ABSTRACT

HEARING LOSS AND FLUCTUATIONS IN MENIERE'S DISEASE/COCHLEAR

HYDROPS

By

Huy Nguyen

Meniere's disease is a clinical disorder of the inner ear defined by periodic

vertigo, fluctuating hearing loss, tinnitus, and aural fullness. Cochlear Hydrops is similar

to Meniere's but without vertigo. It is appropriate to mention Cochlear Hydrops because

it may precede Meniere's disease.

Clinical care focuses on reducing the severity and frequency of vertigo because it

is the most crippling symptom of Meniere's disease. Vertigo, tinnitus, and aural fullness

are subjective; therefore many studies include hearing measurement as a secondary

endpoint. Currently, there are no reliable metrics to describe hearing loss and

fluctuations. The lack of information on hearing changes restricts its use as the primary

endpoint in clinical trials. The purpose of this paper is to quantify both the probability of

fluctuations (logistic regression) and the expected hearing losses over a period of time

(longitudinal data analysis).

HEARING LOSS AND FLUCTUATIONS IN MENIERE'S DISEASE/COCHLEAR
HYDROPS

A PROJECT REPORT

Presented to the Department of Mathematics & Statistics

California State University, Long Beach

In Partial Fulfillment

of the Requirements for the Degree

Master of Science in Applied Statistics

Committee Members:
Olga Korosteleva, Ph.D (Chair)
Kagba Suaray, Ph.D
Alan Safer, Ph.D

College Designee:
Robert Mena, Ph.D

By Huy Nguyen

B.S., 2004, University of California, Irvine

May 2012
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 TABLE OF CONTENTS

Page

LIST OF TABLES iv

LIST OF FIGURES v

CHAPTER

1. INTRODUCTION 1

2. DATA AND BASIC STATISTICS 4

3. STATISTICAL METHODOLOGY 7

Longitudinal Data Analysis 7

Logistic Regression 13

4. RESULTS 16

5. CONCLUSION 19

APPENDICES 21

A. SASCODE 22

B. TABLES 33

C. FIGURES 45

REFERENCE 52

in
 LIST OF TABLES

TABLE Page

1. Steps taken to Clean Data 34

2. Basic Statistics at First evaluation 34

3. Basic Statistics on All evaluation 35

4. Longitudinal analysis full model Without Interaction terms 36

5. Longitudinal analysis full model With Interaction terms 37

6. Longitudinal analysis Reduce Model with only Significant variables 38

7. Longitudinal analysis Comparing Parameter Estimation 39

8. Influential data 39

9. Longitudinal analysis Reduce Model using Reduce Data 40

10. Distribution of Continuous variable 41

11. Logistic regression using Stepwise Selection 42

12. Logistic regression using Stepwise Selection on Binned Variable 43

13.. Logistic regression using Stepwise Selection with Interaction terms 44

IV
 LIST OF FIGURES

FIGURE Page

1. Individual response profiles 46

2. Mean response profiles for Meniere' s vs Cochlear Hydrops 46

3. Histogram for PTA affected ear (response) 47

4. QQ plot for PTA affected ear (response) 47

5. Graph PTA vs age 47

6. Graph PTA vs intervaldxm 48

7. Raw conditional residuals for reduce longitudinal model 48

8. Fixed effects influence diagnostic for reduce longitudinal model 48

9. Co variance influence diagnostic for reduce longitudinal model 49

10. Raw conditional residuals for reduce data longitudinal model 49

11. Fixed effects influence diagnostic for reduce data longitudinal model 49

12. Co variance influence diagnostic for reduce data longitudinal model 50

13. ROC curve of stepwise logistic regression 50

14. ROC curve of stepwise logistic regression using binned variable 51

15. ROC curve of stepwise logistic regression with interaction terms 51

v
 CHAPTER 1

INTRODUCTION

Meniere's disease is a clinical disorder of the inner ear. It is named after Prosper

Meniere, a French physician, who first reported in 1861 that vertigo (defined below) is

caused by inner ear disorders. This disease was recognized prior to 1972, but it was in

1972 when the American Academy of Otolaryngology-Head and Neck Surgery

Committee on Hearing and Equilibrium (AAO HNS CHE) first defined Meniere's

disease as having periodic vertigo, fluctuating hearing loss, tinnitus, and aural fullness

[1]. Vertigo is the sensation of motions when no motions are actually occurring, causing

a patient to feel dizzy and disoriented. Vertigo lasts for at least 20 minutes and up to

several hours at a time, accompanied by nausea and vomiting. Hearing fluctuates

randomly from good to bad and back to good, but progressively worsens over time.

Tinnitus is a loud ringing noise in the ear. Aural fullness is pressure in the ear similar to

fullness experienced on an airplane. Cochlear Hydrops is a sub category of Meniere's

disease. Many patients with Cochlear Hydrops are eventually diagnosed with Meniere's

disease because its symptoms are similar but without vertigo [2].

Clinical care and most research papers focus on reducing the severity and

frequency of vertigo because it is the most crippling symptom of Meniere's disease.

Vertigo, tinnitus, and aural fullness are subjective to the patient; therefore, many studies

include hearing measurement as a secondary endpoint. Hearing fluctuation is a known

1
aspect of Meniere's disease, but how large a change in hearing occurring over a defined

time period is unknown. In the dataset, hearing is measured by air conduction

(headphones or loud speakers) in decibel (dB), and is recorded on an audiogram. An

audiogram is a graph that evaluates the softest sounds a person can hear at different

frequencies. The average hearing thresholds at 500, 1000, 2000, and 3000 Hz (if 3000

Hz is missing, then 4000 Hz will be used) are called pure tone average (PTA). Presently

there are no reliable metrics to evaluate hearing and fluctuations. The lack of information

on PTA changes restricts the use of hearing as the primary endpoint in clinical trials.

The purpose of this paper is to quantify both the probability of fluctuations and

the expected hearing loss over time. The goals are the following:

1. Obtain basic statistics on the data to validate with known facts about the

disease.

2. Use longitudinal data analysis in SAS to predict patients' hearing over time.

3. Use logistic regression to find characteristics that lead to a higher probability

of fluctuation.

Currently, there are no "gold standards" of treatment for Meniere's/Cochlear

Hydrops [3]. The purpose of this paper is not to find a treatment, but to provide a

description of hearing to serve as a stepping stone for future treatments. By quantifying

the progression of hearing loss over time, we can give patients an estimate of what to

expect as the disease progresses. As a result, patients can then make well informed

decisions that may help provide a better quality of life as they cope with the lifelong

disease. Additionally, we hope that the results will provide a reliable metric to describe

hearing loss and fluctuations. Future clinical trials may benefit from our analysis and

2
conclusions by allowing hearing to be used as the primary endpoint, and a baseline for

future studies. The results will allow researchers to make statements such as "A sample

of 300 Meniere's disease patients show that hearing depreciates X amount per year and

have Y probability to fluctuate before the next examination."

3
 CHAPTER 2

DATA AND BASIC STATISTICS

Data

The data consist of patient's records from the House Ear Institute, located in Los

Angeles, California. Originally, the dataset contained over 3,000 evaluations from 363

patients collected over the past 50 years. After extensive cleaning, there were 2,478

observations from 345 patients. The variables are the following:

1. PID = Patient ID number

2. Age = Age at the current evaluation date

3. AgeCenter = Age minus the mean age of all evaluations

4. DateDx = Date of diagnosis

5. Date = Date of evaluation

6. BeforeafterMD = Date Cochlear patient was diagnose with Meniere's

7. Firstdxl = Number of evaluation since diagnosed date

8. BiUni = Bilateral (0) if the disease affects both ears or unilateral (1) affects one

ear

9. Doce = Documented affected Ear, right (1), left (2), bilateral (3)

10. MDCH = Documented disease. Meniere's Disease (1) and Cochlear Hydrops (0)

11. Evalb4surgery = Whether evaluation is before (0) or after (1) surgery

12. Sex = Male (0) and female (1)

4
 13. IntervalDxM = Time between diagnosis date and evaluation date

14. IntervalDxMCenter = IntervalDxm minus the mean of IntervalDxM

15. PTAaf = 4 frequency pure tone average of the affected ear

16. PTAafCHANGE = Difference in PTA between the current evaluation and the

last one

Data Cleaning

The dataset was examined to ensure accuracy, to identify outliers, and to deal with

possible missing values. Before and during the analysis phase, many discrepancies were

found. The patients with discrepancies were identified, and hard copy records were

ordered for comparison to ensure that the data was entered correctly. If the data was

entered correctly and it was considered an outlier, then the data point was examined

closely and actions based on recommendations from doctors at HEI were taken. If the

value was missing, we had to determine whether it was missing at random, missing

completely at random, or missing not at random. Missing values were either fixed or

deleted depending on why it was missing (Table 1).

