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A alternative

An lt ti f
reference t d d for
standard f tructural
str t l progression
i in
i glaucoma:
l Program #4010
i silico
an in ili d l off scanning
model i er tomography
llase h iimage series
i
NO Leary1,22 DF Garway
O’Leary H
Heath
Garway-H 3 DP Crabb1

1.Department
1 Department of Optometry and Visual Science
Science, City University London
London, UK
2.Department
p off Ophthalmology
ph h l l gy and
d Visuall Sciences,, Dalhousie
lh University,
y, Halifax,
H l f , NS,, Canada
d
3.NIHR
3 NIHR Biomedical Research Centre for Ophthalmology,
Ophthalmology Moorfields Eye Hosp
pital NHS Foundation Trust and UCL Institute of Ophthalmology,
Ophthalmology
London,, UK
Purpose Methods Results
There is no established gold standard to measure structural progression of C
Case  I
I PHSDW Map  C
Case II
II PHSDW Map 
Mean Reflectance 
M R fl t (SD of Mean 
(SD of Mean Mean Reflectance 
M R fl t (SD of Mean 
(SD of Mean
glaucomatous
l neuropathy
h in
i longitudinal
l i di l image
i series
i from
f patients.
i Quantitative Simulation Testing Image
Mean Topography
Topography)
p g p y) Image
Mean Topography
p g p y)
Topography)
The purpose of the study was to develop an in silico model to simulate realistic The appropriateness of the simulated images was assessed on a global scale by (a) (b) (c) ((a)) (b) (c)

variability in stable series and compare measurement variability from comparing the following measures for real and simulated
s
sim lated mean topographies:
topographies

Reaal
Reaal
simulated
i l t d seriesi against
i t that
th t measured d in
i reall short‐term
h tt ti
time series.
i g Standard Deviationss within scan ((MPHSDW) and
• Mean of Pixel Height
Simulated stable series may be used to test progression algorithm specificity. between scan (MPHSDB) – Figure 2 (a) & (b)
Methods • Rim Area (RA)
( ) variability
b l ‐ Coefficient
ff off Variatiion ((CV)) – Figure 2 ((c)) (d) (e) (f) (d) (e) (f)

ulateed
Local variability was assessed by calculating:

S ulateed
Data

SSimu
Simu
• Pixel Height
g Standard Deviation mapped pp at each
e p
pixel within scan ((PHSDW)
Three confocal image stacks from each of 5 sets of Heidelberg Retina
and between scan (PHSDB)
Tomograph h (HRT)
( ) II scans, obtained
b i d within
i hi a 6 weekk follow‐up
f ll period,
i d in
i a
short time series study,y 1 of 127 eyes
y from 66 p
patients were selected. Th similarity
The i il it off local
l l variability
i bilit produced
d d in i simulated
si l t d seriesi tot that
th t off reall g
Figure 4. Q p y of within scan,, local variabilityy for real and simulated p
Qualitative display pairs. ((a)) Real mean
series was examined by the normalised cross‐ccorrelation (NCC) of PHSDW and reflectance image. (b) Corresponding simulated mean reflectance image. (c) Real mean topography
Simulation
i l i Methodology
h d l PHSDB maps p between simulated and real topogr
p graphy
p y series ‐ Figure
g 4 (MPHSDW 20µm (Case I) 17µm (Case II)). (d) Corresponding simulated mean topography (MPHSDW 22µm
Rather than post
post‐processed
processed single topographies as used in previous HRT (Case I) 16µm (Case II)).
II)) (e) Log of PHSDW maps of real mean topography ‐ darker areas represent areas of
methodologies 2,3 this method uses the data from all the optical
simulation methodologies, higher variability.
variability (f) Log of PHSDW maps of corresponding simulated mean topography.
topography NCC of maps (e)
R lt
Results 0 55 (Case I) and 0.37
and (f) is 0.55 0 37 (Case II).
II)
ti
sections off a baseline
b li confocal
f l Scanning
S i Laser
L O hth l
Ophthalmoscopy (CSLO) iimage
Case I
C I Case II
C II
stack before topography formation as the basis for simulation. (a) (b) (c)
Map
PHSDB Map  Series Mean 
Series Mean Series Mean 
Series Mean
S i M
Series Mean  S i M
Series Mean  Map
PHSDB Map 
• Fixational eye‐movements: ocular micro‐tremor,
micro‐tremor micro‐saccades and drift Reflectance Image
Reflectance Image Topography (SD of Series)
(SD of Series) Reflectance Image
Reflectance Image Topography (SD of Series)
(SD of Series)
(a) ((b)) (c) ((a)) ((b)) ((c))
sim lated during
are simulated d ring acquisition
acq isition with
ith empirical parameters
• Device measurement noise is simulated in each optical p section ((normal
Reaal

Reaal
[Nyquist‐thermal]
additive [Nyquist thermal], intensity proportional/Poisson [Shot])
• The
h simulated
l confocal
f l stacks k are imported into theh HRT software
f to form
f
topography
p g p y imagesg ‐ Figure
g 1 (d) (e) (f) (d) (e) (f)
ulateed

ulateed
• These topographies are combined to form simulated mean topographies ‐ Figure
g 2. Comparison
p of simulated topography
p g p y seriess to real topography
p g p y series showingg
Simu

