8) (96-100) (0.5-0.6) (1-1) 0)

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6.2.6 Diagnostic ability of VT6:

The study VT6 had good sensitivity of 77% (95%CI; 61-88) when clinical was

combined with NMFP with good ROC and likelihood ratios. However, with

NMFP alone the diagnostic parameters seem to be good.

Table 6.6 – Diagnostic ability in different screening paradigms – VT 6

Mode of Sensitivity Specificity PPV NPV ROC PLR NLR n Screening (95% CI) (95% CI) (95% CI) (95% CI) (95% CI) (95% CI) (95% CI)

67 95 41 0.81 13 0.3 Clinical 98 (97-99) 886 (51-81) (93-96) (29-53) (0.7-0.8) (7-20) (0.5-0.2)

33 93 18 0.6 5 0.7 NMFP 97 (95-98) 971 (20-50) (91-95) (10-29) (0.5-0.7) (2-10) (0.9-0.5)

Clinical+ 77 83 17 0.8 5 0.3 99 (98-99) 976 NMFP (61-88) (81-85) (12-23) (0.7-0.8) (3-6) (0.5-0.1)

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6.2.7 Diagnostic ability of VT7:

Table 6.7 Shows the performance of a VT with poor sensitivity in detecting

glaucoma but was specific enough in identifying normal. A combination of

NMFP with clinical had an improvement in the diagnostic performance.

Table 6.7 - Diagnostic ability in different screening paradigms – VT 7

Mode of Sensitivity Specificity PPV NPV ROC PLR NLR n Screening (95% CI) (95% CI) (95% CI) (95% CI) (95% CI) (95% CI) (95% CI)

49 94 29 97 0.71 8 0.5 Clinical 906 (34-64) (92-95) (19-40) (96-98) (0.6-0.7) (4-13) (0.7-0.4)

9 99 30 96 0.5 9 0.9 NMFP 844 (2-24) (98-100) (7-65) (95-98) (0.4-0.5) (1-0) (1-0.8)

Clinical+ 62 93 28 98 0.7 9 0.4 838 NMFP (44-78) (91-95) (19-40) (97-99) (0.6-0.8) (5-16) (0.6-0.2)

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6.2.8 Diagnostic ability of VT8:

Study VT 8 also showed a poor sensitivity in detecting glaucoma but was

specific enough in identifying normal. A combination of NMFP with clinical had

an improvement of 100% (95% CI: 83-100). The results are detailed in Table 6.

Table 6.8 - Diagnostic ability in different screening paradigms – VT 8

NPV ROC PLR Mode of Sensitivity Specificity PPV NLR (95% (95% (95% n Screening (95% CI) (95% CI) (95% CI) (95% CI) CI) CI) CI)

55 96 31 98 0.7 14 0.5 Clinical 594 (32-77) (94-97) (17-49) (97-99) (0.6-0.8) (5-26) (0.7-0.2)

10 100 40 97 0.5 α 0.9 NMFP 645 (1-32) (99-100) (5-85) (96-98) (0.4-0.6) (1-0) (1-0.7)

100 Clinical+ 100 99 87 0.5 100 0 (99- 642 NMFP (83-100) (99-100) (66-97) (0.4-0.6) (83-α) (0.2-0) 100) NMFP- Non mydriatic fundus pictures, FDT- Frequency doubling technology, PPV- Positive predictive values, NPV- Negative predictive values, ROC- Receiver operating characteristics, PLR- Positive likelihood ratio, NLR- Negative likelihood ratio

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6.4 Discussion:

Our results suggest that, with minimal amount of additional training in glaucoma detection, a VT can detect a leading cause of irreversible blindness, based on clinical evaluation alone and also exhibits improved abilities when added with technological support such as FDT or NMFP. Additive technologies, FDT and

NMFP were added to the VTs abilities in improving glaucoma detection in addition to clinical examination. Results showed that training had good impact on glaucoma detection as compared to the information obtained from the baseline study. In addition, the overall diagnostic performance had improved with addition of NMFP and further improved with FDT along with clinical evaluation.

Thomas et al [1] reported that the VTs sensitivity for disease detection rate in referral efficiency was increased by 20% by adding FDT to the clinical evaluation but as a consequence of high false positives specificity dropped by

10%. With the use of FDT alone the VT can achieve almost 50% improvement in his ability for any case of ocular pathology which needs a referral to the secondary centre.

