University of Southern California Dissertations and Theses

Medical comorbidities and multiple sclerosis in the Hispanic population: linking healthcare disparities

(USC Thesis Other)

Medical comorbidities and multiple sclerosis in the Hispanic population: linking healthcare disparities

PDF

Download a page range

Download transcript

Copy asset link

Request this asset

Transcript (if available)

Content Copyright 2020 Michael Vincent Robers
Medical Comorbidities and Multiple Sclerosis in the Hispanic population:
Linking Healthcare Disparities

By
Michael Vincent Robers, MD

A Thesis Presented to the
FACULTY OF THE USC KECK SCHOOL OF MEDICINE
UNVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
Master of Science
(Clinical, Biomedical, and Translational Investigations)

August 2020
ii

Acknowledgements

This work could not have been completed without the support, input, and participation by the
following individuals and groups:
-Lilyana Amezcua MD, MS whose mentorship, guidance, and expertise was invaluable in
developing as a researcher and whose previous research provided the foundation for my current
work.
-Cecilia Patino-Sutton MD, PhD and Melissa Wilson PhD, who’s instruction on translational
research, and statistical methods directly improved the quality of my work on this and future
projects.
-The participants of the USC Hispanic MS registry who dedicated their time and personal
information to the cause of advancing knowledge.
-Andrea Martinez MPH, who provided time and support in accessing and cleaning the Hispanic
registry data.
-The faculty and staff of the USC Division of Neuroimmunology whom provided support and
education for my clinical and scholarly work.
-The National Multiple Sclerosis Society who funded my research and education through a
Sylvia Lawry Physician Fellowship award.

iii

Table of Contents
Acknowledgements ......................................................................................................................... ii
List of Tables .................................................................................................................................. v
List of Figures ................................................................................................................................ vi
Abstract ......................................................................................................................................... vii
Introduction: .................................................................................................................................... 1
Health burden of multiple sclerosis: ........................................................................................... 1
Predicting and preventing MS disability: ................................................................................... 1
Health Disparities in MS:............................................................................................................ 2
Comorbidities in MS: .................................................................................................................. 4
HTN as a Comorbidity in MS ..................................................................................................... 6
HTN in Minorities: ..................................................................................................................... 7
Methods: ......................................................................................................................................... 8
Study Design: .............................................................................................................................. 8
Clinical variables: ....................................................................................................................... 9
Comorbidities:............................................................................................................................. 9
Definition of Hypertension: ...................................................................................................... 10
Outcome Measurements: .......................................................................................................... 10
Statistical analysis: .................................................................................................................... 10
Results: .......................................................................................................................................... 13
Study Population: ...................................................................................................................... 13
Association of HTN and Disability: ......................................................................................... 17
Association of Blood Pressure Measurements and Disability: ................................................. 18
Discussion of Results: ................................................................................................................... 19
Important Findings: ................................................................................................................... 19
Comparison to Existing Literature: ........................................................................................... 20
Limitations: ............................................................................................................................... 21
Conclusions of these findings: ...................................................................................................... 22
Future Directions: ......................................................................................................................... 24
Proposed Hypotheses: ............................................................................................................... 24
Literature support of the proposed hypotheses: ........................................................................ 24
Proposed Study Design: ............................................................................................................ 25
iv

Data Collection: .................................................................................................................... 26
Statistical Analysis: ............................................................................................................... 27
Power Analysis: .................................................................................................................... 27
Potential pitfalls and alternative strategies: .......................................................................... 27
Final Conclusions: ........................................................................................................................ 28
References ..................................................................................................................................... 29

v

List of Tables
1. A sample of previous literature showing adverse outcomes in MS patients with
comorbidities..............................................................................................................................5
2. A sample of previous literature showing the effects of HTN on MS outcomes. .......................7
3. Baseline Characteristics for all participants and those with and without comorbidities. ........14
4. Presence of comorbidity or ischemic risk factors by age group. .............................................15
5. Baseline frequency statistics of the total and subset cohort. ....................................................16
6. Logistic Regression evaluating associations between comorbidity diagnoses and EDSS≥6
Multivariable regression adjusted for age, sex, disease duration. ............................................17
7. Logistic Regression of blood pressure categories (compared to those with normal blood
pressure) with EDSS≥6. ..........................................................................................................19
8. Logistic Regression of blood pressure categories with EDSS≥4. Multivariable regression
adjusted for age, sex, and disease duration. .............................................................................19

vi

List of Figures
1. Flowchart of selection of participants. .....................................................................................13
2. Components of RAAS observed to be involved in HTN, MS, or both ...................................25

vii

Abstract: Background: Hispanics with MS have worse outcomes than whites. Cardiovascular
risk factors may contribute to disparities, as they are more likely to be poorly controlled in
Hispanics and are associated with disability in MS patients. These comorbidities or their
relationships to disease severity have not been well described in Hispanics with MS. Methods:
We retrospectively evaluated individuals enrolled in the USC Hispanic MS Registry between
November 2007 and April 2019, with available data on medical comorbidities. Recorded
exposures of interest included the presence of any medical comorbidity or any of 5
cardiovascular risk factors including hypertension (HTN), diabetes (DM), hyperlipidemia
(HLD), past ischemic events, or smoking. Available blood pressure measurements (BP) were
classified according to the American Heart Association’s Guidelines. The primary outcome
measure was the use of walking assistance (EDSS ≥ 6). Multivariable logistic regression was
used to evaluate the associations between vascular comorbidities and EDSS ≥ 6. Results: A total
of 451 individuals were included most of whom were female (63.0%), RRMS (92.6%), and on
treatment (86.0%). The mean age was 38.8 ± 11.8 years with a mean disease duration was 8.7 ±
8.0 years. Medical comorbidities were present in 41.9% with 24.2% having a cardiovascular
comorbidity, including smoking (13.6%), HTN (7.3%), DM (5.1%), and HLD (4.7%). Stratified
by age, cardiovascular risk factors (27.3% vs. 17.5%) including HTN (12.6% vs. 3.2%) were
more common in those >40. Those with HTN are 3 times more likely to have EDSS ≥ 6 adjusted
for age, sex, and disease duration (OR 3.12, 95%CI 1.37, 7.12). This was also true for those with
stage II HTN BP (OR 2.89, 95%CI 1.11, 7.55). Conclusion: Medical and cardiovascular
Comorbidities are common in Hispanics with MS. Having a HTN diagnosis or stage II HTN BP
increases the odds of having greater disease severity. We propose further research to investigate
physiological changes and longitudinal outcomes in MS patients with and without HTN.
1