Basic Statistics

Although there are no reliable metrics describing hearing loss and fluctuations,

there are a few things that we do know about Meniere's/Cochlear Hydrops. Basic

statistics on all evaluations, and the first evaluation after diagnosis were attained to

confirm what is already known. This will give us a better understanding of what the

average PTA is when a patient is first diagnosed. Frequencies of patients' characteristics

(sex, mdch, bilateral or unilateral, and its cross product) were also attained to ensure that

our dataset is comparable to others, and not biased. For example, we don't want our

5
dataset to have more males than females in comparison to the diseased population. What

we already know about Meniere's disease and Cochlear Hydrops are the following:

1. Surgery reduces vertigo but it causes hearing to worsen [4].

2. Meniere's patients have a higher PTA compared to Cochlear Hydrops [2].

3. Bilateral cases have a higher PTA than unilateral cases [2].

4. Cochlear Hydrops may become Meniere's, and unilateral may become bilateral

overtime [2].

Basic statistics on all evaluations and the first evaluation after diagnosis confirms

three of the above statements (Table 2 & Table 3). The PTA difference between male

and female patients at first evaluation is 5 dB, but the difference over all evaluation

between the two groups converges to less than 1 dB. After surgery, hearing worsens by

13 dB. Meniere's patients and bilateral cases have a higher PTA at first evaluation, and

the difference continues to grow over all evaluations. Bilateral males and Meniere's

bilateral cases have the highest PTA of 51 dB at first evaluation, whereas Cochlear

Hydrops females have the lowest PTA of 19 dB. The average PTA increases from the

first evaluation for all explanatory variables. Female Cochlear Hydrops patients have the

lowest average PTA at first evaluation, and over all evaluations.

6
 CHAPTER 3

STATISTICAL METHODOLOGY

Longitudinal Data Analysis

Longitudinal data analysis will be applied to estimate hearing over time. It can

model individual change over time, and allows the repeated measures to be flexible.

Meaning, patients do not need to have the same number of observations and time can be

continuous, rather than a fixed set of time points. It is also flexible in the specification of

the covariance structure and can generalize for non normal data. The covariance

structure is important because repeated measurements taken on the same patient are

correlated. The advantages of longitudinal analysis directly apply to this dataset because

the number of observations per patient varies from 2 to 43. The data does not come from

a planned clinical study; therefore, evaluations are not completed at a fixed time.

There are many types of models that can be used for longitudinal data analysis.

The most appropriate model for this dataset is the random slope and intercept model that

allows for heterogeneity of variance and covariance over time. The random intercept is

needed because patients with either Meniere's or Cochlear Hydrops do not start at the

same level of hearing when they are diagnosed. The random slope is needed because in

practice the variance and covariance of the response variable, PTA, is rarely constant.

Examining the individual response profile graph (Figure 1), we will see that the amount

of change at different time periods varies greatly. A closer look at the mean response

7
profiles for Meniere's disease versus Cochlear Hydropds (Figure 2) shows that the

standard deviation varies across time as well. The primary assumptions of the

longitudinal analysis performed by Proc Mixed are as follows [5]:

1. The response variable is normally distributed.

2. The means of the data are linear in terms of a certain set of parameters.

3. The variance and covariance of the data are in terms of a different set of

parameters and exhibit a structure matching one of those available in Proc Mixed.

The assumptions of longitudinal analysis are examined to ensure that they are met

before any analysis is completed. The histogram shows the response variable is

distributed like a bell curve around its mean (Figure3), and the QQPlot looks as if it could

be fitted with a straight line (Figure 4). Both of these plots confirm that our response

variable is normally distributed. According to the age vs PTA graph (Figure 5) and time

vs PTA graph (Figure 6), we see that a linear line could be fitted through the data. The

unstructured covariance estimation in Proc Mixed will be used. The data meets the

assumptions; therefore, the random slope and intercept model will be applied. In this

model, ytj is the observation of the response variable on the ith subject at time tj9

i = 1,..., n , j = 1,..., k , is of the following form [6]:

ytj = Po + PlXuj + - + PpXpij + Pp+ltj + Utl + Ui2tj + Sij

are
Where utl~i. i. d N(0, a^i) the random intercepts which are the individuals'

deviation from the average intercept. And u ^ ^ i . i- d N(0, <r^2) a r e the random slopes

which are the individuals' deviation from the average change. Also, €ov(uilf ui2) =

8
a
uiu2 -> i = 1' — #rc> and Cov (i%,i^ >2 J = 0 for i =£ V. The error terms are

Eij~i.i.d N(0, a 2 ) , and independent of u x and u 2 .

A random slope and intercept model was created using agecenter, biuni, doce,

mdch, evalb4surgery, sex, and intervaldxmcenter as the predictor variable. By default,

the parameters are estimated using restricted maximum-likelihood method (REML). The

purpose of this model is to determine whether these variables are significant in estimating

the response variable, pta_af. This is done first because often times, the addition of

interaction terms reduce the significance of the main effect terms. From SAS output, all

the variables are significant with a p-value <0.05 except for doce (Table 4). Medically,

this makes sense because documented affected ear does not affect one ear more than the

other; both ears have an equal probability of being affected.

Now, a full model with interaction terms are created on the following variables:

evalb4surgery, mdch, agecenter, intervaldxmcenter, biuni, sex, sex*mdch,

bi_uni*mdch, sex*evalb4surgery, sex*evalb4surgery*mdch, evalb4surgery*mdch, and

bi_uni*sex. Results from SAS show that most of the interaction terms have no

significance at 0.05 except for mdch*sex, but now one of the main effect term, biuni,

has become insignificant (Table 5). Backward selection is done by removing one

variable at a time until all the remaining variables are significant. Variables with the

highest p-value were removed first and interaction terms have precedence over main

effect terms. Although biuni has the second highest p-value, it was not removed second

because interaction terms with biuni causes it to be insignificant. After the removal of

all insignificant variables, the following reduced model remains (Table 6) [6]:

9
 pta_aflJ = 50.685 + 9.0949evalb4surgerylJ + 9.1308mdchlJ
+ §AttAtage_centerl} — \\&\\\biunil} — 14.6667sex l7
+ O.llQinterva^dxmsenter^ + 10.83\mdch l} * sextJ + utl
+ ul2interval_dxm_centerj + el}

Where utl~i. i. d N(0,372.26) are the random intercepts and u l 2 ~i. i. d N(0,0.03182)

f =
are the random slopes. The £ov(ullful2) = 1.3757 , i = 1, ...,n, and £ov lullfut 2)

0 for i =£ V. The error terms £tJ~i. i. d N(0,101) are independent of u± and u 2 .

A few more reduced models were created using the same predictor variables, but

with different methods of parameter estimations and covariance structures. The

maximum-likelihood method (ML) and the minimum variance quadratic unbiased

estimation (MIVQUE0) were used to estimate the parameters. Aside from the

unstructured (UN) covariance estimation, the variance components (VC) covariance

estimation will also be applied. The fit statistics are compared for all the reduced models

(Table 7), and results show that our current reduced model with the REML parameter

estimates and the UN covariance estimates have the lowest fit statistics, where lower is

better.

Residual analysis and influence diagnostic are used to validate the model's

assumptions, detect for outliers, and potentially influential data points [5]. In PROC

MIX, conditional residual is the difference between the observed data and the predicted

value of the observations. The residual plot of the raw conditional residuals fluctuates

randomly around zero without a pattern. The normal probability plot fits a linear line,

except for at both endpoints. It is a bit curvy at the endpoints, but does not violate the

10
assumption of normality. The histogram is a symmetric bell shaped curve around the

mean zero. These three plots confirm that the error terms are normal (Figure 7).

Influence diagnostic help indicate outliers and possibly influential data. This is

achieved by removing all of a single patient's observations and re-estimating the model's

parameters for every patient, one patient at a time. The reduced data estimates are

compared to the full data estimates. The fixed effects influence diagnostic for PTA

reveals several important factors. There are patients that have more influence (restricted

likelihood distance) on the estimated fixed parameters than others (Table 8). Those same

patients exert the most change (Cook's D), and reduce the precision of the fixed

parameters (COVRATIO) (Figure 8). The covariance parameter influence diagnostic for

PTA shows the same patients that affect the fixed parameter estimates also exerts the

most change in the covariance parameter estimates (Cook's D and MDFFITS CovParms)

and reduce its precision (COVTRACE and COVRATIO CovParms) (Figure 9). Those

patients have two things in common, either they have very high PTA, or they have

several back to back observations with a PTA = 120. The influences from patients with

high PTA are left alone because it is a fact of the disease. The influence from patients

with several observations of PTA =120 are troublesome because there are no more

changes possible in hearing. A single observation of PTA = 120 is kept for each patient

and the rest are removed.

