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Age related macular degeneration in Latinos: risk factors and impact on quality of life
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Age related macular degeneration in Latinos: risk factors and impact on quality of life
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AGE RELATED MACULAR DEGENERATION IN LATINOS:
RISK FACTORS AND IMPACT ON QUALITY OF LIFE
by
Farzana Choudhury
A Dissertation Presented to the
FACULTY OF THE USC GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(EPIDEMIOLOGY)
December 2012
Copyright 2012 Farzana Choudhury
ii
Dedication
Dedicated to my parents
iii
Acknowledgements
I would like to express my utmost gratitude to Dr. Stanley P. Azen and Dr. Roberta
McKean-Cowdin for their inspiration and guidance throughout my thesis experience. I
am extremely grateful to Dr. Rohit Varma for allowing me to work on this wonderful
data and guiding me with his valuable knowledge. I am grateful to Drs, W. James
Gauderman, and Michael B. Nichol for their guidance and support in preparing the thesis.
I am also thankful to my friends and colleagues Mina Torres, Towhid, Roksana and Talat
for their additional suggestions and encouragement. Special thanks go to my husband, my
children and my family for their persistent and generous support.
iv
Table of Contents
Dedication ........................................................................................................................... ii
Acknowledgements ............................................................................................................ iii
List of Tables ..................................................................................................................... vi
List of Figures .................................................................................................................. viii
Abstract .............................................................................................................................. ix
Chapter 1: Background and Overview ................................................................................ 1
1.1 Overview of Ocular Anatomy and Physiology ......................................................... 1
1.2 Normal Macula and Macular Degeneration .............................................................. 3
1.3 Pathogenesis of AMD ............................................................................................... 4
1.4 Classification of Age Related Macular Degeneration (AMD) ................................. 7
1.5 Severity of AMD....................................................................................................... 9
1.6 Risk Factors of AMD .............................................................................................. 10
1.7 AMD and Health Related Quality of Life ............................................................... 13
1.8 Latinos and the Los Angeles Latino Eye Study (LALES) ...................................... 14
1.9: Primary Aims ......................................................................................................... 16
Chapter 1 References .................................................................................................... 17
Chapter 2: Risk Factors for Four-Year Incidence and Progression of Age Related
Macular Degeneration: The Los Angeles Latino Eye Study ............................................ 27
2.1 Abstract ................................................................................................................... 27
2.2 Introduction ............................................................................................................. 29
2.3 Methods................................................................................................................... 31
2.4 Results ..................................................................................................................... 35
2.5 Discussion ............................................................................................................... 46
Chapter 2 References .................................................................................................... 53
Chapter 3: Age-Related Macular Degeneration and Health Related Quality of Life
in Latinos: The Los Angeles Latino Eye Study (LALES) ................................................ 61
3.1 Abstract ................................................................................................................... 61
3.2 Introduction ............................................................................................................. 64
3.3 Methods................................................................................................................... 65
3.4 Results ..................................................................................................................... 74
3.5 Discussion ............................................................................................................... 85
Chapter 3 References .................................................................................................... 91
v
Chapter 4: Longitudinal Changes in Age Related Macular Degeneration and
Health Related Quality of Life in Latinos......................................................................... 95
4.1 Introduction ............................................................................................................. 95
4.2 Methods................................................................................................................... 96
4.3 Results ................................................................................................................... 103
4.5 Discussion ............................................................................................................. 120
Chapter 4 References .................................................................................................. 126
Chapter 5: Summary and Future Research Directions .................................................... 136
5.1 Summary ............................................................................................................... 136
5.2 Conclusion and Implications................................................................................. 137
5.3 Future Research Directions ................................................................................... 138
Chapter 5 References .................................................................................................. 142
Bibliography ................................................................................................................... 145
Appendices ...................................................................................................................... 171
vi
List of Tables
Table 1.1. The WARMGS-BDES classification of AMD severity .................................... 9
Table 2.1 Comparison of Participants and Non-participants in the 4 year follow-up ...... 37
Table 2.2: Distribution of Baseline Sociodemographic, Clinical &
Ocular characteristics by AMD incidence status .............................................................. 38
Table 2.3: Independent Risk Factors of Incidence and Progression of
AMD ................................................................................................................................. 41
Supplemental Table 2.1: Univariate Associations of Socio-demographic
& behavioral Factors with Incidence and Progression of AMD ....................................... 58
Supplemental Table 2.2: Univariate Associations of Clinical Factors with
Incidence and Progression of AMD .................................................................................. 59
Supplemental Table 2.3: Univariate Associations of Ocular Risk Factors
with Incidence and Progression of AMD.......................................................................... 60
Table 3.1: Sociodemographic and Clinical characteristics stratified by
presence or absence of AMD in participants in the Los Angeles
Latino Eye Study.............................................................................................................. 75
Table 3.2: Mean health related quality of life scores and the effect size
(ES) stratified by severity of AMD in participants in the Los Angeles
Latino Eye Study............................................................................................................... 76
Table 3.3: Mean health related quality of life scores and the effect size
(ES) stratified by drusen type in participants in the Los Angeles
Latino Eye Study............................................................................................................... 79
Table 3.4: Mean change in health related quality of life scores and effect
size (ES) stratified by pigmentary changes in participants in the Los Angeles
Latino Eye ......................................................................................................................... 80
Table 3.5: Mean change in health related quality of life scores and effect
size (ES) stratified by type of advanced AMD in participants in the Los Angeles
Latino Eye Study............................................................................................................... 82
Table 4.1: Sociodemographic and Clinical characteristics stratified by
Progression of AMD ...................................................................................................... 106
vii
Table 4.2: Mean changes and proportion of people with MIC in HRQoL
by status of AMD progression ........................................................................................ 108
Table 4.3: Mean changes in QoL by status of stratified by four levels
of AMD Longitudinal change status ............................................................................... 109
Table 4.4: Mean changes and proportion of people with MIC in HRQoL by
status of AMD progression (without any other eye disease) .......................................... 111
Table 4.5: Proportion of people with significant changes in NEI-VFQ-25 scores
by status of AMD progression as determined by the reliable change
index (RCI). ................................................................................................................... 112
Table 4.6: Proportion of people with significant changes in NEI-VFQ-25 scores
by status of AMD progression as determined by the reliable change index
(RCI) in those without any other eye disease. ................................................................ 113
Table 4.7: Mean changes and proportion of people with MIC in HRQoL by
change in severity of Soft Indistinct drusen (SID).......................................................... 115
Table 4.8: Mean changes and proportion of people with MIC in HRQoL by
change in severity of Increased Retinal Pigmentation (IRP) ......................................... 116
Table 4.9: Mean changes and proportion of people MIC in HRQoL by
change in severity of Depigmentation of retinal pigmentary epithelium (RPE) ........... 117
Supplemental table 4.1: Definitions of 4 year changes (Progression and Incidence)
of Age-related Macular Degeneration (AMD) in the Los Angeles Latino Eye
Study ............................................................................................................................... 131
Supplemental Table 4.2: Mean changes in QoL by status of new AMD incidence ....... 132
Supplemental Table 4.3: Mean changes in QoL by new incidence of Soft
Indistinct drusen (SI)...................................................................................................... 133
Supplemental Table 4.4: Mean changes in QoL by new incidence of increased retinal
pigment (IPR).................................................................................................................. 134
Supplemental Table 4.5: Mean changes in QoL by new incidence of
Depigmentation of retinal pigmentary epithelium (RPE) ............................................... 135
viii
List of Figures
Figure 1.1: Normal anatomy of human eye ........................................................................ 2
Figure 1.2 : Structure of retina ............................................................................................ 2
Figure 1.3: Macula .............................................................................................................. 3
Figure 1.4: Conceptual framework of AMD pathogenesis ................................................. 5
Figure 2.1: Flow-chart of analysis cohort 1 ...................................................................... 36
Figure 2.2: Pulse pressure & predicted 4-year incidence of early AMD .......................... 42
Figure 2.3: Age & predicted 4-year incidence of early AMD .......................................... 42
Figure 2.4: Pulse pressure & predicted 4-year incidence of soft indistinct drusen ........... 43
Figure 2.5: Age & predicted 4-year incidence of soft indistinct drusen ........................... 43
Figure 2.6: Age and predicted 4-year progression of AMD ............................................. 45
Figure 3.1: Flow-chart of analysis cohort 2 ...................................................................... 73
Figure 3.2: AMD severity and composite NEI-VFQ score (in worse eye) ...................... 83
Figure 3.3: AMD severity and composite NEI-VFQ score (in better eye) ....................... 83
Figure 3.4: Bilateral AMD severity and composite NEI-VFQ score ................................ 84
Figure 3.5: Comparison of generic and vision-specific HRQoL ...................................... 85
Figure 4.1. Flow-chart of analysis cohort 3 .................................................................... 105
Figure 4.2: Changes in bilateral AMD severity and Changes in
Composite NEI-VFQ score ............................................................................................. 118
Figure 4.3: Changes in bilateral AMD severity and Changes in
driving difficulty score .................................................................................................... 119
Figure 4.4: Changes in bilateral AMD severity and Changes in
general vision score......................................................................................................... 119
Figure 4.5: Changes in bilateral AMD severity and Changes in
social functioning score .................................................................................................. 120
ix
Abstract
Age related macular degeneration (AMD) is a progressive, potentially irreversible
disorder of the macular region of retina that can cause severe loss of central vision in the
late stages. Despite the recent advances in the treatment of AMD, it remains the leading
cause of blindness in people over the age of 60 in the Western world with significant
impact on their health related quality of life (HRQoL). The global prevalence of AMD
remains largely unknown and the full impact of this debilitating disease has not been
fully characterized.
The relationship between factors influencing incidence and progression of AMD in
Latinos and the impact of AMD on HRQoL in Latinos remain largely unexplored.
Therefore, to address these issues, I have used the baseline and 4 years cumulative
incidence data from the Los Angeles Latino Eye Study (LALES), a population based
cohort study of eye disease in Latinos to investigate predictors of AMD incidence and
progression and the impact of AMD on HRQoL. In the first chapter I gave an overview
of AMD and my primary aims. I discussed briefly about the retina, macula, the
definition, brief pathogenesis, grading scheme and classification of AMD. Then, I
discussed briefly about what is known about the risk factors of AMD and its impact on
HRQoL. Finally I describe the study population and enumerate the primary aims.
In my first paper (chapter 2) I evaluated the risk factors associated with 4 year
incidence and progression of AMD. The risk factors were selected based on literature
review and expert clinical opinion. Stepwise logistic regression was used to develop
parsimonious multivariable predictive models for each AMD end- points. The results
from these analyses revealed that older age and higher pulse pressure were independently
x
associated with the incidence of any AMD and different early AMD lesions in this group
of Latinos. Additionally, presence of diabetes mellitus was independently associated with
increased retinal pigment and male gender was associated with retinal pigment epithelial
depigmentation. Older age and current smoking were independently associated with
progression of AMD. Some of the findings were similar to those reported by studies in
non-Hispanic whites. The interesting and unique finding in this paper was the association
of pulse pressure with incidence of some early maculopathies that were not previously
reported in Caucasians. Given the equivocal results for risk factors of AMD in other
population based studies and the paucity of data in Latinos, these finding will aide in our
understanding of AMD in this unique ethnic group.
The short term and long term impact of AMD on quality of life in Latinos has not
been investigated to a great extent. Given the unique socio-demographic, ethnic and
cultural characteristics of Latinos it is important to estimate the impact of the patient
reported outcomes in this unique group of people. Therefore, for my second paper I
investigated the association of prevalent AMD and HRQoL, described in the third chapter.
Two validated instruments of HRQoL were used to assess general HRQoL and vision
specific HRQoL. In this analysis, I assessed and compared covariate-adjusted mean QOL
scores between participants without any AMD and participants with different end-point of
early and late Maculopathies by using analysis of covariance (ANCOVA). I also
calculated Effect sizes (ES) to quantify the impact of HRQoL. AMD is associated with a
measurably lower in HRQOL, even for lesions defined as early AMD. There was also
evidence of a measurable loss in health related quality of life is associated with lesions
defined as early AMD.
xi
Results from my second paper on cross-sectional data lead to conceptualize and
design the third paper (chapter 4). In this paper I further evaluate the impact of AMD on
HRQoL by investigating the association of intra-individual changes in AMD status with
changes in HRQoL status over a 4-year period. For this analysis I looked at the mean
changes in QoL scores after adjusting for possible confounders. I applied two methods of
analysis to focus on minimally important clinical change and significant individual
change. I followed an anchor based approach to define and test a threshold of clinically
meaningful change. To further evaluate the impact of AMD on QoL at the individual
level, we calculated reliable change index. Results from these analyses confirm a number
of the results from the cross-sectional analysis. Overall the results suggest that people with
clinically meaningful progression of AMD have diminished health-related quality of life.
Even progression to early AMD can have measurable impact independent of other ocular
condition. There were also evidence of significant changes with progression of early AMD
lesions like soft drusen and pigmentary changes.
To further our knowledge of AMD in Latinos there are many lines of investigation
could be undertaken to extend present work. In chapter 5, I summarized our main
findings and briefly discussed about these potential future research questions. I believe,
results from these studies will help us identify factors that can increase the risk of AMD
incidence and further progression in Latinos and will help us to understand the adverse
impact of AMD on the quality of life of a sufferer. Further studies will help in
developing evidence based screening and intervention programs to reduce incidence and
retard the progression of AMD to minimize the negative impact on quality of life.
1
Chapter 1: Background and Overview
Age related macular degeneration is an ocular disease in people, 50 or older,
that involves progressive damage in different layers of retina due to age-related oxidative
injury. AMD is considered to be the leading cause of visual disability and blindness in the
western hemisphere and third major cause of blindness globally (Zarbin 2004; de Jong
2006; Wong, Chakravarthy et al. 2008). With a growing number of aging populations in
these countries AMD is expected to double in the coming decades and continue to be an
increasing public health problem with high social and financial cost (Zarbin 2004).
A brief overview of the normal anatomy of the eye, the pathophysiology of the
disease, and the characteristics used in the classification of the severity of AMD are
described below.
1.1 Overview of Ocular Anatomy and Physiology
The eye consists of a numbers of structures in the anterior and posterior pole
(Clemente 1997; Junquera L 1998; Lim 2008). The main structures include: cornea,
conjunctiva, lens, iris, pupil, aqueous humor, vitreous humor and retina.
The Retina: This is the light-sensitive tissue lining the inner surface of the eye. Light
striking the retina initiates a cascade of chemical and electrical events that ultimately
trigger nerve impulses. These are sent to various visual centers of the brain through the
fibers of the optic nerve. The retina and the optic nerve originate as outgrowths of the
developing brain, so the retina is considered part of the central nervous system (CNS). It
is the only part of the CNS that can be visualized non-invasively (Clemente 1997;
Junquera L 1998; Lim 2008).
2
Figure 1.1: Normal anatomy of human eye
Figure 1.2: Structure of retina
The retina is a complex, layered structure with several layers of neurons
interconnected by synapses (Fig 1.2). The only neurons that are directly sensitive to light
are the photoreceptor cells. These are mainly of two types: the rods and cones. Rods
function mainly in dim light and provide black-and-white vision, while cones support
3
daytime vision and the perception of color. A third, much rarer type of photoreceptor, the
photosensitive ganglion cell, is important for reflexive responses to bright daylight
(Junquera L 1998).
1.2 Normal Macula and Macular Degeneration
The macula is a highly pigmented area near the center of the retina of the human
eye that is responsible for central, high resolution vision (de Jong 2006; Lim 2008). It has
a diameter of around 5 mm and is often histologically defined as having two or more
layers of ganglion cells. With aging there is inevitable yet normal cumulative oxidative
injury resulting in biological changes in the macula (Zarbin 2004).
Figure 1.3: Macula
In some people the oxidative stress results in additional pathological changes in
retinal pigment epithelial (RPE), retina Bruch’s membrane and chorio-capillary in the
macula leading to Age-related Macular degeneration (AMD). This is a progressive
4
disorder of macular area, most often clinically apparent after 50 years of age. In the late
stages central vision can be severely compromised leading to considerable impact in
health related quality of life.
1.3 Pathogenesis of AMD
AMD is a progressive disorder of the macular region that becomes more clinically
apparent with age. Causes, risk factors and pathogenesis of AMD remain a focus of
investigation and a complex pathway is postulated (Zarbin 2004; de Jong 2006). One of
the most important steps in the pathogenesis for AMD appears to be oxidative stress.
Although AMD involves changes related to aging, there are additional pathological
changes involved (Zarbin 2004).
Oxidative stress can result in inflammation and different other pathological
changes, like changes in pigmentation, accumulations of extracellular material, retinal
detachment and new vessels formation. These pathological changes in the AMD lesions
occur in various structures of the in the posterior region of the eye including the retinal
pigment epithelial (RPE), Bruch’s membrane or chorio-capillary in the macula (de Jong
2006; Lim 2008).
Early lesions of AMD characterized by presence of soft indistinct drusen or any
drusen with presence of pigmentary changes in RPE and located between the epithelial
and basement membrane layers (Lim 2008). Drusen represents the earliest clinical
finding in AMD (Zarbin 2004). These appear as yellowish white spots between the RPE
and Bruch’s membrane.
5
Figure 1.4: Conceptual framework of AMD pathogenesis
Drusen varies in type and size. Hard drusens are mainly composed of protein,
compliment components and lipids. Soft drusens are mainly of deposits of debris and
extracellular matrix (Zarbin 2004; Lim 2008). Both of these are further classified into
distinct and indistinct type based on the outline of the borders. Characteristics of the
drusen influence AMD progression (Lim 2008).
There are 2 types of retinal pigmentary changes: increased retinal pigmentation
(IRP) and RPE depigmentation. In IRP there is deposition of clumps of gray or black
6
pigment beneath the retina resulting in hyperplasia and hypertrophy of RPE cells (Davis,
Gangnon et al. 2005). In RPE depigmentation there is ill defined focal areas of atrophy of
RPE cells resulting in partial depigmentation. Presence of either any soft indistinct
/reticular drusen or drusen of any size and type with a pigmentary abnormality is
considered to be early AMD in most well-known epidemiologic studies (Klein, Moss et
al. 1989; Klein, Davis et al. 1991; Mitchell, Smith et al. 1995; Klein, Klein et al. 1997;
Mitchell and Foran 2005; Leske, Wu et al. 2006).
As the disease process progresses, the early form can develop into two types of
advanced ARM: (1) Geographic Atrophy involving atrophy of the RPE cells in the
macula or (2) Exudative ARM, involving the development of choroidal
neovascularization in the sub-RPE and sub-retinal spaces through breaks in Bruchs
membrane. Geographical atrophy (GA) is also known as dry AMD which can be
identified by a sharply demarcated zone of partial or complete depigmentation of RPE.
The underlying processes involved in the pathogenesis possibly involve atrophy of the
RPE cells, thickening of Bruch’s membrane and decrease in choriocapillary density. The
hallmark in exudative AMD, on the other hand, is choroidal neo-vascularization (CNV)
which represents new blood vessel formation from choroid into retina.(Lim 2008) The
initial neo-vascularization can be followed by serous or hemorrhagic detachment of RPE
and overlying retina (Lim 2008). These changes occur in about 10-15 % of the AMD
affected population resulting in severe loss of central vision and significantly affecting
their quality of life. Whether the 2 forms constitute two stages of the same disease
process or two distinct diseases is still a matter of debate (de Jong 2006). However, a
number of investigators believe these are the same disease due to the high concurrent
7
involvement of CNV and GA in the same patients and the increasing risk of CNV in
patients with GA (Zarbin 2004; de Jong 2006).
1.4 Classification of Age Related Macular Degeneration (AMD)
AMD is diagnosed and classified by different scales and schemes (Klein, Moss et
al. 1989; Klein, Davis et al. 1991; Davis, Gangnon et al. 2005). The modified Wisconsin
age-related maculopathy system (WARMGS), also known as Beaver Dam steps,
describes AMD in six semi-quantitative steps or stages (Appendix A) (Klein, Davis et al.
1991). More recently, the Age-Related Eye Disease Study group (AREDS) developed a
scale based on review of fundus photographs to describe AMD severity (Davis, Gangnon
et al. 2005).
Despite these newer classifications AMD is still widely classified and studied as
early and late AMD in major Epidemiological studies. Moreover, different Maculopathies
are also studied as separate disease end-point due to the complexity and possible
differences in pathogenesis (Klein, Klein et al. 1993; Klein, Rowland et al. 1995;
Clemente 1997; Klein, Klein et al. 1997; Mitchell, Wang et al. 2002; Mitchell and Foran
2005). The diagnosis of AMD is primarily based on exclusion and the operational
definitions of early and late AMD used in LALES and other major ocular epidemiologic
studies (Klein, Davis et al. 1991).
Late AMD
If any of the following are true, then late stage ARM is present:
1. Geographic Atrophy is present
8
2. Pigment epithelial detachment or age-related retinal detachment (PED-RD) is
present
3. Subretinal Hemorrhage is present
4. Subretinal Scar (subretinal fibrous scar) is present
5. Laser treatment for exudative ARM (ARM_Rx) is present
Advanced AMD is further classified as:
a) Atrophic AMD: Geographic Atrophy is present in absence of other late lesions,
and
b) Exudative AMD: At least one of the exudative lesions (Pigment epithelial
detachment or age-related retinal detachment, Subretinal Hemorrhage, Subretinal
Scar, or AMD treatment) is present with or without presence of GA.
Early AMD:
If Late ARM is not present and any of the following conditions are true:
1. Any drusen is present with increased retinal pigmentation.
2. Any drusen is present with RPE Depigmentation.
3. Soft Indistinct Drusen is present.
No AMD:
No AMD is defined as absence of late and early AMD when drusen size is gradable.
9
Table 1.1. The WARMGS-BDES classification of AMD severity
1.5 Severity of AMD
Table 1.1 summarizes the levels of AMD severity according WARMGS-BDES
classification. The differences between this and AREDS scales are driven primarily by
drusen size. WARMGS scale looks not only at drusen area and pigmentary abnormalities,
but also drusen size when assigning a severity score.
The differences between this and AREDS scales are driven primarily by drusen
size. WARMGS scale looks not only at drusen area and pigmentary abnormalities, but
also drusen size when assigning a severity score. The AREDS scale doesn't take drusen
size into account, thus it is conceivable that an eye could get a severe AREDS score with
a large drusen area, but be scored quite low in the BD scale because the largest drusen
BD
Level
Description
10 Hard drusen or small soft drusen (< 125 microns in diameter) only, regardless of area of
involvement, and no pigmentary abnormality (increased retinal pigment or RPE
depigmentation) present.
20 Hard drusen or small soft drusen (< 125 microns in diameter), regardless of area of
involvement, with any pigmentary abnormality (increased retinal pigment present and/or
RPE depigmentation) present,
OR
Soft drusen ( > 125 microns in diameter) with drusen area < 196,350 square microns
(equivalent to a circle with a diameter of 500 microns) and no pigmentary abnormalities
30 Soft drusen ( > 125 microns in diameter) with drusen area < 196,350 square microns
(equivalent to a circle with a diameter of 500 microns) with any pigmentary abnormality
(increased retinal pigment present and/or RPE depigmentation) present,
OR
Soft drusen ( > 125 microns in diameter) with drusen area > 196, 350 square microns
(equivalent to a circle with a diameter of 500 microns) with or without increased retinal
pigment but no RPE depigmentation.
40 Soft drusen ( > 125 microns in diameter) with drusen area > 196,350 square microns
(equivalent to a circle with a diameter of 500 microns) and RPE depigmentation present ,
with or without increased retinal pigment.
50 Pure geographic atrophy in the absence of exudative macular degeneration.
60 Exudative macular degeneration with or without geographic atrophy present.
10
size is <63 microns. While this may seem to make the scales quite different, both scales
are found to be equally predictive as to the risk of progressing to late AMD.
1.6 Risk Factors of AMD
AMD is considered a multi-factorial disease where different causative factors may
play role in damaging macula, all resulting in common clinical manifestations we
recognize collectively as AMD (Lim 2008). The causes and risk factors of this disorder
remain under investigation and few factors have consistently been associated with AMD
across studies (Smith, Assink et al. 2001). A number of factors have been investigated as
possible risk factors. Age remains the most consistent finding across most
epidemiological studies. Among the modifiable factors only smoking has been found to
be associated with AMD in multiple epidemiologic studies (Smith, Assink et al. 2001).
Other studies have found some association with socio-demographic risk factors including
gender, European ancestry, socioeconomic status, hypertension, heredity and a positive
family history, Ocular factors like iris color, cataract surgery, macular pigment optical
density, cup to disc ratio and refractive error. Environmental and dietary factors such as
smoking, sun exposure, antioxidants, zinc were also found to be associated with AMD
(Klein, Klein et al. 1993; Klein, Rowland et al. 1995; Klein, Klein et al. 1998; Smith,
Assink et al. 2001; Mitchell, Wang et al. 2002; Mitchell, Wang et al. 2002; Klein, Klein
et al. 2003; Fraser-Bell, Donofrio et al. 2005; Fraser-Bell, Wu et al. 2006; Leske, Wu et
al. 2006; Fraser-Bell, Wu et al. 2008; Lim 2008). Other systemic factors found to be
associated with AMD are: hypertension, higher pulse pressure, serum lipid level,
diabetes, body mass index (BMI) and early menopause in women. These factors still
11
remain inconsistent and hence, inconclusive as definite risk factors (Klein, Moss et al.