Introduction:
Health burden of multiple sclerosis:
Multiple Sclerosis (MS) is an autoimmune disease of the central nervous system with an
estimated prevalence of 700,000 in the US
1
. This is approximately double the previous estimates
of 300,000-400,000 cases
1
. It is also reported as the most common progressive neurologic
disease of young adults world-wide
2,3
. Individuals affected by MS experience significant
increase in disability, mortality, and healthcare utilization
3-11
. Despite the availability of effective
treatment, 16% of patients will use a walking aid after 20 years
12
. For example, MS accounted
for a loss of over 1,100 disability adjusted life years globally in 2016
3
. The effect of MS on
adjusted life years includes a loss of between 6 and 14 years of life for the average MS patient
4-
6,13
. While individuals are living with MS, they experience significant disability resulting in over
half of patients being on disability insurance after 11 years of the disease
8
and a majority of
untreated individuals will progress to needing a walking aid
7
. Additionally, MS has been shown
to significantly decrease patients’ quality of life
14
. This increased morbidity leads to significant
utilizations in healthcare resources. One study estimated that there are approximately 20,000
hospital admissions related to MS in the United States annually accounting for over 400 million
US dollars in billed services
11
. The number of admissions and cost of admission are increasing
over time
11
.
Predicting and preventing MS disability:
The disease course of MS is highly variable with some individuals with “benign MS”
accruing very little disability, while over 50% of untreated patients will need an aid to walk after
about 20 years of the disease
5,7,15
. Reasons behind these observations are multifactorial and likely
include environmental, social and genetic factors. Nevertheless, there are clinical characteristics
such as number of relapses, recovery from relapses, phenotype at presentation and MRI findings
2

that have been associated with future disability
7,16-20
. While many of these characteristics are
associated with some measure of disability, they have significant limitations. For example, a
progressive phenotype has been accepted to carry a worse prognosis than a relapsing phenotype
because those patients accumulate disability faster. Using the Expanded Disability Status Scale
(EDSS)
21
(a standardized disability assessment where 0 is no disability, 6 requires a walking aid,
and 10 represents death due to MS), progressive from onset patients reach an EDSS of 7
(wheelchair dependent) in an average of 13.4 years compared to 33.1 years for relapsing from
onset patients
7
. However, when evaluating prognosis as the age a patient reaches a specific level
of disability, there is no difference between progressive or relapsing forms of MS
7
. This is true
for EDSS end points of 3,4, 6, or 7
5,7
.
Age and gender are important demographics that play a role in prognosis. Both male and
older age are reported to have a worse prognosis
7,17
. Age at onset, however, carries similar
contradictions to MS phenotype when evaluating its utility as a prognostic feature. Younger age
of onset is associated with slower disability accrual, but ultimately leads to a younger age of
disability
5
. Relapses and MRI lesions early in the disease course have been associated with
disability accrual, and are now standard outcomes in clinical trials
16,18,22
. However, relapses and
MRI markers later in the disease course have not been found to be associated with disability
accrual, and the absence of relapses or MRI lesions early in the course has not been predictive of
long term favorable outcomes
12,16,18
.
Health Disparities in MS:
One prognostic factor now recognized to predict poor outcomes is that of race and
ethnicity. Minorities in the US with MS, such as African American/Black (AA) and Hispanic
populations, have been reported to have a more rapid disease, reach higher disability levels at a
younger age, and have a higher mortality (blacks only) due to MS than whites
23-25
. A study of
3

MS related mortality rates in the US showed that AA had the highest rate of MS mortality of any
race under the age of 45
23
. Additionally, AA have been reported to have worse ambulatory
disability, including patient reported disability, and cognitive outcomes than white MS patients
throughout the disease course
25,26
.
Hispanics with MS also appear to be at risk of worse disability than whites with MS.
Studies have found that Hispanics with MS reached similar levels of ambulatory disability at a
younger age than whites, and had higher age adjusted patient reported disability than whites
24,25
.
While the causes of this increase in disability are not fully understood, it is multi-factorial and
several contributing factors have previously been reported. Hispanics are reported to present at a
younger age than whites and may have a higher incidence of pediatric MS
24,27,28
. Younger age of
onset is in turn associated with a younger age of disability attainment
5
. Additionally, the initial
presentation has been shown to be predictive of future disability in MS, and Hispanics are twice
more likely to present with transverse myelitis than white MS patients
24
. Factors behind the
initial presentation in MS are not well understood but recent studies indicate that initial
presentation of MS could be related to genetic admixture. Hispanics are not a homogenous
population, and significant variations in genetic ancestry exist between those living on the east
and west cost of the united states
28
. This variation has been shown to be associated with
differences in initial MS presentation where Native American ancestry is associated is associated
with a presentation of optic neuritis as well as younger age of onset
29
. Additional biological
factors contributing to the disparities in outcomes experienced by Hispanics with MS may also
include other genetic polymorphisms, and environmental exposures. Social factors also likely
play a role in disparities. In Hispanics living in the U.S., place of birth and age of immigration
have both been associated with disability
30
. It is also known that Hispanics and other minority
4