Though false positives can increase the patient's financial burden and can affect psychologically, in conditions such as glaucoma, it can be acceptable considering the condition as a more serious issue that leads to irreversible blindness.[203] Likelihood ratios showed good post-test probabilities of glaucoma detection for all the screening paradigms reported in this study.

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6.5 Summary:

Of the various models of glaucoma detection by a VT, overall sensitivity of glaucoma detection clinically was 57% (95%CI; 52-61), 64% (95%CI; 35-84) for

NMFP and 18% (95%CI; 10-28) for FDT. Combining clinical with NMFP improved the sensitivity to 77% (95%CI; 72-82), FDT with NMFP was 29%

(95%CI; 17-42) and the highest sensitivity was achieved when FDT was combined with clinical at 97% (95%CI; 89-100). Specificities were above 80% for clinical and NMFP individually and rest all were above 70%.

Though a combination of a clinical examination with FDT revealed 97% sensitivity, practically, many false positives for glaucoma will be expected as various other conditions can also lead to a defect on an FDT report.

Combining NMFP with clinical examination also yielded sensitivity as high as

100%, for half of the study VTs who participated. The same model could be replicated for other conditions where retinal changes are critical diagnostic indicators such as in diabetic retinopathy.

Hence the ideal combination in a community based setting is a clinical examination combined with NMFP. Though the sensitivity has reached 100% in combinations, the positive predictive values dropped. This drop in the predictive values can be explained as a result of the drop in the prevalence of the disease of interest in each set and also due to the fact that the sample is from a population based study where more number of normal subjects would be present in the sample rather than diseased.[101] However, when measuring diagnostic accuracy in combinations, predictive values are not to be considered.[145] There exists a gain in sensitivity when combinations were 148

introduced with a compromise on the net specificity, which is a fact when a simultaneous screening method is applied.[145] Likelihood ratios showed a large post-test probability for all the VTs in clinical diagnostic accuracies alone but all other paradigms either in isolation or in combination only had a small to moderate post-test probabilities of detecting the disease.

Based on the results, it was concluded that VT’s ability in detecting glaucoma based on a clinical examination had reasonably high post-test probabilities and the ability of the VTs in glaucoma detection had improved with access to technology additives such as NMFP and FDT. However, the post-test probabilities were having moderate effects of glaucoma being positive when combined with FDT or NMFP.

In a situation where diagnosing glaucoma in the community presents a significant challenge, this study suggests that a VT can be trained to detect glaucoma using clinical methods and that their performance can be enhanced if technology additives are available within a vision centre. Future studies can be considered comparing the glaucoma related findings from the OCT (anterior and posterior) as compared to the clinical glaucoma diagnosis and grading the stages of glaucomatous damage based on the severity of functional damage on

SAP.

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Chapter 7: Conclusion

7.1 Introduction:

The rapid growth in the aged population highlights the need to develop eye care systems that will address the prevalence of chronic posterior segment pathologies by establishing early detection procedures, treatment strategies, rehabilitation and support services. Such activities require adequate human resources and infrastructure to be present at a local level.[204] Glaucoma has become one of the major ocular morbidities, where half of the cases remain undetected either due to the lack of eye care services, or because insufficient numbers of trained personnel are available to deliver effective eye care. If the intention is to reduce the prevalence rates of glaucoma globally [102], trained eye care personnel, with good diagnostic accuracy, along with appropriate infrastructure are required, to detect those with disease at the community level.

In order to address the eye care needs in rural and remote populations, L V

Prasad Eye Institute has introduced a bottom-up approach by introducing vision technicians in vision centres at a community level.[27, 128] These individuals are trained intensively, for a year, under the supervision of experienced optometrists at tertiary centres. With this background, the evidence is that they are competent enough to be the providers of primary eye care within remote and rural populations, where access to tertiary centres is limited or impossible.

By building on this platform and providing VTs with additional training in posterior segment examination, the hypothesis was that they would then be able to effectively detect glaucoma. The advantage of this situation would be that referrals of patients with glaucoma to the secondary centres could be 150

increased, over and above what is possible using only specialist ophthalmologists The effectiveness of this conjecture was evaluated based on the clinical abilities of the vision technicians in identifying cases of the disease and looking to see how this changed with the addition of tests like NMFP and

FDT..