1989; Klein, Rowland et al. 1995; Klein, Wang et al. 1995; de Jong 2006; Lim 2008).
The majority of the risk factors were found to be associated with late stages of
AMD, GA or neovascular AMD, the advanced forms frequently results in severe vision
loss and blindness (Klein, Klein et al. 1993; Klein, Rowland et al. 1995; Klein, Klein et
al. 1998; Smith, Assink et al. 2001; Mitchell, Wang et al. 2002; Mitchell, Wang et al.
2002; Klein, Klein et al. 2003; Fraser-Bell, Donofrio et al. 2005; Fraser-Bell, Wu et al.
2006; Leske, Wu et al. 2006; Fraser-Bell, Wu et al. 2008; Lim 2008). While early AMD
does not often affect vision adversely, individuals with specific types of early AMD, such
as individuals with large soft drusen or bilateral drusen, are more likely to progress to
advanced AMD (Klein, Wang et al. 1995; Mitchell, Smith et al. 1995; Klein, Klein et al.
1997; Mitchell, Wang et al. 2002; Klein, Klein et al. 2003; Leske, Wu et al. 2004; Leske,
Wu et al. 2006). Thus, in order to better understand progression, it is critical to
investigate the etiology underlying early AMD and the specific characteristics of early
and late AMD. This is crucial because AMD is a progressive, potentially irreversible
disease; despite the recent advances in treatment options, few medical or surgical
interventions has been shown to prevent the progression of AMD from the early stages to
vision threatening late maculopathy (Klein, Klein et al. 1998). At the late stages treatment
is appropriate for a small percentage of people if they are diagnosed with a particular type
of wet or neovascular AMD but for Geographical atrophy or dry AMD, very few
treatment prove to be promising enough (Mitchell and Bradley 2006).
Risk factor analysis for AMD is hindered by the relative infrequency of AMD in
most population based studies (Smith, Assink et al. 2001). So far there have been very
12
few large population based studies that could provide the proper sample size for robust
risk factors analysis. Moreover, the chronic nature of the disease makes the establishment
of risk factors for AMD challenging because of several methodological issues including:
long lead times between exposures and disease expression, potential recall bias when
interviewing cases about past exposures, and survivor biases related to investigating a
disease that impacts older individuals (De Jong 2004; Klein, Knudtson et al. 2008; Lim
2008). One of the major challenges in evaluating risk factors for AMD is that there is no
universally accepted definition and classifications of AMD. This problem is further
compounded by usage of different grading by different studies making direct comparison
of the results very difficult (Smith, Assink et al. 2001; De Jong 2004; Lim 2008).
So far, most population-based longitudinal studies of eye disease have been
conducted on non-Hispanic whites, which include the Beaver Dam Eye Study in
Wisconsin, U.S. (Klein, Klein et al. 1997) and the Blue Mountains Eye Study in Australia
(Mitchell, Wang et al. 2002). Other studies such as the Barbados Incidence Study of Eye
Disease (Leske, Wu et al. 2004) have focused on a population of African origin.
Although these studies have presented data on the risk factors of incidence and
progression of age-related macular degeneration (AMD), it remains to be determined if it
is appropriate to generalize the findings across different racial and ethnic populations
especially since there is known difference in prevalence and incidence across ethnicities
(Klein, Rowland et al. 1995).
13
1.7 AMD and Health Related Quality of Life
A great deal of research is carried out to assess the quality of life (QoL) or heath
related quality of life (HRQoL) in patients with different diseases (Mitchell and Bradley
2006). The simplest definition is: “Quality of life is how good or bad you feel your life to
be” (Bradley, Todd et al. 1999; Mitchell and Bradley 2006). Implicit in this definition is
that QoL is a subjective measure. HRQoL is a patient reported outcome that measures an
individual’s perception of functioning and well being in the physical, mental and social
realms of life. The instruments and questions to measure QoL differ and remain a topic of
debate and new research (Bradley, Todd et al. 1999; Mitchell and Bradley 2006).
The National Eye Institute Visual Function Questionnaire (NEI-VFQ) was
designed to measure areas of vision-targeted, health-related functioning and well-being
that were identified as important by persons with eye disease. The NEI-VFQ was
constructed to evaluate the impact of visual disability on health-related quality of life
across several common eye conditions. This questionnaire consists of 25 targeted
questions representing 11 vision-related construct or domain and an additional single
item general health related question. The vision related constructs are: color vision, vision
related dependency, driving difficulty, distant vision, general vision, vision related mental
health, near vision, ocular pain, peripheral vision, vision related role function and vision
related social function. These 11 of the 12 scale scores (excluding the general health
rating question) were averaged to yield a composite score for NEI-VFQ-25 (Mangione,
Lee et al. 1998; Mangione, Lee et al. 2001). This instrument has been well validated in
people with AMD, including Latinos (Broman, Munoz et al. 2001; Lindblad and
Clemons 2005; Mitchell and Bradley 2006; Coleman, Yu et al. 2010).
14
Since macula is responsible for central, high acuity vision, any degeneration in
macula results in detrimental effect on central vision. Central vision plays a crucial role
in daily activities like driving, reading, walking as well as human interaction with
surrounding environment. Hence, central vision impairment associated with AMD can
significantly compromise health-related quality of life (HRQoL), qualitatively and
quantitatively. People with AMD may find performing even the most trivial tasks much
more challenging than people without the disease even at earlier stages of the disease.
Moreover, the lower visual functioning impacts mobility and even emotional status of the
patient (Mitchell and Bradley 2006).
The impact of AMD on HRQOL has been investigated in a number of studies,
mostly in Caucasians. While a number of studies have established the significant impact
of late AMD on HRQOL, the consensus on impact of early AMD and maculopathies
remain equivocal (Broman, Munoz et al. 2001; Mitchell and Bradley 2006; Brown and
Brown 2010; Coleman, Yu et al. 2010). Some studies suggest that ophthalmologists
underestimate patient quality of life associated with AMD, even up to 750%, more so at
the better end of the visual spectrum (Brown and Brown 2010). Since treatment options
are limited for the management of late AMD, the impact of earlier maculopathies may
aide informed decision by a clinician to start intervention earlier.
1.8 Latinos and the Los Angeles Latino Eye Study (LALES)
Latinos (Hispanics, Hispanic Americans, and Latino Americans) are individuals
who are born into or have descended from a Spanish-speaking community, regardless of
race. In the United States, Latinos are a heterogeneous group, with the majority being of
15
Mexican ancestry (66%) (Varma, Paz et al. 2004). Latinos represent the largest of
minority populations in the United States. According to a projection by U.S. Census
bureau (2004), 35.6 million people or 12.5% of the nation’s residents are Latino, and
this proportion is expected to increase to 20.1% by the year 2030. The Latino population
has unique demographic, socioeconomic, as well as ocular health characteristics that
influence the development of eye disease and the subsequent impact on quality of life
for the people of this ethnicity (Varma, Wu et al. 2006; McKean-Cowdin, Varma et al.
2007). Despite the fact that this is the largest growing population in USA, there is
paucity of ocular epidemiologic data on this population. The Los Angeles Latino Eye
Study (LALES) was designed to fill this void.
At baseline and follow-up, in-home interviews were conducted to obtain detailed
demographic, clinical and health care outcome measures(Varma, Paz et al. 2004).
Subsequent detailed eye examinations were performed in a standardized manner at the
LALES Local Eye Examination Center (Varma, Paz et al. 2004). Clinical examination
was also performed at baseline and follow-up. AMD was diagnosed from stereoscopic
fundus photography using the Age-Related Eye Disease Study (AREDS) grading system
as well as the modified Wisconsin Age-Related Maculopathy Grading System
(WARMGS).
LALES is currently the only population-based Latino eye study that has collected
longitudinal incidence data and one of the largest population based cohort studies on eye
in the world. The detailed and comprehensive LALES data from baseline and follow-up
data gives us a unique opportunity to assess risk factors of 4 year incidence and
16
progression of AMD and investigate the impact of AMD on health related quality of life in
the largest and fastest growing segment of United States population.
1.9: Primary Aims
In summary, the crucial yet complex relationship between incidence and progression
of AMD and different clinical and non clinical factors in Latinos as well as the impact of
AMD on HRQoL in Latinos remain largely unexplored. Therefore, we plan to utilize the
baseline and 4 years cumulative incidence data from the Los Angeles Latino Eye Study
(LALES) to address these issues and hence, our primary aims are:
1. Performing risk factor analyses by utilizing the 4 year incidence data from the
LALES:
2. To assess the cross-sectional association of prevalent AMD & HRQoL
3. To assess the association between changes of AMD status and changes in
HRQoL over a 4 year follow-up period
17
Chapter 1 References
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Origin. from . Accessed
November 6, 2007
Bradley, C., C. Todd, et al. (1999). The development of an individualized questionnaire
measure of perceived impact of diabetes on quality of life: the ADDQoL. Qual
Life Res 8(1-2): 79-91.
Broman, A. T., B. Munoz, et al. (2001). Psychometric properties of the 25-item NEI-
VFQ in a Hispanic population: Proyecto VER. Invest Ophthalmol Vis Sci 42(3):
606-613.
Brown, G. and M. M. Brown (2010). Let us wake the nation on the treatment for age-
related macular degeneration. Curr Opin Ophthalmol 21(3): 169-171.
Clemente, C. D. (1997). Regional Atlas of Human Body: Part VII : The Neck and Head,
Urban & Schwanberg.
Coleman, A. L., F. Yu, et al. (2010). Impact of age-related macular degeneration on
vision-specific quality of life: Follow-up from the 10-year and 15-year visits of
the Study of Osteoporotic Fractures. Am J Ophthalmol 150(5): 683-691.
Davis, M. D., R. E. Gangnon, et al. (2005). The Age-Related Eye Disease Study severity
scale for age-related macular degeneration: AREDS Report No. 17. Arch
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De Jong, P. T. (2004). Risk profiles for ageing macular disease. Ophthalmologica 218
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de Jong, P. T. (2006). Age-related macular degeneration. N Engl J Med 355(14): 1474-
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Fraser-Bell, S., J. Donofrio, et al. (2005). Sociodemographic factors and age-related
macular degeneration in Latinos: the Los Angeles Latino Eye Study. Am J
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Fraser-Bell, S., J. Wu, et al. (2008). Cardiovascular risk factors and age-related macular
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Fraser-Bell, S., J. Wu, et al. (2006). Smoking, alcohol intake, estrogen use, and age-
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Junquera L, C. J., Kelley R. (1998). Basic Histology, Lange.
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Klein, R., B. E. Klein, et al. (2003). The association of cardiovascular disease with the
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Klein, R., Q. Wang, et al. (1995). The relationship of age-related maculopathy, cataract,
and glaucoma to visual acuity. Invest Ophthalmol Vis Sci 36(1): 182-191.
Leske, M. C., S. Y. Wu, et al. (2006). Nine-year incidence of age-related macular
degeneration in the Barbados Eye Studies. Ophthalmology 113(1): 29-35.
Leske, M. C., S. Y. Wu, et al. (2004). Four-year incidence of macular changes in the
Barbados Eye Studies. Ophthalmology 111(4): 706-711.
Lim, J. I. (2008). Age-related macular degeneration. New York, Informa Healthcare.
Lindblad, A. S. and T. E. Clemons (2005). Responsiveness of the National Eye Institute
Visual Function Questionnaire to progression to advanced age-related macular
degeneration, vision loss, and lens opacity: AREDS Report no. 14. Arch
Ophthalmol 123(9): 1207-1214.
20
Mangione, C. M., P. P. Lee, et al. (2001). Development of the 25-item National Eye
Institute Visual Function Questionnaire. Arch Ophthalmol 119(7): 1050-1058.
Mangione, C. M., P. P. Lee, et al. (1998). Psychometric properties of the National Eye
Institute Visual Function Questionnaire (NEI-VFQ). NEI-VFQ Field Test
Investigators. Arch Ophthalmol 116(11): 1496-1504.
McKean-Cowdin, R., R. Varma, et al. (2007). Severity of visual field loss and health-
related quality of life. Am J Ophthalmol 143(6): 1013-1023.
Mitchell, J. and C. Bradley (2006). Quality of life in age-related macular degeneration: a
review of the literature. Health Qual Life Outcomes 4: 97.
Mitchell, P. and S. Foran (2005). Age-Related Eye Disease Study severity scale and
simplified severity scale for age-related macular degeneration. Arch Ophthalmol
123(11): 1598-1599.
Mitchell, P., W. Smith, et al. (1995). Prevalence of age-related maculopathy in Australia.
The Blue Mountains Eye Study. Ophthalmology 102(10): 1450-1460.
Mitchell, P., J. J. Wang, et al. (2002). Five-year incidence of age-related maculopathy
lesions: the Blue Mountains Eye Study. Ophthalmology 109(6): 1092-1097.
Mitchell, P., J. J. Wang, et al. (2002). Smoking and the 5-year incidence of age-related
maculopathy: the Blue Mountains Eye Study. Arch Ophthalmol 120(10): 1357-
1363.
Smith, W., J. Assink, et al. (2001). Risk factors for age-related macular degeneration:
Pooled findings from three continents. Ophthalmology 108(4): 697-704.
Varma, R., S. H. Paz, et al. (2004). The Los Angeles Latino Eye Study: design, methods,
and baseline data. Ophthalmology 111(6): 1121-1131.
21
Varma, R., J. Wu, et al. (2006). Impact of severity and bilaterality of visual impairment
on health-related quality of life. Ophthalmology 113(10): 1846-1853.
Wong, T. Y., U. Chakravarthy, et al. (2008). The natural history and prognosis of
neovascular age-related macular degeneration: a systematic review of the
literature and meta-analysis. Ophthalmology 115(1): 116-126.
Zarbin, M. A. (2004). Current concepts in the pathogenesis of age-related macular
degeneration. Arch Ophthalmol 122(4): 598-614.
27
Chapter 2: Risk Factors for Four-Year Incidence and Progression of
Age Related Macular Degeneration: The Los Angeles Latino Eye Study
2.1 Abstract
Purpose: To identify risk factors for 4-year incidence and progression of age-related
macular degeneration (AMD) in adult Latinos.
Design: Population-based prospective cohort study.
Methods: Participants, aged 40 or older, from the Los Angeles Latino Eye Study
(LALES), a Population-based prospective cohort study, underwent standardized
comprehensive ophthalmological examinations at baseline and at 4years of follow-up.
Age-related macular degeneration was detected stereoscopic fundus photographs using
the modified Wisconsin Age-Related Maculopathy Grading System. Multivariate
stepwise logistic regression was used to examine the independent association of
incidence and progression of AMD and baseline sociodemographic, behavioral, clinical
and ocular characteristics.
Results: Multivariable analyses revealed that older age (OR per decade of age: 1.52; 95%
CI: 1.29, 1.85) and higher pulse pressure (OR per 10 mmHg: 2.54; 95% CI: 1.36, 4.76)
were independently associated with the incidence of any AMD. The same factors were
associated with early AMD, soft indistinct drusen, and retinal pigmentary abnormalities.
Additionally, presence of clinically diagnosed diabetes mellitus was independently
associated with increased retinal pigment (OR: 1.66; 95% CI: 1.01, 2.85), and male
gender was associated with retinal pigment epithelial depigmentation (OR 2.50; 95% CI:
28
1.48, 4.23). Older age (OR per decade of age: 2.20; 95% CI: 1.82, 2.67) and current
smoking (OR: 2.85; 95% CI: 1.66, 4.90) were independently associated with progression
of AMD.
Conclusions: Several modifiable risk factors were associated with 4-year incidence and
progression of AMD in Latinos. The results suggest that interventions aimed at reducing
pulse pressure and promoting smoking cessation may reduce incidence and progression
of AMD, respectively.
29
2.2: Introduction
Age-related macular degeneration (AMD) is a progressive disorder of the macular
area that becomes clinically apparent usually after 50 years of age. When it progresses to
advanced stages it can result in severe loss of central vision with significant impact on
quality of life (de Jong 2006; Mitchell and Bradley 2006; Lim 2008). Age-related
macular degeneration is the leading cause of irreversible blindness in the western world
(Cooper 1990; Klein, Wang et al. 1995). With the shifting of population distribution to
older age groups, the prevalence, effect, and healthcare cost of AMD is expected to
increase substantially in these countries. In the United States alone, expenditure
associated with AMD treatment in 2004 was $ 525 million (Rein, Wittenborn et al.
2009). Prevalence of AMD in the United States is expected to increase from about 10
million in 2010 to about 20 million in 2050 (Rein, Wittenborn et al. 2009) and, hence,
will continue to be an increasing public health problem, (de Jong 2006) resulting in
significant increase in healthcare expenses attributable to AMD (Salm, Belsky et al.
2006).
Latinos constitute the largest and fastest growing minority segment of the US
population (Varma, Paz et al. 2004; Berstein 2006). If recent trends continue, the US
Latino population is estimated to increase to 102.6 million in 2050, or 24.4% of the total
population (Berstein 2006). But there is relative lack of population-based data regarding
ocular health in Latinos and the factors associated with AMD incidence and progression
among Latinos remain largely unexplored (Fraser-Bell, Donofrio et al. 2005; Fraser-Bell,
Choudhury et al. 2010). Data from the Los Angeles Latino Eye Study (LALES)
demonstrates a lower prevalence and incidence of early and late AMD compared to other
30
populations (Fraser-Bell, Wu et al. 2006; Fraser-Bell, Wu et al. 2008). Therefore, it is
important to understand whether different and modifiable factors are operative in Latinos
that influence disease risk and progression and may explain the differences in rates.
In the LALES, examination of baseline data revealed several demographic (age,
male gender, Native American ancestry, family history), behavioral (smoking, alcohol
consumption), clinical (higher diastolic blood pressure (DBP), uncontrolled diastolic
hypertension, pulse pressure) and ocular (presence of cataract, cataract surgery, and
myopic refractive error) factors to be associated cross-sectionally with the prevalence of
different AMD lesions in Latinos (Klein, Davis et al. 1991; Klein, Klein et al. 1997;
Varma, Fraser-Bell et al. 2004).
In the current analysis, we examine the relationships between these factors and
the 4-year incidence and progression of AMD in the cohort to tease out factors that are
associated with disease development versus those associated with disease duration. While
cross-sectional studies can identify associations between risk factors and existing AMD,
longitudinal incidence studies are required to determine the indicators that may be
associated with the development of future AMD.
We believe that for the overall improvement of the public health status of the
country it is imperative to reduce the incapacitating, and costly burden of AMD in the
fastest growing segment of US population. Hence, it is crucial to identify the unique risk
factors that are associated with and possibly, contribute to the development of AMD in
Latinos which can aide in developing evidence based public health programs to prevent
vision loss in this population.
31
2.3 Methods
Latinos (Hispanics, Hispanic Americans, and Latino Americans) are individuals
who are born into or have descended from a Spanish-speaking community, regardless of
race. In the United States, Latinos are a heterogeneous group, with the majority being of
Mexican ancestry (66%). The Los Angeles Latino Eye Study (LALES) is a population-
based longitudinal study of eye disease in self-identified Latinos, aged 40 years and
older, living in 6 census tracts in the city of La Puente, Los Angeles County. Baseline
examination was performed from 2000-2003, with 4-year follow-up examination from
2004-2008. Details of the study design, methods, and baseline data have been reported
elsewhere (Varma, Paz et al. 2004).
All eligible participants in the baseline LALES examination were invited to return
for a home interview and a clinical examination. Similar questionnaire and examination
procedures were used for both baseline and follow-up studies. In-home interviews were
conducted after obtaining informed consent. Trained ophthalmologists and technicians
performed a comprehensive ocular examination using standardized protocols, which
included 30p stereoscopic color fundus photographs of Diabetic Retinopathy Study field
one (centered on the optic disc), field two (centered on the macula) and a modified field
three (nonstereoscopic, temporal to and including the fovea) on all participants.
Risk Factor Assessment: For this analysis, factors examined as possible risk factors
included a number of sociodemographic, behavioral, clinical, and ocular characteristics
selected in light of literature review and expert opinion. Among these, age, gender,
country of birth, acculturation, working status, years of education, marital status, income,
32
insurance coverage, smoking, alcohol intake, history of high blood pressure, history of
heart attack, and history of stroke were self reported (obtained from home questionnaire).
Diabetes, systolic blood pressure (SBP), diastolic blood pressure (DBP), pulse pressure,
height, and weight were clinically assessed. Ocular factors such as cataract, lens
opacities, refractive error, iris color, and axial length were assessed by comprehensive
ophthalmologic examination. Age was defined as age at the baseline examination.
Systolic and diastolic blood pressures were the average of 3 baseline measurements.
Body Mass Index was calculated as body weight in kilograms/height in meter squared.
AMD Grading: In LALES, strict, uniform grading methods were adopted was used by
experienced, masked graders at the Wisconsin Ocular Epidemiology Reading Center to
grade individual AMD lesions following a modification of the Wisconsin Age-Related
Maculopathy Grading System (WARMGS) (Klein, Davis et al. 1991). Detailed
descriptions of all grading procedures and definitions were previously reported (Klein,
Davis et al. 1991). In brief, a lesion-by-lesion evaluation was performed at each
examination to determine maximum drusen size, type, area, and retinal pigmentary
abnormalities. Each eye was graded independent of the contralateral eye. Any clinically
meaningful differences between two initial graders were adjudicated by a senior grader
using standardized edit rules. Graders were masked to the year the photographs were
taken. A side-by-side longitudinal grading of all eyes with meaningful (e.g., defining
incidence or progression of AMD and its lesions) clinical changes over the 4-year period
was done before a final AMD grade was assigned. Strict quality control measures were
also applied.
33
Definitions of incident AMD: Definitions of AMD component lesions, including
specific drusen size, drusen types, and retinal pigmentary abnormalities and incidence
and progression of AMD, are the same as used in the Beaver Dam Eye Study and have
been described in detail elsewhere
(Klein, Davis et al. 1991; Klein, Klein et al. 1997).
Incident early AMD was defined as the absence of signs of advanced AMD and
the presence of 1) soft indistinct or reticular drusen or 2) hard distinct or soft distinct
drusen with pigmentary abnormalities (retinal pigment epithelial (RPE) depigmentation
or increased retinal pigment) at 4-year follow-up in participants who did not have any
evidence of AMD at baseline. Incident Advanced AMD was defined as the presence of
either 1) geographic atrophy or 2) exudative AMD at follow-up in people who had no
evidence of AMD at baseline.
The six-step modified Beaver Dam Eye Study severity scale was used to estimate
the 4-year progression of AMD. Person-specific progression was reported by
concatenating the score given for each eye, thus defining overall severity using the score
from the more affected eye. Progression of AMD was defined as two steps or more
increase in severity at 4-year follow-up in subjects with a severity level of 1-3 at baseline
(Klein, Klein et al. 1993; Klein, Klein et al. 1997). We also restricted the definition of
progression to a 2 step progression in those with definitive evidence of AMD at baseline.
Per eye progression was also defined and examined for risk factors in this restricted
group.
Statistical analyses: The baseline characteristics of the cohort of this analysis and
nonparticipants were analyzed using t-tests for comparison of means, and chi-square tests
34
for comparison of proportions. Sociodemographic, clinical, and ocular characteristics of
participants with and without AMD were analyzed using t-tests for comparison of means,
and chi-square tests for comparison of proportions. Each AMD end-point (any AMD,
early AMD, soft indistinct drusen, increased retinal pigmentation, and decreased RPE)
were modeled separately to investigate their association with different risk indicators.
The continuous variables of age, SBP, DBP and pulse pressure were initially
modeled as both continuous and categorical variables. Due to departure from log-linearity
assumption for the SBP, DBP and pulse pressure, we modeled these in different ways and
eventually dichotomized them into clinically meaningful categories. Age was modeled as
a continuous variable (per decade of age). Other than employment status (employed,
unemployed, retired) and smoking status (never, past, current), all other variables were
dichotomous.
The unadjusted associations between the risk indicators and different end points
were assessed by univariate logistic regression and odds ratios (OR) for each of the
significant variables were calculated. The independent associations of significant
predictors were evaluated by multiple logistic regression analyses with forward stepwise
selection using a P 0.20 criterion for entry into the model. The final multivariable
predictive model comprised of those factors that were significant at an alpha level of 0.05
after mutual adjustment. Generalized estimating equation was used to examine the risk
factors for progression per eye.