populations experience other high-risk social influences including living in poverty, being poorly
educated, reduced health literacy, and decreased access to healthcare
28
.
Unfortunately, the understanding of these disparities and possible interventions is limited
by a lack of participation of Black and Hispanic populations in MS research. We recently
conducted a systematic review of MS disease modifying therapies and found only 4 studies
evaluating their efficacy or effectiveness in Hispanic patients and only 10 evaluating Black
populations
31
. This is in contrast to the white population that represents the majority of
participants in > 70 trials included in the most recent review by the American Academy of
Neurology
32
.
Comorbidities in MS:
Comorbidities in MS have recently gained tremendous attention. Medical comorbidities
in MS have been associated with worse outcomes and have the potential of being modifiable.
There is a wide variation in the reported prevalence of comorbidities in MS, however they are
clearly common with large registries reporting between 35 and nearly 85% of participants having
comorbidities
33-35
. The most frequent comorbidities reported include hypertension (HTN),
hyperlipidemia (HLD), and diabetes (DM), as well as migraine, depression, and arthritis
33-35
.
While the wide estimation range makes it difficult to compare to the population on a whole, one
Canadian study did not find differences in the prevalence of HTN or DM between individuals
with or without MS
36
. Another study of one Canadian province did find statistically less DM,
and HTN in individuals with MS than those without, though the numerical differences were not
large (HTN 34.9% vs. 37.8% p<0.001, DM 12.8% vs. 13.9% p=0.046)
34
. There may be
differences in the individuals who have these comorbidities within the populations, as
individuals with MS and a comorbidity were younger than those without MS but with a
comorbidity
36
. Additionally, while comorbidities are more common in older individuals for both
5

the MS and general populations, there appeared to be less of an age gradient in the MS
population than the non-MS population
36
. Medical comorbidities have been reported to be
associated with a wide variety adverse outcomes in MS including increased relapses,
hospitalizations, disability, and mortality as well as decreased quality of life (table 1)
33,34,37-46
. In
particular, vascular comorbidities as a group have been associated with diagnostic delays,
disability progression, and mortality
40,41,45
. Vascular comorbidities have also been associated
with MRI findings including T2 MS typical lesions and brain atrophy
47,48
.
Table1: previous literature showing adverse outcomes in predominantly white MS cohorts with
comorbidities. *bullet points in comorbidity are associated with the same line bullet point in outcome.
Author/year Comorbidity*

Outcome*
Marrie/
2009
• obesity, smoking, physical,
psychiatric.

• obesity, vascular

• psychiatric, musculoskeletal
• increased diagnostic delay

• moderate disability

• severe disability
Marrie/
2010
vascular increased ambulatory disability
Marrie/
2011
vascular, visual increased visual disability
Marrie/
2011
• Vascular, autoimmune, cancer,
visual, musculoskeletal,

• psychiatric

• gastrointentional, obesity
• later age of onset

• relapsing course

• relapsing course in women
Marrie/
2012
physical, psychiatric

decreased quality of life
Marrie/
2014
any comorbidity increased hospitalizations
Kowalec/
2017
migraine, hyperlipidemia, ≥ 3
comorbidities
increased relapses
Thormann/
2017
• cerebrovascular, cardiovascular,
lung disease, diabetes, cancer

• cerebrovascular, cardiovascular,
lung disease, diabetes, cancer,
psychiatric, neurologic
• increased diagnostic delay

• increased mortality
Thormann/
2017
• physical, psychiatric

• psychiatric

• decreased income

• increased broken relationships
6

Author/year Comorbidity* Outcome*
Goldman/
2020
blood pressure variability increased disability
Al-Sarkran/
2020
any comorbidity, diabetes, ischemic heart
disease, lung disease, epilepsy, mood
disorders
increased hospitalizations

HTN as a Comorbidity in MS
HTN, a known vascular comorbidity, may be a driver of adverse outcomes in MS in
whites as outlined in Table 2
34,38,44,45,47
. It is one of the most common comorbidities with
estimates ranging between 8% and 35% of MS patients
33,34,36,49
. HTN has been associated with
clinical and radiological markers of disease severity
34,45,47
. Clinically, HTN has been
significantly associated with early gait disability (hazard ratio (HR) 1.29, 95% CI 1.20-1.39),
unilateral walking assistance (EDSS=6, HR 1.25, 95% CI 1.15-1.36), and bilateral walking
assistance (EDSS 6.5, HR 1.17, 95% CI 1.05-1.31)
45
, as well as increased hospitalizations (rate
ratio 1.57, 95% CI 133- 1.58)
34
. Radiographically, brain atrophy as measured by the percentage
change in lateral ventricle volume over time, was significantly worse in MS patients with HTN
than without (24.5% SD 15.3 vs. 14.1% SD 14.7, p=0.05)
47
. Additionally, there is evidence that
differing levels of HTN control result in varying disability outcomes with increasing tertials of
blood pressure variability (differences in readings over time) being associated with increased
disability (T2 OR =3.48 95% CI 1.08-11.25, T3 OR=5.19 95% CI 1.53-17.62)
44
. A large
retrospective cohort indicates that HTN may also be undermanaged in the MS population with
significantly less use of anti-hypertensive medications than hypertensives without MS
36
. These
data indicate that HTN has the potential to be a point of intervention for patients with MS,
however gaps in our understanding of cardiovascular risk factors and HTN specifically in MS
continue.
7

Despite the building evidence that HTN and other comorbidities are associated with
adverse outcomes in MS, more research is needed to further evaluate this association. There is
limited data on the effects of blood pressure control or treatment and MS outcomes. While there
is early evidence that worse blood pressure control as measured by blood pressure variance may
be associated with disability, no studies have yet evaluated nor applied the American Heart
Association’s classifications of HTN severity in MS
50
. Establishing a dose-response relationship
with HTN severity and MS could have clinical applications.
Table 2: Previous literature evaluating the effects of HTN on MS related outcomes in predominantly
white cohorts. *for studies with multiple outcomes the outcome column and result column are paired by
bullet point. HR= hazard ratio, OR=odds ratio, PDDS=Patient Reported Disability.