The parameter estimates of the reduce model is recalculated using the reduced

data set and the following model was attained (Table 9) [6]:

11
 pta_aflJ = 49.5329 + 8.1185ei;a//?4surgery l7 + 9A645mdchlJ
+ 0AS9Sage_centerlJ - 10.8981bi_ura i; - 14.3167 * sextJ
+ 0.1187intervaldxmcenter^ + lQA261mdchl] * sexl} + utl
+ ul2interval_dxm_centerj + elJ

Where utl~L i. d N(0, 341.67) are the random intercepts and ul2~i. i. d N(0,0.02872)

are the random slopes. The £ov(ullful2) = 1.1615 , i = 1, ...,n, and £ov ( u ^ i ^ ' 2 J =

0 for i =£ i'. The error terms £ i ; ~i. i. d N(0,96.2583) are independent of ux and u2.

The residual analysis and influence diagnostic were conducted for this reduce model on

the reduced data set. Raw conditional residuals fluctuate randomly around zero without a

pattern, the normal probability plot fits a linear line except, for at both endpoints, and the

histogram is a symmetric bell shape curve around the mean zero (Figure 10). These three

plots confirm the error terms are normal. Influential patients with no observations

removed in the full data set are influential in the reduced data set (Figure 11 & 12). The

patients are influential due to their high PTA, and do not warrant their removal from the

reduced data set.

Comparing the reduced data to the full data model, there seems to be a several

improvements. Some suspicious points on the raw conditional residuals plot have been

removed, and the fit statistics have improved by nearly 400 points (Figure 7 & 10).

Although influential patients still exist, those patients have been carefully examined.

Most importantly it is understood that the reason they are influential is due to their high

PTA. The removal of 32 observations from the analysis has increased the precision of

the fixed and covariance estimates, which can be seen by the difference of the lower and

upper bound of the parameter estimates at 0.05 significance.

12
 Logistic Regression

Meniere's disease is defined to have fluctuating hearing losses over time and

logistic regression will be applied to investigate this aspect. A significant fluctuation is

considered to be a change of hearing in the effected ear of 10 dB or greater between

evaluations. Logistic regression is useful in this case because given a set of

characteristics, it will provide a probability of an event (significant fluctuation). The

model will use sex, mdch, doce, evalb4surgery, biuni, age, and intervaldxm as the

input variables and fluctuation as the target variable.

Three logistic regression models were created in SAS using different selection

methods (stepwise, forward, and backward selection) [7]. SAS output shows that

regardless of what selection method used, results ended up being the same. The three

models have the exact same variables selected, and the same parameter estimates for

each. It then produced the same model fit statistics (AIC, SC, -2LogL) and ROC curve.

With all three models being the same, we decided to move forward using the logistic

regression model with stepwise selection. The model has the intercept AIC of 2581.7,

intercept and covariate AIC of 2545.2 (Table 11), and the area under the ROC curve of

0.5909 (Figure 13). The model looks as follow [7]:

1
Probability of Fluctuation = f(z) = - —

Where z = -0.7943 + 0.4626 * mdch + 0.4214 * biuni - 0.0154 * age

—0.00228 * intervaljdxm

There are two continuous input variables (age and intervaldxm) in our data. We

will try to bin those variables into groups to see if a better model can be created. Proc

13
univariate was ran to get the estimates at 25%, 50%, and 75% quartiles (Table 10). The

variables are grouped based on these quartiles. A stepwise logistic regression model was

created using sex, mdch, doce, evalb4surgery, biuni, agebin, and intervaldxmbin as

the input variable. SAS output reveals that this model has the same intercept AIC as the

model above, slightly higher intercept and covariate AIC of 2552.5 (Table 12), but a

lower area under the ROC curve of 0.5816 (Figure 14). The model looks as follow [7]:

1
Probability of Fluctuation = f(z) = - —

Where z = -1.2232 + 0.4022 * mdch + 0.4463 * biuni - 0.2068 * age bin

We notice that interval_dxm_bin is not selected in this model because the binning effect

has reduced its significance. At this point, due to lower ROC, higher AIC, and omission

of intervaldxm, the stepwise model with the continuous variables above is still the better

model.

Next, interaction terms were added to the stepwise logistic model with continuous

variables. The interaction terms added were mdch*doce, mdch*evalb4surgery,

mdch*bi_uni, doce*evalb4surgery, doce*bi_uni, and evalb4surgery*bi_uni. The results

show that this model has the same intercept AIC as the model without interaction terms,

slightly lower intercept and covariate AIC of 2542.409 (Table 13), and a higher area

under the ROC curve of 0.5951 (Figure 15). The model looks as follow [7]:

1
Probability of Fluctuation = f{z) = —

Where z = 0.5316 - 0.9157 * mdch - 0.9542 * biuni - 0.0155 * age

—0.00228 * intervaljdxm + 1.4431 * mdch * bi_uni

14
This model found an interaction term, mdch*bi_uni, to be significant in estimating the

probability of fluctuation. Although this model has a higher ROC area, it seems to have a

few flaws. The interaction term has cause mdch and biuni to have a reverse effect/sign

compared to the stepwise model with no interaction terms. This result contradicts the

effect of those variables if the interaction terms were not added. The odds ratio for the

main terms associated with mdch*bi_uni can no longer be calculated by SAS.

Comparing the five logistic models, SAS results suggest the goodness of fit (AIC)

and predictive accuracy (ROC curve) are very close to each other. The stepwise binned

continuous variable model has the highest intercept and covariates AIC of 2552.5, lowest

ROC of 0.5816, and intervaldxm is not significant. It is believed that time since

diagnose plays a very important role in both disease because fluctuation is more likely to

occur in the early stages. Once a patient has lost most of their hearing, they are less

likely to have a significant fluctuation. The stepwise model with interaction terms have

the lowest intercept and covariates AIC of 2542.4 and the highest ROC of 0.5951.

Although it has the best model statistically, the addition of an interaction term has

removed the odds ratio for mdch and biuni, which is important in describing the strength

of the input variables and the target variable [7]. The three remaining models produced

the same results and only differ in the selection method, so we will look at the stepwise

model. Although it does not have the lowest AIC or highest ROC, it does include

variables that are significant to Meniere's Disease/Cochlear Hydrops and the odds ratio

are available.

15
 CHAPTER4

RESULTS

Longitudinal data analysis provided a model to estimate hearing over time. For

the average patient age 54, and 53 months since diagnose (Table 9), the results show:

1. After surgery patients have a higher PTA of 8.1185 dB

2. Meniere's disease have a higher PTA of 9.4645 dB

3. Unilateral have a lower PTA of 10.8981 dB

4. Females have a lower PTA of 14.3167 dB

5. Female Meniere's have a higher PTA of 10.4261 dB

6. An Additional year of age increases PTA by 0.4595 dB

7. An Additional month since diagnose increases PTA by 0.1187 dB

The parameters significant in this model and its estimations confirm with the basic

statistics for all evaluations (Table 3), and to what is already known about the disease

prior from doing any analyses. Doce, documented affected ear, is not significant in our

final model and that makes sense medically. Both ears have equal chance of being

affected, and the severity of an ear is more dependent on other factors than where the ear

is located. The inclusion of an interaction term, MDCH*Sex, is a bit of surprise. Basic

statistics on Female Meniere's patients did not suggest anything significantly different

from other interaction terms. Medically, we know Meniere's vs. Cochlear Hydrops does

affect PTA, but we did not know sex made a difference. At first diagnose, male and

16
female have a 5 dB difference, but over time it converges to 1 dB. Further investigation

of why MDCH*Sex was significant reveals the difference between female Meniere's and

female Cochlear Hydrops at first evaluation is 19.65 dB and 30.63 dB over all

evaluations. Those differences are the highest between any two possible interaction

terms. The inclusion of MDCH*Sex is statistically sound and suggests something new

about the disease that we did not know prior to these results.

Agecenter and intervaldxmcenter made it easier to interpret the other input

variables. For example, we can make statements such as "The average female patient age

54, and 53 months since diagnoses has a lower PTA of 14.3167 dB than males." The

difficulties arise when we translate it back to real age and intervaldxm. A 53 year old

patient is 1 year younger than the average patient age, and has a lower PTA of 0.4595 dB.

Although it adds difficulties in interpretation, it adds more accuracy in the interpretation

of the intercept. We know the disease does not start until the age of 30; therefore by

centering, we reduce the range of age to its true range. If age were not centered, age 0-30

would produce an expected PTA that does not make sense. Finally, both agecenter and

intervaldxmcenter have a positive effect on PTA, which confirms that hearing is lost

over time.

Parameters estimate from the logistic regression model indicates the effect

predictor variables have on the probability of a significant fluctuation. Meniere's have a

higher probability compared to Cochlear Hydrops, which makes sense because Cochlear

Hydrops is the less severe form of Meniere's. As age and intervaldxm increases, the

probability to fluctuate decreases. This is true because as you get older, or as the disease

progresses, hearing becomes worse and has less room to fluctuate back. The results

17
suggest that unilateral patients have a higher probability to fluctuate than bilateral

patients. This is intriguing because we would assume that bilateral is worse, and there

would be a higher chance of a significant fluctuation with both ears affected, but a closer

look will tell us otherwise. We know that unilateral has a chance of becoming bilateral,

and most bilateral patients were once unilateral. It takes time for unilateral to become

bilateral, but time has a negative effect on fluctuation.