To further assess the nature of the relationship between these risk factors and the
endpoints, we used local regression methods adjusting for other covariates from the final
logistic regression model and generated LOWESS (locally weighted smoothing
35
regression) plots. The LOWESS plot uses an iterative, locally weighted, least-squares
method to plot the best-fit line that (Cleveland and Devlin 1988) shed light on the
qualitative nature of the relationship.
Possible effect modification of the association between AMD and the predictors
was tested by incorporating the proper interaction term in the logistic regressions models.
The analyses were performed using SAS software 9.2 (SAS, Inc, Cary, NC) and Stata
version 11 (StataCorp, TX). All tests for significance were at P-value 0.05 level.
2.4 Results
Study cohort: Of the 6100 living eligible participants identified, 4658 (76%) participated
in the 4-year follow-up study. Mean follow-up period was 4.3 (±0.03) years. Mean age of
participants was 54.7±10.5 years, 60% were females, and 76% were born outside of the
United States. At baseline, the demographic and socioeconomic characteristics of the
participants were determined to be representative of the overall Latino population in Los
Angeles County (Fraser-Bell, Donofrio et al. 2005).
Living eligible subjects not included in the analysis sample comprised non-
participants of the follow-up study, as well as participants with either missing or non-
gradable fundus photographs at baseline or follow-up examinations (Figure 2.1). Of those
who completed the ophthalmologic examination (n=4658), fundus photographs gradable
for AMD lesions in at least one eye were available for 4029 participants. Of the 3931
follow-up participants with gradable fundus photo, 3908 had gradable fundus
photographs in at least one eye from their baseline examination, thus making this the
analysis cohort.
Living participants
eligible for 4-year
follow-up examination
(n= 6100)
undus pho ph k
Participants with clinical
examination at
4-year follow-up
(n= 4658)
Participants examined
at baseline
(n= 6357)
Non-participants at
4-year follow-up
(n= 1442)
Deceased
(n= 257)
With fundus photograph gradable for
AMD in the same eye(s) at baseline
(n=3908)
(Analysis Cohort)
Fundus photograph gradable for
AMD in at least one eye taken at4
year follow-up
(n=3931)
No gradable fundus photograph of
both eyes at 4-year follow-up
(n=98)
Fundus photograph taken at
4 year follow-up
(n=4029)
Missing fundus photographs at
4-year follow-up
(n=629)
No gradable fundus
photographs in the same
eye(s) at baseline
(n=23)
Figure 2.1: Flow-chart of analysis cohort 1
36
37
The comparison of different demographic and clinical characteristics between
participants included in the analysis cohort and the excluded subjects are summarized in
Table 2.1. The major differences were that those in final analysis cohort were more
educated, more likely to be married, more likely to have comorbidities, and less likely to
report worse visual health status.
Table 2.1 Comparison of Participants and Non-participants in the 4 year follow-up
Characteristics Analysis cohort
a
N =3908
Nonparticipants
or excluded
N = 2192
P-value
b
N (%) N (%)
Demographic characteristics at baseline
Gender (female) 2346 60.09 1257 57.53 0.05
Age group
Mean (± SD) 54.29 10.10 54.37 11.35 0.77
Country of birth (United States)
Acculturation (low |<1.9|)
c
1281 32.81 703 32.17 0.61
Working status (employed) 2001 51.26 1068 48.88 0.08
Education level< 12 years 1348 34.53 695 31.81 0.03
Marital status (married) 2791 71.49 1447 66.22 <0.001
Income level > $40,000 499 12.90 266 12.26 0.48
Health insurance 1292 33.09 905 41.42 <0.001
2 comorbidities§ 1594 40.83 801 36.66 0.001
Self-reported health excellent/very good 742 19.01 430 19.68 0.52
History of hypertension 1162 29.84 598 27.41 0.05
History of diabetes 689 17.65 414 18.95 0.21
Self-reported vision excellent/good 1643 42.09 846 38.72 0.01
Status of ocular disease at baseline
Any ocular disease 1310 33.52 735 33.53 0.99
Cataract 597 15.55 371 19.49 0.002
Glaucoma 149 3.81 106 4.84 0.06
AMD 361 9.24 183 10.37 0.18
Diabetic retinopathy 521 13.34 289 15.55 0.02
a
Data are presented as mean (SD) for age, acculturation, SBP, DBP and comorbidities; frequency (%) for all
other variables.
b
P-values were calculated using t-test for continuous variables and chi-square for categorical variables.
c
Acculturation was measured using the short-form Cuellar Acculturation Scale.
38
In addition, a lower proportion of the final analysis cohort had cataract or diabetic
retinopathy compared to those who were not included. While the differences were
statistically significant, the differences in frequencies between the participants and the
non-participants tended to be small.
Table 2.2 compares the socio-demographic and clinical risk indicators of
participants with any AMD to those without any AMD. The major differences between
these two groups were age and age-related characteristics. Participants with AMD were
Table 2.2: Distribution of Baseline Sociodemographic, Clinical & Ocular
characteristics by AMD incidence status
a
Data are presented as mean (SD) for age, acculturation, SBP, DBP and comorbidities; frequency (%) for
all other variables.
b
P-values were calculated using t-test for continuous variables and chi-square for categorical variables.
c
Acculturation was measured using the short-form Cuellar Acculturation Scale.
Variables
a
No AMD Incident AMD P-value
b
(N =3808 ) (N = 100)
Socio-demographic Characteristics
Age 54.3 (10.1) 60.8 (12.2) <0.001
Gender: female 2285 (59.9) 58 (58.0) 0.57
Unemployed/ retired 1860 (49.1) 66 (66.7) 0.006
Income <$20,000 1640 (43.1) 47 (47.0) 0.65
Education<12 years 2497 (65.6) 64 (64.0) 0.77
Health insurance: Yes 2546 (66.9) 74 (74.0) 0.11
Vision insurance: Yes 2007 (52.7) 51 (51.0) 0.74
Acculturation score
c
1.8 (0.8) 1.8 (0.9) 0.93
Country of birth (USA) 903 (23.7) 22 (22.0) 0.77
Marital status
(Married/ Partner)
2706 (71.2) 35 (35.0) <0.001
Smokers 496 (13.1) 17 (17) 0.24
Clinical Characteristics
Comorbidities§ 1.5 (1.5) 1.9 (1.6) 0.004
History of hypertension 1137 (29.9) 44 (44) 0.001
Systolic BP (SBP) 122.9 (18.5) 129.5 (17.4) 0.006
Diastolic BP (DBP) 75.8 (10.8) 76.0 (10.7) 0.92
Pulse pressure (PP) 47.1 (14.4) 53.4 (13.5) <0.001
Ocular Characteristics
Any lens opacity 616 (16.5) 21 (21.0) 0.08
Cataract surgery 118 (3.1) 8 (8.0) 0.005
Iris color (black/brown) 3409 (89.6) 89 (89.0) 0.70
Ocular perfusion pressure (OPP)
46.5 (8.1) 47.2 (8.2)
0.37
39
statistically significantly older (P <0.001), had more comorbidities (P=0.004) and were
more likely to be unemployed or retired (P=0.006) than those without AMD. The AMD
incident cases were also more likely to have a history of hypertension, higher mean SBP,
higher mean pulse pressure, and a history of any lens opacity or cataract surgery.
Incidence of AMD and Risk Factors: The incidence of late AMD (n= 8), incident
geographical atrophy (n=3) and incident exudative AMD (n=5) were too small to allow
robust risk factor analysis. At 4-year follow-up, 100 (2.5%) participants were found to
have any AMD (92 early and 8 late AMD). Out of these 35 participants were at the level
10, 25 at level 20, 31 at level 40, 3 at level 50 and 4 at level 60 of BDES severity scale.
In univariate analysis, age was the strongest risk factor. After age adjustment, the
socio-demographic and clinical factors associated with the incidence of any AMD
included older age, retirement, higher SBP, higher pulse pressure, presence of any
cataract, cortical opacity, history of cataract surgery, and refractive error (myopia).
Using stepwise logistic regression we found only older age (OR per decade of
age: 1.52; 95% CI: 1.29, 1.85) and higher pulse pressure (OR 2.54; 95% CI: 1.36, 4.76
for >40 compared to <= 40 mm Hg) to be independently associated with incidence of any
AMD (Table 2.3).
To further evaluate whether the effect of pulse pressure was independent of
hypertension, we restricted the analysis to normotensive participants with a baseline SBP
of 140 mm Hg or less and baseline DBP of 90 mm Hg or less. The analysis revealed
similar age-adjusted independent relationship between pulse pressure and any AMD (OR
for AMD: 2.60; 95% CI: 1.38, 4.87).
40
Increasing age (OR per decade of age: 1.61; 95% CI: 1.32, 1.96) and higher pulse
pressure (OR 2.79; 95% CI: 1.45, 5.35 for >40 mm Hg compared to <= 40 mm Hg) were
statistically significant independent predictors of the incidence of early AMD, similar to
any AMD (Table 2.3). The Lowess plot revealed a relatively insidious increase in
predicted probability of early AMD incidence up to 40 mm Hg of pulse pressure and a
steep increase when pulse pressure reached more than 40 mm Hg (Figure 2.2).
Lowess analysis was suggestive of a nominal increase of predicted incidence of
early AMD with increasing age from 40 to 65 years. The increasing trend was
pronounced after age 65 years with a very steep rise in people aged 80 year or older
(Figure 2.4).
A total of 77 (2.3%) persons developed soft indistinct drusen in one or both eyes.
Similar to the previous analyses, multivariable analyses revealed increasing age (OR per
decade of age: 1.69; 95% CI: 1.37, 2.10) and increased pulse pressure (OR 2.69; 95% CI:
1.31, 5.52 for >40 mm Hg compared to <= 40 mm Hg) to be the statistically significant
independent predictors of soft indistinct drusen (Table 2.3). Using a lowess plot we found
a steep increase in predicted probability of soft drusen incidence, similar to early AMD,
when pulse pressure is 40 mm Hg or more (Figure 2.3).
Also, similar to early AMD, the predicted incidence of soft drusen increased
gradually with increasing age, with a pronounced increase after 65 years and highest
incidence in the oldest age group (Figure 2.5).
41
Table 2.3: Independent Risk Factors of Incidence and Progression of AMD
Any AMD Early AMD Soft Indistinct
drusen
Increased retinal
pigment
Decreased retinal
pigment
Progression of AMD
Characteristic OR (95%CI)
a
OR (95%CI)
a
OR (95%CI)
a
OR (95%CI)
a
OR (95%CI)
a
OR (95%CI)
a
Age (per decade) 1.52 (1.29, 1.85) 1.61 (1.32, 1.96) 1.69 (1.37, 2.10) 1.20 (1.01, 1.50) 1.30 (1.02, 1.65) 2.20 (1.82, 2.67)
Pulse pressure
40 mm Hg 1 1 1 1 1 ~
>40 mm Hg 2.54 (1.36, 4.76) 2.79 (1.45, 5.35) 2.69 (1.31, 5.52) 3.18 (1.56, 6.52) 1.91 (1.00, 3.77)
Diabetes ~ ~ ~ ~ ~
No 1
Yes 1.66 (1.01, 2.85)
Smoking status ~ ~ ~ ~ ~
Non smoker 1
Ever/ Past smoker 1.25 (0.75, 2.07)
Current smoker 2.85 (1.66, 4.90)
Gender ~ ~ ~ ~ ~
Female 1
Male 2.50 (1.48, 4.23)
a
Odds ratios and confidence intervals adjusted for other variables in the model.
42
Figure 2.2: Pulse pressure & predicted 4-year incidence of early AMD
Figure 2.3: Age & predicted 4-year incidence of early AMD
1 2 3 4 5 6 7 8
Predicted 4-year incidence of Early AMD (in%)
0
20
30
40
50
60
70
80
90
Pulse pressure (mm Hg)
0 10 20 30 40 50
Predicted 4-year Incidence of Early AMD (in%)
40 45 50 55 60 65 70 75 80
Age (in years)
43
Figure 2.4: Pulse pressure & predicted 4-year incidence of soft indistinct drusen
Figure 2.5: Age & predicted 4-year incidence of soft indistinct drusen
1 2 3 4 5 6 7 8
Predicted 4-year ncidence of Soft Drusen(%)
0
20
30
40
50
60
70
80
90
Pulse pressure (mm Hg)
0 10 20 30 40 50 60
Predicted 4-year Incidence of Soft Drusen (in%)
40 45 50 55 60 65 70 75 80
Age (in years)
44
At the end of LALES II there were 80 (2.3%) cases of increased retinal pigment.
Multivariable analyses revealed increasing age (OR per decade of age: 1.20; 95% CI:
1.01, 1.50), high pulse pressure (OR 3.18; 95% CI: 1.56, 6.52 for >40 mm Hg compared
to <= 40 mm Hg) and presence of clinically diagnosed diabetes mellitus at baseline (OR
1.66; 95% CI 1.01, 2.85) as independent risk factors. There were a total of 66 (1.9%)
persons with incident RPE depigmentation. In univariate analysis, age was the strongest
risk factor. After age adjustment, male gender, low income (<20,000 USD/year), high
pulse pressure and history of cataract surgery were significant risk factors with age (OR
per decade of age: 1.30; 95% CI: 1.02, 1.65), male gender (OR 2.50; 95% CI: 1.48, 4.23)
and pulse pressure (OR 1.91; 95% CI: 1.01, 3.77 for >40 mm Hg compared to <= 40 mm
Hg) remained independent predictors after multivariable stepwise logistic analyses.
Progression of AMD and risk factors: At 4-year follow-up, 87 (1.5%) participants had
progression of AMD. Age-adjusted analysis revealed that the socio-demographic,
behavioral, and clinical factors that increased the risk of progression of AMD included
increased age; being widowed, , unmarried, or divorced; being retired; being a current or
former smoker; having a high pulse pressure; and the presence of any cataract or history
of cataract surgery, cortical opacity, or refractive error (myopia). Stepwise logistic
regression was suggestive of an independent association of age and smoking status in that
older people (OR per decade of age: 1.30; 95% CI: 1.02, 1.65) and current smokers (OR
2.85; 95% CI: 1.66, 4.90 compared to non-smokers) were at a higher risk of progressing
to late maculopathies. Ex-smokers, however, were not significantly at a higher risk than
non-smokers (OR 1.25; 95% CI: 0.75, 2.07compared to non-smokers) (Table 2.3).
45
When multivariate analysis was restricted to the 42 participants, excluding anyone
with any evidence of AMD at baseline, who had progressed from step 2 or more at
baseline, the results were similar, with increasing age (2.03; 95% CI: 1.52, 2.71) and
current smoking (OR 2.69; 95% CI: 1.19, 6.07,compared to non-smokers) revealed as
independent risk factors.
Progression was further defined and examined for each eye and similar
independent association of age and smoking status was found in that older people (OR
per decade of age: 2.15; 95% CI: 1.61, 2.89) and current smokers (OR 2.44; 95% CI:
1.09, 5.44 compared to non-smokers) were at a higher risk of progressing to late
maculopathies.
Figure 10: Figure 2.6: Age and predicted 4-year progression of AMD
0 5 10 15 20 25 30
Predicted 4-year progression of AMD (in%)
0 40 45 50 55 60 65 70 75 80
Age (in years)
46
Figure 2.6 illustrates the qualitative nature of relationship between age and AMD
progression. The predicted probability of progression increased gradually with increasing
age with a pronounced increase after 65 years and the highest incidence in the oldest age
group.
2.5 Discussion
In this longitudinal study, over a 4 year period we found older age, increased
pulse pressure, diabetes mellitus, and male gender to be associated with incident early
AMD in Latinos. Older age and current smoking were associated with increased risk of
progression of AMD. Some of these findings are consistent with data from other
population-based longitudinal studies, including the Beaver Dam Eye Study (BDES) and
the Blue Mountains Eye Study, which have used similar methodologies to detect and
define AMD (Klein, Klein et al. 1993; Klein, Klein et al. 1994; Mitchell, Smith et al.
1995; Klein, Klein et al. 1997; Klein, Klein et al. 1998; Hyman and Neborsky 2002;
Mitchell, Wang et al. 2002). However, we have found several novel associations
especially when the outcomes were defined as early AMD and soft drusen that were not
reported in earlier studies.
Socio-demographic risk factors: Numerous studies have demonstrated older age as the
strongest risk factor of AMD prevalence, incidence and progression. The relationship
between age and prevalence of AMD was demonstrated previously with the prevalence
LALES data (Fraser-Bell, Donofrio et al. 2005). The present analyses demonstrated the
increased risk of AMD incidence and progression with increasing age. It has been
suggested that the ongoing subclinical pathogenetic processes, such as deposition of
47
lipofuschin, thickening and loss of elasticity of Bruch’s membrane, begin earlier in life
These changes are likely to manifest as clinical signs of early AMD as people age, due in
part to the inability of the RPE in some individuals to process these degenerative products
(Klein, Klein et al. 1994; Lim 2008).
Gender difference in incident or prevalent AMD has been an inconsistent finding
in most population based studies (Lim 2008). The previous report from LALES
prevalence data was suggestive of an increased risk of all and early AMD prevalence in
males (Fraser-Bell, Donofrio et al. 2005). In the present report we found an increased risk
in males for RPE depigmentation only. The Blue Mountains Eye Study found a similar
association with higher prevalence of pigmentary changes in males (Christen, Glynn et al.
1996); however, other studies failed to find similar association (Christen, Glynn et al.
1996).
The reasons for increased risk of RPE depigmentation in Latino men are not
known, although several other known risk factors of AMD (e.g., smoking, alcohol use,
and cardiovascular disease) are found to be more prevalent in males (Lim 2008) (Fraser-
Bell, Donofrio et al. 2005). Indeed, in LALES we noted that Latino men were more likely
to smoke (19% vs 9 % P<0.001) and drink alcohol regularly compared to Latino women
(22% vs 3%). But even after adjusting for these variables men were more likely than
women to develop RPE depigmentation (OR 2.73; 95% CI: 1.52, 4.94).
Behavioral risk factors: The results of this study suggest an almost threefold increased
risk of progression of AMD in current smokers (P=0.0004). There was no such
significant association in former smokers.
48
Smoking has been the most consistent modifiable behavioral risk factor in most
population-based ocular epidemiologic studies (Smith, Mitchell et al. 1996; Klein, Klein
et al. 1998; Smith, Assink et al. 2001; Hyman and Neborsky 2002; Tomany, Wang et al.
2004; Fraser-Bell, Wu et al. 2006; Lim 2008). It has been found to be associated with all
stages of AMD. In particular, the risk has been found strongest in those who are current
smokers (Smith, Mitchell et al. 1996; Smith, Assink et al. 2001). Reports from pooled
studies including the BDES, Blue Mountains Eye Study and Rotterdam Eye Study
confirm the strength of this association in both prevalent and incident AMD (Smith,
Mitchell et al. 1996; Smith, Assink et al. 2001). Some investigators have suggested the
effect of cigarette smoking on the AMD may be due to its negative effect on anti-
oxidants (Tamakoshi, Yuzawa et al. 1997; Espinosa-Heidmann, Suner et al. 2006). In an
experimental study, exposure to cigarette smoke resulted in the formation of sub-RPE
deposits, thickening of Bruch’s membrane, and accumulation of deposits in Bruch’s
membrane (Espinosa-Heidmann, Suner et al. 2006). In this report we found smoking to
be associated with progression but not with incidence of AMD in Latinos.
Clinical risk factors: The association of blood pressure and AMD has been inconsistent
in epidemiologic population-based studies. Our results suggest increased risks of all
measures of AMD incidence with increased pulse pressure. The BDES found a positive
association of pulse pressure with prevalence of RPE depigmentation and increased
retinal pigmentation in males only (Klein, Klein et al. 1993). However, in the 5-year
cumulative incidence in BDES, higher pulse pressure was significantly associated with
increased incidence of retinal pigment epithelial depigmentation (OR per 10 mmHg 1.27,
95% CI 1.14, 1.42) and exudative macular degeneration (OR per 10 mmHg 1.29, 95% CI
49
1.02, 1.65), irrespective of gender (Klein, Klein et al. 1997). These findings were further
confirmed by BDES 10-year incidence data (Klein, Klein et al. 2003); however, a number
of other studies did not report this association (Vingerling, Dielemans et al. 1995; Chae,
Pfeffer et al. 1999). The association of pulse pressure with soft drusen was not reported in
other ethnicities. Pulse pressure emerged as the most important modifiable risk factor in
this cohort.
To further evaluate whether the effect of pulse pressure was independent of
hypertension, we restricted the analysis to normotensive participants and found a similar
age-adjusted independent relationship (OR for AMD: 2.6; 95% CI: 1.4, 4.9). The steep
increase in predicted probabilities of incidence of both early AMD and soft drusen at 40
mm Hg of pulse pressure is consistent with the frequently used clinical cut point to
distinguish low and high pulse pressure (Mitchell 1999; Domanski, Norman et al. 2001;
Mitchell, Vasan et al. 2007). The underlying mechanism of increased pulse pressure on
AMD risk may be due to age-related degenerative changes in collagen and elastin,
resulting in a decrease in distensibility of blood vessels. This in turn results in higher
systolic and lower diastolic BP and widening of pulse pressure. Klein et al. (Klein, Klein
et al. 2003) postulated that a wide pulse pressure may be a marker of such degenerative
changes occurring in Bruch’s membrane in eyes at risk of incidence and progression of
AMD. Other studies suggest that as one ages there is a gradual shift in the strength of
prediction of cardiovascular disease risk from diastolic to systolic to pulse pressure with
pulse pressure being more predictive of cardiovascular disease risk than systolic or
diastolic blood pressure in people 65 or older (Franklin, Khan et al. 1999; Domanski,
Norman et al. 2001; Mitchell, Vasan et al. 2007).
50
Diabetes is a disparate finding as a risk factor for AMD. In this study, presence of
clinically diagnosed diabetes mellitus was independently associated with incidence of
increased retinal pigmentation. The Blue Mountains Eye Study found an association of
diabetes with geographical atrophy but not with increased retinal pigment or any other
measure of early AMD (Mitchell and Wang 1999). In BDES, diabetes was not associated
with early AMD but was associated with neovascular AMD in persons 75 or older (Klein,
Klein et al. 1998). A large number of studies found no association. The paucity of
literature suggests caution in drawing any inference. However, diabetes as a risk factor of
any disease in Latinos require more attention as diagnosed diabetes are 1.7 times more
likely in Latinos than in non-Hispanic whites. Results from the most recent National
Health and Nutrition Examination Survey demonstrate that diabetes is 1.7 times more
prevalent in Mexican Americans than in non-Hispanic whites. Results from different
population-based studies have demonstrated that persons with diabetes are predisposed to
developing different ocular conditions (Mitchell and Wang 1999; Augood, Vingerling et
al. 2006; Chopra, Varma et al. 2008; Varma, Choudhury et al. 2010). Therefore, timely
prevention, diagnosis and proper control of diabetes will likely to have a positive impact
on the burden of ocular disease in Latinos.
In LALES, there was a relative low rate of AMD progression. In this analysis we
could not identify any protective factors that may affect AMD progression in Latinos.
However, a previous analysis from LALES was suggestive of a low prevalence of the
genetic risk factor of CFH Tyr402 polymorphism in Latinos (Tedeschi-Blok, Buckley et
al. 2007). Further analysis of distributions of genetic risk factors, both protective and
51
deleterious, and their relationship to AMD may shed more light on factors that are likely
to play a role in progression or relative lack of it in this population.
The suggested associations or lack of them in this study should be interpreted
with caution due to some limitations. The most important of these limitations is the
relative infrequency of AMD cases in our cohort, which may have limited our ability to
confirm some expected associations. Also, a very low incidence for late AMD,
geographical atrophy, and neovascular AMD precluded robust risk factor analyses for
these lesions. A longer follow up study in the future may help us address this limitation.
Second, one potential limitation of the study is measurement error of the presence
and severity of AMD. In LALES, strict, uniform grading methods were employed and
adhered to as described in the methods. Moreover, since graders were masked to baseline
disease status of the any measurement error is unlikely to be differential. Any impact of
such an error would attenuate the results and would not change any association.
Third, participants and nonparticipants for these analyses differed in several
demographic and clinical indicators. But, as demonstrated in Table 1, even when the
differences are statistically significant, the magnitudes of these differences are small and
unlikely to have a significant effect on the results or unlikely to change the direction of
association. Further, there were no significant differences in risk factors that were
associated with different measures of AMD (like age, gender or diabetes). Moreover, the
factors that did differ between the participants and non-participants cannot explain the
observed association. As for example, the participants were more likely to be
hypertensive. But as discussed previously pulse pressure was associated independent of
hypertension. Then again, the participants were more likely to report better visual health,
52
so it is unlikely that we would have more cases of AMD in our cohort of participants. If
anything we would have had less AMD cases which is more likely to attenuate the effect
estimates and thus, unlikely to explain the associations.
Fourth, LALES lacked person time data and hence, logistic regression was used
for this analysis, which can potentially overestimate some associations. Also, these
results may not be generalizable to all Latinos globally. However, the similarity of
Latinos in LALES and US suggest that these results can be generalized to all Latinos of
USA (Varma, Paz et al. 2004).