HTN in Minorities:
The evaluation of vascular comorbidities in minorities with MS is less known but may be
important given their disparities in minority populations. Interestingly, minorities are at risk of
Author/year Exposure Outcome measure* Result* (95%CI)
Marrie/
2010
HTN • early gait disability

• unilateral walking
assistance

• bilateral walking assistance
• HR 1.29 (1.20, 1.39)

• HR 1.25 (1.15, 1.36)

• HR 1.17 (1.05, 1.31)
Marrie/
2015
HTN hospitalizations HR 1.57 (1.33, 1.85)
Conway/
2017
HTN • 25-foot walk time

• performance scale score

• PHQ-9 score
• mean difference -
0.18 sec (-0.26, -
0.09)

• mean difference 0.63
pts (0.40, 0.87)

• mean difference 0.70
pts (0.41, 0.98)
Jakimovski/
2018
HTN % change in lateral ventricle over 5
years
24.5% vs. 14.1% p=0.0.05
Goldman/
2020
Blood pressure
variability
tertials
PDDS increased category 2nd tertial: OR 3.48 (1.08,
11.25)
3
rd
tertial: OR 5.19 (1.53,
17.61)
8

higher rates of cardiovascular comorbidities including DM and HTN
51,52
. For example, in the
US, both Hispanics and AA have a reported prevalence of DM > 20% compared to only 12% in
non-Hispanic whites
51
. Disparities also exist in the level of HTN control. Hispanics and AA with
a diagnosis of HTN each had a 40% increase in the odds of their HTN being uncontrolled
compared to whites
53
. Hispanics in particular have the lowest rates of both HTN awareness and
HTN treatment compared to AA or whites
54
. For example, a U.S. base multiethnic study reported
lower HTN treatment for Mexican men and women (54.0% and 68.1%) compared to white men
and women (69.5% and 78.2%)
55
. Unfortunately, ethnic specific estimates of comorbidity
prevalence or effects in MS are lacking, and it is unknown if disparities of comorbidities in
minority populations may play a role in the disparities seen in MS disability. This study aimed to
evaluate the prevalence of chronic medical conditions and cardiovascular risk factors in self-
identified Hispanic MS patients using the Alliance for Research in Hispanic MS database at
USC. Given the literature on under awareness of HTN in Hispanics, we specifically looked to
evaluate the prevalence of hypertension using objective blood pressure measurements in addition
to reported diagnoses. We then aimed to evaluate the associations between any comorbidity,
grouped cardiovascular risk factors, or individual cardiovascular risk factors and disability in
Hispanics with MS using both subject reported and objective data.
Methods:
Study Design:
This is a retrospective cohort study of Hispanic patients with MS enrolled in the USC
Hispanic MS registry. This registry is a part of the Alliance for research in Hispanic MS
(ARHMS) group described elsewhere
29
. Self‐identified Hispanics were included using the NIH
minority inclusion criteria; defined as a person who self‐identifies as Hispanic or Latino of
Cuban, Mexican, Puerto Rican, Southern or Central American, or other Spanish culture or origin,
9

regardless of race
56
. The study included all those enrolled in the USC site of the ARHMS
Hispanic registry between November 2007 and April 2019, who had available data on medical
comorbidities and clinical measures. To ensure our results reflected the effects of comorbidities
in MS, individuals who were found to have a misdiagnosis after enrolling in the study were
excluded. The study is approved by the institutional review board at USC.
Clinical variables:
Clinical characteristics including age at time of evaluation, year of diagnosis, disease
duration, the presence of any medical comorbidities, smoking status, location of care (private or
public clinic), place of birth, disease modifying therapies, education level, and body mass index
(BMI) were abstracted from the ARHMS. Disease duration was calculated using the patient’s
reported year of first symptoms subtracted from the year of their examination for the study
consistent with previous studies. For individuals who did not report symptoms before diagnosis,
symptom onset and diagnosis year were accepted to be the same. Location of care was collected
as a proxy for socioeconomic status between the private Keck Medicine of USC and the public
LAC+USC county hospital. Patients seen at Keck typically have private insurance, while
LAC+USC does not accept private insurance and typically sees individuals of lower SES.
Average socioeconomic status at LAC is approximately $45,000 annually. Place of birth was
divided as US or foreign born. Education level was categorized as less than high school, trade
school or some college, or college degree or above. BMI was calculated as a continuous variable.
Comorbidities:
Comorbidity data was obtained using semi-structured patient questionnaires and review
of medical records. Comorbidity was defined as any chronic condition not attributable to MS.
The presence of any comorbidity and the number of medical comorbidities were recorded for
each individual. Additionally, participants were identified as having a cardiovascular risk factor
10