Odds ratios from SAS results (Table 11) compare the likelihood to fluctuate

between different groups. Meniere's patients are 58.8% more likely to fluctuate than

Cochlear Hydrops. Unilateral patients are 52.4% more likely to fluctuate than bilateral.

As age increase by one year, the likelihood to fluctuate is 1.5% less. As intervaldxm

(time since diagnose) increases by one month, the likelihood to fluctuate is 0.2% less.

18
 CHAPTER 5

CONCLUSION

Meniere's and Cochlear Hydrops are defined as having hearing loss and

fluctuations over time. With these results, we know how much hearing loss is expected

over any time period, and what causes a person to experience more significant fluctuation

than others. It enables us to make a statement such as "A sample of 345 Meniere's

/Cochlear Hydrops patients show that male Meniere's patient ( age 54, bilateral, and

before surgery) are expected to have a PTA of 59 dB after 53 months since diagnose, and

have a 22% probability of a significant fluctuation on the next evaluation." These results

can provide future clinical trials with a reliable benchmark for hearing progression, and it

may also open up the possibility to use hearing measurements as the primary endpoint.

Hearing measurements as the primary endpoint can definitely help clinical trials because

whereas vertigo, tinnitus, and aural fullness are all subjective to the patient, hearing is a

concrete measurement taken by doctors. Some patients might overstate or understate the

extent of what they feel and that may distort the findings of any clinical trial.

Currently, there is no cure for Meniere's/Cochlear Hydrops. Although there are

many treatments, these treatments focus on the relief of vertigo or tinnitus, rather than the

disease itself [3]. This paper neither cures nor relieves the symptoms, but rather

describes hearing as the disease progresses. Doctors can inform patients of how much

hearing they should expect to lose over time, and that fluctuations are more likely to

19
occur in the earlier stages. Usually, a change in hearing for the worse is emotionally

stressful. It takes time for patients to adjust to their daily activities, speaking tone, and

become comfortable with a hearing aid. Knowledge and preparation can ease the

transition, and help the patient cope with the lifelong disease.

The results of this project may or may not be immediately significant to

Meniere's/Cochlear Hydrops, but what is important is that it provides additional

information that was not previously available. Although the analysis provided two great

models that validated what we already know, there are a few things that can further

improve our results. The data could be significantly improved by collecting it in a

planned clinical trial, where all evaluations are taken on the same time interval. In our

data, the reasons for evaluation are not known, and the time between evaluations varies.

Both factors are important because the reason a patient had an evaluation may have an

effect on their hearing, and time also has an effect. If time between evaluations was long,

or a patient came back because they felt a change in hearing, then we could expect a

higher PTA. Additionally, having access to a greater amount of data would definitely

improve our results. This could be made possible if we coordinate with other ear

institutes and use their data. A larger data set allows us to be more selective of which

evaluations to exclude due to bias. For example, if a patient's next visit were five years

after the date of diagnoses, then we could expect a change of 10 dB or more, but this does

not mean that it was a significant fluctuation.

20
APPENDICES

21
APPENDIX A

SAS CODE
/ * •

-Code Missing Data from excel table "Cleanded3"

libname huy 'e:\hei';

proc import out=cleaned3sas replace
datafile-e:\hei\cleaned3.xls';
sheet-'sheet 1";
run;

data huy.cleaned3sas3 (drop=evalb4surg docdiag doce biuni interaural p t a a f ptaunaf

af_250 af_500 af_1000 af_2000 af_3000 af_4000 af_6000 af_8000 af_sds af_srt
pta_af_change unaf_250 unaf_500 unaf_1000 unaf_2000 unaf_3000 unaf_4000
unaf_6000 unaf_8000 unafsds unafsrt pta_unaf_change); set cleaned3sas;

*after surgery=l before surgery=0;

if evalb4surg-fafter" then evalb4surgnew=l; else evalb4surgnew=0;

^cochlear hydrops=0 and menierefs=l;

if docdiag-f Cochlear Hydrops" then docdiagnew=0;
if docdiag-'cochlear Hydrops" then docdiagnew=0;
if docdiag-'Meniere's" then docdiagnew=l;

*R=1 L=2 Bi=3;

ifdoce="R" then docenew=l
else if doce="L" then docenew=2
elseifdoce="B" then docenew=3

*unilateral=l bilateral=0;
if bi uni="U" then bi uninew=l;
else if bi_uni="B" then bi_uninew=0;

*here any missing coded with 999 will become . in sas because that is how sas reads in
missing. Else if it is not missing then the number remains unchanged;

if interaural=999 then interauralnew else interauralnew=interaural;

if pta af=999 then pta afnew=.; else pta afnew=pta af;
if pta unaf=999 then pta unafnew=. else pta unafnew=pta unaf;
ifaf 250=999 then af 250new=.; else af 250new=af 250;
ifaf 500=999 then af 500new=.; else af 500new=af 500;
ifaf 1000=999 then af 1000new=. elseaf 1000new=af 1000;
ifaf 2000=999 then af 2000new=. else af 2000new=af 2000;
ifaf 3000=999 then af 3000new=. else af 3000new=af 3000;
ifaf 4000=999 then af 4000new=. else af 4000new=af 4000;
ifaf 6000=999 then af 6000new=. elseaf 6000new=af 6000;
ifaf 8000=999 then af 8000new=. else af 8000new=af 8000;
23
ifaf sds=999 then af sdsnew=.; else af sdsnew=af sds;
if af_srt=999 then af_srtnew=.; else af_srtnew=af_srt;

if pta_af_change=999 then pta_af_changenewr else

pta af changenew=pta af change;
if unaf 250=999 then unaf 250new=.; else unaf 250new=unaf 250;
if unaf 500=999 then unaf 500new=.; else unaf 500new=unaf 500;
if unaf 1000=999 then unaf lOOOnew- else unaf 1000new=unaf 1000
if unaf_2000=999 then unaf 2000new=.; else unaf 2000new=unaf 2000
ifunaf 3000=999 then unaf 3000new=. else unaf 3000new=unaf 3000
if unaf 4000=999 then unaf 4000new=. else unaf 4000new=unaf 4000
if unaf_6000=999 then unaf 6000new=. else unaf 6000new=unaf 6000
ifunaf 8000=999 then unaf 8000new=v else unaf 8000new=unaf 8000
ifunaf sds=999 then unaf sdsnew=.; else unaf sdsnew=unaf sds;
ifunaf srt=999 then unaf srtnew=.; else unaf srtnew=unaf srt;
if pta_unaf_change=999 then pta_unaf_changenew=
elsepta_unaf_changenew=pta_unaf_change;
run;

* Renaming variable so that it looks nice. This will be the official dataset worked with.
Last changes made on 05/20/10;

data huy.startcleaned (drop=docdiagnew docenew evalb4surgnew biuninew

interauralnew ptaafnew ptaunafnew af_250new af_500new aflOOOnew af_2000new
af_3000new af_4000new af_6000new af_8000new afsdsnew afsrtnew
ptaafchangenew unaf_250new unaf_500new unaflOOOnew unaf_2000new
unaf_3000new unaf_4000new unaf_6000new unaf_8000new unafsdsnew unafsrtnew
ptaunafchangenew); set huy.cleaned3sas3;

mdch=docdiagnew;
doce=docenew;
evalb4surgery=evalb4surgnew;
bi_uni=bi_uninew;
interaural=interauralnew;
pta_af=pta_afnew;
pta_unaf=pta_unafnew;
af_250=af_250new;
af_500=af_500new;
af_1000=af_1000new;
af_2000=af_2000new;
af_3000=af_3000new;
af_4000=af_4000new;
af_6000=af_6000new;
af_8000=af_8000new;
af_sds=af_sdsnew;
af_srt=af_srtnew;
24
pta_af_change=pta_af_changenew;
unaf_250=unaf_250new;
unaf_5 00=unaf_5 OOne w;
unaf_l 000=unaf_l OOOnew;
unaf_2000=unaf_2000new;
unaf_3000=unaf_3000new;
unaf_4000=unaf_4000new;
unaf_6000=unaf_6000new;
unaf_8000=unaf_8000new;
unaf_sds=unaf_sdsnew;
unaf_srt=unaf_srtnew;
pta_unaf_change=pta_unaf_changenew;

* originally sex is m=l and f=2 but we are going to recode it as m=0 f=l;
if sex=l then sex=0;
if sex=2 then sex=l;
run;

proc sort data=huy.start_cleaned out=huy.start_cleaned;

by pid;
run;

/*
Removing Observations we don't need/Adding mean center Variables
*/

/*This data only looks at observation on and after diagnose. Everything before diagnose
will be removed. Obs for Cochlear patients after they were diagnose with Meniere's will
be removed.*/

data huy. start cleaned first; set huy.startcleaned;

if firstDxl=0 then delete;
if before_after_MD=l then delete;
run;