In conclusion, in Latinos, increasing age, increased pulse pressure, and diabetes
mellitus were associated with higher risks of incidence of early AMD, and increasing age
and current smoking were associated with the progression of AMD. Some of the findings
are similar to those reported by studies in non-Hispanic whites, suggesting some
similarities in the pathogenesis of the disease between the two ethnic groups. Studies of
genetic risk factor may explain the differences in risk factors for incidence of some early
maculopathies like soft drusen. Because Latinos represent the largest minority group in
the US and exhibit different patterns of AMD incidence and progression than other ethnic
groups, it is empirical to address the unique risk factors of AMD in Latinos. The fact that
easily modifiable factors like pulse pressure was associated with Latinos may provide
clinicians with important guidelines for preventive interventions. Further longitudinal
studies of AMD progressions in Latinos are needed for conclusive inferences. It remains
to be seen whether interventions aimed at reducing pulse pressure or stopping smoking
would affect the incidence and progression of AMD in Latinos.
53
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Vingerling, J. R., I. Dielemans, et al. (1995). Age-related macular degeneration is
associated with atherosclerosis. The Rotterdam Study. Am J Epidemiol 142(4):
404-409.
Supplemental Table 2.1: Univariate Associations of Socio-demographic & behavioral Factors with Incidence and
Progression of AMD
Characteristic Any AMD Early AMD Soft Indistinct
Drusen
Increased Retinal
Pigment
Decreased Retinal
Pigment
Progression
OR (95%CI) OR (95%CI) OR (95%CI) OR (95%CI) OR (95%CI) OR (95%CI)
Age (per decade) 1.68 (1.42,2.01) 1.78 (1.47, 2.15) 1.86 (1.52, 2.29) 1.36 (1.11, 1.68) 1.40 (1.11, 1.77) 2.13 (1.76, 2.56)
Gender
Female 1 1 1 1 1 1
Male 1.08 (0.72, 1.62) 1.13 (0.74, 1.72) 1.62 (1.03, 2.55) 1.41 (0.89, 2.22) 2.51 (1.48, 4.24) 0.97 (0.63, 1.49)
Marital Status
Married/Living with Partner 1 1 1 1 1 1
Unmarried/Widowed/Divorced 1.29 (0.84, 1.98) 1.49 (0.96,2.33) 1.15 (0.69-1.90) 1.18(0.71, 1.96) 0.84 (0.45, 1.56) 1.84 (1.19, 2.84)
Employment Status
Employed 1 1 1 1 1 1
Unemployed 1.73 (1.08, 2.76) 1.81 (1.12, 2.92) 1.56 (0.92, 2.65) 1.22 (0.72, 2.06) 0.71 (0.33, 1.53) 1.68 (0.98, 2.86)
Retired 2.92 (1.74, 4.90) 3.07 (1.76, 5.34) 3.17 (1.77, 5.69) 2.12 (1.17, 3.86) 1.60 (0.81, 3.16) 5.07 (3.01, 8.52)
Income < 20,000/yr
No 1 1 1 1 1 1
Yes 1.19 (0.78, 1.84) 1.23 (0.79, 1.92) 1.20 (0.74, 1.92) 1.00 (0.60, 1.62) 1.97 (1.11, 3.52) 1.48 (0.93, 2.35)
Smoking status
Never 1 1 1 1 1 1
Ex-smoker 1.33 (0.84, 2.12) 1.28 (0.79, 2.07) 1.49 (0.89, 2.49) 1.19 (0.69, 2.06) 1.14 (0.62, 2.10) 1.42 (0.86, 2.34)
Current Smoker 1.51 (0.87, 2.63) 1.31 (0.72, 2.38) 1.54 (0.82, 2.89) 1.52 (0.81, 2.86) 1.58 (0.79, 3.14) 2.31 (1.36, 3.92)
58
Supplemental Table 2.2: Univariate Associations of Clinical Factors with Incidence and Progression of AMD
Characteristic Any AMD Early AMD Soft Indistinct
Drusen
Increased
Retinal Pigment
Decreased Retinal
Pigment
Progression
OR (95%CI) OR (95%CI) OR (95%CI) OR (95%CI) OR (95%CI) OR (95%CI)
History of hypertension 2.03(1.36, 3.03) 2.18 (1.43, 3.31) 1.55 (0.97, 2.48) 2.00 (1.26, 3.18) 1.24 (0.74, 2.09) 1.75 (1.14, 2.68)
History of Stroke 2.23 (1.01, 4.90) 2.42 (1.03, 5.69) 2.41 (0.95, 2.38) 3.39 (1.52, 7.58) 2.34 (0.83, 6.57) 1.94 (1.05, 3.62)
History of Angina/heart attack 2.19 (0.94, 5.10) 2.48 (1.05, 5.82) 1.94 (0.69, 5.43) 1.87 (0.67, 5.24) 2.45 (0.87, 6.90) 2.38 (1.02, 5.58)
Systolic blood pressure
<140 (mmHg) 1 1 1 1 1 1
140 (mmHg) 1.78(1.41, 2.78) 2.16 (1.37, 3.42) 2.19 (1.34, 3.60) 1.59 (0.93, 2.72) 1.67 (0.92, 3.02) 1.47 (0.90, 2.42)
Diastolic blood pressure
<85 (mmHg) 1 1 1 1 1 1
85 (mmHg) 1.29(0.80, 2.07) 1.35 (0.82, 2.21) 1.38 (0.81, 2.36) 1.22 (0.70, 2.13) 1.25 (0.67, 2.33) 1.09 (0.65, 1.84)
Pulse pressure (mmHg)
<40 1 1 1 1 1 1
>=40 3.53(1.92, 6.47) 3.86 (2.05, 7.27) 3.89 (1.93, 7.82) 3.79 (1.88, 7.62) 2.24 (1.16, 4.32) 2.09 (1.23, 3.56)
59
Supplemental Table 2.3: Univariate Associations of Ocular Risk Factors with Incidence and Progression of AMD
Characteristic Any AMD Early AMD Soft Indistinct
Drusen
Increased Retinal
Pigment
Decreased Retinal
Pigment
Progression
OR (95%CI) OR (95%CI) OR (95%CI) OR (95%CI) OR (95%CI) OR (95%CI)
Cataract
Absent 1 1 1 1 1 1
Present 1.70 (1.05, 2.74) 1.97 (1.18, 3.28) 1.72 (0.96, 3.06) 1.47 (0.81, 2.65) 1.27 (0.64, 2.52) 3.88 (2.44, 6.17)
Nuclear sclerosis
Absent 1 1 1 1 1 1
Present 1.95 (1.05, 3.61) 2.69 (1.37, 5.31) 2.52 (1.19, 5.35) 1.94 (0.88, 4.30) 0.64 (0.15, 2.64) 4.52 (2.59, 7.87)
Posterior subcapsular opacity
Absent 1 1 1 1 1 1
Present 0.94 (0.23, 3.88) 1.01 (0.14, 7.46) 1.18 (0.16, 8.71) 1.99 (0.47, 8.33) 2.44 (0.58, 10.28) 2.19 (0.67, 7.12)
Cortical opacity
Absent 1 1 1 1 1 1
Present 1.48 (0.86, 2.56) 1.68 (0.94, 3.01) 1.75 (0.93, 3.28) 1.16 (0.57, 2.35) 1.71 (0.86, 3.41) 3.58 (2.19, 5.86)
Cataract surgery
None 1 1 1 1 1 1
Yes 3.01 (1.48, 6.11) 4.03 (1.69, 9.61) 3.98 (1.55, 10.22) 2.73 (0.97, 7.67) 3.40 (1.20, 9.62) 7.36 (4.01, 13.49)
Refractive error
Emetropia 1 1 1 1 1 1
Hyperopia 1.82 (1.15, 2.89) 2.03 (1.27, 3.27) 1.91 (1.15, 3.15) 1.49 (0.89, 2.51) 1.34 (0.70, 2.74) 2.87 (1.71, 4.82)
Myopia 1.78 (1.05, 3.02) 1.69 (0.96, 2.99) 1.30 (0.68, 2.49) 1.49 (0.81, 2.72) 1.39 (0.75, 2.40) 2.70 (1.50, 4.84)
60
61
Chapter 3: Age-Related Macular Degeneration and Health Related
Quality of Life in Latinos: The Los Angeles Latino Eye Study (LALES)
3.1 Abstract
Purpose: To assess the impact of early (soft indistinct drusen, retinal pigment
abnormalities) and advanced (exudative, geographic atrophy [GA]) age-related macular
degeneration (AMD) on health-related quality of life (HRQoL) in adult Latinos.
Design: Cross-sectional, population-based study
Participants: A total of 4,857 participants of the Los Angeles Latino Eye Study were
included in this analysis.
Methods: A standardized, detailed ophthalmologic examination, including stereoscopic
fundus photography, was performed on each participant. A modification of the Wisconsin
Age-Related Maculopathy Grading System (WARMGS) was used to grade individual
AMD lesions. Severity of AMD was defined by a modified WARMGS scale into 6 steps.
Generic HRQoL was assessed by the Short Form 12-item Health Survey (SF-12). Self-
reported vision-related HRQoL was assessed by the National Eye Institute Visual
Function Questionnaire (NEI-VFQ-25). Analysis of covariance was used to compare the
HRQoL scores across subgroups of no AMD versus different outcome measures of
AMD. Covariates included age, gender, education, employment, comorbidities and ocular
disease history. Effect sizes for NEI-VFQ scores and SF-12 scores were calculated for all
AMD lesions.
62
Main Outcome Measures: HRQoL scores measured by the NEI-VFQ25 and SF-12
questionnaires
Results: Compared to participants without AMD, participants with soft drusen had lower
score in composite NEI-VFQ 25 scale (p=0.004) and nine subscales including vision-
related dependency, driving difficulty, distance vision, vision-related mental health, near
vision, vision related role function, vision related social function and color vision (p-
values from 0.02 to 0.00). Similar associations were observed in people with increased
retinal pigmentation (IRP) (P-values from 0.03 to <0.001) with the exception of color
vision but including general vision (P=0.03). Participants with RPE depigmentation had
lower mean scores for all NEI-VFQ subscales (P=0.008 to <0.001) except for ocular
pain, general health and general vision.
Compared to those without AMD, participants with GA had significantly lower mean
scores for the composite scale(P=<0.001) than those without any AMD and for eight of
12 subscales (P<0.001 for 7 subscales and <0.003 for 2 subscales).
Results were similar, albeit more pronounced, when participants with exudative
AMD were compared to those without any lesion. Statistically lower mean scores for 10
of the 12 NEI-VFQ subscales and composite score for those with exudative AMD. The
effects were very large in 10 subscales (ES >1.00), with the largest effect observed in
driving difficulty (ES= -2.79), composite, vision-related dependency driving difficulty,
distance vision, vision-related mental health, near vision, vision related role function and
vision related social function (p<0.001 for all). Statistically lower mean scores for 10 of
the 12 NEI-VFQ subscales and composite score for those with exudative AMD. QoL
63
scores were inversely related to severity and, compared to the QoL scores of participants
with unilateral lesions; the scores for those with bilateral lesions were significantly lower.
Conclusions: Our results suggest that AMD is associated with a measurably lower in
HRQOL, even for lesions defined as early AMD. We also found that both severity and
bilaterality of AMD is associated with worse HRQoL. Better management of AMD at an
early stage and prevention of progression to late stages may prevent further deterioration
of QoL for the patients.
64
3.2 Introduction
Age-related macular degeneration (AMD) is the leading cause of irreversible
blindness in adults over the age of 60 years in the western world. A chronic, progressive
disorder that mainly affects people over the age of 50, AMD can lead to severe loss of
central vision (de Jong 2006; Lim 2008; Coleman, Seitzman et al. 2010). With limited
and expensive treatment options available and an aging world population, this ocular
disorder is expected to continue to grow as a major public health problem, with
significant clinical, emotional and financial effects on patients and marked adverse
consequences for the economy (Mitchell and Bradley 2006; Covert, Berdeaux et al.
2007).
Central vision impacts a person’s interaction with their environment and plays a
crucial role in daily activities such as driving, reading, and walking, as well as in human
interaction with the surrounding environment. Hence, loss of central vision can lead to
reduced mobility, increased dependency in activities of daily living and even social
isolation (Mitchell and Bradley 2006). The central vision impairment associated with
AMD can significantly compromise health-related quality of life (HRQoL). People with
AMD may find performing daily tasks much more challenging than do people without
the disease, even when the disease is in its earlier stages (Mitchell and Bradley 2006;
Covert, Berdeaux et al. 2007). These changes in HRQoL can lead to other outcomes, such
as assisted living, restriction of physical activity, and ultimately, increased morbidity and
mortality.
The impact of AMD on HRQoL has been investigated in a number of studies; the
majority of these studies has been conducted in small clinical settings and has involved
65
mostly Caucasian (Mitchell and Bradley 2006; Covert, Berdeaux et al. 2007). While a
number of studies have established the significant impact of late AMD on HRQoL, the
consensus on impact of early AMD remains equivocal. Some studies suggest that
ophthalmologists underestimate the negative impact of AMD on patients’ quality of life,
especially for those with early AMD (Brown and Brown 2010). Since treatment options
for the management of late AMD are limited; knowledge about the impact of early AMD
may help clinicians make informed decisions about when to begin intervention.
The HRQoL associated with AMD among Latinos remains largely unexplored,
even though Latinos constitute the largest and fastest growing minority segment of the
US population (Varma, Paz et al. 2004; Ennis S 2010). The Los Angeles Latino Eye
Study (LALES) is a population-based cohort study designed to study the prevalence and
incidence of ocular disease in adult Latinos, to evaluate risk indicators of ocular disease,
and to measure the impact of ocular disease on HRQoL (Varma, Paz et al. 2004). The
objectives of the current analyses are to examine the association between AMD and
vision-specific HRQoL, as measured by the National Eye Institute Vision Specific
Questionnaire (NEI-VFQ-25) (Mangione, Lee et al. 1998; Mangione, Lee et al. 2001),
and on general HRQoL, as measured by the Short Form 12-item Health Survey (SF-12)
(Ware 1995; Ware, Kosinski et al. 1996).
3.3 Methods
Design and Sample
The data for these analyses were collected as part of a population-based, cross-
sectional study of adults, the Los Angeles Latino Eye Study (LALES). Details of the
66
study design, sampling plan, and baseline data have been previously reported (Varma,
Paz et al. 2004). In brief, a door-to-door census of all residents living within 6 census
tracts in La Puente, California, was conducted between February 2000 and May 2003 to
identify eligible individuals. Demographic and socioeconomic characteristics of Latinos
in the 6 census tracts of La Puente were similar to those of the Latino populations of Los
Angeles County. Latinos are individuals who are born into or have descended from a
Spanish-speaking community, regardless of race. In the United States Latinos are
heterogeneous, with the majority being of Mexican ancestry (66%).(Ennis S 2010) About
90% of LALES participants reported Mexican ancestry (Varma, Paz et al. 2004).
All eligible participants (40 years or older at the time of the census and self-
identified as Latino) were informed of the study and invited to participate in both a home
interview and a clinical eye examination. Institutional Review Board (IRB) approval was
obtained from the Los Angeles County/University of Southern California Medical Center
IRB.
Socio-demographic and Clinical Data
After informed consent was obtained, an in-home interview was conducted to
obtain detailed demographic information, history of ocular and medical conditions,
access to health care, acculturation, and insurance status. A detailed eye examination was
subsequently performed in a standardized manner at the LALES Local Eye Examination
Center.
67
AMD Grading
A modification of the Wisconsin Age-Related Maculopathy Grading System
(WARMGS) (Klein, Davis et al. 1991) was used by masked graders at the Wisconsin
Ocular Epidemiology Reading Center to grade individual AMD lesions. Detailed
descriptions of all grading procedures and definitions were previously reported (Klein,
Klein et al. 1997; Varma, Fraser-Bell et al. 2004). In brief; a lesion-by-lesion evaluation
was performed at each examination to determine maximum drusen size, type, and area
and retinal pigmentary abnormalities. Each eye was graded independent of the contra
lateral eye. Any clinically meaningful differences between the results of two initial
graders were adjudicated by a senior grader using standardized edit rules.
Various classifications are used to define the presence of early and advanced
AMD. The WARMGS (Klein, Davis et al. 1991) defined early AMD as the absence of
signs of advanced AMD and the presence of 1) soft indistinct or reticular drusen or 2)
hard distinct or soft distinct drusen with pigmentary abnormalities (retinal pigment
epithelial (RPE) depigmentation or increased retinal pigment (IRP). With respect to
drusen type, the presence of any soft indistinct or reticular drusen is considered early
AMD, as well as any other type with pigmentary abnormality.
Advanced or late AMD was defined as the presence of either 1) GA or 2)
exudative AMD. Exudative AMD was defined as the presence of any of the following
exudative lesions: 1) pigment epithelial detachment or age-related retinal detachment, 2)
subretinal hemorrhage, 3) subretinal scar (subretinal fibrous scar), or 4) laser treatment
for exudative ARM. Population-based studies that have used this definition include the
68
Beaver Dam Eye Study, the Blue Mountains Eye Study, and the Los Angeles Latino Eye
Study for baseline data.
To assess the qualitative relationship between AMD severity and QoL, we used
the modified WARMGS 6-step severity scale (level 10-60) for a subgroup of the total
sample. The descriptions of the levels are as follows:
Level 10: Hard drusen or small soft drusen < 125 microns in diameter only, regardless of
area of involvement, and no pigmentary abnormality (increased retinal pigment or RPE
depigmentation) present.
Level 20: Hard drusen or small soft drusen < 125 microns in diameter, regardless of area
of involvement, with any pigmentary abnormality (increased retinal pigment present
and/or RPE depigmentation) present,
OR
Soft drusen > 125 microns in diameter with drusen area < 196,350 square microns
(equivalent to a circle with a diameter of 500 microns) and no pigmentary abnormalities
Level 30: Soft drusen > 125 microns in diameter with drusen area < 196,350 square
microns with any pigmentary abnormality (increased retinal pigment present and/or RPE
depigmentation) present,
OR
Soft drusen > 125 microns in diameter with drusen area > 196, 350 square microns with
or without increased retinal pigment but no RPE depigmentation.
Level 40: Soft drusen > 125 microns in diameter with drusen area > 196,350 square
microns equivalent to a circle with a diameter of 500 microns) and RPE depigmentation
present, with or without increased retinal pigment.
69
Level 50: Presence of pure geographic atrophy in the absence of exudative macular
degeneration.
Level 60: Presence of exudative macular degeneration with or without geographic
atrophy present.
According to this scheme, a severity level of 10 corresponds to no AMD, levels 20-40
correspond to different levels of early AMD; levels 40 and 50 represent late AMD.
We also derived a per person composite scale to incorporate severity and
bilaterality for each person by concatenating per person bilateral severity using a scheme
similar to that previously used by Klein et al (Klein, Moss et al. 1989) for diabetic
retinopathy. In brief, the severity of AMD for a participant was derived by combining the
severity levels for each eye but giving greater weight to the eye with the higher level of
severity (Appendix C). This resulted in an 11-step scale; (10/10, 20/<20, 20/20, 30/<30,
30/30, 40/<40, 40/40, 50/<50, 50/50, 60/<60, 60/60). If the severity of AMD could not be
graded in one eye of an individual, that eye was considered to have a score equivalent to
the score of the other eye.
Assessment of Health-Related Quality of Life
HRQoL was evaluated using general and vision-specific instruments. Interviewers
administered the questionnaires in either English or Spanish (according to participant
preference) prior to the clinical examination at the LALES Local Eye Examination
Center. General HRQoL was assessed by the Short Form 12-item Health Survey (SF-12),
version 1 (Ware, Kosinski et al. 1996). The standard U.S. norm-based SF-12 Physical
70
Component Summary (PCS) and Mental Component Summary (MCS) scores were
calculated,(Ware 1995) with higher scores representing better HRQoL. Self-reported,
vision-related HRQoL was assessed by the National Eye Institute Visual Function
Questionnaire (NEI-VFQ-25), a disease-targeted set of measures designed to complement
the SF-12 by focusing on aspects of HRQoL particularly relevant to visually impaired
adults, regardless of the cause of visual disability (Mangione, Lee et al. 1998; Mangione,
Lee et al. 2001).
The NEI-VFQ-25 consists of 12 vision-targeted scales: general vision,
general health, near and distance vision activities, ocular pain, vision-related social
function, vision-related role function, vision-related mental health, vision-related
dependency, driving difficulties, color vision, and peripheral vision. The standard
algorithm was used to calculate the scale scores, which have a possible range from 0 to
100. Eleven of the 12 scale scores (excluding the general health rating question) were
averaged to yield a composite score (Mangione, Lee et al. 1998; Mangione, Lee et al.
2001), with higher scores representing better visual functioning and well-being.
Statistical Analyses
Comparison of socio-demographic and clinical factors across subgroups defined by status
of AMD (AMD versus no AMD) was conducted using t-tests for continuous variables
and chi-square tests for discrete variables. Covariate-adjusted mean QoL scores were
compared between no, early and late AMD using analysis of covariance (ANCOVA).
Covariates previously found to be associated with self-reported visual functioning, as
well as those that changed the effect size >10%, were included in the model. Covariates
included were age, gender, vision insurance, comorbidities, income and other ocular
71
disease. Because of the high correlation between age and employment status, only age
was retained. The similar correlation between income and education precluded the
inclusion of education in the model. Since some of the HRQoL scores were not normally
distributed, a logarithmic transformation was performed to approximate the normal
distribution during analysis, and the data was back transformed for reporting of the
results. Similar analyses were used to compare the HRQoL scores between those with no
AMD and other subgroups, as defined by alternative measures of AMD. The same
baseline comparison group of no AMD was used for all analyses for ease of interpretation
of the results.
Effect size (ES) for NEI-VFQ scores and SF-12 scores was calculated for any
AMD and separately for early and late AMD. The ES is an index used to measure the
magnitude of impact of one variable on an outcome variable. The ES was calculated as
the difference in the mean lesion scores between those with no AMD and those with a
particular AMD lesion, divided by the standard deviation of the baseline group. The
standard deviation for the no AMD group was used to provide a common denominator
for all pair-wise comparisons. Based on Cohen’s suggestion, an absolute value of ES of
0.20-0.49 is considered small, 0.50-0.79 moderate and 0.80 or greater is large (Cohen
1988; Cohen 1977). The analyses were repeated for different types of AMD, and subjects
with no AMD were considered as the comparator group in all analyses.
To further assess the nature of the relationship and to examine the possible non-
linear relationship between these risk factors and the severity of AMD, we used local
regression methods, adjusting for other covariates from the final logistic regression
model, to generate LOWESS (locally weighted smoothing regression) plots (Cleveland
72
and Devlin 1988). These analyses were performed on a subset of the whole sample
(3850/4876) with available modified WARMGS grading at baseline. For these analyses,
predicted QoL values were derived for the composite NEI-VFQ score, driving difficulty,
distant vision, near vision, role function, and social function, as well as for the SF-12
PCS and MCS. Regression was adjusted for age, gender, vision insurance, comorbidities,
income and other ocular disease. Because of the non-normal distribution some of the QoL
scores, median values were reported for raw and predicted scores by clinical severity as a
robust measure for characterizing the trend in HRQoL scores. We fitted models of AMD
severity for both eyes (concatenated) and separately for the worse eye and the better eye.
To examine the rate of descent of the HRQoL score and to determine the
inflection point or threshold at which there is a considerable decrease in QoL scores, we
computed the slope m between all consecutive points (y
i
,y
i+1
) of the LOWESS curve,
where 1 i 11 predicted median values and 0 y 100. This collection of slopes
provides a unified way to summarize the magnitude of change in HRQoL between
consecutive steps of severity. We also compared the change in slope values for each pair
of consecutive points by measuring the decrease in consecutive slopes.
Possible effect modification of the association between AMD and the predictors
was tested by incorporating the proper interaction term in the logistic regressions models.
The analyses were performed using SAS software 9.2 (SAS, Inc, Cary, NC) and Stata
version 11 (StataCorp, TX). All tests for significance were at P-value 0.05 level.
Had Fundus photo
taken
(n= 6052)
Had fundus photo gradable for
AMD
(n = 5888)
Participants completed
clinical exam in LALES I
(n= 6357)
Fundus photo not
gradable for AMD
N =164
No fundus photo
at baseline
N = 305
Had no missing value in major
QOL subscales
N = 4876
(analysis cohort)
Missing values in QOL subscales
N =588
Had Clinical Questionnaire
data
(N = 5464)
(n 5888)
No clinical questionnaire data
N =424
Figure 3.1: Flow-chart of analysis cohort 2
73
74
3.4 Results
Description of Study Cohort
Figure 3.1 presents the flow-chart leading to the AMD study cohort. Of the 6,357
participants who completed an ophthalmic examination, 6,052 had fundus photographs.