if they had any of four relevant diagnoses: HTN, DM, HLD, and prior ischemic vascular disease,
or if they had a history of smoking tobacco.
Definition of Hypertension:
In addition to medical comorbidities, blood pressure readings at the time of the
participants’ first visit at enrollment were reviewed. If no blood pressure was available at study
entry, the closest reading within 1 year was included if disability level was also verified at the
time of the blood pressure reading. Individuals who did not have disability verification at the
same time as a blood pressure reading were not included in the objective blood pressure analysis
but remained in the primary comorbidity analysis. These readings were categorized according to
the American Heart Association’s 2017 Guideline for the Prevention, Detection, Evaluation, and
Management of High Blood Pressure in Adults
50
. These categories include normal (≤120/80),
elevated (systolic blood pressure (SBP) 121-129), stage I HTN (SBP 130-139 or Diastolic blood
pressure (DBP) 81-89), or stage II HTN (SBP≥140 or DBP≥90). For individuals categorized as
hypertensive (stage I or stage II), A second blood pressure reading at a separate time point was
used to confirm the diagnosis of HTN
50
. The confirmed diagnosis of HTN was used to estimate
prevalence. For evaluation of associations, only the blood pressure reading at the time of
disability measurement was used.
Outcome Measurements:
To assess disability we used the EDSS
21
. The primary outcome was to evaluate if having
a comorbidity is associated with severe ambulatory disability defined as the need for a unilateral
assistance device (EDSS ≥6). Secondary outcomes of mild motor disability (EDSS ≥4.0), and
EDSS as a continuous outcome was also used when available.
Statistical analysis:
To evaluate the characteristics of our cohort at time of enrollment, descriptive statistics of
the cohort including sex, age at enrollment, MS type, comorbidity types and frequencies, place of
11

birth, location of clinic, education level, and proportion of those with severe ambulatory
disability were calculated. To compare differences in the population characteristics, descriptive
features of those with and without any comorbidity were analyzed with chi square analysis for
proportions and T tests to compare means. To evaluate if cardiovascular risk factors could be
stratified by age, the frequency and presence of comorbidities was calculated for those under vs.
equal or greater than 40 years of age. To assess whether there were differences between
individuals with or without available blood pressure readings, we compared these two
populations with respect to the same characteristics. In addition, to evaluate the level of HTN
awareness, we evaluated the frequency of objective HTN level blood pressure readings (stage I
or stage II HTN) compared to the frequency of HTN diagnosis in the subset with available blood
pressure data.
To evaluate putative associations between comorbidities and severe ambulatory disability
(EDSS≥ 6), multivariable logistic regression was used to calculate the odds ratios (OR) and 95%
confidence intervals (CIs). Independent variables of interest were the dichotomized presence of
any comorbidity, the presence of any cardiovascular comorbidity or the individual presence of
HTN, HLD, DM, past ischemic event, or smoking individually. Age, sex, being on an MS
treatment, socioeconomic status, place of birth, education level, and disease duration were all
tested for confounding using regression models evaluating the change in primary effect with the
addition of individual covariates. A cut-off of 20% was chosen as a conservative definition to
avoid including potential confounders whose effects may be only due to missing data. To ensure
no standardly accepted confounders were excluded, the final multivariable model was chosen to
include any confirmed confounders and variables known to the researchers to be important
contributors to MS disability such as age, sex and disease duration. Age (statistical confounder),
12

sex (disability contributor), and disease duration (disability contributor) were found to be
important and thus were included in the final analysis. In addition to adjustment of age as a scale,
the cut-off of 40 years of age was tested for effect modification.
To test associations between objective blood pressure readings and disability, multivariable
logistic regression was performed on the subset of individuals with objective blood pressure
readings. The 3 stages of HTN as defined by the American College of Cardiology were used as
an ordinal exposure, and disability endpoints of EDSS ≥ 6.0 (vs. EDSS<6) or EDSS ≥ 4.0 (vs.
EDSS<4) were used as the outcome variables. The models were again adjusted for age, sex, and
disease duration. This analysis was performed with all individuals who had available blood
pressure data. The blood pressure at or nearest the time of study entry with disability
measurement was used for a sensitivity analysis excluding individuals who did not have a second
blood pressure reading confirming a diagnosis of HTN was also performed. To evaluate for a
linear relationship between blood pressure readings and disability, we used linear regression to
test for associations between SBP or DBP and raw EDSS scores. Multivariable regression was
preformed adjusting for age, sex, and disease duration. In addition, BMI was evaluated as a
potential confounder in the subset analysis as it was only available in those who had recorded
vitals. Results adjusted for BMI are reported separately but are not considered part of the
specified final model due to differential missing data where higher disability led to more missing
BMI measurements. All statistical analyses were performed on SPSS 26 and used an a priori α-
level of 0.05 to declare statistical significance.
13

Results:
Study Population:
Of 527 individuals available in the registry, only 451 were used for analysis due to 36
being found to be misdiagnosed, and 40 with missing comorbidities or level of disability (Figure
1).

Clinical characteristics of the population are shown in Table 3 of which most had
relapsing forms of MS (92.6%) and were female (63.0%) with a mean age of 38.8 years. The
majority were on disease modifying treatment (86.0%) and were US born (65.4%). In addition,
most fell in higher SES status (67.0%) and were well educated (college graduates, 59.3%).
Severe ambulatory disability (EDSS>6) was found in 27.3%.
A medical comorbidity in addition to MS was found in 41.9% with depression being the
most common (8.9%). Almost a quarter (24.2%) had at least one cardiovascular risk factor
including: smoking (13.6%), HTN (7.3%), DM (5.1%), and hyperlipidemia (4.7%). When those
with and without comorbidities were compared, those with comorbidities were more likely to
smoke (20.3% vs. 8.7% p<0.01). In addition, those with comorbidity were slightly older (39.9
vs. 37.9 p=0.08) and more likely to have higher SES (72.0 vs. 63.4% p=0.06) though these
14

differences were not statistically significant. There were no differences in sex, disease duration,
relapsing form of disease, or being on treatment.
Table 3: Baseline Characteristics for all participants and those with and without comorbidities.
Proportions compared using chi square analysis, means compared using independent T test. Results
displayed as mean ± SD or N (%).

