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closure glaucoma
Pallavi Basu
Abhishek Pal Majumder
Anirban Basak
Priyam Biswas
May 29, 2007
Abstract
We examine longitudinal data of visual field score and IOP from patients having chronic angle closure glaucoma. In
determinig a relationship between field score and IOP , linear regression technique is used . Serious concerns can be raised
about the normality assumption. A Box-Cox transformation is hence applied.We try to analyze the assumption that each
subfield is equally affected by glaucoma .Resampling technique is used to estimate distribution of test statistic . Predicting
Progression was not feasible due to shortage of data.
1
Contents
1 Outlining situation and framing objectives. 4
1.1 Explaining the variables . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
1.2 Inclusion criterion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
1.3 Categorization by glaucoma stage(by AGIS system) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
1.4 Objectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
2
8 References 16
9 Acknowledgements 17
List of Figures
1 Scatter plot of left and right IOP at different time points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
2 Scatter plot of residual . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
3 Normal probability plot of residuals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
4 Empirical cdf for T1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
5 Empirical cdf for T2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
6 Empirical cdf for T . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
3
1 Outlining situation and framing objectives.
90 patients each having chronic angle closure glaucoma in one or both pairs of eyes were diagonised at 4 different time points
within a time span of two years.The purpose of this project is to resolve out issues that are of help to medical experts.
1.4 Objectives
1. To evaluate characteristic visual field defect .
2. To assess the relationship between IOP and visual field damage.
3. To evaluate Progression of visual field damage.
4
3 Using this dataset
3.1 Dealing with missing data
Missing data will be categorised into dropouts and other.A separate section 3 deals with this problem.However, not much
missing data - specially the dropout variety is present in this particular dataset.
1 if (d − b)(c − a) > 0
where, Q((a,b),(c,d)) = −1 if (d − b)(c − a) < 0
0 if (d − b)(c − a) = 0
0 0
RejectH0 if K ≥ kα/2 or K ≤ kα/2 where, kα/2 is upper α/2 tail probability of the null distribution of K and kα/2 is lower
α/2 tail probability of the null distribution of K.
3 refer section 8
4 technically called Snellen chart
5 for detailed theory refer Nonparametric statistical methods(Hollander and Wolfe)
6 termed ’Permutation distribution in literature
5
Time point 1 Time point 2
60 60
40 40
20 20
0 0
0 20 40 60 0 20 40 60
30
20
20
10
10
0 0
0 20 40 60 0 10 20 30 40 50
Figure 1: Scatter plot of left and right IOP at different time points
4.2.4 Results
The results for the 4 time points are as follows :
6
4.3 Choice of model
˜ = β0 + X˜age β1 + Xgender
YIOP ˜ β2 + Xvisualacuity
˜ ˜ β4 + X˜iol β5 + Xtrab
β3 + Xdrop ˜ β6 + X˜pi β7 + Xneedling
˜ β8 + XM˜ILD β9 +
˜ ˜ ˜
XM ODERAT E β10 + XSEV ERE β11 + XEN DST AGE β12 + ε̃
Since, the IOP is taken as a response variable and all others as explanatory variables, from the earlier conclusions the
left and right eyes of an individual are taken as independent experimental units.However, measurements of an unit over
different time points cannot be taken uncorrelated.
GLM for longitudinal data treats y as a realization of a multivariate Gaussian random vector Y with
Y ∼ M V N (Xβ, σ 2 V )
where, V is a block diagonal matrix with nonzero 4 × 4 blocks V0 , each representing the variance matrix for the vector of
measurements on a single experimental unit.
4.4.3 Justification
In the exponential correlation model the correlation between jth and kth time points of an individual depends on j and k only
through their absolute difference.As, the sample correlation matrix almost satisfies this property ,the exponential correlation
model is selected.
Y ∼ M V N (Xβ, σ 2 V )
. Calculation7 shows that the REML estimator maximises the loglikelihood equation
where,
RSS(V0 ) = (y − X β̂(V0 ))0 V −1 (y − X β̂(V0 ))
and
β̂(V0 ) = (X 0 V −1 X)−1 X 0 V −1 y
To solve V0 method of iteration is used.Subsequently, β̂ and σ̂ are obtained.
7 Refer Analysis of longitudinal dataDiggle Chapter 4
7
4.5.2 Box-Cox transformation
Original data on IOP being integer valued it is wise to apply a Box-Cox transformation 8 to ensure normality.
½ λ
(y − 1)/λẏ λ−1 if λ 6= 0
y (λ) =
ẏ ln y if λ = 0
where ẏ is the geometric mean of the response variable.Applying this transformation SS E (λ) is calculated for different values
of λ and that value of λ is chosen for which SSE (λ) is minimum.
4.6 Results
4.6.1 Estimates of the parameters of the model
ρ̂=0.6
λ̂=0.36
29.22
−0.01
−1.42
−0.26
−3.06
5.21
ˆ
β̃= −9.16
−1.84
−7.08
2.41
3.27
4.57
3.03
• The normal probability plot of the residuals (Figure 3 ) appears to be in a straight line indicating that the fact errors
are indeed normal,emphasizing normality assumption of the response is valid .