Out of the 6052 person with fundus photograph 5888 had gradable photographs
for AMD; 5,464 had completed the SF-12 and NEI-VFQ-25 questionnaires; and the 4876
participants with no missing values in primary QoL subscales were included in the
analyses. Out of the 4,876 participants included in the analysis, 4402 (54%) had no
AMD; 474 had any AMD (9.7%), with 453 having early (9.2%) and 21 (0.5%) having
late stages of the disease. Other than income (P<0.001) and reported history of ocular
disease (P=<0.004), there were no major differences between participants included and
excluded from this cohort (Table not shown). Participants were more likely to have
higher income and more likely to report other ocular conditions compared to non-
participants.
The comparisons of different demographic and clinical characteristics between
participants with or without AMD are summarized in Table 3.1. Participants with AMD
were significantly older (P <0.001) and more likely to be female (P<0.001) than those
without AMD. Also, participants were less likely to be educated (P=0.003) or to have
higher earnings (P=0.001), more likely to have vision insurance (P=0.02) and more likely
to be unemployed or retired (P=0.006) than those without AMD. Those with AMD were
also more likely to report a history of any ocular disease (P<0.001).
75
Health-related Quality of Life and AMD status
Table 3.2 summarizes the results of mean differences in HRQoL scores and effect
sizes by AMD status. We found statistically significant differences (P<0.01 for all) across
sub-groups of no, early, and late AMD in all subscales of the NEI-VFQ except general
health and ocular pain.
Table 3.1: Sociodemographic and Clinical characteristics stratified by presence or
absence of AMD in participants in the Los Angeles Latino Eye Study (N= 4,876)
†Data are presented as mean (SD) for age, acculturation and comorbidities; frequency (%) for all other variables.
P-values were calculated using t-test for continuous variables and chi-square for categorical variables. Acculturation was
measured using the short-form Cuellar Acculturation Scale.
Variables No AMD AMD P-value
†
(N =4402 ) (N =474)
Age (years)
54.2 (10.3) 60.2 (12.6) <0.001
Gender: female
2650 (60.2) 225 (47.5) <0.001
Unemployed/ retired
2219 (50.4) 179 (37.8) <0.001
Income <$50,000
1919 (49.8 ) 169 (41.4) 0.001
Education<12 years
2874 (65.5) 349 (73.8) 0.003
Health insurance: Yes
2839 (64.6) 327 (70.0) 0.06
Vision insurance: Yes
2190(49.9) 264 (55.7) 0.02
Acculturation score‡
1.9 (0.9) 1.8 (0.9) 0.72
Country of birth (USA)
1068 (24.3) 121 (25.5) 0.54
Marital status (Married/ Partner)
3212 (73.2) 331 (70.1 ) 0.15
Comorbidities§
1.5 (1.5) 1.6 (1.6) 0.12
History of any ocular disease
514 (11.7) 95 (20.0) <0.001
Table 3.2: Mean health related quality of life scores and the effect size (ES) stratified by severity of AMD in participants in
the Los Angeles Latino Eye Study
No AMD (N=4402 ) Early AMD (N=453) Late AMD (N=25)
P-value
Mean SD Mean SD ES
††
Mean SD ES
††
SF12
Physical Composite Score 50.4 10.8 49.8 10.5 -0.05 50.9 10.7 0.05 0.25
Mental Composite Score 47.0 9.6 46.8 9.8 -0.02 44.0 12.5 -0.32 0.51
NEI-VFQ-25
Composite Score* 80.7 13.2 79.4 14.5 -0.10 59.5 26.6 -1.60 <0.001
Color Vision* 95.1 14.3 94.2 16.1 -0.06 84.3 28.1 -0.76 0.002
Vision Related Dependency* 75.7 19.0 74.0 21.6 -0.09 45.2 35.1 -1.58 <0.001
Driving Difficulty*
†
82.5 16.2 80.7 20.5 -0.12 43.3 43.0 -2.43 <0.001
Distance Vision* 83.3 17.8 82.2 19.3 -0.07 56.5 35.4 -1.51 <0.001
General Health 59.4 23.4 58.9 23.6 -0.02 54.1 21.4 -0.23 0.48
General Vision* 63.5 16.4 63.0 15.5 -0.03 47.7 20.6 -0.96 <0.001
Vision Related Mental Health* 70.6 21.4 68.8 22.3 -0.09 46.4 30.3 -1.14 <0.001
Near Vision* 75.9 19.6 74.4 20.2 -0.08 46.9 31.8 -1.49 <0.001
Ocular Pain 76.3 20.3 74.9 21.1 -0.07 71.7 24.8 -0.23 0.24
Peripheral Vision* 86.8 20.1 86.0 21.0 -0.04 72.3 31.1 -0.72 0.003
Vision Related Role Function* 86.1 20.4 84.5 22.4 -0.08 59.2 34.4 -1.32 <0.001
Vision Related Social Function* 92.4 13.6 91.6 14.5 -0.06 67.7 32.6 -1.82 <0.001
*One way ANOVA P<0.05. age, gender, comorbidities, history of ocular disease and health insurance status
†
Score could be generated for only 3507 of the participants in the whole sample.
††
Effect size (ES) is defined as mean difference of scores by AMD status (no vs early; no vs late) divided by standard deviation of scores for controls.
ES: small (0.2-0.49), moderate (0.50-0.79), large: 0.80
76
77
Although the mean differences were significant, the ES for each of these QoL
scores were quite modest (all ES<0.2) for early AMD. However, there were small to very
large effect sizes with late AMD in all subscales. Effects were greatest for driving
difficulty (ES= -2.43), composite scores (ES= -1.60), vision-related dependency (ES=-
1.58), near vision (ES= -1.49), distance vision (ES= -1.51 and vision-related social
function (ES=-1.82). There were no significant mean differences in the SF-12 HRQoL
scores among the AMD groups.
Health-related Quality of Life and Early AMD lesions
We examined the mean differences in participants, stratifying them by presence of
early AMD lesions and comparing them with those without any evidence of AMD. There
were no statistically significant differences in QoL scores between participants with soft
distinct drusen and those without any evidence of AMD (Table 3.3). However, compared
to those without AMD, participants with soft drusen had lower score in composite NEI-
VFQ 25 scale (p=0.004) and nine subscales including vision-related dependency
(p=0.003), driving difficulty (p=0.001), distance vision (p=0.001), vision-related mental
health (p=0.01), near vision (p=0.003), vision related role function (p=0.002), vision
related social function and color vision (p=0.02). For these participants, there were small
effects in composite score (ES= -0.20) and driving difficulty (ES= -0.20).
Table 3.4 summarizes the results of QoL analyses on subjects with IRP
and RPE depigmentation. Increased pigmentation was associated with lower scores in
composite (p<0.001), vision-related dependency (p<0.001), driving difficulty (p<0.001),
distance vision (p=0.007), general vision (p=0.03), vision-related mental health
(p=0.002), near vision (p=0.002), vision related role function (p=0.001) and vision
78
related social function (p<0.001). Similarly, compared to people without any AMD
lesion, people with depigmentation had lower scores in composite (p<0.001), vision-
related dependency (p<0.001), driving difficulty (p<0.001), distance vision (p<0.001),
vision-related mental health (p=0.032), near vision (p<0.001), vision related role function
(p<0.001), and vision related social function (p<0.001) and color vision (p=0.008).
Additionally, there were small effects on composite score (ES= -0.27) and six other
subscales, including driving difficulty (ES= -0.34).
Similarly, compared to people without any AMD lesion, people with RPE
depigmentation had lower scores in composite (p<0.001), vision-related dependency
(p<0.001), driving difficulty (p<0.001), distance vision (p<0.001), vision-related mental
health (p=0.032), near vision (p<0.001), vision related role function (p<0.001), and vision
related social function (p<0.001) and color vision (p=0.008). No significant associations
were observed for SF-12 MCS or PCS for any of the early AMD lesions.
Health-related Quality of Life and Late AMD lesions
Similar analyses were repeated in people with late AMD lesions (Table 3.5).
Participants with GA had statistically significant lower mean scores (P<0.001 for 7
subscales and <0.003 for 2 subscales) and larger effects than those without any AMD for
eight of 12 subscales and the composite score (P=<0.001; ES=-1.87). Some of the effects
were very large with the largest effect being -2.22 for driving difficulty.
Results were similar, albeit more pronounced, when participants with exudative
AMD were compared to those without any lesion. Statistically lower mean scores for 10
of the 12 NEI-VFQ subscales and composite score for those with exudative AMD.
Table 3.3: Mean health related quality of life scores and the effect size (ES) stratified by drusen type in participants in the
Los Angeles Latino Eye Study
No AMD
(N=4402 )
Soft Distinct Drusen(N=879)** Soft Indistinct Drusen(N=347)
Mean SD Mean SD ES
††
P-value Mean SD ES
††
P-value
NEI-VFQ-25
Composite Score* 80.7 13.2 80.2 13.4 -0.04 0.56 58.1 26.6 -0.20 0.004
Color Vision* 95.1 14.3 94.8 14.2 -0.02 0.44 86.1 29.6 -0.13 0.02
Vision Related Dependency* 75.7 19.0 75.0 19.4 -0.04 0.59 44.4 35.3 -0.16 0.003
Driving Difficulty*
†
82.5 16.2 81.3 18.7 -0.08 0.18 37.3 51.5 -0.20 0.001
Distance Vision* 83.3 17.8 83.4 18.3 0.00 0.21 53.5 34.1 -0.17 0.001
General Health 59.4 23.4 60.3 23.3 0.04 0.93 58.5 21.9 -0.01 0.91
General Vision* 63.5 16.4 62.2 15.8 -0.07 0.47 46.0 17.5 -0.04 0.55
Vision Related Mental Health* 70.6 21.4 69.9 21.1 -0.03 0.23 46.6 31.1 -0.14 0.01
Near Vision* 76.0 19.6 75.8 19.5 -0.01 0.88 42.9 32.4 -0.16 0.003
Ocular Pain 76.3 20.3 75.5 20.5 -0.04 0.75 73.0 21.0 -0.10 0.09
Peripheral Vision* 86.8 20.1 86.6 20.5 -0.01 0.69 61.8 30.9 -0.09 0.09
Vision Related Role Function* 86.1 20.4 85.8 21.2 -0.02 0.97 60.9 36.3 -0.16 0.002
Vision Related Social Function* 92.4 13.6 92.4 14.1 0.00 0.54 68.8 29.8 -0.15 0.006
*One way ANOVA P<0.05,adjusted for age, gender, comorbidities, history of ocular disease and health insurance status
†
Score could be generated for only 3507 of the participants in the whole sample. ** This group is not mutually exclusive with the baseline group
††
Effect size (ES) is defined as mean difference of scores by status of the lesion (Soft Distinct drusen vs no AMD etc.) divided by standard deviation of scores for controls
(no AMD): ES: small (0.2-0.49), moderate (0.50-0.79), large: 0.80
79
Table 3.4: Mean change in health related quality of life scores and effect size (ES) stratified by pigmentary changes in
participants in the Los Angeles Latino Eye
No AMD (N=4402 ) Increased pigmentation(N=267) RPE depigmentation (N=107)
Mean SD Mean SD ES
††
P-value Mean SD ES
††
P-value
SF12
Physical Composite Score 50.4 10.8 50.3 10.1 -0.09 0.28 50.3 10.4 -0.003 0.75
Mental Composite Score 47.0 9.6 46.5 10.11 -0.05 0.47 46.5 10.6 -0.049 0.65
NEI-VFQ-25
Composite Score* 80.7 13.2 75.1 17 -0.27 <0.001 75.1 20.3 -0.42 <0.001
Color Vision* 95.1 14.3 91.2 17.1 -0.11 0.14 91.2 20.5 -0.27 0.008
Vision Related Dependency* 75.7 19.0 69.5 23.7 -0.24 <0.001 69.5 26.4 -0.33 <0.001
Driving Difficulty*
†
82.5 16.2 75.9 25.7 -0.35 <0.001 75.9 26.4 -0.41 <0.001
Distance Vision* 83.3 17.8 76.8 22.7 -0.21 0.007 76.8 26.5 -0.36 <0.001
General Health 59.4 23.4 59.3 23 -0.05 0.28 59.3 23.3 -0.01 0.83
General Vision* 63.5 16.4 60.2 16.63 -0.18 0.03 60.2 17.8 -0.20 0.08
Vision Related Mental Health* 70.6 21.4 63.6 23.38 -0.23 0.002 63.7 25.2 -0.32 0.003
Near Vision* 76.0 19.6 67.7 22.14 -0.22 0.002 67.7 27.1 -0.42 <0.001
Ocular Pain 76.3 20.3 73.8 21.14 -0.11 0.23 73.8 20.9 -0.12 0.38
Peripheral Vision* 86.8 20.1 82.4 22.49 -0.11 0.25 82.4 25.6 -0.22 0.05
Vision Related Role Function* 86.1 20.4 78.5 25.37 -0.23 0.001 78.5 29.1 -0.37 <0.001
Vision Related Social Function* 92.4 13.6 87.2 18.35 -0.26 <0.001 87.2 21.5 -0.39 <0.001
*One way ANOVA P<0.05,adjusted for age, gender, comorbidities, history of ocular disease and health insurance status
†
Score could be generated for only 3507 of the participants in the whole sample
††
Effect size (ES) is defined as mean difference of scores Status of the
pigmentary lesion (IRP vs no AMD,) divided by standard deviation of scores for controls (no AMD)
ES: small (0.2-0.49), moderate (0.50-0.79), large: 0.80
80
81
Severity of AMD and Health-related Quality of Life
Based on LOWESS plots, we observed decreasing scores in HRQoL with
increasing severity of AMD for different domains of the NEI-VFQ QoL. This was true
when severity was defined for the worse eye, the better eye, or both eyes.
When we looked at the severity of AMD in the worse eye and the composite NEI-
VFQ-25 score, the decrease in median predicted QoL score begins relatively early in the
moderate stages of early AMD with the decrease in scores beginning at a severity level of
40 with a slope of -0.6 (Figure 3.2).
The level of severity where we observe this change corresponds to having a soft
drusen > 125 microns in diameter with involvement of drusen area > 196,350 square
microns and presence of RPE depigmentation with or without increased retinal pigment.
When we repeated the analyses for the better eye, the drop in the QoL score from level 30
to 40 was more pronounced, with a slope of –2.79 (Figure 3.3).
To explore the role of bilaterality we plotted the bilateral concatenated severity of
AMD against the QoL scores. Figure 3.4 shows the LOWESS plot for 11 steps of
bilateral severity of AMD and its relationship with NEI-VFQ-25 composite score.
This figure and the slopes were suggestive of a gradual decrease in QoL in the
initial stages of early AMD (slope m
10/10-40/<40
= -0.53) up to a unilateral severity of level
40, after which there isa sudden and sharp decrease in HRQoL between steps 6 and 7
(slope m
40/<40-40/40
= -19.17), corresponding to a bilateral severity of level 40. The change
in slope continued to decrease, with another sharp drop between steps 60/<60 (unilateral
neovascular AMD) and 60/60 (bilateral neovascular AMD).
Table 3.5: Mean change in health related quality of life scores and effect size (ES) stratified by type of advanced AMD in
participants in the Los Angeles Latino Eye Study
No AMD (N=4402
)
Geographical Atrophy (N=12) Exudative AMD (N=17)
Mean SD Mean SD ES
††
P-value Mean SD ES
††
P-value
SF12
Physical Composite Score 50.4 10.8 49.1 12.1 -0.12 0.83 50.9 10.7 0.16 0.41
Mental Composite Score 47.0 9.6 42.1 11.3 -0.51 0.05 44.0 12.5 -0.25 0.31
NEI-VFQ-25
Composite Score* 80.7 13.2 55.9 25.7 -1.87 <0.001 59.5 26.6 -1.70 <0.001
Color Vision* 95.1 14.3 81.8 22.5 -0.93 0.002 84.3 28.1 -0.63 0.04
Vision Related Dependency* 75.7 19.0 43.1 33.3 -1.72 <0.001 45.7 35.0 -1.65 <0.001
Driving Difficulty*
†
82.5 16.2 46.6 39.3 -2.22 <0.001 43.3 43.0 -2.79 <0.001
Distance Vision* 83.3 17.8 50.9 36.0 -1.82 <0.001 56.5 35.4 -1.67 <0.001
General Health 59.4 23.4 54.8 20.9 -0.20 0.41 54.1 21.4 -0.04 0.80
General Vision* 63.5 16.4 43.7 23.1 -1.20 <0.001 47.7 20.6 -1.07 0.004
Vision Related Mental Health* 70.6 21.4 41.8 26.2 -1.35 <0.001 46.4 30.3 -1.13 <0.001
Near Vision* 76.0 19.6 45.9 29.5 -1.53 <0.001 46.9 31.8 -1.69 <0.001
Ocular Pain 76.3 20.3 65.7 26.4 -0.52 0.09 71.7 24.8 -0.16 0.66
Peripheral Vision* 86.8 20.1 76.3 30.4 -0.52 0.08 72.3 31.1 -1.24 <0.001
Vision Related Role Function* 86.1 20.4 50.3 35.1 -1.76 <0.001 59.2 34.4 -1.24 <0.001
Vision Related Social Function* 92.4 13.6 62.8 35.5 -2.18 0.83 67.7 32.6 -1.73 <0.001
*One way ANOVA P<0.05, adjusted for age, comorbidities and health insurance status
†
Score could be generated for only 3507 of the participants in the whole sample.
††
Effect size (ES) is defined as mean difference of scores by status of Status of late AMD lesions (GA vs no AMD, Exudative Vs no AMD) divided by standard deviation of
scores for controls (no AMD):
ES: small (0.2-0.49), moderate (0.50-0.79), large: 0.80
82
83
Figure 3.2: AMD severity and composite NEI-VFQ score (in worse eye)
Figure 3.3: AMD severity and composite NEI-VFQ score (in better eye)
30 40 50 60 70 80 90
Predicted mean composite score
10 20 30 40 50 60
Severity of AMD
30 40 50 60 70 80 90
Predicted mean composite score
10 20 30 40 50 60
Severity of AMD
84
Figure 3.4: Bilateral AMD severity and composite NEI-VFQ score
Figure 3.5 shows a comparison of AMD associated vision specific QoL pattern
represented by composite NEI-VFQ-25 score and generic QoL pattern by represented by
SF-12 PCS score. Compared to the pronounced slope changes in composite NEI-VFQ-25
score there was very little change in the SF-12 PCS score associated with bilateral
severity of AMD.
Similar trends of decrease in median predicted score were observed when these
plots were repeated in most of the other NEI-VFQ25 subscales, including driving
difficulty, near vision, distant vision, role function and social function. The associations
were similar for the worse eye, the better eye and both eyes. All these domains showed a
sharp drop from a unilateral severity level 40 to a bilateral severity level 40 with slopes of
-33.31 for driving difficulty, -28.47 for near vision, -25.35 for distant vision, -60.42 for
role function and -15.63 for social function (figures not shown).
20 30 40 50 60 70 80 90
Predicted mean composite score
10/10
20/<20
20/20
30/<30
30/30
40/<40
40/40
50/<50
50/50
60/<60
60/60
concatenated severity of AMD
85
Figure 3.5: Comparison of generic and vision-specific HRQoL
To assess the statistical significance of the threshold effect or turn-point, the
Wilcoxon test was applied to compare the HRQoL scores by severity of DR (group
10/10-
40/<40
vs. group
40/40 –60/60
). The P-values were <0.0001 for all of the subscales mentioned.
These results indicate that in patients suffering from bilateral intermediate stages of
AMD, which is still considered early in the course of the disease, QoL is significantly
diminished. In other words, the presence of bilateral drusen of > 125 microns
accompanied by bilateral RPE depigmentation in both eyes resulted in the most
significant drop in most QoL parameters in this population group.
3.5 Discussion
Using the NEI-VFQ-25, we found that participants with AMD had lower vision-
specific HRQoL scores compared to participants without AMD. Participants with early
30 40 50 60 70 80 90
Predicted mean QoL scores
10/10
20/<20
20/20
30/<30
30/30
40/<40
40/40
50/<50
50/50
60/<60
60/60
Concatenated severity of AMD
NEI-VFQ-25 composite SF-12 PCS
86
AMD lesions, including soft indistinct drusen and pigmentary abnormalities had
statistically significantly lower mean scores for several vision-specific HRQoL subscales
like driving, near vision, and distant vision, as well and role and social function.
Participants with late AMD lesions (i.e. GA and/ or neovascular AMD) had statistically
significantly lower mean QoL scores and large effects compared to those without AMD in
almost all of the NEI-VFQ subscales. Additionally, lower scores in color vision (p=0.002)
were associated with both late AMD lesions and lower scores peripheral vision (p=0.003)
was associated with presence of neovascular AMD. Measures of general health, as
indicated by the SF-12 were not affected in our cohort.
We observed a strong, inverse association between severity of AMD and HRQoL.
Both severity and bilaterality of disease was associated with lower QoL scores, such that
participants with more severe AMD had lower HRQoL scores than participants with early
AMD, and participants with bilateral disease had lower scores than those with unilateral
disease. When examining the pattern of QoL scores with increasing severity of AMD, the
scores were lower in moderate levels of AMD with involvement of both eyes. Our results
indicate that there was an inverse association of AMD severity with vision specific
quality of life. Specifically, the presence of bilateral drusen 125 microns with an area of
involvement of 196,350 square microns, accompanied by bilateral RPE depigmentation
in both eyes was associated with the most substantially low HRQoL mean scores in this
population.
Our results are consistent with previously published results on AMD and HRQoL
(Mitchell and Bradley 2006; Covert, Berdeaux et al. 2007; Coleman, Yu et al. 2010).
Several studies
have found similar evidence of the significant impact of late AMD on
87
QoL. There are few studies showing the effect of early AMD on QoL despite the fact that
early AMD are much more common than late AMD. However, our results for early AMD
lesions are consistent with those reported by Scilley et al (Scilley, Jackson et al. 2002),
who found that persons in early phases of AMD are more likely to experience difficulty
in driving and to have trouble with daily tasks involving near and far vision tasks than
people without AMD.
Overall, the differences in QoL scores between persons with unilateral and
bilateral moderate levels of AMD (with large drusen and depigmentation) were the
largest and most substantial across the spectrum of AMD severity in our study. A number
of studies have demonstrated lower HRQoL scores in patients with bilateral AMD,
especially in the late stages, compared to patients with unilateral disease (de Jong 2006;
Mitchell and Bradley 2006; Covert, Berdeaux et al. 2007). Moderate macular
degeneration of the one eye is compensated for by the better eye, allowing individuals
with unilateral AMD to sustain a relatively good QoL. Hence, the prevention of both the
occurrence of AMD and its progression from unilateral to bilateral disease can potentially
have a positive impact on HRQoL. The detrimental impact of bilateral eye disease had
also been observed in other ocular conditions in the LALES population (McKean-
Cowdin, Wang et al. 2008; Mazhar, Varma et al. 2011; Patino, Varma et al. 2011).
The lower scores in QoL scales such as driving difficulty, near vision and distant
vision can be explained by the decline in visual acuity and impaired contrast sensitivity of
those with late AMD. Although visual acuity is not affected in early AMD, contrast
sensitivity is postulated to be affected, thereby resulting in reduced visual function.
Specifically, scotopic dysfunction has been demonstrated as a marker of early AMD in
88
some studies. Impaired visual function may eventually lead to loss of independence and
reduced mobility, which may contribute to reduced physical activity and social isolation.
In this analysis we found no significant negative association of AMD with general
measures of HRQoL, as assessed by the SF-12 physical and mental composite scores.
These findings are consistent with other studies that found these instruments not to be
sensitive to ocular disease, including AMD
(Mitchell and Bradley 2006). Studies with the
LALES data on other ocular conditions also reported similar low responsiveness
(McKean-Cowdin, Wang et al. 2008; Mazhar, Varma et al. 2011; Patino, Varma et al.
2011). Mitchell et al (2006) postulated that general measures of health status may not be
sensitive to ocular conditions, as patients with AMD or other ocular disease may
otherwise be considerably healthy.
The current analysis has several strengths. This analysis was performed on a large
population base with adequate statistical power to study different phenotypes, especially
the early onset ones. Use of a standardized protocol for objective measurement and
grading of AMD cases minimized the chance of measurement error (Klein, Davis et al.
1991; Varma, Paz et al. 2004). Although HRQoL is a self-reported patient outcome, we
used validated measures of HRQoL that have been evaluated in a different population
(Broman, Munoz et al. 2001; Lindblad and Clemons 2005; Mitchell and Bradley 2006).
Specifically, the NEI-VFQ-25 has been validated for macular degeneration (Mitchell and
Bradley 2006) and for Hispanic populations in particular (Broman, Munoz et al. 2001).
This instrument has also been used previously for the LALES population (Broman,
Munoz et al. 2001; McKean-Cowdin, Varma et al. 2007; McKean-Cowdin, Wang et al.