The frequency of cardiovascular risk factors varied by age group (table 4) with those over
40 having significantly higher frequency of cardiovascular risk factors (27.3% vs. 17.5%,
p=0.04). This included HTN (12.6% vs. 3.2%, p<0.01), DM (7.6% vs. 3.2%, p=0.03), HLD
(7.1% vs. 3.8%, p=0.03), and past ischemic events (1.5% vs. 0.0%, p=0.05). Smoking was the
one exception being more common in younger individuals (16.1% vs. 10.4%, p=0.08) though
this difference was not statistically significant.

Characteristic N Total Cohort (n=451) Subset without
Comorbidities
(n=262)
Subset with
Comorbidities
(n=189)
P
value
Age 451 38.8 ± 11.8 37.9 ± 11.0 39.9 ± 12.7 0.08
Disease Duration
(years)
451 8.7 ±8.0 8.7 ± 7.9 8.6 ± 8.2 0.95
Female 451 284 (63.0) 158 (60.3) 126 (66.7) 0.17
Relapsing Disease 443 410 (92.6) 238 (93.3) 172 (91.5) 0.29
On Treatment 451 388 (86.0) 225 (85.9) 163 (86.2) 0.91
Private clinic 451 302 (67.0) 166 (63.4) 136 (72.0) 0.06
US Born 410 268 (65.4) 154 (64.2) 114 (67.1) 0.54
College Educated 423 251 (59.3) 149 (60.1) 103 (58.3) 0.71
EDSS≥6 451 123 (27.3) 69 (26.3) 54 (28.6) 0.60
Medical
Comorbidity
451 189 (41.9) 0 (0) 189 (100) n/a
Cardiovascular risk
factor
451 109 (24.2) 22 (8.4) 87 (46.0) <0.01
HTN Diagnosis 451 33 (7.3) 0 (0) 33 (17.5) n/a
DM 451 23 (5.1) 0 (0) 23 (12.2) n/a
Hyperlipidemia 451 21 (4.7) 0 (0) 21 (11.1) n/a
Ischemic vascular
disease
451 3 (0.7) 0 (0) 3 (1.6) n/a
Smoking 440 60 (13.6) 22(8.7) 38 (20.3) <0.01
15

Table 4: Presence of comorbidity or ischemic risk factors by age group.
Proportions compared using chi square analysis, means compared using independent T test. Results
displayed as mean ± SD or N (%).
Characteristic Patients < 40 years old
(n=253)
Patients ≥ 40 years
(n=198)
P value
Medical Comorbidity 105 ± 41.5 84 ±42.4 0.84
Cardiovascular risk factor 52 ± 20.6 57 ± 28.8 0.04
HTN Diagnosis 8 (3.2) 25 (12.6) <0.01
DM 8 (3.2) 15 (7.6) 0.03
Hyperlipidemia 7 (2.8) 14 (7.1) 0.03
Ischemic vascular disease 0 (0) 3 (1.5) 0.05
Smoking 40 (15.8) 20 (10.4) 0.08

Approximately 56.5% of the participants had BP measurements at the time of EDSS
(Table 5). The subset with BP measurements was predominantly representative of the total
cohort with few differences between those with and those without BP data. Those with blood
pressure readings, were younger (35.3 years vs. 43.2 years, p<0.01), earlier in their disease
course (disease duration 7.2 years vs. 10.5 years, p<0.01), and more likely to be U.S born (71.7%
vs. 56.5%, p<0.01) than those without blood pressure measurements. There were no differences
by sex (female, 60.8% vs. 65.8, p=0.27), relapsing type of disease (92.9% vs. 92.0%, p=0.72),
SES (67.1% vs. 66.8%, p=0.96), education (59.1% vs. 59.7%, p=0.91), or being on treatment
(85.9% vs. 86.2% p=0.92). Those with BP readings were less likely to have severe ambulatory
disability (24.3% vs. 31.1%, p=0.11) but this was not statistically significant. In terms of
comorbidity, the subset had a similar rate of medical comorbidities (44.3% vs. 38.8%, p=0.24)
and cardiovascular risk factors (23.9% vs. 24.5%, p=0.89). There was no difference in the
proportion having a documented diagnosis of HTN (7.1% vs. 7.7%, p=0.81), ischemic vascular
disease (0.4% vs. 1.0%, p=0.42), DM (4.7% vs. 5.6%, p=0.66), HLD (4.7% vs. 4.6%, p=0.96), or
smoking (14.2% vs. 12.9%, p=0.70).
When evaluating the objective BP readings, there is evidence of undiagnosed or low
awareness of HTN (table 5). While only 7.1% of participants with available BP readings had a
16