Previous studies[167] [168] [152] which used NMFP and FDT alone as screening tools to detect glaucoma have reported satisfactory results. As the vision technicians are not allowed to dilate the patient’s pupils at a vision centre, they use direct ophthalmoscopy to examine the fundus. The results presented in this thesis suggest that the viewing opportunity provided by nonmydriatic fundus pictures helps VTs to make a more accurate diagnosis than is available from direct ophthalmoscopy alone. Adding FDT to provide information on the visual fields is a further benefit that helps VTs make a correct decision of the disease.

As it is known that glaucoma detection cannot be achieved through a single test it was hypothesized that a combination of tests would be helpful. Hence, the vision technicians were trained to detect glaucoma both clinically and in combination with FDT and NMFP.

Though, the use of advanced technology helps in early detection of these changes, stereo-photography remains the gold standard[205] and hence in this study the final diagnosis was also in consideration of the stereo fundus examination using a slit lamp biomicroscope for the posterior segment by the study optometrist.

Glaucoma is a potentially sight threatening condition which leads to irreversible blindness. Its high prevalence around the world leads to significant economic 151

effects in many countries. Most rural communities in the developing world suffer visual impairment due to a lack of eye care services and many individuals simply ignore the effects of reduced vision. [23-25]. Thus, there is a pressing need for strategies that will promote early detection and these must be implemented, starting from the community level.

Studies on early detection have been conducted to report the prevalence existing globally. In conducting such community based screening and population based studies, many individuals identified with disease positive receive further referral for treatment and management. This seems to be more beneficial in remote and rural communities where poor eye care services are offered. In regard to this, the question of availability of adequate eye care personnel for all the rural communities arises. L V Prasad eye institutes pyramidal eye health delivery model is designed to provide equitable eye care services without compromising on quality. Keeping this model in view optometrists were introduced at the base of the pyramid with some emphasis on glaucoma detection by VTs clinically and with additive technologies.

7.2 Study findings:

Early detection helps in monitoring the disease progression and functional vision loss. A high level of agreement was found between the glaucoma specialist and trained optometrist in gonioscopy and optic disc assessments suggesting that the study optometrists can appropriately detect glaucoma using these indicators. 152

In situations where glaucoma specialist ophthalmologists are desirable, but unavailable for whatever reason, it is proposed, therefore, that it would be reasonable to utilize optometrists to facilitate the screening and diagnosis of glaucoma, provided that they have been suitably trained and have access to the appropriate equipment. For successful use of optometrists in delivering eye care between any levels of the LVPEI eye health pyramidal model as part of a shared care, the most important prerequisite is the accuracy of clinical measurements. The current study shows that high levels of diagnostic accuracy, comparable to those of a specialist ophthalmologist, can be achieved by suitably trained and experienced optometrists.

Diagnostic accuracy parameters in clinical, FDT and NMFP both individually and in combinations have shown similar, to marginally higher values, when only one eye of each subject was included in the analysis. Our results indicate that a

VTs glaucoma detection rates fairly improved with clinical evaluation alone and with further improved abilities when added with technological support such as

FDT in a more generalised manner and NMFP in a more disease specific manner.

Considering the devastating nature of the angle closure glaucoma, an assessment of peripheral anterior chamber angle with slit lamp and gonioscopy was performed as was also recommended in the literature and the same is supported in our results.[199]

No previous study has reported the VTs abilities to identify specifically for conditions like glaucoma and this study was designed based on the existing performance shortfalls of the eye care delivery system. 153

In conclusion, it is recommended that a careful clinical evaluation by a vision technician, trained in glaucoma diagnostic methods, combined with technology additives, FDT to be more general or a NMFP to be disease specific, can be productive at a community level. Media opacities, experience of the operator and patient cooperation play an important role in acquiring good quality photographs.

Recruitment, in rural areas, of personnel with the potential to become skilled in eye health delivery, and their subsequent retention, is often challenging.

However, use of these 1 year trained VTs appears to offer a viable means of combating blindness and visual impairment starting from the community level where hundreds of millions are in need of such high-quality services.

Strengths of the study:

1. A sample size of 3833 in a unique set up of a clinic based in the

community level which helps provide a case finding opportunity unlike a

screening program. Lieberman et al, had recommended a similar set up

for glaucoma detection.[199]

2. The proposed set up works well in both low and high resource areas

3. Minimal training period required for a VT to get trained in clinical and

diagnostic evaluations. Where there is no literature on the time required

for this level of training.