89
2008; McKean-Cowdin, Varma et al. 2010; Mazhar, Varma et al. 2011; Patino, Varma et
al. 2011).
A common concern when using a QoL instrument to measure the impact of AMD
is the potential impact of the participant’s knowledge that they have AMD on the
responses to the QoL questionnaire. We believe this is not likely to be an issue in this
study as the HRQoL interview was completed before AMD was graded and ascertained,
and hence, the participant did not know about their visual health status.
While our overall sample of AMD was large compared to previous studies, we
did not have a large number of participants with late AMD (GA/neovascular AMD).
Another limitation of our study is the use of cross-sectional data, which limits our ability
to make conclusions with respect to the effect of longitudinal changes in AMD on
HRQoL over time. Because our study focused primarily on the adult Latino population
in Los Angeles County, our findings may not be generalizable to the entire adult U.S.
population or U.S. Latinos who are not of Mexican ancestry. However, one would expect
the biological impact of AMD to be similar. Nonetheless, cultural differences may
influence how participants respond to items in standardized survey instruments.
Additional research on a more diverse population or other sub-populations is needed to
complement our study findings.
In conclusion, patients with AMD have worse health-related quality of life early
in the disease process with lesions defined as early AMD (soft indistinct drusen,
pigmentary changes). Persons with late AMD lesions have significantly worse QoL
scores overall than participants with early AMD and no AMD. We observed a strong,
inverse association between severity of AMD and HRQoL. These associations were
90
impacted by laterality of disease so that participants with bilateral large drusen and
depigmentation had a significantly worse QoL than people with a unilateral condition of
the same severity. Further longitudinal analysis is needed to confirm these associations to
guide clinicians on evidence-based intervention programs targeting the groups at risk of
most severe decline in visual functioning and quality of life.
91
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quality of life in glaucoma: the Los Angeles Latino Eye Study. Ophthalmology
115(6): 941-948 e941.
Mitchell, J. and C. Bradley (2006). Quality of life in age-related macular degeneration: a
review of the literature. Health Qual Life Outcomes 4: 97.
Patino, C. M., R. Varma, et al. (2011). The impact of change in visual field on health-
related quality of life the los angeles latino eye study. Ophthalmology 118(7):
1310-1317.
Scilley, K., G. R. Jackson, et al. (2002). Early age-related maculopathy and self-reported
visual difficulty in daily life. Ophthalmology 109(7): 1235-1242.
Varma, R., S. Fraser-Bell, et al. (2004). Prevalence of age-related macular degeneration
in Latinos: the Los Angeles Latino eye study. Ophthalmology 111(7): 1288-1297.
Varma, R., S. H. Paz, et al. (2004). The Los Angeles Latino Eye Study: design, methods,
and baseline data. Ophthalmology 111(6): 1121-1131.
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construction of scales and preliminary tests of reliability and validity. Med Care
34(3): 220-233.
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Ware, J. E., Ed. (1995). SF-12: How to Score the SF-12 Physical and Mental Health
Summary Scales. Boston, MA, New England Medical Center Hospital Health
Institute.
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Chapter 4: Longitudinal Changes in Age Related Macular Degeneration
and Health Related Quality of Life in Latinos
4.1 Introduction
Age-related Macular degeneration (AMD) is the leading cause of irreversible
visual disability in the western world in the older population (Kahn HA 1977; Varma,
Fraser-Bell et al. 2004; de Jong 2006; Coleman, Chan et al. 2008). Severe central vision
loss associated with AMD can significantly compromise health-related quality of life
(HRQoL), qualitatively and quantitatively (Mitchell and Bradley 2006; Coleman, Yu et
al. 2010).
There are few large epidemiologic studies that have investigated the relationship
between AMD and QoL and even fewer studies have investigated the true impact of
changes in AMD status on QoL (Mitchell and Bradley 2006; Coleman, Yu et al. 2010).
The majority of studies involving AMD and QoL were done as part of clinical trials
exploring different interventions for lesions characteristic of late AMD, especially
neovascular AMD (Dong, Childs et al. 2004). In epidemiologic studies, investigators
found strong associations between presence of late AMD and HRQoL (Mangione,
Gutierrez et al. 1999; Mitchell and Bradley 2006; Coleman, Yu et al. 2010). A small
number of studies found a measurable impact of early AMD on QoL (Scilley, Jackson et
al. 2002; Maguire 2004). Some studies suggest that impact of early AMD on HRQoL is
greatly underestimated and under-investigated (Scilley, Jackson et al. 2002; Brown and
Brown 2010).
96
To date, there have been no published studies on the impact of changes in AMD
status and severity on HRQoL in Latinos. Results from our cross-sectional analyses of
data from participants in the Los Angeles Latino Eye (LALES) on the association
between prevalent AMD and HRQoL suggest an inverse association between severity of
AMD and Quality of life. Specifically persons with late AMD lesions experience
significant decrease in vision specific quality of life, measured by National Eye Institute
Vision Specific Questionnaire (NEI-VFQ-25), compared to persons with early AMD and
persons with no AMD. Our results also suggest that a measurably lower quality of life is
associated with lesions defined as early AMD (soft indistinct drusen, increased retinal
pigmentation, RPE depigmentation). We also found that both severity and bilaterality of
AMD is associated with worse vision specific QoL. However, general HRQoL, measured
by the Short Form 12-item Health Survey (SF-12), was not associated with any type of
AMD lesion.
To further investigate the true impact of AMD on individuals it is important to see
the intra-individual longitudinal changes in AMD over a period of time and the
associated changes in HRQoL. To address this we have analyzed the baseline and 4
year follow-up data from LALES to look at the changes of AMD and the impact on
vision specific and general HRQoL.
4.2 Methods
Design and Sample
The Los Angeles Latino Eye Study (LALES) is a population-based cohort study of eye
disease in self-identified Latinos aged 40 years and older living in 6 census tracts in the
97
city of La Puente, Los Angeles County, California (Varma, Paz et al. 2004). Baseline
examination was performed from 2000-2003 with 4-year follow-up examination from
2004-2008. All living eligible individuals from the baseline LALES were invited to
participate in the 4-year follow-up incidence study. Data collection for the incidence
study began in 2004 and was completed in 2008. Approval for both phases of the LALES
study was obtained from the Los Angeles County/University of Southern California
Medical Center Institutional Review Board (Varma, Paz et al. 2004; Varma, Chung et al.
2010; Varma, Foong et al. 2010).
Interview and Examination Procedures
Both at baseline and 4 year follow-up an in-home interview was conducted (including
socio-demographic, medical and ocular history and quality of life), after informed
consent was obtained. Details of the interview are available elsewhere (Varma, Paz et al.
2004). Participants were scheduled for a detailed eye examination conducted at the
LALES local eye examination center. Similar questionnaire and examination procedures
were used for both baseline and follow-up studies (Varma, Paz et al. 2004; Varma,
Chung et al. 2010; Varma, Foong et al. 2010). As in the baseline study, individuals who
did not complete a clinical examination at the examination center were asked to undergo
an in-home examination by a trained technician.
Age Related Macular Degeneration (AMD) Grading: A modification of the Wisconsin
Age-Related Maculopathy Grading System (WARMGS) (Klein, Davis et al. 1991) was
used to perform grading of individual age-related macular degeneration (AMD) lesions
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by masked graders at the Wisconsin Ocular Epidemiology Reading center. AMD
characteristics and severity were graded on a 6-level scale used in the Beaver Dam Eye
Study (Klein, Klein et al. 1997; Varma, Foong et al. 2010). Overall, according to this
scheme, a severity level of 10 corresponds to no AMD, levels 20-40 correspond to levels
of early AMD; levels 40 and 50 represent late AMD. All data from the detailed grading
were checked for progression or regression of AMD lesions using a custom program.
The descriptions of the levels of AMD by WARMGS are as follows:
Level 10: Hard drusen or small soft drusen < 125 microns in diameter only, regardless of
area of involvement, and no pigmentary abnormality (increased retinal pigment or RPE
depigmentation) present.
Level 20: Hard drusen or small soft drusen < 125 microns in diameter, regardless of area
of involvement, with any pigmentary abnormality (increased retinal pigment present
and/or RPE depigmentation) present, OR
Soft drusen > 125 microns in diameter with drusen area < 196,350 square microns
(equivalent to a circle with a diameter of 500 microns) and no pigmentary abnormalities
Level 30: Soft drusen > 125 microns in diameter with drusen area < 196,350 square
microns with any pigmentary abnormality (increased retinal pigment present and/or RPE
depigmentation) present, OR
Soft drusen > 125 microns in diameter with drusen area > 196, 350 square microns with
or without increased retinal pigment but no RPE depigmentation.
99
Level 40: Soft drusen > 125 microns in diameter with drusen area > 196,350 square
microns equivalent to a circle with a diameter of 500 microns) and RPE depigmentation
present, with or without increased retinal pigment.
Level 50: Presence of pure geographic atrophy in the absence of exudative macular
degeneration.
Level 60: Presence of exudative macular degeneration with or without geographic
atrophy present.
Definitions of Progression of Age Related Macular Degeneration: For eyes that had
changes in lesion severity by 2 or more steps on the modified WARMGS scale between
the baseline and 4-year follow-up examinations, a longitudinal review was conducted
through side-by-side comparison of photographs from both examination periods. Graders
were masked to the year the photographs were taken (Klein, Davis et al. 1991; Varma,
Foong et al. 2010).
The definitions of major longitudinal changes in AMD characterized as
progression of AMD for purposes of the study are described (supplemental Table 1).
Progression was defined as 2 or more step increase at follow-up in people who had a
level 10 through 30 at baseline and a 1 step increase in people who had a grading of 40 or
more at baseline
Definitions of progression of AMD component lesions which include specific
drusen types and retinal pigmentary abnormalities are also summarized in the
supplemental table. In brief, progression of drusen was defined as involvement of two or
more additional involved subfields at follow-up without change in drusen type from
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baseline. Progression for both pigmentary changes were defines as either: (i) involvement
of two or more additional involved subfields at follow-up without change in maximum
score from baseline, or (ii) increase in the maximum score at follow-up. Other large
ocular epidemiologic studies like Beaver Dam Eye Study (Klein, Davis et al. 1991; Klein,
Klein et al. 1997) and the Blue Mountains Eye Study (Mitchell, Smith et al. 1995) also
use similar definition.
Similar to the analysis with the LALES cross-sectional data, we derived a per
person composite scale to incorporate severity and bilaterality for each person. We
created the scale by concatenating per person bilateral severity using a scheme similar to
that previously used by Klein et al (Klein, Moss et al. 1989)
to assess the four- year
change in bilateral severity (Appendix C). The severity of AMD for a participant was
derived by combining the severity levels for each eye but giving greater weight to the eye
with the higher level of severity This resulted in an 11-step scale; (10/10, 20/<20, 20/20,
30/<30, 30/30, 40/<40, 40/40, 50/<50, 50/50, 60/<60, 60/60). If the severity of AMD
could not be graded in one eye of an individual, that eye was considered to have a score
equivalent to the score of the other eye.
Assessment of Health-Related Quality of Life
An interviewer-administered questionnaire was used at baseline and 4 year
follow-up study to assess general and vision-specific HRQoL. General HRQoL was
assessed by the Short Form 12-item Health Survey (SF-12), version 1
(Mangione, Lee et
al. 2001) and Physical Component Summary (PCS) and Mental Component Summary
(MCS) scores were calculated by using the standard U.S. norm-based procedure for SF-
101
12
(Ware 1995; Ware, Kosinski et al. 1996; Mangione, Lee et al. 1998; Mangione, Lee et
al. 2001) . Self-reported, vision-related HRQoL was assessed by the National Eye
Institute Visual Function Questionnaire (NEI-VFQ-25).(Mangione, Lee et al. 1998;
Mangione, Lee et al. 2001) his questionnaire consists of 25 targeted questions
representing 11 vision-related construct or domain and an additional single item general
health related question. The vision related constructs are: color vision, vision related
dependency, driving difficulty, distant vision, general vision, vision related mental health,
near vision, ocular pain, peripheral vision, vision related role function and vision related
social function. These 11 of the 12 scale scores (excluding the general health rating
question) were averaged to yield a composite score for NEI-VFQ-25. (Mangione, Lee et
al. 1998; Mangione, Lee et al. 2001)
Statistical Analyses
Student t-test for continuous variables and chi-square tests for discrete variables
were used to compare socio-demographic and clinical factors between participants who
had either worsening or progression of AMD severity versus those who did not progress.
There were 5 persons with evidence of regression of just one step through the severity
scale and hence, did not meet the criterion for overall progression. So, these individuals
were included in the baseline comparison group with no progression.
Intra-individual change in vision-specific HRQoL composite score and subscales
were calculated by subtracting scores at baseline from scores at 4-year follow-up;
negative values indicate loss in HRQoL and positive values indicate improvement.
102
Change in subscales and composite score were normally distributed and modeled as both
continuous and categorical variables.
Covariate adjusted paired t-test was calculated to assess the significance of within
group difference of QoL over the 4–year follow-up period. Analysis of covariance was
used to model mean differences of change in HRQoL scores across severity levels of
AMD, adjusted for baseline covariates that resulted in a change in effect of 10%.
Covariates included were age (in years), gender, vision insurance (yes/no), number of
comorbidities (continuous), and presence of other ocular disease (yes/no). Tests of linear
trends were completed using F- tests. Interaction between AMD and covariates was
evaluated using multiplicative interaction terms in the multivariable model using analysis
of covariance and corresponding F-tests to evaluate statistical significance.
We further investigated the impact of AMD severity on change in HRQoL by
examination of minimally important change and significant individual change. We
defined minimally important clinical change (MIC) as a -5 point change in HRQOL
based on an assessment of late AMD patients from the Sub macular Surgery Trial (SST)
(Miskala, Hawkins et al. 2003), using NEI-VFQ-25 data. The selection of a -5 point
change in HRQOL has been used in other studies as an acceptable threshold of minimally
important clinical change in AMD patients (Coleman, Yu et al. 2010). In our analyses,
proportions of individuals with a clinically important change in vision-specific HRQoL
were compared across severity levels of AMD using Pearson chi-square and tests for
trend. All tests were repeated for progression of lesion types of early AMD; subjects
without the specific lesion were considered as the control group.
103
To evaluate the proportion of individuals with significant change (loss or
improvement) in HRQoL among people with or without progression of AMD we
calculated the reliable change index (RCI). RCI is a z-test of change in HRQOL scores
between the baseline and follow-up measures, divided by the standard error of difference.
A change in RCI of 1.96 or more is considered to be indicative of reliable or statistically
significant individual change at the p<.05 level.
To further assess the nature of the relationship and to examine the possible non-
linear relationship between the between change in bilateral severity of AMD and change
in quality of life, we used local regression methods, adjusting for other covariates from
the final regression model, to generate LOWESS (locally weighted smoothing regression)
plots (Cleveland and Devlin 1988). For these analyses, predicted QoL values were
derived for the composite NEI-VFQ score and other NEI-VFQ-25 scales that were
suggestive of being significantly impacted by changes in AMD severity and included
driving difficulty, distant vision, general vision, and social function and were plotted
against the bilateral concatenated scale of AMD severity scale for these analyses were.
All hypothesis testing was 2-sided assuming a .05 significance level. All analysis
was conducted using Stata 10.0 software (Stata Corporation, College Station, Texas).
4.3 Results
Description of Study Cohort
The LALES participants included in this analysis are presented in Figure 4.1. At
the end of the 4-year follow-up, 4,658 participants had a complete clinical and
ophthalmic examination at both baseline and the 4-year follow-up. Fundus photograph
104
were taken for 4029 persons at follow-up; 3,931 had gradable photographs for AMD at
both baseline and follow-up; 3,191 additionally had complete clinical questionnaire data;
and 3,001 participants had no missing data values for primary HRQOL subscales and
were therefore included in the final analyses.
Other than reported history of ocular disease (P 0.004), there were no major
differences in demographic or clinical characteristics between participants included and
excluded from this cohort (data not shown). Participants were more likely to report other
ocular conditions compared to non-participants. Over the 4-year follow-up window, there
were only 71 cases that met our study criteria for AMD progression (2-step change in
severity). There was a progression of soft indistinct drusen in 20 participants, a
worsening of increased retinal pigmentation (IRP) in 19 participants, and a progression of
depigmentation of retinal pigment epithelium in 11 participants.
The comparisons of different demographic and clinical characteristics between
participants with or without progression AMD are summarized in Table 4.1. Participants
with progression of AMD were significantly older (P <0.001), less likely to be married
(P=0.002) and more likely to be unemployed or retired (P=0.006) than those without
AMD. Also, those with AMD were also more likely to report a history of other
comorbidities and other ocular disease (P<0.001) and were more likely to be active
smokers (P=0.004).
105
106
Table 4.1: Sociodemographic and Clinical characteristics stratified by Progression
of AMD (N=3001)
†Data are presented as mean (SD) for age, acculturation and comorbidities, visual acuity & visual field; frequency
(%) for all other variables. *data from best corrected better eye;
P-values were calculated using t-test for continuous variables and chi-square for categorical variables.
‡ Acculturation was measured using the short-form Cuellar Acculturation Scale.
Health-related Quality of Life and AMD progression status
Table 4.2 summarizes the results of covariate adjusted mean 4 year changes in
HRQoL scores and proportion of people with minimally important change by AMD
progression status. The decrease in mean score change in the majority of the NEI-VFQ-
25 scales were more pronounced for participants with progression than those without
progression, after adjusting for age, smoking status, employment status, comorbidities
and other ocular diseases. However, the differences in mean score change between these
2 groups failed to reach statistical significance. When we looked at the proportion of
Variables No Progression Progression P-value
†
(N =2930 ) (N =71)
Socio-demographic Characteristics
Age (years) 54.29(9.8) 63.88(10.7) <0.001
Gender: female 1784(61.0) 46(64.8) 0.50
Unemployed/ retired 1481(50.7) 13(25.3) <0.001
Income <$50,000 2404(82.2) 60(84.5) 0.21
Education<12 years 1910(65.3) 47(66.2) 0.88
Vision insurance: Yes 1542(52.7) 39(54.9) 0.71
Acculturation score‡ 1.8(0.9) 1.9(0.9) 0.36
Marital status (Married/ Partner) 2176(74.4) 41(57.8) 0.002
Clinical characteristics
Smokers 365(12.5) 18(25.4) 0.004
Comorbidities§ 1.49(1.4) 2.15(1.7) 0.002
History of any ocular disease 977(33.3) 46(64.8) <0.001
Baseline visual acuity* 19.0(3.7) 26.1(45.3) 0.19
107
people with a MIC in HRQoL, we observed statistically significant differences in the
subscales of color vision (P=0.009), vision-related dependency (P=0.008), driving
difficulty (P=0.03), distant vision (P=0.02), general vision (P=0.01) and vision related
social function (P=0.01). There were no significant differences in proportion with MIC in
the SF-12 HRQoL scores among the AMD progression groups. We also evaluated the
change of HRQoL score by stratifying the participants into 4 levels based on their
baseline and follow-up AMD status (Table 4.3). The results suggest that people with 2
step worsening of their AMD status experienced worsening of QoL status regardless of
their baseline AMD status. However, other than driving difficulty, none of the results
reached statistical significance.
Although we adjusted for other co-existing ocular conditions to further minimize
the possibility of confounding by co-existing eye conditions, we repeated these analyses
restricting to people without any evidence of co-existing ocular conditions (Table 4.4). In
this analysis, mean changes in HRQOL reached statistical significance for vision-related
dependency (P=0.02), driving difficulty (P=0.004), distant vision (P=0.05), general
vision (P=0.04) and vision related social function (P=0.04) but not for color vision; a
marginal association was found for the overall composite score (P=0.05). Also, the
proportion of people with a MIC in HRQOL remained statistically significantly different
for these subscales other than color vision.
Table 4.2: Mean changes and proportion of people with MIC** in QoL by status of AMD progression
Mean changes in QoL scores
(±SE)
Proportion of people with 5 point decrease in QoL
(%)
No progression
(N=2930)
Progression
(N=71)
p-value*
No progression
(N=2930)
Progression
(N=71)
p-value
NEI-VFQ 25
Color Vision -1.03 (0.4) -3.02 (1.9) 0.31 11.3 21.4 0.009
Vision Related Dependency -2.81 (0.5) -5.68 (2.3) 0.23 26.0 40.0 0.008
Driving Difficulty
†
0.22 (0.4) -3.27 (2.8) 0.14 44.4 57.1 0.03
Distance Vision 0.29 (0.4) -2.35 (2.2) 0.23 28.2 37.1 0.10
General Health 2.20 (0.5) -0.15 (2.2) 0.29 27.1 24.3 0.60
General Vision 2.09 (0.5) -1.81 (2.7) 0.16 19.2 31.4 0.01
Vision Related Mental Health -3.10 (0.5) -1.00 (2.6) 0.41 47.7 38.6 0.14
Near Vision -1.42 (0.5) -2.01 (2.5) 0.81 39.6 42.9 0.58
Ocular Pain -2.71 (0.5) -4.03 (2.5) 0.60 40.0 44.3 0.37
Peripheral Vision -1.93 (0.5) -2.90 (2.5) 0.72 20.1 27.1 0.14
Vision Related Role Function -0.29 (0.5) -1.83 (2.6) 0.55 22.5 27.1 0.35
Vision Related Social Function -0.06 (0.4) -1.46 (2.6) 0.44 19.6 31.4 0.01
Composite Score -1.50 (0.5) -1.91 (2.3) 0.88 29.0 31.8 0.70
* Adjusted for age, smoking status, employment status, comorbidities & other ocular diseases; MIC: minimally important change
** MIC : minimally important change, defined as 5 point decrease in HRQoL from baseline to follow-up
108
Table 4.3: Mean changes in QoL by status of stratified by four levels of AMD Longitudinal change status
Mean changes in QoL scores (±SE)
No progression
( no AMD at baseline)
(N=2711)
No progression
(AMD at baseline)
(N=319)
Progression
( no AMD at
baseline)
(N=46)
Progression
(AMD at
baseline)
(n=25)
P-value
NEI-VFQ 25
Color Vision -1.16(0.4) -0.95(1.2) -1.49 (2.4) -4.60(3.2) 0.85
Vision Related Dependency -2.74(0.6) -1.36(1.4) -5.68 (2.3) -6.32(4.0) 0.15
Driving Difficulty
†
0.21(1.3) 2.62(1.4) -3.27 (2.8) -5.50(4.0) 0.002
Distance Vision 0.31(0.5) 1.67(1.3) -2.60 (2.7) -0.25(3.6) 0.69
General Health 2.23(0.7) 1.69(1.6) -5.7 (3.4) -4.30(4.6) 0.12
General Vision 0.21(0.6) -0.24(1.3) -1.81 (2.7) -0.93(3.7) 0.26
Vision Related Mental Health -2.73(0.7) -2.19(1.6) -1.00 (2.6) -0.20(4.3) 0.25
Near Vision -1.52(0.6) -2.08(1.5) -0.99 (2.5) -1.47(4.1) 0.12
Ocular Pain -2.56(0.6) -4.67(1.5) -4.03 (2.5) -1.73(4.2) 0.10
Peripheral Vision -1.60(0.6) -1.00(1.5) -5.04 (2.5) -1.37(4.2) 0.09
Vision Related Role Function -0.67(0.7) -0.82(1.5) -1.29 (2.6) -0.60(4.3) 0.61
Vision Related Social Function -0.08(0.7) -0.04(1.4) -1.46 (2.6) -1.59(4.2) 0.03
Composite Score -1.42(0.4) -1.23(0.8) -1.91 (1.7) -1.34(2.3) 0.30
* Adjusted for age, smoking status, employment status, comorbidities & other ocular diseases; MIC: minimally important change
-
109
110
To further examine the effect of QoL changes at the individual level, we
calculated the reliable change index for the whole sample (Table 4.5) and for AMD cases
compared to participants without any evidence of eye disease (Table 4.6). For
participants with progression in AMD, the largest proportions of people with significant
losses in HRQoL were found for vision-related dependency (30%), distant vision (31%),
general vision (32%), near vision (31%) and vision related social function (30%). Similar
results, albeit more pronounced, were found in the analysis restricting to participants
without any co-existing ocular conditions and these included changes in driving difficulty
but not near vision (bolded in Table 4.6). The largest proportional loss in HRQoL was
found in vision-related dependency. These changes were not observed in the in the SF-12
HRQoL scales.