recorded diagnosis of HTN, 31.8% had BP readings in the hypertensive range. These included
22.0% with stage I HTN readings, and 9.8% with stage II HTN readings. Of the 83 individuals
with Hypertensive BP readings, 70 had a second blood pressure reading confirming a diagnosis
of HTN. This indicates that 27.5% of individuals in this subgroup met objective guidelines for a
diagnosis of HTN, while only 7.1% reported or had medical records documenting this diagnosis.
BMI data was only available in individuals who had vitals recorded in the EMR. A total
of 225 individuals had a recorded BMI. Of these individuals the mean BMI was 28.8. There
appeared to be differential attainment of weight where individuals needing ambulation assistance
were less likely to have a recorded BMI. In individuals with a blood pressure recorded, those
with an EDSS <6 had only 8% missing BMI while those with an EDSS ≥ 6 had 23% missing.
Table 5: Baseline frequency statistics of the total and subset cohort: Proportions compared using chi
square analysis, means compared using independent T test. Results displayed as mean ± SD or N (%).
Characteristic N Total Cohort
(n=451)
Subset with BP
data (n=255)
Subset without BP
data (n=196)
P
value
Age 451 38.8 ± 11.8 35.3 ± 11.6 43.2 ± 10.5 <0.01
Disease Duration (years) 451 8.7 (8.0) 7.2 (6.6) 10.5 ± 9.2 <0.01
Female 451 284 (63.0) 155 (60.8) 129 (65.8) 0.27
Relapsing Disease 443 410 (92.6) 237 (92.9) 173 (92.0) 0.72
On Treatment 451 388 (86.0) 219 (85.9) 169 (86.2) 0.92
Private clinic 451 302 (67.0) 171 (67.1) 131 (66.8) 0.96
US born 410 268 (65.4) 172 (71.7) 96 (56.5) <0.01
College Educated 423 251 (59.3) 143 (59.1) 108 (59.7) 0.91
EDSS≥4 254 n/a 71 (28.0) n/a n/a
EDSS≥6 451 123 (27.3) 62 (24.3) 61 (31.1) 0.11
Medical Comorbidity 451 189 (41.9) 113 (44.3) 76 (38.8) 0.24
Cardiovascular risk
factor
451 109 (24.2) 61 (23.9) 48 (24.5) 0.89
HTN Diagnosis 451 33 (7.3) 18 (7.1) 15 (7.7) 0.81
Elevated BP reading 255 n/a 34 (13.3) n/a n/a
Stage I HTN reading 255 n/a 56 (22.0) n/a n/a
Stage II reading 255 n/a 25 (9.8) n/a n/a
Objective HTN
Diagnosis
255 n/a 70 (27.5) n/a n/a
DM 451 23 (5.1) 12 (4.7) 11 (5.6) 0.66
Ischemic vascular
disease
451 3 (0.7) 1 (0.4) 2 (1.0) 0.42
17

Association of HTN and Disability:
Logistic regression (table 6) showed that the presence of any cardiovascular risk factor
was associated with having an EDSS ≥ 6 in univariate analysis (OR 1.91; p=0.01; 95% CI 1.21,
3.03). When individual covariates were tested for potential confounding, only age was found to
change the odds ratio by 20%. Based on the known relationships between MS disability, sex, and
disease duration, we chose to also include those in the final model. Age stratification of <40
years vs. ≥ 40 years was also tested for effect modification with no significant effect. When
adjusted for age, sex, and disease duration, having at least one cardiovascular risk factor was
associated with almost twice (OR 1.65) increase in the odds of having severe ambulatory
disability, but this was barely short of statistical significance (p=0.05; 95%CI 1.00, 3.03). When
evaluating individual cardiovascular comorbidities, the association with ambulatory disability
appears to be driven by the effect of HTN. An individual having HTN is three times more likely
to have severe ambulatory disability (OR 3.12; p=0.01; 95%CI 1.37, 7.12; adjusted for age, sex,
and disease duration). Having DM, HLD, past ischemic events, or smoking were not
significantly associated with severe ambulatory disability. In some of the categories including
DM, and past ischemic events, the low prevalence likely led to unstable estimates with wide
confidence intervals. DM and past ischemic events had OR estimates of 1.8 and 3.0 respectively.

Characteristic N Total Cohort
(n=451)
Subset with BP
data (n=255)
Subset without BP
data (n=196)
P
value
Hyperlipidemia 451 21 (4.7) 12 (4.7) 9 (4.6) 0.96
Smoking 440 60 (13.6) 36 (14.2) 24 (12.9) 0.70
BMI (n=225) 226 n/a 28.7 ± 6.45 n/a n/a
18

Table 6: Logistic Regression evaluating associations between comorbidity diagnoses and EDSS≥6.
Multivariable regression adjusted for age, sex, disease duration.
Risk Factor Unadjusted OR (p; 95% CI) Adjusted OR (p; 95% CI)
Any cardiovascular risk factor 1.91 (p=0.01; 1.21, 3.03) 1.65 (p=0.05; 1.00, 2.73)
HTN 4.71 (p<0.01; 2.26, 9.79) 3.12 (p=0.01; 1.37, 7.12)
Past ischemic event 5.41 (p=0.17; 0.49, 60.15) 2.97 (p=0.42; 0.21, 42.12)
DM 2.14 (p= 0.08; 0.92, 5.03) 1.77 (p=0.22; 0.72, 4.40)
HLD 1.69 (p=0.26; 0.68, 4.17) 1.20 (p=0.72; 0.45, 3.19)
smoking 0.97 (p= 0.91; 0.52, 1.79) 1.08 (p=0.83; 0.56, 2.09)
Any medical comorbidity 1.12(p=0.60; 0.74, 1.70) 1.09 (p= 0.71; 0.69, 1.72)

Association of Blood Pressure Measurements and Disability:
To evaluate HTN using objective BP readings (table 7) we used logistic regression.
Those that have stage II HTN were found to be nearly 3 times more likely to have severe
ambulatory disability (OR 2.89; p=0.03; 95%CI 1.11, 7.55) compared to those with normal
blood pressure readings when adjusted for age, sex, and disease duration. Readings in the
elevated range (OR 1.47; p=0.42; 95%CI 0.57, 3.79) and stage I HTN (OR 1.22; p=0.63; 95%CI
0.55, 2.72) also increased the likelihood but were not statistically significant. When BMI was
evaluated for confounding, it did qualify based on our prespecified definition but is reported
separately due to the observed differentially missing data. When BMI was added to the model,
the association between stage II HTN and disability became stronger (OR 3.96; p=0.01; 95%CI
1.36, 11.57).
A sensitivity analysis was performed on those with moderate levels of disability in the
group with BP readings (71 with EDSS ≥ 4) using logistic regression (table 8). The odds of
having EDSS ≥ 4 were increased for each category of BP, but none were significant when
adjusted for age, sex, and disease duration. Those with elevated BP and stage II HTN were
significantly more likely to have worse disability when adjusted for age, sex, disease duration
and BMI (elevated BP OR 2.82, 95% CI 1.08, 7.37; stage II HTN OR 3.23, 95% CI 1.12, 9.29
We did not find a linear relationships between blood pressure readings and moderate disability.
19