H0 ≡ Qβ = 0
,where
ˆ L = σˆ2 (X 0 V −1ˆ X)−1
RREM REM L
ˆ L 0 Q0 (QRREM
T = βREM ˆ L
ˆ L Q0 )−1 QβREM
8
Plot of residual
20
15
10
−5
−10
−15
−20
0 100 200 300 400 500 600
0.999
0.997
0.99
0.98
0.95
0.90
0.75
Probability
0.50
0.25
0.10
0.05
0.02
0.01
0.003
0.001
−15 −10 −5 0 5 10 15
Data
9
4.8 Results
It is required to find out whether there is a field category effect on the IOP.Each of the p-values listed below indicate the
result for :
ˆ
H0 ≡ βcorrespondingcategory =0
versus
ˆ
H1 ≡ βcorrespondingcategory 6= 0
• P-value of βSEVˆERE ≈ 0
ˆ AGE = .02
• P-value of βEN DST
or,
mild < endstage < moderate < severe
• In cases where outliers have positive residuals trabeculectomy has been done just after the time point at which residual
is an outlier
• In cases where outliers have negative residuals trabeculectomy has been done just before the time point at which residual
is an outlier
This emphasizes the fact that trabeculectomy has an enormous effect in reducing the IOP of patients having glaucoma .
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5 To evaluate characteristic visual field defect
It is of interest to medical experts given a glaucomatous eye at a certain stage which is defined by the category , which
subfield has greater damage.The main emphasis in this analysis is given to mild and moderate category as in the other
higher(severe and endstage) categories the scores in each subfield already being high enough ,is impossible to compare the
degree of damage.
5.2 Methodology
Visual field scoring method is the same throughout all the subfields..Each subfield has test locations - 6 for nasal , 23 for
superior and 23 for inferior.As a result a maximum of 20 score is possible , with a maximum of 2 from the nasal field, and
maximum of 9 from each of superior and inferior hemifield.With this scoring methodology, if it is assumed that each of the
subfields is affected equally by glaucoma it is expected on the average the subfield scores should be 2N/20 for nasal,9N/20 for
inferior and 9N/20 for superior where N is the total field score.Using these fact, from the available dataset using simulation
, a CI of the mean(s) is obtained.This gives a way to test H0 vs H1 .
Consider,
AND
Now, X
T1 = S1N /]U nitsM ILD
N ∈M ild
X
T2 = S2N /]U nitsM ILD
N ∈M ild
From the definitions,it is clear that if the dataset is in accordance with the null T 1 and T2 should be close to zero.
11
80
70
60
50
40
30
20
10
0
0 0.2 0.4 0.6 0.8 1 1.2 1.4
45
40
35
30
25
20
15
10
0
0.8 1 1.2 1.4 1.6 1.8 2
12
5.3.4 Results
Two sided CI for T1 is (0.3596, 0.9585)
Two sided CI for T2 is (1.2372, 1.7734)
Note any of the CI(s) does not contain the value 0 and in both the cases 0 is smaller than the lower cut-off points. In both
the cases p-values are almost equal to zero(indeed p value obtained using emperical cdf was actually found to be zero).
Now, X
T = S N /]U nitsM ODERAT E
N ∈M oderate
From the definitions,it is clear that if the dataset is in accordance with the null T should be close to zero.
5.4.4 Results
Two sided CI of T is (1.1290,2.8710)
Note the CI does not contain the value zero and zero is smaller than the lower cut-off point.
13
350
300
250
200
150
100
50
0
0 0.5 1 1.5 2 2.5 3 3.5 4
The time span over which this data is collected is less than two years.Only 3% of the units have progressed (in cardi-
nality 4-5).It is not of much worth to try to predict progression in this dataset.More time span is necessary to put forward
any comment on progression.Also, from medical perspective it not much interesting to study progression in this dataset.
• As the field score is a count data,taking field score as a response and a poisson distribution on the errors the joint
distribution of field scores upto the future time point that is needed to be predicted can be obtained.Hence,using the
conditional probability on all the data available before the time point needed to be predicted, a range of field score can
be given which may be able to determine progression.
• Also, the stochastic nature of the field scores can be used.The transition probabilities may be estimated given the
dataset and hence a prediction can be obtained.
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7 Dealing with missing data
In the dataset two different types of missing data were observed.
• During the first visit of a few patients very high IOP was observed.Medical expertise says that it is not justified to
measure the visual field score of a patient while he/she having a very high IOP because high IOP causes a great deal
of variation in visual field score which perturbs to prepare a baseline field score .Proper medicine(s) are suggested to
control high IOP value.In the subsequent follow ups while the patient has a reasonably lower IOP visual field score is
measured and a baseline field score value is prepared.
• In some of the cases it is seen that patients did not come for subsequent follow ups.
• All other types of missing values are considered to intermittent missing values.
Different methods exist in literature9 to test whether dropouts are comletely random,random or informative.However in all
methodology large enough data on dropouts required.Thereafter different models follow for different types of dropouts.
In the dataset total number of dropout cases were 3 which fails to suffice the minimum number of dropouts required to test
for randomness.So analysis was done discarding those dropouts.
9 Refer Analysis of longitudinal data Diggle
15
8 References
• Analysis of longitudinal data (Diggle)
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9 Acknowledgements
We are grateful to Dr. Sanchita Ray for her constant help and support. We extend sincere thanks to Prof. Arijit Chakraborty
and Prof. Saurabh Ghosh for their fruitful suggestions. Finally , we thank our batchmates and seniors.
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