Table 4.4: Mean changes and proportion of people with MIC** in QoL by status of AMD progression
(without any other eye disease)
NEI-VFQ 25
Mean changes in QoL scores
(±SE)
Proportion of people with 5 point
decrease in QoL (%)
No progression
(N=1854)
Progression
(N=28)
p-value*
No progression
(N=1854)
Progression
(N=28)
p-value
Color Vision -1.08(0.4) -3.61(2.9) 0.38 10.3 17.9 0.17
Vision Related Dependency -2.52(0.5) -10.43(3.5) 0.02 24.8 53.6 0.001
Driving Difficulty
†
-0.27(0.5) -9.91(3.4) 0.004 40.7 60.7 0.03
Distance Vision 0.07(0.5) -6.21(3.3) 0.05 27.4 46.4 0.02
General Health 2.81(0.6) --0.18(4.3) 0.48 26.5 35.7 0.27
General Vision 0.05(0.5) -6.02(3.5) 0.04 18.8 39.3 0.01
Vision Related Mental Health -3.29(0.6) -6.24(3.9) 0.45 47.6 53.6 0.52
Near Vision -1.65(0.6) -3.92(3.8) 0.56 38.7 35.7 0.74
Ocular Pain -2.89(0.6) -3.53 (3.8) 0.86 39.3 42.9 0.70
Peripheral Vision -2.47(0.6) -7.06 (3.8) 0.23 19.2 21.4 0.76
Vision Related Role Function -1.17(0.5) -4.47(3.5) 0.19 17.7 28.6 0.13
Vision Related Social Function -2.08(0.6) -9.03(3.7) 0.04 17.6 35.7 0.04
Composite Score -1.18(0.3) -6.03(2.5) 0.05 32.2 42.9 0.09
* Adjusted for age, smoking status, employment status & comorbidities; ** MIC : minimally important change,
111
Table 4.5: Proportion of people with significant changes in NEI-VFQ-25 scores by status of AMD progression
as determined by the reliable change index (RCI)
Change in AMD between LALES baseline and follow-up examination
No Progression
(N=2930)
Progression
(N=71)
Loss No change Improvement Loss No change Improvement
NEI-V-FQ-25
RCI* -1.96 >-1.96 - <1.96 RCI*
†
1.96 RCI*
†
-1.96 >-1.96 - <1.96 RCI* 1.96
N (%) N (%) N (%) N (%) N (%) N (%)
Color Vision 232(8) 2366(81) 329(11) 14(20) 48(69) 8(11.4)
Vision Related Dependency 180(6) 2370(81) 380(13) 21(30) 40(56) 10(14)
Driving Difficulty 273(13) 1626(77) 218(10) 10(22) 29(63) 7(15)
Distance Vision 450(15) 2042(70) 438(15) 22(31) 36(51) 13(18)
General Health 797(27) 1572(54) 561(19) 18(25) 36(51) 17(24)
General Vision 550(19) 1419(48) 794(27) 23(32) 26(37) 22(31)
Vision Related Mental Health 246(8) 2214(76) 470(16) 8(11) 56(79) 7(10)
Near Vision 300(10) 2163(74) 467(16) 22(31) 33(46) 17(24)
Ocular Pain 347(12) 2045(70) 538(18) 9(13) 48(68) 14(20)
Peripheral Vision 447(15) 1894(65) 589(20) 19(27) 35(49) 19(27)
Vision Related Role Function 299(10) 2234(76) 397(14) 16(23) 46(65) 9(13)
Vision Related Social Function 176(6) 2466(84) 288(10) 21(30) 45(63) 5(7)
Composite Score 243(8) 2285(78) 402(14) 18(25) 47(66) 6(8)
*RCI: Reliable change index; Numbers may not add up due to missing values in the subscales of HRQoL
†
Bolded number and percent indicate those NEI-VFQ scores with a large (30% or greater) percent of individuals with statistically significant change in score
in the same direction as the direction of AMD progression
112
Table 4.6: Proportion of people with significant changes in NEI-VFQ-25 scores by status of AMD progression as
determined by the reliable change index (RCI) in those without any other eye disease
NEI-VFQ-25
Change in AMD between LALES baseline and follow-up examinations
No Progression
(N=1854)
Progression
(N=28)
Loss No change Improvement Loss No change Improvement
RCI* -1.96 >-1.96 - <1.96 RCI*
†
1.96 RCI*
†
-1.96 >-1.96 - <1.96 RCI* 1.96
N (%) N (%) N (%) N (%) N (%) N (%)
Color Vision 132(7.1) 1536(82.9) 184(9.9) 5(17.9) 21(75.0) 2(7.1)
Vision Related Dependency 93(5.0) 1539(83.0) 222(11.9) 12(42.8) 15(53.6) 1(3.6)
Driving Difficulty 141(9.9) 1121(78.7) 162(11.4) 10(35.7) 14(73.7) 1(3.6)
Distance Vision 269(14.5) 1323(71.4) 262(14.1) 11(39.3) 12(42.9) 5(17.9)
General Health 513(27.7) 992(53.5) 349(18.8) 4(21.1) 14(73.7) 1(5.3)
General Vision 161(16.0) 1202(64.8) 491(26.5) 10(35.7) 12(42.9) 6(21.4)
Vision Related Mental Health 128(6.9) 1434(77.4) 292(15.8) 5(17.9) 22(78.6) 1(3.8)
Near Vision 295(15.9) 1368(73.8) 191(10.3) 5(17.9) 21(75.0) 2(7.1)
Ocular Pain 213(11.5) 1311(70.7) 330(17.8) 4(14.3) 22(78.6) 2(7.1)
Peripheral Vision 251(13.5) 1248(67.3) 355(19.2) 6(21.4) 19(67.8) 3(10.7)
Vision Related Role Function 156(8.4) 1460(78.8) 238(12.8) 8(28.6) 17(60.7) 3(10.7)
Vision Related Social Function 98(5.3) 1603(86.5) 153(8.3) 11(39.3) 15(53.6) 2(7.1)
Composite Score 137(7.4) 1482(79.9) 235(12.7) 9(32.1) 16(57.1) 3(10.7)
*RCI: Reliable change index. * Numbers may not add up due to missing values in the subscales of HRQoL
†
Bolded number and percent indicate those NEI-VFQ scores with a large (30% or greater) percent of individuals with statistically significant change
in score in the same direction of AMD progression
113
114
Health-related Quality of Life and progression of AMD lesions:
We examined the differences of mean QoL changes in participants, with
progression of early AMD lesions compared to participants without any evidence of
progression of that particular lesion.
There were no statistically significant differences in mean 4 year QoL score
change between participants with progression to soft distinct drusen (SI) and those
without any evidence of progression to soft indistinct drusen (Table 4.7). However,
compared to those without progression to SI, there were a larger proportion of
participants with progression with a MIC in HRQOL for general vision subscale
(p=0.02).
Table 4.8 summarizes the results of the analyses on subjects with progression of
IRP. These results show no statistically significant difference in mean HRQoL change or
a MIC in HRQOL between the 2 groups with and without progression. However, when
we repeated the analyses for people with progression of RPE depigmentation, we found
that progression of depigmentation was associated with significantly decreased scores in
general vision (p=0.02), vision related social function (p=0.03) and driving difficulty
(p=0.05). We found significant differences in the same scales when we evaluated the
proportion of participants with a MIC in HRQOL (Table 4.9). No differences were found
for general health or vision measures of HRQoL.
Table 4.7: Mean changes and proportion of people with MIC** in HRQoL by change in severity of
Soft Indistinct drusen (SID)
Mean changes in QoL scores (±SE)
Proportion of people with 5 point
decrease in QoL (%)
No progression
(N=89)
Progression
(N=20)
p-value*
No progression
(N=89)
Progression
(N=20)
p-value
NEI-VFQ 25
Color Vision -0.99(4.30) -1.28(6.00) 0.85 10 15 0.52
Vision Related Dependency 0.17(5.0) -5.35(6.9) 0.32 20 35 0.15
Driving Difficulty
†
-3.11(7.0) -7.01(10.0) 0.63 40 51 0.39
Distance Vision -5.60(3.8) -8.14(5.3) 0.54 17 25 0.55
General Health -7.12(5.2) 13.3(0.29) 0.29 16 17 0.75
General Vision 3.35(5.0) -3.55(6.9) 0.21 25 53 0.02
Vision Related Mental Health -1.98(5.0) -0.45(6.9) 0.78 35 40 0.41
Near Vision -0.31(4.9) -6.6(6.8) 0.20 20 33 0.23
Ocular Pain -6.54(4.9) -8.8(6.9) 0.67 42 60 0.13
Peripheral Vision 4.71(5.6) 2.5(7.8) 0.72 15 15 0.96
Vision Related Role Function -0.03(6.1) -4.8(5.6) 0.85 21 30 0.40
Vision Related Social Function -4.8(3.7) -9.3(5.2) 0.28 20 10 0.28
Composite Score -0.32(2.7) -1.49(3.8) 0.70 25 30 0.63
* Adjusted for age, smoking status, employment status, comorbidities & other ocular diseases** MIC : minimally important change, defined as
5 point decrease in HRQoL from baseline to follow-up.
115
Table 4.8: Mean changes and proportion of people with MIC** in HRQoL by change in severity of
Increased Retinal Pigmentation (IRP)
Mean changes in QoL scores
(±SE)
Proportion of people with 5 point
decrease in QoL (%)
No progression
(N=55)
Progression
(N=19)
p-value*
No progression
(N=55)
Progression
(N=19)
p-value
NEI-VFQ 25
Color Vision 2.77(3.0) -1.82(3.4) 0.12 3.64 5.26 0.76
Vision Related Dependency 3.66(6.2) -0.06(7.0) 0.53 15.8 29.1 0.26
Driving Difficulty† -0.85(6.8) -1.39(7.9) 0.76 43.4 47.4 0.78
Distance Vision 6.31(4.8) 9.95(5.5) 0.44 15.8 16.4 0.95
General Health -0.47(5.5) 3.89(6.2) 0.41 16.4 10.5 0.53
General Vision -0.01(5.5) -3.66(6.2) 0.49 26.3 27.3 0.93
Vision Related Mental Health -2.66(6.5) 8.80(7.3) 0.23 41.8 36.8 0.70
Near Vision -0.59(4.6) -5.05(6.8) 0.71 45.5 42.1 0.80
Ocular Pain -5.05(4.6) -4.36(5.2) 0.88 38.2 36.8 0.92
Peripheral Vision 5.03(5.8) 15.31(6.6) 0.07 5.3 10.9 0.46
Vision Related Role Function 7.06(7.6) 7.35(8.6) 0.96 21.1 21.8 0.94
Vision Related Social Function 1.56(3.5) 4.26(4.1) 0.09 10.5 18.2 0.43
Composite Score 0.41(3.2) -2.7(3.6) 0.31 21.1 27.3 0.59
* Adjusted for age, smoking status, employment status, comorbidities & other ocular diseases; ** MIC : minimally important change,
defined as 5 point decrease in HRQoL from baseline to follow-up.
116
Table 4.9: Mean changes and proportion of people MIC** in HRQoL by change in severity of
Depigmentation of retinal pigmentary epithelium (RPE)
Mean changes in QoL scores
(±SE)
Proportion of people with 5 point
decrease in QoL (%)
No progression
(N=22)
Progression
(N=11)
p-value*
No progression
(N=22)
Progression
(N=11)
p-value
NEI-VFQ 25
Color Vision 2.17(2.7) 3.35(3.5) 0.78 4.6 9.1 0.60
Vision Related Dependency 0.96(4.8) -1.9(6.2) 0.72 27.3 36.4 0.59
Driving Difficulty
†
11.69(7.7) -7.07(7.4) 0.05 18.2 59.1 0.02
Distance Vision 7.49(5.4) 0.81(4.5) 0.42 9.1 18.2 0.45
General Health 2.86(3.4) 3.80(4.2) 0.84 9.1 9.2 0.99
General Vision 7.24(4.1) -8.26(5.3) 0.02 13.6 63.6 0.003
Vision Related Mental Health 0.71(3.7) 1.60(4.9) 0.87 50.0 63.6 0.46
Near Vision 5.49(6.5) -1.27(8.6) 0.51 36.4 54.6 0.32
Ocular Pain 2.36(3.89) -2.92(5.1) 0.38 18.2 50.0 0.08
Peripheral Vision 7.71(6.8) -0.71(8.8) 0.93 18.2 27.3 0.54
Vision Related Role Function 7.58(6.6) 4.66(8.6) 0.59 18.2 36.4 0.25
Vision Related Social Function 7.05(5.6) -11.9(7.2) 0.03 18.2 42.0 0.05
Composite Score 3.18(3.3) -0.14(4.3) 0.26 27.3 36.4 0.59
* Adjusted for age, smoking status, employment status, comorbidities & other ocular diseases
** MIC : minimally important change, defined as 5 point decrease in HRQoL from baseline to follow-up
117
118
The LOWESS plots show a minimal decrease in NEI-VFQ-25 composite score
with increasing severity of bilateral AMD progression (Figure 4.2). These changes were
much more pronounced for driving difficulty, general vision and social function (figure
4.3, 4.4 & 4.5) scores. These figures were suggestive of decreasing HRQoL scores with
increasing severity of bilateral progression.
Figure 4.2: Changes in bilateral AMD severity and Changes in Composite NEI-VFQ
score
-15 -10 -5 0 5
Predicted mean composite score change
-8 -7 -6 -5 -4 -3 -2 -1 0 1
Change in bilateral severity of AMD
119
Figure 4.3: Changes in bilateral AMD severity and Changes in driving difficulty
score
Figure 4.4: Changes in bilateral AMD severity and Changes in general vision score
-15 -10 -5 0 5
Predicted mean driving difficulty score change
-8 -7 -6 -5 -4 -3 -2 -1 0 1
Change in bilateral severity of AMD
-15 -10 -5 0 5
Predicted mean general vision score change
-8 -7 -6 -5 -4 -3 -2 -1 0 1
Change in bilateral severity of AMD
120
Figure 4.5: Changes in bilateral AMD severity and Changes in social functioning
score
4.5 Discussion
In this population-based longitudinal study of adult Latinos, we found that
clinically meaningful change in severity of AMD (2 levels or greater) over the 4-year
follow-up period were associated with measurable and important changes in vision
specific HRQoL. Compared to people with no change in AMD severity, participants who
progressed 2 or more steps from no or minimal AMD or 1 step from moderate AMD had
diminished HRQoL.
People with progression of AMD had lower scores in several vision-specific
HRQOL scales after adjusting age, gender other ocular and non-ocular comorbidities.
-15 -10 -5 0 5
Predicted mean social function score change
-8 -7 -6 -5 -4 -3 -2 -1 0 1
Change in bilateral severity of AMD
121
These changes were statistically significant when we restricted our analysis to those
without any other ocular conditions.
The statistical significance of within and between group differences in HRQOL
scores are strongly impacted by sample size and do not necessarily imply that the
observed changes are clinically important (Wright 1996). Further, group level changes in
means may not necessarily reflect clinically important changes at the level of the
individual (Hays, Brodsky et al. 2005). To address these issues, we used an anchor based
method to explore minimally important changes in HRQOL scores (i.e. used the minimal
important change in HRQoL scores associated with clinically important changes in AMD)
and examined the proportion of individuals with statistically significant changes in
HRQoL scores over time using the reliable change index.
For changes in HRQoL that are minimally important we applied an anchor based
approach based on existing literature. Although no universally accepted definition of
minimum clinically meaningful change in vision-specific QOL has been established for
AMD patients, a recent evaluation based on NEI-VFQ-25 assessment in late AMD
patients from the Submacular Surgery Trial (SST) (Miskala, Hawkins et al. 2003) suggests
a 4 point change for NEI-VFQ-25 composite score and a 5 point change for all other
vision specific scales. We defined a conservative estimate of a 5 point change for all scales
as our minimally important change (MIC), which has been used in other studies as an
acceptable threshold (Coleman, Yu et al. 2010). Results of this analysis are suggestive of
greater proportions of individuals with AMD progression had a minimally important
change in several NEI-VFQ subscales. For example, 40% percent participants with
progression of AMD reported increased social dependence (based on NEI-VFQ-25 social
122
dependence scale), compared to 26% participants with progression. When we further
restricted the analysis to people without any other prevalent or incident ocular condition
the differences were even larger (53.6% for progression vs 24.8% for no progression).
Similar changes were also found for other NEI-VFQ-25 subscales like driving difficulty,
general vision, distant vision and vision related social function.
To further evaluate the significance of changes we also examined the proportion
of individuals with significant changes in NEI-VFQ scores by change in AMD
progression status using the RCI. The results from these analyses were consistent with the
analysis based on MIC, with a greater proportion of individual participants receiving
lower HRQoL scores among participants with progression of the disease.
There also was evidence of an association between AMD progression and some
vision specific HRQoL scales by type of early AMD lesions including soft indistinct
drusen (SI) and depigmentation of retinal pigment epithelium (RPE). There was no
association between AMD progression and general health measures of HRQOL including
measures of the SF-12.
Overall, these results show a clear association between AMD progression and
change in HRQoL; similarly, we found a strong association between prevalent AMD and
HRQOL in our cross-sectional data and the few available data on impact of longitudinal
changes in AMD on HRQoL (Brown, Brown et al. 2002; Mitchell and Bradley 2006;
Covert, Berdeaux et al. 2007; Coleman, Yu et al. 2010). While the majority of previous
studies on AMD and HRQOL focused on cases of late AMD, very few studies looked at
the association of early AMD and QoL. Some of these studies suggest that people with
early AMD also report lower quality of life (Scilley, Jackson et al. 2002; Coleman, Yu et
123
al. 2010). A recent study by Coleman et al. assessed the association between10 year and
15 year change in AMD status and HRQoL. Compared to people with no AMD at
baseline and follow-up, people who progressed to early or late AMD showed a significant
decrease in an abbreviated composite NEI-VFQ scale score (Coleman, Yu et al. 2010).
The greatest impact of AMD progression was among people who progressed from no
disease to late AMD. (Coleman, Yu et al. 2010) Scilley et al also reported that persons in
early phases of AMD are more likely to experience difficulty in driving and to have
trouble with daily tasks involving near and far vision tasks than people without AMD
(Scilley, Jackson et al. 2002).
The sample size of people with AMD progression was small and not adequate to
stratify cases based on severity levels at baseline and/or follow-up. The study included
only 6 cases that progressed from early to late stages of AMD, and no cases progressed
from disease free to late AMD over the 4-year follow-up period. To explore the impact of
early AMD on HRQoL, we repeated some analysis for cases of incident AMD (any
severity level) and by type of early AMD lesion (SI, IRP, and RPE). For incident AMD,
only the driving difficulty scale was impacted significantly (supplemental Table 2).
Results from supplemental tables 3, 4 and 5 were suggestive of greater decrease driving
difficulty, distant vision and social function score for new incidence of three of early
AMD lesions (p<0.05 for all). Since the majority of our cases progressed from no
disease to early AMD, our results are largely driven by the impact of early AMD on
change in HRQOL.
Since visual acuity is not affected in early AMD, other properties associated with
vision, such as depth perception and contrast sensitivity, should be investigated to explain
124
the loss in HRQOL scores associated with progression through early severity levels of
AMD. Previously, scotopic dysfunction has been demonstrated as a marker of early
AMD in some studies (Scilley, Jackson et al. 2002).
Similar to our cross-sectional analysis, we found no associations between
progression of AMD with general measures of HRQoL, as assessed by the SF-12
physical and mental composite scores. These findings are consistent with other studies
that found these instruments not to be sensitive to ocular disease, including AMD and
may as imply the fact that a person can have relative good health despite having an ocular
condition (Mitchell and Bradley 2006).
There are several important strengths of the current study. First, it was based on
population-based, longitudinal data that allows us to be certain that change in vision
status precedes the collection of HRQOL measures. Other strengths include objective
measurements of AMD collected through a comprehensive and standardized ophthalmic
examination; a large overall sample size with adequate statistical power to study different
phenotypes, especially early AMD. Although HRQoL is a self-reported outcome subject
to measurement error, we used the NEI-VFQ-25, a validated instrument in different
racial/ethnic groups including Latinos (Broman, Munoz et al. 2001; Lindblad and
Clemons 2005). Also, we used multiple statistical measures to examine the association
between change in AMD and change in HRQOL, including MIC and RCI, which are not
influenced by sample size and are reflective of clinically meaningful changes at the
individual level (Wright 1996; Hays, Brodsky et al. 2005).
There were several limitations of the study that need to be recognized in
interpreting the findings. Despite a large overall sample, we did not have a large number
125
of participants with a 2-step progression in AMD over the 4-year follow-up period. The
majority of cases with progression were early, rather than late AMD (GA/neovascular
AMD). Further, there were only 8cases of regression with only one step change from
moderate to early stage of AMD, which limited our ability to explore the impact of
direction of change (progression or regression) of AMD on HRQoL. The literature
suggests that clinically meaningful change may be different for progression versus
regression of AMD and that a greater threshold may be needed to detect HRQoL changes
following improvement of a health condition (Cella, Hahn et al. 2002; Coleman, Yu et al.
2010). We may be better able to address the issue of directionality after the 8-year
evaluation of LALES is completed. Also, our study was based on a sample of Latino
adults that may limit the generalizibility of the results to the general population. Although
the socio-cultural background may influence perception of life and quality, we expect the
impact of an objectively measured ocular condition to be similar.
In summary, people with clinically meaningful progression of AMD have
diminished health-related quality of life. Even progression along early stages of severity
of AMD can have a measurable impact on HRQOL. The impact was measurable when
exploring average change, however was most apparent when studying data and using
measures at the individual level. With limited treatment option for less severe spectrum
of disease, progression and consequent visual impairment may eventually lead to loss of
independence and reduced mobility and eventually may impact both morbidity and
mortality. Hence, it is important to develop intervention programs targeting people with
all levels of AMD to reduce further progression of disease when possible and prevent
further deterioration of their visual functioning and health related quality of life.