/*Basic statistics on age and interval which will be used for mean centering*/
proc univariate data=huy.start_cleaned_first;
var age intervaldxm;
run;

/* Adding the mean center of age and inteval dxm*/

data huy. start center (drop= Jype freq_); merge huy.startcleanedfirst; by pid;
age center=age- 54.4056039;
interval_dxm_center=interval_dxm-53.2088504;
run;
25
/*To double check the new means of age & intervaldxm center*/
proc univariate data=huy.start_center;
var age intervaldxm age_center intervaldxmcenter;
run;
/*
Basic Statistics
*/

*all evaluations;
proc univariate data=huy.start_center;
var age intervaldxm; run;

proc freq data=huy.start_center;

table evalb4surgery/chisq;
table sex / chisq;
table mdch/ chisq;
table biuni/ chisq;
table mdch*bi_uni/ chisq;
table sex*mdch/ chisq;
table bi_uni*sex / chisq;
table evalb4surgery*sex/ chisq;
table evalb4surgery*mdch/ chisq;
table evalb4surgery*bi_uni/chisq;
run;

proc sort data=huy. start center; by mdch;

proc means data=huy.start_center;
by mdch; var ptaaf; run;

proc sort data=huy. start center; by evalb4surgery;

proc means data=huy.start center;
by evalb4surgery; var ptaaf; run;

proc sort data=huy.start center; by sex;

proc means data=huy.start_center;
by sex; var ptaaf; run;

proc sort data=huy. start center; by biuni;

proc means data=huy.start_center;
by biuni; var ptaaf; run;

proc sort data=huy.start_center; by b i u n i mdch;

26
proc means data=huy. start center;
by biuni mdch; var pta_af; run;

proc sort data=huy. start center; by sex mdch;

proc means data=huy.start center;
by sex mdch; var ptaaf; run;

proc sort data=huy.start center; by bi_uni sex;

proc means data=huy. start center;
by b i u n i sex; var ptaaf; run;

proc sort data=huy.start center; by evalb4surgery sex;

proc means data=huy. start center;
by evalb4surgery sex; var ptaaf; run;

proc sort data=huy.start center; by evalb4surgery mdch;

proc means data=huy. start center;
by evalb4surgery mdch; var ptaaf; run;

proc sort data=huy.start center; by bi uni mdch sex;

proc means data=huy.start_center; by biuni mdch sex; var pta_af; run;

proc sort data=huy.start center; by evalb4surgery bi uni;

proc means data=huy.start_center; by evalb4surgery biuni; var ptaaf; run;

*First evaluation;
data huy.start freq; set huy.startcenter;
if firstdxl~=l then delete; run;

proc univariate data=huy.start_freq;

var age; run;

proc freq data=huy.start_freq;

table sex / chisq;
table mdch/ chisq;
table biuni/ chisq;
table mdch*bi_uni/ chisq;
table sex*mdch/ chisq;
table bi_uni*sex / chisq;
run;

proc sort data=huy.start freq; by mdch;

proc means data=huy.start_freq;
by mdch; var ptaaf; run;

27
proc sort data=huy.start freq; by sex;
proc means data=huy.start_freq;
by sex; var ptaaf; run;

proc sort data=huy. start freq; by biuni;

proc means data=huy.start_freq;
by bi_uni; var ptaaf; run;

proc sort data=huy. start freq; by b i u n i mdch;

proc means data=huy.start freq;
by b i u n i mdch; var ptaaf; run;

proc sort data=huy.start freq; by sex mdch;

proc means data=huy.start freq;
by sex mdch; var ptaaf; run;

proc sort data=huy. start freq; by b i u n i sex;

proc means data=huy. start freq;
by biuni sex; var ptaaf; run;

proc univariate data=huy.start_freq;

var age; run;

*average number of evaluations and interval dxm for all patients;

proc sort data=huy.start center; by pid; run;
proc means data=huy.start_center max;
var firstdxl intervaldxm; by pid;
output out=eval_time max=maxfirstdxl maxint;
run;

proc means data=eval time;

var maxfirstdxl maxint; run;

/*
Longitudinal Data Analysis
*/
*Huy.start_center is the data set I will use to do all the modeling. 5/24/10 date started to
do analysis. At this point all data has been completely cleaned and ready to analyze.;

*full model without interactions;

proc mixed data=huy.start_center method=reml covtest;
model pta_af= evalb4surgery mdch doce agecenter intervaldxmcenter b i u n i sex/
solution;
random intercept intervaldxmcenter / subject=pid type=un;
run;
28
*with interactions;
proc mixed data=huy.start_center method=reml covtest;
model pta_af= evalb4surgery mdch agecenter intervaldxmcenter b i u n i sex
sex*mdch bi_uni*mdch sex*evalb4surgery sex*evalb4surgery*mdch
evalb4surgery*mdch bi_uni*sex/ solution;
random intercept intervaldxmcenter / subject=pid type=un;
run;

* reduce model with interactions;

ods html; ods graphics on;
proc mixed data=huy.start_center method=reml covtest cl ic;
class pid;
model pta af= evalb4surgery mdch age center bi uni sex interval dxm center
sex*mdch / solution cl outp=huy.residual residual influence(iter=5 effect=hec est);
random intercept intervaldxmcenter / subject=pid type=un ;
run;
ods graphics off; ods html close;

*—Trying to find a better model by using different method &covariance structure—

*ml method;
proc mixed data=huy.start_center method=ml covtest cl ic;
class pid;
model pta_af= evalb4surgery mdch agecenter b i u n i sex intervaldxmcenter
sex*mdch / solution cl;
random intercept intervaldxmcenter / subject=pid type=un ;
run;

*mivqueO method;
proc mixed data=huy.start_center method=mivqueO covtest cl ic;
class pid;
model pta_af= evalb4surgery mdch agecenter b i u n i sex intervaldxmcenter
sex*mdch / solution cl;
random intercept intervaldxmcenter / subject=pid type=un ;
run;

* VC (variacne components) covariance estimation;

proc mixed data=huy.start_center method=reml covtest cl ic;
class pid;
model pta_af= evalb4surgery mdch agecenter b i u n i sex intervaldxmcenter
sex*mdch / solution cl;
random intercept intervaldxmcenter / subject=pid type=vc ;
run;

29
* After residual analysis and influence diagnositic the reduce data set was applied to the
reduce model. Work done to correct influential data was done in excel. Complete results
can be found in the table.

*Reduce model on reduce data set;

ods html;
ods graphics on;
proc mixed data=huy.start_center method=reml covtest cl ic;
class pid;
model pta af= evalb4surgery mdch age center bi uni sex interval dxm center
sex*mdch / solution cl outp=huy.residual residual influence(iter=5 effect=hec est);
random intercept intervaldxmcenter / subject=pid type=un ;
run;
ods graphics off;
ods html close;

/*
Graphs for Longitudinal Data Analysis
*/
title "Individual Response Profiles";
proc gplot data=start_center;
label interval dxm="Time in Month From Diagnosed" pta af="PTA Affected Ear";
plot pta_af*interval dxm=pid / nolegend haxis=0 to 400 by 50;
symbol 1 interpol=join value=none color=black line=l repeat=275;
symbol2 interpol=join value=none color=black line=l repeat=70;
run;

*Time and age is continuous so when we graph there is a lot of zig zag, therefore I will
group then get the mean so that we get better view;
data int; set startcenter;
time int=int(interval dxm);
year=int(time int/12);
yearl0=year/10;
age=int(age/10);
run;

title "Mean Response Profiles for Meniere's Disease vs Cochlear Hydrops";

footnote 1 "Solid line = Cochlear Hydrops, dashed line = Meniere's Disease";
footnote2 " Vertical line is plus/minus one sample standard deviation";
proc gplot data=int;
label pta_af="PTA Affected Ear" year="Time in Year From Diagnosed";
plot pta aPyear^mdch / nolegend;
symbol 1 interpol=stdmlj color=black line=l repeat=l;
symbol2 interpol=stdmlj color=black line=3 repeat=l;
run;

30
title "Mean Response Profiles for Overall";
footnote " Vertical line is plus/minus one sample standard deviation";
proc gplot data=int;
label pta_af="PTA Affected Ear" year="Time in Year From Diagnosed";
plot pta af*year / nolegend;
symbol 1 interpol=stdmlj color=black line=l;
run;

*checking normality assumptions and model assumptions;

proc univariate data=start_center normal;
label pta_af="PTA Affected Ear";
title "Histogram for PTA Affected Ear";
var ptaaf;
histogram/ normal;
run;

proc univariate data=start_center normal;

label pta_af="PTA Affected Ear";
title "QQPlot for PTA Affected Ear";
var ptaaf;
qqplot/normal;
run;