4. As far as could be ascertained, this is the first study to report the usage

of monoscopic NMFP and an optometrist as a reference standard for the

diagnosis of glaucoma in a community based set up. 154

5. Hands on experience in glaucoma detection for optometrists under

supervision of glaucoma specialists are expected to be more beneficial

than didactic lectures.[191]

Weakness of the study:

1. The set up demands an appropriate clinical acumen in the form of the

study optometrist or a glaucoma specialist ophthalmologist to increase

the usefulness of the model.

2. The increase in the diagnostic ability of VTs in glaucoma detection with

such a minimal training period could have ‘targeted effect of intervention.

3. A lack of detection of secondary glaucoma’s will inevitably reduce the

absolute effectiveness of the VT cadre

7.3 Limitations:

One limitation of the current study was that, due to logistical reasons it was not possible to assess the agreement among the three glaucoma specialists or the two study optometrists as the assumption is that there exists substantial agreement which could not be formally verified. Due to technical reasons, FDT was not done for all the study participants and hence there was a compromise in sample size in FDT alone or in screening paradigms involving a combination with FDT. Another limitation of the study is that, in order to extrapolate the results a new VT was selected for every 500 subjects which might result in less number of glaucoma cases in each group as compared to others which in turn 155

have an effect on the diagnostic accuracy parameters for VTs. However, to overcome this mean diagnostic abilities are reported.

Motivation levels of individual VTs could also be the reason for differences in their ability to detect glaucoma either clinically or based on the FDT reports or

NMFPs. An interesting finding to correlate with their motivational levels is, VTs who had good diagnostic accuracies were still present in the LVPEI system aspiring to join the optometry cadre and those with poor diagnostic accuracies were all found to be leaving the system which can be considered a problem to overcome in future. However, this may not be sufficient enough to draw conclusion on that aspect.

The results of this study could have a limited extrapolation and would be applicable only to those VTs trained at the LVPEI.

7.4 Future research:

From the results of this study, future plans are to develop a random controlled trial to see the impact of the vision centre models with clinical alone and with clinical+NMFP in about 4 vision centres each with examinations carried out by the vision technician. The outcomes of clinical and clinical+NMFP compared between the test and control is to determine the utility or effectiveness of clinical+NMFP in glaucoma detection and to demonstrate its applicability in the community. The expected outcome of such a model would be validating the clinical+NMFP model considering the higher diagnostic yield, which, in a broader perspective, would help identify those becoming visually impaired or blind at an early stage. Based on such an RCT, the value of adding a 156

technology such as NMFP can be understood in terms of increased capture of glaucoma cases and the cost vs benefit of such an approach subsequently calculated.This model gives an understanding of the impact of a set up with

NMFP along with clinical examination in a community based set up.

157

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Glossary

1. Accuracy: The actual value of measurement

2. Categorical data: Statistical data segregated as a group or a category

(ex: Gender)

3. Confidence Intervals: A range of values given where the specified value

falls within the range.

4. Drainage angle: An angle through which the aqueous humor in the eye

drains

5. Glaucoma: An insidious sight threatening disease which affects the optic

nerve and causes irreversible vision loss

6. Gold standard: An accurate reliable reference for comparison

7. Haemorrhage: bleeding due to ruptured blood vessels

8. Impairment: (in this context) – visual function damage or visual loss; can

be caused due to ocular pathologies

9. Incidence: The rate of frequency of a disease

10. Kappa: A statistic term (usually termed Cohen’s kappa coefficient) which

measures the agreement for categorical items

11. Perimeter: (in this context) – relates to extent of boundary of vision

(imaginary to a closed geometrical figure) 168

12. Referrals: (in this context) - Abnormal directed to a specialist

(ophthalmologist) for further evaluation by the vision technicians

13. Refractive error: An error in the refractive status of the eye where the

light is usually not focussed on retina causing blurred vision.

14. Screening: A procedure designed and conducted in a population to

identify abnormal individuals without any symptoms

15. Vision centre: Primary eye care units developed for eye care delivery for

the remote and rural communities in villages.

16. Visual acuity: Measure of sharpness in vision (can be either distance or

near) usually placing target at 6 meters or 20 feet for distance and 40cms

at near

17. Visual field: The extent of the surrounding field of vision which a person

can perceive (includes peripheral and central)

169