126
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Supplemental table 4.1: Definitions of 4 year changes (Progression and Incidence)
of Age-related Macular Degeneration (AMD) in the Los Angeles Latino Eye Study
Incidence Progression
Baseline Follow-up
Wisconsin Age-Related Maculopathy Grading System Definitions
Early AMD No early or advanced
AMD lesions in both
eyes
Either (i) any soft
indistinct or reticular
drusen, or (ii) retinal
pigmentary abnormalities
with any type of drusen, in
either eye
2-step increase from Level 10-
30, or 1-step increase from
Level 40
Advanced AMD No advanced AMD
lesions in both eyes
Exudative AMD or
geographic atrophy in
either eye
Drusen type No evidence of soft
drusen at baseline
Evidence of soft drusen at
follow-up
2 additional involved subfields
at follow-up without change in
drusen type from baseline
Increased retinal
pigment
No increased retinal
pigment in any
subfield
Increased retinal pigment
in any subfield
Either (i) 2 additional involved
subfields at follow-up without
change in maximum score from
baseline, or (ii) increase in the
maximum score at follow-up
RPE depigmentation No RPE
depigmentation in any
subfield
Definite RPE
depigmentation in any
subfield
Either (i) 2 additional involved
subfields at follow-up without
change in maximum score from
baseline, or (ii) increase in the
maximum score at follow-up
Geographic atrophy No geographic
atrophy
Definite geographic
atrophy
Increase of 2 disc areas, or
movement of lesion towards the
center
Exudative AMD No exudative AMD Exudative AMD Increase of 2 disc areas, or
movement of lesion towards the
center
132
Supplemental Table 4.2: Mean changes in QoL by status of new AMD incidence
Mean changes in QoL scores (±SE)
No Incidence
(N=2923)
Incidence
(N=78)
p-value*
NEI-VFQ 25
Color Vision 3.51(3.9) 5.55(4.3) 0.28
Vision Related Dependency -4.74(4.7) -7.38(5.7) 0.25
Driving Difficulty
†
-4.86(3.8 ) -10.73(4.4) 0.009
Distance Vision 0.21(4.3) 0.58(4.8) 0.86
General Health 1.03(5.4) 0.27(3.0) 0.77
General Vision -5.40(4.8) -6.17(4.8) 0.74
Vision Related Mental Health -3.61 (5.1) 0.89(5.7) 0.08
Near Vision -0.29(4.8) -0.51(5.3) 0.14
Ocular Pain 0.32(4.4) 0.68(5.9) 0.86
Peripheral Vision -1.33(4.5) -1.52(2.7) 0.62
Vision Related Role Function -5.46(4.4) -5.57(5.7) 0.96
Vision Related Social Function 0.47(4.3) -0.8(5.3) 0.43
Composite Score -0.41(2.9) -1.58(3.3) 0.41
SF12
Mental Composite Score -1.05(2.8) -1.62(3.0) 0.67
Physical Composite Score 1.59(2.2) 1.71(2.5) 0.81
* Adjusted for age, smoking status, employment status, comorbidities & other ocular diseases
133
Supplemental Table 4.3: Mean changes in QoL by new incidence of
Soft Indistinct drusen (SI)
Mean changes in QoL scores (±SE)
No SI
(N=2879)
SI in one eye
(N=57)
SI in both eyes(N=20) p-value*
NEI-VFQ 25
Color Vision -1.29(0.3) 1.89(2.1) -8.58(3.6) 0.12
Vision Related Dependency -0.90(0.4) 0.63(2.6) -3.03(4.40) 0.06
Driving Difficulty
†
-0.14(0.3) -4.8(2.4) -2.90(3.9) 0.002
Distance Vision 0.17(0.3) 2.50(2.4) -4.1(4.0) 0.67
General Health 2.62(0.4) 1.64(3.0) -0.14(5.1) 0.29
General Vision -2.04(0.4) 0.10(2.6) -2.80(4.5) 0.002
Vision Related Mental Health 3.78(0.4) 4.01(2.8) 1.67(4.8) 0.20
Near Vision -0.29(0.3) -0.59(2.4) -1.90(4.1) 0.14
Ocular Pain -2.83(0.4) 1.5(2.8) 5.90(4.6) 0.77
Peripheral Vision -1.92(0.4) -1.52(2.7) -7.75(4.6) 0.62
Vision Related Role Function -1.96(0.4) 2.19(2.8) 0.26(4.7) 0.50
Vision Related Social Function -1.51(0.3) -0.92(1.9) 7.82(3.2) 0.05
Composite Score -1.05(0.2) 0.63(1.5) 3.34(2.6) 0.42
SF12
Mental Composite Score -1.50(0.2) 0.37(1.5) -2.35(2.5) 0.56
Physical Composite Score 0.59(0.2) 1.38(1.2) 0.08(2.0) 0.81
* Adjusted for age, smoking status, employment status, comorbidities & other ocular diseases
134
Supplemental Table 4.4: Mean changes in QoL by new incidence of increased
retinal pigment (IPR)
Mean changes in QoL scores (±SE)
No IRP
(N=2879)
IRP in one eye
(N=75)
IRP in both eyes
(N=12)
p-value*
NEI-VFQ 25
Color Vision -1.28(0.31) -2.26(1.6) -3.99(4.6) 0.79
Vision Related Dependency -3.07(0.4) -3.27(2.3) -5.34(5.7) 0.41
Driving Difficulty
†
0.22(0.3) 3.21(2.2) -2.45(4.7) 0.01
Distance Vision 0.33(0.3) -2.23(5.2) 5.21(5.2) 0.10
General Health 0.69(0.4) 0.35 (2.6) -0.48(6.6) 0.16
General Vision -2.00(0.4) 2.87(2.3) -4.22(5.8) 0.002
Vision Related Mental Health -3.66(0.4) -6.35(2.4) -5.45(6.2) 0.73
Near Vision 0.63(0.4) -0.15(2.1) -1.41(5.3) 0.76
Ocular Pain -2.66(0.4) -4.44(2.4) -4.47(5.9) 0.73
Peripheral Vision -1.70(0.4) 6.13(2.4) -6.50(6.0) 0.26
Vision Related Role Function -1.97(0.4) -2.05(2.5) -2.33(6.2) 0.79
Vision Related Social Function -1.51(0.3) -2.26(1.7) -3.93(4.2) 0.46
Composite Score -1.69(.21) -2.47(1.3) -3.66(1.3) 0.64
SF12
Mental Composite Score -1.49(0.2) -1.07(1.3) -1.52 (3.2) 0.70
Physical Composite Score 0.62(0.17) 0.92(1.1) 1.79(2.7) 0.86
* Adjusted for age, smoking status, employment status, comorbidities & other ocular diseases
135
Supplemental Table 4.5: Mean changes in QoL by new incidence of
Depigmentation of retinal pigmentary epithelium (RPE)
Mean changes in QoL scores (±SE)
No RPE
(N=2879)
RPE in one eye
(N=29)
RPE in both eyes
(N=13)
p-value*
NEI-VFQ 25
Color Vision -1.27(0.3) -1.41(2.3) -4.34(6.6) 0.46
Vision Related Dependency -2.93(0.4) -4.15(2.8) -14.6(8.1) 0.41
Driving Difficulty
†
-0.19(0.3) -3.66(2.6)
-11.24(7.4)
7.53(6.9)
0.03
Distance Vision -0.13(0.3) -3.13(2.6) -7.63(7.5) 0.20
General Health 2.48(0.4) 3.53(3.3) -0.98(9.3) 0.86
General Vision 2.09(0.4) -0.39(2.9) -1.63(8.2) 0.002
Vision Related Mental Health -3.62(0.4) -3.39(3.1) -9.99(8.8) 0.20
Near Vision -0.70(0.3) 0.15(2.6) -3.07(7.5) 0.30
Ocular Pain -2.74(0.4) -4.60(2.9) -10.72 (8.4) 0.10
Peripheral Vision -1.91(0.4) -0.24(3.0) -8.49(8.5) 0.56
Vision Related Role Function -1.96(0.4) 0.17(3.1) -2.41(8.7) 0.79
Vision Related Social Function -1.56(0.3) 1.07(2.1) -2.25(6.0) 0.26
Composite Score -1.73(0.3) -0.90(1.6) -2.66(4.7) 0.63
SF12
Mental Composite Score -1.52(0.2) 0.23(1.6) -2.18(4.6) 0.62
Physical Composite Score 0.61(0.2) 0.22(1.3) -3.04(3.8) 0.82
* Adjusted for age, smoking status, employment status, comorbidities & other ocular diseases
136
Chapter 5: Summary and Future Research Directions
5.1 Summary
Age related macular degeneration (AMD), the vision-threatening disorder of
macular region, that affects people 50 years of age or older, can significantly diminish
visual functioning and health related quality of life (HRQoL) in advanced stages. Despite
being such a devastating disease there is paucity of epidemiologic data on risk factors of
AMD and the impact of AMD on patient reported outcome. Availability of data is even
less in Latinos, despite the fact that they constitute the largest and fastest growing
minority in the United States. We aimed to look at the risk factors of AMD and its impact
on quality of life among Latinos of southern California.
Our major findings were:
1) Older age and higher pulse pressure were independently associated with the
incidence of any AMD, early AMD, soft indistinct drusen, and retinal pigmentary
abnormalities. Additionally, presence of diabetes mellitus was independently
associated with increased retinal pigment and male gender was associated with
retinal pigment epithelial depigmentation. Older age and current smoking were
independently associated with progression of AMD.
2) AMD was associated with measurably lower values of HRQOL. We also found
that both severity and bilaterality of AMD is associated with worse HRQoL and
137
that lower HRQoL scores were even found in participants with lesions defined as
early AMD (soft indistinct drusen, any pigmentary change)
3) People with clinically meaningful longitudinal change of AMD severity status had
diminished health-related quality of life. Even progression through early severity
levels of AMD can have measurable impact on HRQoL independent of other
ocular conditions. The impact was also found when we compared the proportion
of people with progression who had clinically meaningful change, measured by
minimally important change and compared to those without progression.
Moreover, people with and without worsening also differed in proportion with
significant individual change, measured by reliable change index.
5.2 Conclusion and Implications
In adults Latinos, AMD has significant adverse effect on visual functioning and
quality of life. Even with early lesions there is evidence of a negative impact of AMD on
HRQoL including measures of self-reported general and distant vision as well as
increased dependency and decreases social functioning. We also found that HRQoL is
further impacted by severity and bilaterally of the lesion. The negative impact on HRQoL
can eventually lead to social isolation and ultimately, increased morbidity and mortality
of the sufferer.
Other than the late wet variety of AMD (neovascular AMD), there are no
effective treatment modalities for AMD including early or the dry variety of late AMD.
Hence, it is imperative to investigate modifiable factors that are associated with AMD
incidence and progression. Even though age remains the most consistent and strong risk
138
factor of AMD, there is evidence of easily modifiable risk factors like pulse pressure,
smoking and diabetes being associated with AMD incidence and progression in Latinos.
Hence, future studies should be designed to see whether interventions aiming at reducing
pulse pressure, cessation of smoking and better control of diabetes can reduce incidence
and further progression of AMD in Latinos. These results may be helpful in designing
evidence based programs and policies to better handle AMD in general population.
5.3 Future Research Directions
Age related macular degeneration remain an understudied topic in Epidemiology
despite the devastating effect it has on central vision and on quality of life. As a whole,
ocular disease in Latinos need further exploration with respect to risk factors, impact on
patient reported outcomes and projection of overall burden of disease. Several lines of
investigation could be undertaken to extend present work and further our understanding
of risk factors and impact of AMD. The potential research questions I propose to
investigate are described briefly below.
Ocular disease prevalence varies by race/ethnicity and it is therefore important to
assess the burden of disease by race (Kahn HA 1977; Congdon, O'Colmain et al. 2004;
Congdon, Vingerling et al. 2004; Friedman, Wolfs et al. 2004). Prevalence of AMD
varies greatly by ethnicity and demography (Mitchell, Smith et al. 1995; Friedman,
O'Colmain et al. 2004; Varma, Fraser-Bell et al. 2004; Munoz, Klein et al. 2005;
Augood, Vingerling et al. 2006). Trends in prevalence are also subjected to change due to
the changes in demographic variations. For example, a recent projection of glaucoma
prevalence in the US through 2050 suggestive of a greater burden of Glaucoma among
139
older non-Hispanic white women which is expected to shift to Hispanic men in the
coming decades (Vajaranant, Wu et al. 2012). This elucidates how demographic changes
in United States population over time impact the groups that most experience the burden
of eye disease. For future research I am interested in exploring the ethnic and geographic
variations in US populations in the coming decades and how these changes impact the
burden of AMD in different populations and potentially help to assess the yield from
screening programs. I propose to apply rates from the latest census data to address this
issue.
Results from baseline data from LALES revealed several demographic (age, male
gender, Native American ancestry, family history), behavioral (smoking, alcohol
consumption), clinical (higher diastolic blood pressure (DBP), uncontrolled diastolic
hypertension, pulse pressure) and ocular (presence of cataract, cataract surgery, and
myopic refractive error) factors to be associated cross-sectionally with the prevalence of
different AMD lesions in Latinos (Fraser-Bell, Donofrio et al. 2005; Fraser-Bell, Wu et
al. 2006; Fraser-Bell, Wu et al. 2008; Fraser-Bell, Choudhury et al. 2010). The current
analysis based on 4-year longitudinal data revealed that older age and higher pulse
pressure at baseline, male gender, recent smoking status and diabetes were independently
associated with the incidence of any AMD and various component early AMD lesions
(Choudhury, Varma et al. 2011). I would like to further explore the risk factors of 8 year
cumulative incidence of AMD. I hope this would help us confirm some of our previous
findings but, more importantly, help us to study the risk factors for the lesions that we
were not adequately powered to study at 4 years including geographical atrophy and
neovascular AMD.
140
Our current analyses are suggestive of impact of AMD on HRQoL using both
cross-sectional and longitudinal data. These results also suggest that at the individual
level, progression through early stages of AMD, when impact on visual acuity is
minimal, still measurably impact HRQoL. I would like to further explore these findings
investigating the long term impact of AMD by utilizing the 8-year follow-up LALES
data. It would help us to investigate the impact of changes in AMD on HRQoL stratified
by baseline and follow-up status of AMD and may help to identify people at risk of most
significant decrease of visual functioning and quality of life. Secondly, as visual acuity
does not exclusively explain the impact of early AMD changes on HRQoL, it is worth
exploring the impact of other visual properties associated with AMD on HRQoL. One of
those properties is contrast sensitivity, the visual ability that makes an object (or its
representation in an image) distinguishable from other objects and the background. In
visual perception of the real world, contrast is determined by the difference in the color
and brightness of the object and other objects within the same field of view. Some studies
suggest that measurement of contrast sensitivity is better related to a person's HRQoL
that visual acuity (Bansback, Czoski-Murray et al. 2007). Also, it is postulated that
contrast sensitivity is impacted more than visual acuity by AMD, especially in the early
stages (Tran, Despretz et al. 2012). I would like to utilize LALES data to examine
whether the contribution of contrast sensitivity helps to explain the diminishing HRQoL
in patients with worsening of AMD.
Research has consistently shown that, compared to other racial/ethnic groups,
Latinos have substantially worse access to care and lower utilization rates of medical
services (Livingston 2008; Morales, Varma et al. 2010). Access to and utilization of
141
primary care by Latinos is limited by a number of factors, including low rates of
insurance coverage, cultural and linguistic barriers, and poor access to primary care and
specialty care, such as eye care, irrespective of insurance status. I would like to
investigate how self-reported utilization of ocular heath care (e.g., ever having had a eye
care visit, having had a dilated examination in the past 12 months, ever having had a
dilated examination etc.) impacts vision related quality of life in Latinos.
In conclusion, we believe these results adds to our understanding of risk factors of
AMD and its impact of HRQoL in adult Latinos and several lines of future studies can be
undertaken that can further our understanding of AMD and potentially guide to develop
programs for screening and management of AMD in this population.
142
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Appendices
APPENDIX A
SIX STEP ARM SCALE for LALES
Level Description
10 Hard drusen or small soft drusen (< 125 microns in diameter (codes 2 or
3) only, regardless of area of involvement, and no pigmentary abnormality (increased
retinal pigment (0, 1 or 7) or RPE depigmentation (0 or 1) present.
20 Hard drusen or small soft drusen (< 125 microns in diameter ( 2 or 3),
regardless of area of involvement, with any pigmentary abnormality (increased retinal
pigment present (2-6) and/or RPE depigmentation present (2 - 7),
OR
Soft drusen ( > 125 microns in diameter (4, 5, or 6)) with drusen area < 196,350 square
microns (equivalent to a circle with a diameter of 500 microns (10 - 40) and no
pigmentary abnormalities (0, 1, 7).
30 Soft drusen (> 125 microns in diameter (4, 5, or 6) with drusen area <
196,350 square microns (10 – 40) and , with any pigmentary abnormality (increased
retinal pigment present (2-6) and/or RPE depigmentation present (2 - 7),
OR
Soft drusen ( > 125 microns in diameter (4, 5, or 6)) with drusen area > 196, 350 square
microns ( 45 – 70), with or without increased retinal pigment but no RPE depigmentation
(0 or 1).
40 Soft drusen (> 125 microns in diameter (4, 5, or 6)) with drusen area >
196,350 square microns ( 45 – 70) and RPE depigmentation present (20 – 70) , with or
without increased retinal pigment.
50 Pure geographic atrophy (2, 3, 4) in the absence of exudative macular
degeneration.
60 Exudative macular degeneration with or without geographic atrophy
present.
172
APPENDIX B
Summary of BD1/LALES ARM definitions
Late ARM
If any of the following are true, then late stage ARM is present.
1. Geographic Atrophy is present (coded 2-4)
2. PED-RD (pigment epithelial detachment or age-related retinal detachment) is
present (coded 2- 4)
3. Subretinal Hemorrhage is present (coded 2- 4)
4. Subretinal Scar (subretinal fibrous scar) is present (coded 2-4)
5. ARM_Rx (laser treatment for exudative ARM) is present (coded 2- 4)
If you wish to separate Late ARM into Atrophic and Exudative then:
Atrophic ARM
Geographic Atrophy is present (coded 2-4) and all other late lesions (PED-RD, Subretinal
Hemorrhage, Subretinal Scar, or ARM Rx) are None, Questionable or CG
Exudative ARM
173
At least one of the exudative lesions (PED-RD, Subretinal Hemorrhage, Subretinal Scar,
or ARM Rx) should be coded 2-4. (Geographic Atrophy can also be present. This is
called Mixed but is lumped together with the Exudative since that is the more severe
condition.)
Early ARM
If Late ARM is not present and any of the following conditions are true:
Any drusen is present (Drusen Size coded 2-6) and Increased Pigment is coded 2-6.
Any drusen is present (Drusen Size coded 2-6) and RPE Depigmentation is coded 2-7.
Soft Indistinct Drusen is present (Drusen Type coded 4)
Cannot Grade ARM
Late and Early ARM is not present and Drusen Size is not gradable (coded 8).
No ARM
Late, Early ARM are not present and Cannot Grade ARM is not true (Drusen Size is
gradable).
174
APPENDIX C
Concatenated Bilateral AMD severity from modified Wisconsin grading scheme
Step 1 (BD* level 10/10): Bilateral hard drusen or small soft drusen (< 125 microns in
diameter only, regardless of area of involvement, and no pigmentary abnormality
(increased retinal pigment (IRP) or RPE depigmentation present.
Step 2 (BD* level 20/<20): Worse eye: Hard drusen or small soft drusen (< 125 microns
in diameter, regardless of area of involvement, with any pigmentary abnormality
(increased retinal pigment present and/or RPE depigmentation present,
OR
Soft drusen ( > 125 microns in diameter) with drusen area < 196,350 square microns
(equivalent to a circle with a diameter of 500 microns) and no pigmentary abnormalities
Better eye: Bilateral Hard drusen or small soft drusen (< 125 microns in diameter only,
regardless of area of involvement, and no pigmentary abnormality
Step 3 (BD* level 20/20): Bilateral hard drusen or small soft drusen (< 125 microns in
diameter, regardless of area of involvement, with any pigmentary abnormality (increased
retinal pigment present and/or RPE depigmentation present,
OR
175
Soft drusen ( > 125 microns in diameter) with drusen area < 196,350 square microns
(equivalent to a circle with a diameter of 500 microns) and no pigmentary abnormalities
Step 4 (BD* level 30/<30): Worse eye: Soft drusen ( > 125 microns in diameter with
drusen area < 196,350 square microns (equivalent to a circle with a diameter of 500
microns) with any pigmentary abnormality (increased retinal pigment present and/or RPE
depigmentation present,
OR
Soft drusen ( > 125 microns in diameter) with drusen area > 196, 350 square microns
(equivalent to a circle with a diameter of 500 microns) with or without increased retinal
pigment but no RPE depigmentation.
Better eye: Hard drusen or small soft drusen (< 125 microns in diameter, regardless of
area of involvement, with any pigmentary abnormality (increased retinal pigment present
and/or RPE depigmentation present
OR Soft drusen ( > 125 microns in diameter) with drusen area < 196,350 square microns
(equivalent to a circle with a diameter of 500 microns) and no pigmentary abnormalities
Step 5 (BD* level 30/30): Bilateral soft drusen ( > 125 microns in diameter with drusen
area < 196,350 square microns (equivalent to a circle with a diameter of 500 microns)
with any pigmentary abnormality (increased retinal pigment present and/or RPE
depigmentation present,
OR
176
Soft drusen ( > 125 microns in diameter) with drusen area > 196, 350 square microns
(equivalent to a circle with a diameter of 500 microns) with or without increased retinal
pigment but no RPE depigmentation
Step 6 (BD* level 40/<40): Worse eye: Soft drusen ( > 125 microns in diameter) with
drusen area > 196,350 square microns (equivalent to a circle with a diameter of 500
microns) and RPE depigmentation present , with or without increased retinal pigment.
Better eye: Soft drusen ( > 125 microns in diameter with drusen area < 196,350 square
microns (equivalent to a circle with a diameter of 500 microns) with any pigmentary
abnormality (increased retinal pigment present and/or RPE depigmentation present,
OR
Soft drusen ( > 125 microns in diameter) with drusen area > 196, 350 square microns
(equivalent to a circle with a diameter of 500 microns) with or without increased retinal
pigment but no RPE depigmentation.
Step 7 (BD* level 40/40): Bilateral soft drusen ( > 125 microns in diameter) with drusen
area > 196,350 square microns (equivalent to a circle with a diameter of 500 microns)
and RPE depigmentation present , with or without increased retinal pigment.
Step 8 (BD* level 50/<50): Worse eye: Pure geographic atrophy in the absence of
exudative macular degeneration.
177
Better eye: Soft drusen ( > 125 microns in diameter) with drusen area > 196,350 square
microns (equivalent to a circle with a diameter of 500 microns) and RPE depigmentation
present , with or without increased retinal pigment.
Step 9 (BD* level 50/50): Bilateral pure geographic atrophy in the absence of exudative
macular degeneration.
Step 10 (BD* level 60/<60): Worse eye: Exudative macular degeneration with or
without geographic atrophy present.
Better eye: Pure geographic atrophy in the absence of exudative macular degeneration.
Step 11 (BD* level 60/60): Bilateral exudative macular degeneration with or without
geographic atrophy present.
(*BD: Beaver Dam level from Wisconsin maculopathy grading system)
Abstract (if available)
Abstract
Age related macular degeneration (AMD) is a progressive, potentially irreversible disorder of the macular region of retina that can cause severe loss of central vision in the late stages. Despite the recent advances in the treatment of AMD, it remains the leading cause of blindness in people over the age of 60 in the Western world with significant impact on their health related quality of life (HRQoL). The global prevalence of AMD remains largely unknown and the full impact of this debilitating disease has not been fully characterized. ❧ The relationship between factors influencing incidence and progression of AMD in Latinos and the impact of AMD on HRQoL in Latinos remain largely unexplored. Therefore, to address these issues, I have used the baseline and 4 years cumulative incidence data from the Los Angeles Latino Eye Study (LALES), a population based cohort study of eye disease in Latinos to investigate predictors of AMD incidence and progression and the impact of AMD on HRQoL. In the first chapter I gave an overview of AMD and my primary aims. I discussed briefly about the retina, macula, the definition, brief pathogenesis, grading scheme and classification of AMD. Then, I discussed briefly about what is known about the risk factors of AMD and its impact on HRQoL. Finally I describe the study population and enumerate the primary aims. ❧ In my first paper (chapter 2) I evaluated the risk factors associated with 4 year incidence and progression of AMD. The risk factors were selected based on literature review and expert clinical opinion. Stepwise logistic regression was used to develop parsimonious multivariable predictive models for each AMD end- points. The results from these analyses revealed that older age and higher pulse pressure were independently associated with the incidence of any AMD and different early AMD lesions in this group of Latinos. Additionally, presence of diabetes mellitus was independently associated with increased retinal pigment and male gender was associated with retinal pigment epithelial depigmentation. Older age and current smoking were independently associated with progression of AMD. Some of the findings were similar to those reported by studies in non-Hispanic whites. The interesting and unique finding in this paper was the association of pulse pressure with incidence of some early maculopathies that were not previously reported in Caucasians. Given the equivocal results for risk factors of AMD in other population based studies and the paucity of data in Latinos, these finding will aide in our understanding of AMD in this unique ethnic group. ❧ The short term and long term impact of AMD on quality of life in Latinos has not been investigated to a great extent. Given the unique socio-demographic, ethnic and cultural characteristics of Latinos it is important to estimate the impact of the patient reported outcomes in this unique group of people. Therefore, for my second paper I investigated the association of prevalent AMD and HRQoL, described in the third chapter. Two validated instruments of HRQoL were used to assess general HRQoL and vision specific HRQoL. In this analysis, I assessed and compared covariate-adjusted mean QOL scores between participants without any AMD and participants with different end-point of early and late Maculopathies by using analysis of covariance (ANCOVA). I also calculated Effect sizes (ES) to quantify the impact of HRQoL. AMD is associated with a measurably lower in HRQOL, even for lesions defined as early AMD. There was also evidence of a measurable loss in health related quality of life is associated with lesions defined as early AMD. ❧ Results from my second paper on cross-sectional data lead to conceptualize and design the third paper (chapter 4). In this paper I further evaluate the impact of AMD on HRQoL by investigating the association of intra-individual changes in AMD status with changes in HRQoL status over a 4-year period. For this analysis I looked at the mean changes in QoL scores after adjusting for possible confounders. I applied two methods of analysis to focus on minimally important clinical change and significant individual change. I followed an anchor based approach to define and test a threshold of clinically meaningful change. To further evaluate the impact of AMD on QoL at the individual level, we calculated reliable change index. Results from these analyses confirm a number of the results from the cross-sectional analysis. Overall the results suggest that people with clinically meaningful progression of AMD have diminished health-related quality of life. Even progression to early AMD can have measurable impact independent of other ocular condition. There were also evidence of significant changes with progression of early AMD lesions like soft drusen and pigmentary changes. ❧ To further our knowledge of AMD in Latinos there are many lines of investigation could be undertaken to extend present work. In chapter 5, I summarized our main findings and briefly discussed about these potential future research questions. I believe, results from these studies will help us identify factors that can increase the risk of AMD incidence and further progression in Latinos and will help us to understand the adverse impact of AMD on the quality of life of a sufferer. Further studies will help in developing evidence based screening and intervention programs to reduce incidence and retard the progression of AMD to minimize the negative impact on quality of life.
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Asset Metadata
Creator
Choudhury, Farzana
(author)
Core Title
Age related macular degeneration in Latinos: risk factors and impact on quality of life
School
Keck School of Medicine
Degree
Doctor of Philosophy
Degree Program
Epidemiology
Publication Date
10/16/2012
Defense Date
06/26/2012
Publisher
University of Southern California
(original),
University of Southern California. Libraries
(digital)
Tag
age related macular degeneration,Latinos,OAI-PMH Harvest,Quality of life,risk factors
Language
English
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Electronically uploaded by the author
(provenance)
Advisor
Azen, Stanley P. (
committee chair
), McKean-Cowdin, Roberta (
committee chair
), Gauderman, William James (
committee member
), Nichol, Michael B. (
committee member
), Varma, Rohiti (
committee member
)
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fchoudhu@usc.edu,neeparr@gmail.com
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https://doi.org/10.25549/usctheses-c3-105256
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105256
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Choudhury, Farzana
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Tags
age related macular degeneration
risk factors