*make sure that age and interval_dxm are linear;

proc gplot data=int;
title "PTA vs Interval_Dxm";
label pta_af="PTA Affected Ear" yearlO-'Time Since Diagnose in Years in Increments
of 10";
plot pta afyearlO / nolegend;
symbol 1 interpol=stdmlj color=blackline=l;
run;

proc gplot data=int;

title "PTA vs Age";
label pta_af="PTA Affected Ear" age="Age in Increments of 10";
plot pta_af*age / nolegend;
symbol 1 interpol=stdmlj color=blackline=l;
run;

/*
. Logistic Regression
*/

ods graphics on;

proc logistic data=huy.data_mining_data;*stepwise selection;
31
model abs change(event-1')= sex mdch doce evalb4surgery bi uni age interval dxm
/selection=stepwise ctable pprob=(0 to 1 by .l)outroc=roc;
output out=predicted p=phat lower=lcl upper=ucl;
run; ods graphics off; ods html close;

ods graphics on;

proc logistic data=huy.data_mining_data;*forward selection;
model abs change(event='l')= sex mdch doce evalb4surgery bi uni age interval dxm
/selection=forward ctable pprob=(0 to 1 by .1 outroc=roc;
output out=predicted p=phat lower=lcl upper=ucl;
run; ods graphics off; ods html close;

ods graphics on;

proc logistic data=huy.data_mining_data;*backward selection;
model abs change(event=T)= sex mdch doce evalb4surgery bi uni age intervaldxm
/selection=backward ctable pprob=(0 to 1 by .1
outroc=roc;
output out=predicted p=phat lower=lcl upper=ucl;
run; ods graphics off; ods html close;

ods graphics on;

proc logistic data=huy.data_mining_data; *stepwise with continuous variable binned;
model abs_change(event-l')=sex mdch doce evalb4surgery b i u n i agebin
interval dxm bin
/selection=stepwise ctable pprob=(0 to 1 by .l)outroc=roc;
output out=predicted p=phat lower=lcl upper=ucl;
run; ods graphics off; ods html close;

ods graphics on;

proc logistic data=huy.data_mining_data; *stepwise with interaction;
model abs_change(event=T)= sex mdch doce evalb4surgery b i u n i age intervaldxm
mdch*doce mdch*evalb4surgery mdch*bi_uni
doce*evalb4surgery doce*bi uni evalb4surgery*bi uni
/selection=stepwise ctable pprob=(0 to 1 by .1 outroc=roc;
output out=predicted p=phat lower=lcl upper=ucl;
run; ods graphics off; ods html close;

32
APPENDIX B

TABLES
 TABLE 1. Steps taken to Clean Data
Steps Data Cleaning
|1 Examine both ear to make sure that the correct ear was designated as the affected ear
2 Find Diagnose date for those that were missing a date because HEI was not the first option for
several patient and they were diagnose elsewhere
3 Find out why PTA for the affected ear were missing
a. The affected was dead therefore it wasn't tested
b. The patient did not have Meniere's Disease/Cochlear Hydrops
c. The data wasn't inputted but it does exist on hard copy record
d. There was an examination but the data is missing
4 Looked at age because one patient under the age of 20 existed but we know that MD does not start at
such a young age. Record was deleted.
5 Patients with surgery before they were diagnosed with any disease. Those were deleted because it
doesn't make any sense
6 Cochlear hydrops patient with surgery. Records after surgery were deleted because it developed into
Meniere's Disease.
7 Patient with PTA of the affected >=100 at the first evaluation.
Reason:
a. They had surgery for some other reason and the hearing tanked
b. It is naturally that high
c. It is a bilateral case and we have been looking at the worst ear. But the worst ear can't show
any changes. Since it is bilateral we can look at either ear
We either deleted the records, change the designated affected ear, change diagnose date.
8 Added records to 32 patients that were missing from the data set.

TABLE 2. Basic Statistics at the First evaluation

Basic Statistics @ First Evaluation

Variable mean std frequency percentage mean P T A STD P T A

Age 50.99 13.07
ls«t O^MJ^ !?? 513: Sili 2L49;
Haife xm 48,7 34,24 21.14
MDCH 0=CH 70 20.29 24.13 19.64
1=MD 275 79.71 40.32 20.7
IB! Vm OH^tetmt m 11,3 4S,?S 21.59
i^stitetmt 306 m.i 35.54 2t.0!
|MDCH*Bi_Uni 0=CH 9 0=bilateral 4 1.16 21.25 12.79
0=CH, l=unilateral 66 19.13 24.3 20.04!
1=MD, 0=bilateral 35 10.14 51.89 20.181
1=MD, l=uni lateral 240 69.57 38.64 20.24!
|S«^M0€M D^itMie* 0 « C H 33 937 23JI
!§^mak, l ^ M D 144 41-J4 41*92 20*54
\t^fymm,^€H 37. 10.72 . IBM 1436
t*$wmU*, 1-MB m- 37,9? 38.5? 20,76
jBi Uni*Sex 0=bi1atera], 0=male 20 5.8 50.56 19.96
0=bil ateral, 1 =femal e 19 5.51 46.84 23.58
^unilateral, 0=male 157 45.51 38.3 21.34
l=unilateral, l=female 149 43.19 32.63 20.34

34
TABLE 3. Basic Statistics for All evaluations

Basic Statistics for All E v a l u a t i o n s

variable [mean std frequency percentage mean PTA STD P T A
Sage 54.5015 12.9
1 interval d x m 53.0803 6 6 72
jj# evaliiation p e r patient | 7.2 6 22
kW|4»r^fi ....„„,,„,, .0~"fe«$5Mf® 1? ::jgm 44,05 a*?;
1-Mkrr ,sf i 24 At :im 34.4*
sex 0=male 1266 51.05 4 7 57 23.27
L _ _ _ l=female 1214 48.95 47.2 27.93
H U TsM im% , n . , 2.1,1.8!
:I*MD m. .. :::.MM
..iMm mji '7:::MM\
Bi U n i 0=bilateral 376 15.16 63.7 23.39
l=umlateral 2104 84.84 : 44.48 24.94
MDOi*»|t..Uitl . . ^m^^mmmm
i0-Clf,.l.-rt |M*&?%1
IS
&$# .. . 14M .
—:rm
:T*W _ 2 L 3 ? i
15.59!

i«as;-«^i fffl* 1 •• • 361 •::::::i4M . . .«».aii 2,411

i-3fcffia-«a if178
Is mm •:.::MJ7 2C4I
|Sex*MDCH 0=male, 0=CH isst : 7.18 37.21 23.84
0=male, 1=MD 1088 43.87 49.26 22.74i
l=female, 0=CH 206 8 31 21.77 15.381
l=female, 1=MD 1008 40.65 52.4 27.06
bl....OM^Sex ®™MUm^».tP«wm® m, J& »:si 1&/?5|
7J2!
\**mms;*m»* 13 MM $m\
404 4pi$:
E v a l b 4 surgery* Sex GHbefore, 0 = m a l e 965 38.91 44.99 22.711
O=before, l = f e m a l e 917 36.98 43.05 26.18
l=after» 0 = m a l e 301 12.14 55.81 23.17|
l=after, l = f e m a l e 297 11.98 60.03 29.3
iEvaJWmwry*MBCH «H^%^M%fCH
Crt^lbt^J^PB. i4Si- ;,_ MM ::::::.2.I:M . ItABl
;:«54 *m msi0
l«dfe<RJtt • 0
l^H^ra-Mp :;:zzz:::«
24 J 1 ——3M MAS]
Evalb4surgery*Bi Uni O=before, 0=bilateral 292 11.77 62.37 23.84
O=before, l=unilateral 1590 64.11 40.69 23.07
l=after, 0=bilateral 84 3.39 68.32 21.25
l=after, l = u m l a t e r a l 514 20.73 56.19 26.84

35
TABLE 4, Longitudinal analysis full model Without Interaction terms

OimetUtioits
Co variance Parameters 4
Columns in X 8
Columns in Z Per Subject 2
Subjects 345
Mm €>!>$ Per Subjeel 43

N umber <*f Observa ti® sis

Niinifeer #f 0bwt¥iiti$« Read 2480
h number of Obsermticwii If seel. 2478
Number of Ofe^TOttcwis Mot Used 2

{ Itera&onBistor}
jJteriiiiw ;Ev*lllfttfoil& ~2 Rm Lug l i k e Criterion
f - ^ 1 22188.58584763
| ~ ~ 2 19812.76876989 0.00390694
l " 2 1 19775.11453156 0.00134372
1 19762.63265052 0.00030198
j " ^ 1 19759.95058707 0.00003290
j ~ S 1 19759.67977913 0.00000061
j _ _ 1 19759.67505159 0.00000000
Convergence criteria met.]