Simu
Fi
Figure 1 gglobal topography
p g p y variabilityy measures: ((a)) Within‐‐visit Mean Pixel Heightg Standard
• For each eye, a simulated series (5 x 3 single topographies) was propagated Deviation
e at o ((MPHSD S W), (b) Between‐visit
et ee s t Mean e Heeeight
ea Pixel g t Sta da d Deviation
Standard e at o ((MPHSD
S B),
from a baseline confocal image stack (c) Rim Area (RA) Coefficient of Variation (CV)
Figure
g 5. Between scan,, local variabilityy for real and simulated p pairs. ((a)) Real series‐average
g mean
MPHSDW MPHSDB RA CV reflectance image. (b) Corresponding simulated series
series‐average
average mean reflectance image. (c) Real series
series‐
(a) (b)
Mean Difference
Mean Difference 3 5µm
3.5µm 2 0µm
2.0µm ‐2.1%
2 1% average mean topography (MPHSDB 9µm (Case I), 39µm (Case II)). (d) Corresponding simulated series series‐
average mean topography (MPHSDB 9µm (Case I), I) 38µm (Case II)).
II)) (e) Log of PHSDB maps of real mean
(i) 95% CI: Limits of  topography series ‐ darker areas represent areas of higher variability.
variability (f) Log of PHSDB maps of
[[‐20.9µm  28.8µm]
20 9 28 8 ] [[‐5.4
5 4µm  9.3µm]
4 93 ] [ 17 6% 13 6%]
[‐17.6%  13.6%]
(i) g
Agreement corresponding simulated mean topography series.
series NCC of maps (e) and (f) is 0.73
0 73 (Case I) and 0.51
0 51 (Case II).
II)
1 Mean difference and limits of agreement between real and simulated
Table 1.
topography series metrics of variability
(ii)
(ii) Conclusions
((a)) ((b))
Simulation
Si l ti by
b generating
ti acquisition
i iti noise
i withith empirical
i i l eye movementt and d measurementt
(iii) noise parameters before topography formation can realistically reproduce variability inherent
in stable patient
p HRT data.
Future work will examine the results of change detection algorithms on simulated and real
(iv)
series.
i FFurthermore,
h simulation
i l i off topographic
hi changes
h beneath
b h overlying
l i measurement noise i
associated with glaucomatous change in the ONH will need to be investigated.
Eye Eye Eye (iv)

(ii)
Stability in clinical series is uncertain,
uncertain whereas in the modelled series it is certain.
certain This
1 2 127
Figure 3. Distributions of NCC of (a) PHSDW maps and d (b) PHSDB between simulated and method
th d can produce
d benchmark
b h k datasets
d t t on which
hi h various
i statistical
t ti ti l methods
th d for
f detecting
d t ti
Figure
g 1. Schematic of simulation showingg ((a)) ggraphic p ggeneration of new mean real topographies
p g p for each series ((‐1: highly
g y anti‐coorrelated,, 0:uncorrelated,, 1: highly
g y HRT progression can be compared
topography
p g p y from single g baseline CSLO stacks ((b)) input, p , output
p and sequence
q of correlated).
)
simulated measurement noise addition in one mean topography p g p y formation. Beginning
g g The mean CC between real and simulated spatial variability maps was 0.58 (SD 0.12) Acknowledgements
A k l d
(i), intermediate (ii) & (iii) and final (iv) stages of the simulated data in both sub
sub‐figures
figures within mean topographies and 0.54 (SD 0.10) betw ween mean topographies. This is a This work is generously supported by the Special Trustees of Moorfields Eye Hospital
This work is generously supported by the Special Trustees of Moorfields Eye Hospital              
(a) and (b) are highlighted in blue. quantitative measure of the validity of the simulation on
o a local level.
level and by an unrestricted grant from Heidelberg Engineering
and by an unrestricted grant from Heidelberg Engineering
References
R f
1. Strouthidis, N G, White, E T, Owen, V M F, Ho, T A, Hammond, C J, Garway‐Heath, D F,
Strouthidis N G White E T Owen V M F Ho T A Hammond C J Garway‐Heath D F Factors affecting the test‐retest variability of Heidelberg retina tomograph and Heidelberg retina tomograph II measurements, Br J Ophthalmo
Factors affecting the test‐retest variability of Heidelberg retina tomograph and Heidelberg retina tomograph II measurements Br J Ophthalmo
ol 2005 89: 1427‐1432
ol 2005 89: 1427‐1432  oleary.neil@gmail.com
y @g
2. N O'Leary, M Balasubramanian, D F Garway‐Heath, and D P Crabb, Developing and Testing a Heidelberg Retina Tomograph Image Simulation Method for Application to Optimise Glaucoma Progression Algorithms, Invest. Ophthallmol. Vis. Sci. 2009 50: E‐Abstract 2249.
3. Patterson, A J, Garway‐Heath,  D F, Strouthidis,  N G, Crabb, D P, A New Statistical Approach for Quantifying Change in Series of Retinal and Optic Nerve Head Topography Images, Invest. Ophthalmol. Vis. Sci. 2005 46: 1659‐1667.
Author disclosure block: N.
N OO'Leary
Leary, None; D.F.
D F Garway-Heath,
Garway-Heath Carl Zeiss Meditec,
Meditec F; Heidelberg Engineering
Engineering, F; Carl Zeiss Meditec,
Meditec R;
D.P. Crabb, Heidelberg Engineering, F.