Covartaiiee f^mmmm Estimates

C w Farm Subject Estimate Standard Error Z Value TrZ
35.6582 10.60 <.0001
iiSi) PID
VN(2,1) PID
377.98
1.3845 0.3808 3.64 0.0003
UN(2,2) PID 0.03162 0.006511 4.86 <.0001
Residual 101.05 3.4036 29.69 <.0001

Fit Statistic!
»2 Res- Leg Likeiilwoi 19759.7
AIC (smaller f§ belter) 19767'.7
;A1€€ (smaller H better) 19767.7
BIC (smaikr In b t iter) 19783.0

N i l A M c l L i M f t o o d Ettio Test
»F: CfeNScgirore Pr > CiSSfi
3 2428.91 <.0001
j ^ ^ Solution for Fixed Effects
Pr > |l|
p _ _ Estimate Sturidard Error 0F. t Value
jlntereept 45,6426 7.4294 342 6.14 <.0001
jev&lMswgery 9.1094 0.8845 1792 10.30 <.0001
14.7738 2.5722 1792 5.74 <.0001
E?£?
Jdoee 0.1438 2.1555 1792 0.07 0.9468
Jagejeeiiter 0.4583 0.07851 1792 5.84 <.0001
pDtervaLdbciflLceoter 0.1185 0.01664 : 336 7.12 <.0001
[bijHiii -11.5072 4.5303 1792 -2.54 0.0112
i s e x ^ ^ ^ ^ ^ ^ ^ ^ ^ -5.9226 1.9971 1792 -2.97 0.0031

36
TABLE 5. Longitudinal analysis M l model With Interaction terms

Dimensions
jCoYHTOitce Parameters • 4;
(Columns im % 13]
&liii»sM m Z Per Subject 2j
iSubjeets 345]
Ma* Ofeafter Subject 43
Number of Observations
Number af Ob*m"at£ons Head J2480
Number «f Observations lifted |247i
Number of Observations Not t f ^ 5 j 2
| Iteration History
(Iteration Jtvahtatiojis ;-2 Res Leg Litd Criterion
j 0 1 22078.37789002J
—J 2 19767.43201649 0.00213553]
LZZH 1 19746.55032204| 0.00096520
i 3 1 19737.259732801 0.00032823]
1 19734.26532874] 0.000050501
p__
I 3 1 19733.84324286 0.00000145
6| 1_ _ _ _ ^ OJOOOOOOOOJ
Convergence criteria met.|
| Covarlanec Parameter Estimates
\Cm Parra Subject [Estimate Standard Error Z Value ; F r Z
|UN(1,1) PID 1 370L87 35.1550 ~ToI?<.0001
|UN<2,1) PID 1 13742 0.3774 3.64 0.0003
fcNftS) PID 0.03142 0.006459 4.87 <.0001
Residua) 1 ToTTTo 3.4026 29.71 <.0001|
j Fit Statistics
-2 Res L#g Likelihood 19733.8
AIC (smalltr Is better) 19741.8
[AICC (amatieris better) 19741.8^
(1I€ (tinnier is better) 19757.2;
N«ll Made! L I M b o o d Ratio Test
»F Cbs-Scptate Pf >€bs$<i
3| 2344.55 <0001
l ^ ^ ^ ^ _ _ _ ^ ^ ^ ^ ^ Solution for Fii&d Effects
Effect Est! male |S£aitdard Error I OF it Value pPr > |t|!
Intercept | 34.3660 I 10.0459 | 339 1 3.42 [0.0007!
^alMsiirgery | 10.1496 | 1.2919 [1792 | 7.86 K.OOOll
jradeb 26.0667 10.1596 ;1792 _ ^ i 0.0104|
[a^^epter 0.4665 0.07793 11792 5.99 _ _ j
jinterval^dxiB^Genter 0.1183 0.01659 336 7.13 _ _ |
jbijani 5.7313 10.1147 1792 0.57 _ _ |
fe? -12.6521 7.4281 1792 -1.70 008871
|mdcb*sex 11.0562 5.0229 1792 2.20 a0279|
imdeh*bi uni -18.2587 10.1783 1792 -1.79 O0730|
|evalb4surgery*sex -1.9478 1.7339 1792 -1.12
jevalb4$urge*mdch*seK Oi _^l
«¥alM$w^^^iiifl^li ; 0!
ibS »»!*§«JE ] -2.2668! 6.2898) 1792J -0.36| 0.71861

37
TABLE 6, Longitudinal analysis Reduce Model with only Significant variables

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38
 TABLE 7. Longitudinal analysis. Comparing reduce model by using different method of
parameter estimations and covariance structures

Parameter Covariance -2 Res Log AIC AICC BIC

Estimation Structure Likelihood

REML UN 19753.3 19761.3 19761.4 19776.7

ML UN 19763.0 19787.0 19787.1 19833.1

MIVQUEO UN 19830.4 19838.4 19838.4 19853.8

REML VC 19775.3 19781.3 19781.3 19792.8

TABLE 8. Patients that were influential on the reduce model and actions that were taken

1 Patient ID Changes from Influential Diagnostic

21 Nothing just high fluctuating PTA. Kept in data,
30 several observation with back to back 120 so they were deleted
73 Nothing just high fluctuating PTA . Kept in data.
91 several observation with back to back 120 so they were deleted
93 several observation with back to back 120 so they were deleted
102 several observation with back to back 120 so they were deleted
122 Nothing just high fluctuating PTA. Kept in data.
178 Nothing just high fluctuating PTA. Kept in data.
226 several observation with back to back 120 so they were deleted
267 Deleted because sudden profound lost of hearing. Does not meet the definition of
MD
268 Nothing just high fluctuating PTA. Kept in data,
274 Nothing just high fluctuating PTA. Kept in data.
288 several observation with back to back 120 so they were deleted
333 Nothing just high fluctuating PTA. Kept in data.

39
TABLE 9. Longitudinal analysis Reduce Model using Reduce Data (influential data was
removed)

INHMM-BMI
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40
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TABLE 10. Distribution of Age and Interval_dxm for binning into groups

Quantises (Definition 5) QuantHes (Definition 5)

Quantiie Estimate Quantiie Estimate
100% Max : 87.56742 100% Max 384.00000
99% 82.51335 99% 298.19178
95% 77.99863 m% 209.85205
90% 72.73374 m% 162.24658
75% Q3 63.37851 75% Q3 80.84384
50% Median 54.22587 50% Median 32.05479
25% Ql 45.90554 25% Ql 10.78356
39.42505 _ —! 2.99178
10%
5% 35.00342 5% 1.15068
1% 26.37645 1% 0.00000
0% Win 5.52603 0% Min 0.00000

41
TABLE 11. Logistic regression using Stepwise Selection

Mode! Fit Statistics

Intercept
Intercept and
Criterion Only Covariates
AIC 2581.749 2545.231
•SC 2587.452 2573.746
.~2LogL. 2579.749 2535.231

Testing C3lob«» Null Hypotlieii»£ BETA*Q

Test Cfai-Sspare » F Fr > CWLSq
Ltiwltbewl mm 44.5185 4 <.0001
Score 43.2902 4 <.0001
Waid 42.3889 4 <.0Q01

Summary of Stepwise Selection

Effect Number Score Wald. Variable
Step Entered Removed BF In Chi-Square ChkSqnare Fr > ChiS«| Label
1 age 1 1 19.5925 <.0001 age
2 bi imi 1 2 7.2789 0.0070
3 mdch 1 3 8.7225 0.0031
4 Interval feM 1 4 7.8021 0.0052 Interval DxM

AnaJbim of Maximum Likelihood Estimates

Standard Wald
Parameter DF Estimate Error Cfct-Sqoare P r > C n i S q
Intercept 1 -0.7943 0.2691 8.7089 0.0032
mdch 1 0.4626 0.1444 10.2669 0.0014
bi uni 1 0.4214 0.1449 8.4580 0.0036
age 1 -0.0154 0.00401 14.6943 0.0001
Interval Di,M 1 -0.00228 0.000821 7.7423 0.0054

Odds Ratio Estimates

95% Wald
Effect Point Estimate Confidence Limits
mdch 1.588 1.197 2.108
bi uni 1.524 1.147 2.025
age 0.985 0.977 0.993
IrttrvafJDxM 0.998 0.996 0.999

Association, of FredfcWI PretoMlttes anil

Qbserved Reapttuses
Percent Concordant 59.1 Somen?* D. 0.182
Percent Discordant 40.9 Gamma 0.182
Percent Tied O0 Tau-a 0-072
PairT """"964924 c 0.591.

42
TABLE 12. Logistic regression using Stepwise Selection with Binned continuous
variable
Model Fit Statistics
Intercept
Intercept and
Criterion Only Covariates
AIC 2581.749 2552.584
se 2587.452 2575.396
-2 Log!* 2579.749 2544.584

Testing Global Null Hypotbests: B£TA-#

Test CM~Scpj.are OF Pr > CMBq
] Jltttibood fei# 35.1648 3 <.0001
Swe 34.6391 3 <.0001
Wald 34.1276 3 <0001

SUMMITS *>f SstepwMs Selection

Effect Number Score Wald Variable
Step Entered Removed 0 F In. Chi~$«p*are CM~S«pare Fr > ChlSq Label
1 agejbia" 1 1 18.8807 <.0001
2 bi uni 1 2 7.5849 0.0059
3 mdcb 1 3 7.9880 0.0047

Analysis of Maximum Ubdinood Estimates

Standard Wald
Parameter BF Estimate Error CM-Sqware P r > C M $ q
Intercept 1 -1.2232 0.2097 34.0132 <.0001
mdch 1 0.4022 0.1429 7.9211 0.0049
b! uni 1 0.4463 0.1447 9.5207 0.0020
^Ttol 1 -0.2068 0.0442 21.8461 <.0001

Odds Ratio Estimates

9 5 % Wald
Effect Point Estimate Coiiftdeaee Limits
mdch 1.495 1.130 1.979
b i HIS! 1.563 1.177 2.075
agejhin 0.813 0.746 0.887

Association of Predicted frobabilitiea and

Qgiservei Mfryuses
Percent Concordant '•• 51.3 Somers1 B 0.163
Percent Discordant 35.( 0.189
Percent Tied 13.7 Tau-* 0.064
Pairs 964924 c 0.582

43
TABLE 13, Logistic regression using Stepwise Selection with Interaction terms
ftftode! Fit Statistics
Intercept
Intercept and
Criterion Only Covariates
AIC 2581.749 2542.409
-
sc ~* 2587.452 2576.628
-2 Log L 2579.749 2530.409

Testing Global Null Hypothesise BETA*0

Test Cht-Sqyare DP Pr > ChiSq
UHeNitocNl Ratio 49.3396 5 <.0001
Score 47.9898 5 <.0001
Wald 46.8871 5 <.0001

Summary of Stepwise Selection

Effect Number Score Watdl
!
Step Entered Removed DF In Cftl»$qnare Chi»Square Prr>ChiSq Label
19.5925 <.0001 age
7.2789 0.0070
25LH2L
3 mdch 8.7225 0.0031
4 Interval. DxM 7.8021 0.0052 Interval DxM
5mdch*l>i unl 6.2124 0.0127

.Analysis of Maximum Likelihood Estimates

Standard Wald
Parameter DF Estimate Error Chi«Square Pr>ChISq
Intercept 1 0.5316 0.6190 0.7374 0.3905
mdch 1 -0.9157 0.6033 2.3042 0.1290
fcrtunl 1 -0.9542 0.6020 2.5124 0.1130
m® 1 -0.0155 0.00402 14.8109 0.0001
IfrtervaLBxM 1 -0.00228 0.000823 7.6741 0.0056
mdch^bLuni 1 1.4431 0.6202 5.4138 0.0200

Odds Ratio Estimates

9$%WaW
Effect Point Estimate Confidence Limits
0.985 0.977. 0.992
SL
•IntervaLDxM 0.998 0.996. 0.999

Association of Predicted Probabilities %nd

Observed Responses
Percent Concordant 59.5 Somers5 0 0.190
Percent Discordant 40.5Samma 0.190
Percent Tied 0.0 Tau»a 0.075
Pairs 964924 c 0.595

44
APPENDIX C

FIGURES
 Individual Rmponm Profits

•20-.
I i T r • •rj-T-HTH~~T-jnrwrn^
0 §0 100 150 2M 260 $00 350 400
Mmm in ttonth Prom Dfe»j)nased

FIGURE 1. Individual response profiles. Change at different time period varies greatly.

Bmmm ¥s Cochlear Hydrops

In Y*ar From Oiag»osedl

Solid brt» « OseM®f I f etopt, &»h«<* !m«««llwtr#*f Oii#«#

FIGURE 2, Mean response profiles for Meniere's Disease vs Cochlear Hydrops.

Standard deviation varies across time and disease.

46
 Histogram lor PTA A f ectact Ear

__

r-

Lr
-C
L_T_j
e U SO 42
—i—
51 U 7& SD
-v-nvl
162 »H
PTft * f f t c l e t f Ear

FIGURE 3. Histogram for PTA affected ear (response). Distributed like bell curve
around mean.

QQPlot for PTA Affected Ear

125 -
• — - - - ;

100 -

75 -

I-
t 5 -

o -

-25 -
J i" c 'i i i —r

FIGURE 4. QQ Plot for PTA affected ear (response). Linear and could be fitted with
PTA ¥S Ag®

FIGURES. PTA vs Age grapk Linear and could be fitted with straight line.

straight line.
47
 PTA ws lmmmmimOxm
U f e c f m l E@r
120 H

too—
A
tC»~
/'Vl^M
so-

40™

m~

0-

2.6-
Time Since Diagnose In Yearn In Increm&mft ef 10
Vertical Im* is plus/minus on* sample standard delation

FIGURE 6. PTA vs Interval_Dxm graph. Linear and could be fitted with straight line.

'ffr»ct*ttcs
T«I. <tffrfcg« tsftisswsg 54't
i Minimum
^fSWMtC ftMa
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1§?53
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4 ? §

FIGURE 7. Raw conditional residuals for reduce model

m®& Effect* mmm® Diagnostic* for pfcyrf

,Lw Ifo*
ISOS HO is tt» 200 SM
o«t««MiUv«!»rHse B*!ftt«tf!*v«iftfHKe

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ii 01-

:|MiLau
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L Or-

100 2C^ ^y
c

&«t«t*«l*MrfftfHSC 8tf*tttfUv»t«?H*C

FIGURE 8, Fixed effects influence diagnostic for reduce model

48
 o m :OJ *0&
0tft#t*<*Uv*l6fM£C

ii
FIGURE 9. Covariance parameter influence diagnostic for reduce model
itMTfftUtf

4r% <*»$ r s H m ^ « * «r»

f^f&Bftflf IttfeSi?:'"
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list?
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JCT!

FIGURE 10. Raw conditional residuals for reduce model on reduce data.

Li _.
W
&«f«t»«uv*t«rH£e

A iJfu IP& z& m

FIGURE 11. Fixed effects influence diagnostic for reduce model on reduce data,
49
 Ctevwtvnet Ftramttwr Mfetne* Ottgm*lte»for ptau*

At* ^ ^ f e s S ^
^mm^dsM^mMi:
1-
IBf
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0%-

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&4

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»0
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04 ^
ft
^_^ r

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j
jdo
^*--r
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FIGURE 12. Covariance parameter influence diagnostic for reduce model on reduce
data.

nm Curat tor Mftftted M o M

Ansa lAwfer the Cuive » 0 590S

0 75-

I OS0-

Q2S~>

FIGURE 13. ROC curve of logistic regression using stepwise selection*

50
 ROC Curv« for M»ct»<l Med«f
Area Under thft Cwrv* s 0 5816

1 00 -

0 75-

/
I
j...
0 25-

0 00-
!
—r~ i - " r \
1 08
0 00 0 25 §50 G75
1 - $g»®ti»C%

FIGURE 14. ROC curve oflogistic regression using stepwise selection. Binned
continuous variable.

ItOC CummforStftecftwt M * M
Are* Ututer f « Cum* * 059S1

100-

//
0.25 -
/
r
/
j

000-
/
L™~ — . T — - - s t

ODD 0.25 050 0 75 100

1 * !!l|*®u&fieit$f

FIGURE 15, ROC curve oflogistic regression using stepwise selection with interaction
terms.

51
REFERENCES

52
 REFERENCES

1. Committee on Hearing and Equilibrium. "Committee on Hearing and Equilibrium

guidelines for the diagnosis and evaluation of therapy in Meniere's disease."
American Academy Otolaryngology- Head and Neck Surgery 113 (Sep 1995):
181-185.

2. House J.W., Doherty J.K., Fisher L.M., Derebery M.J., and Berliner K.l
"Meniere's Disease: Prevalence of Contralateral Ear Involvement." Otology &
Neurotology 27 (Apr 2006): 355-361.

3. Sen P., and Papesch M. "Is There Any Evidence For Complementary And
Alternative Therapy In Meniere's Disease." The Internet Journal of
Otorhinolaryngology 4.1 (2005).
http://www.ispub.com/ostia/index.php?xmlFilePath=journals/ijorl/
vol4nl/meniere (accessed February 3, 2012).

4. JAMA and Archives Journals. "Time, Surgery Appear To Reduce Episodes Of

Dizziness In Patients With Meniere's Disease." Science Daily (Nov 2008).
http://www.sciencedaily.eom/releases/2008/l 1/081117192913.htm (accessed
February 3, 2012).

5. Littell R.C., Milliken G.A., Stroup W.W., Wolfmger R.D., and Schabenberger O.
SAS for Mixed Models. Cary, NC: SAS Institute Inc., 2006.

6. Korosteleva O. Clinical Statistics: Introducing Clinical Trials, Survival Analysis,

and Longitudinal Data Analysis. Sudbury, MA: Jones and Bartlett Publishers,
2009.

7. Kutner M.H., Nachtsheim C. J., and Neter J. Applied Linear Regression Models.
New York, NY: McGraw-Hill Irvin, 2004.

53