When individuals without a confirmed second hypertensive blood pressure reading were
excluded from the analysis, the results were essentially unchanged.
Table 7: Logistic Regression of blood pressure categories (compared to those with normal blood pressure)
with EDSS≥6. Model 1 is adjusted for age, sex, and disease duration, while model 2 is adjusted for age,
sex, disease duration, and BMI.
Risk factor Unadjusted OR (95%
CI)
Model 1 (95% CI) Model 2 (95% CI)
Elevated BP (SBP 121-129) 1.58 (p=0.31; 0.66,
3.78)
1.47 (p=0.42; 0.57,
3.79)
1.86 (p=0.24; 0.66,
5.26)
Stage I HTN (SBP 130-139
or DBP 81-89)
1.75 (p=0.13; 0.85,
3.60)

1.22 (p=0.63; 0.55,
2.72)
1.65 (p=0.27; 0.68,
4.01)
Stage II HTN (SBP >139 or
DBP >89)
2.92 (p= 0.02; 1.18,
7.24)
2.89 (p=0.03; 1.11,
7.55)
3.96 (p=0.01; 1.36,
11.57)

Table 8: Logistic Regression of blood pressure categories with EDSS≥4. Model 1 is adjusted for
age, sex, and disease duration, while model 2 is adjusted for age, sex, disease duration, and BMI.
Risk factor Unadjusted OR
(95% CI)
Model 1 (95% CI) Model 2 (95% CI)
Elevated BP (SBP 121-
129)
2.16 (p=0.06; 0.97,
4.79)
2.22 (p=0.08; 0.92,
5.34)
2.82 (p=0.04; 1.08,
7.37)
Stage I HTN (SBP 130-
139 or DBP 81-89)
1.52 (p=0.24; 0.76,
3.05)
1.03 (p=0.94; 0.47,
2.29)
1.31 (p=0.54; 0.55,
3.09)
Stage II HTN (SBP >139
or DBP >89)
2.32 (p=0.07; 0.95,
5.68)
2.35 (p=0.08; 0.90,
6.11)
3.23 (p=0.03; 1.12,
9.29)
Discussion of Results:
Important Findings:
Medical comorbidities are important markers of healthcare utilization and disability in
MS patients
33,34,37-41,45,47,48
. In particular, HTN has been noted to increase disability,
hospitalizations, and brain atrophy
39,45,47
. Previous studies however have only included white
cohorts with minimal attention to minority groups such as Hispanics which could represent a
population at higher risk of both MS related disability and medical comorbidities
24,25,51,52,55
.
Using the USC Hispanic MS registry, we found an age effect in the distribution of cardiovascular
comorbidities with HTN being the most common in those over the age of 40 while smoking was
the most common in younger individuals. Second, having HTN alone as a diagnosis is associated
20

with 3 times greater odds of having severe ambulatory disability. When the AHA definition of
HTN was applied, those with BP readings falling in the Stage II HTN category were also ~3
times more likely to have severe ambulatory disability.
Comparison to Existing Literature:
Approximately 40% of Hispanics in this MS registry had any comorbidity which is in
line with previous studies
35,39
. About a quarter (24%) had a vascular comorbidity which was
again similar to previous literature
45
. There is a wide range of reported HTN prevalence in MS
patients
33,36,49,57
. Only 7.3% of participants in our study reported a diagnosis of HTN which is
consistent with a predominantly white study using the North American Research Committee on
Multiple Sclerosis Registry showing 8% of respondents reported having HTN at the time of MS
diagnosis
33
. However, these numbers appear to underestimate the number of MS patients with
objective evidence of HTN as identified by blood pressures readings. Almost 1/3 (27.5%) would
objectively meet the diagnoses of HTN. This finding suggests the possibility that there is a
higher prevalence of HTN in the Hispanic population with MS compared to what has been
reported previously in predominantly white cohorts with MS (8% to 22.8%)
33,36,49
.
Estimates of HTN prevalence in Hispanics has been reported to range between 25% - 30%
55
.
Taken together these data raises concerns that HTN in MS is underdiagnosed and under
controlled and that there is a lack of HTN awareness in Hispanics with MS which is a common
feature of HTN in Hispanics in the US without MS
52,55,58
.
AA and Hispanics have been shown to have alterations in the renin aldosterone system
which may point to genetic predisposition or gene-environment interaction in HTN
59
. However,
HTN disparities are also influenced by numerous social factors which could be points of
intervention
54,55
. Consequently, preventing HTN among high risk populations remains a feasible
approach to narrowing the racial/ethnic hypertension disparities in the U.S. This study shows
21

similar modifiable disparities such as HTN awareness exist within the Hispanic MS community.
A lack of awareness of HTN or other cardiovascular comorbidities in the MS community could
lead to less treatment or compliance with medications and deserves further study.
Several cardiovascular comorbidities have previously been associated with disability in
predominantly white MS cohorts including HTN, blood pressure variability, DM,
hyperlipidemia, and peripheral vascular disease
36,44
. Our study evaluated the effect of any
cardiovascular risk factor or five individual cardiovascular risk factors in a fully Hispanic cohort.
Our study revealed that in contrast to the previous white cohorts, only HTN was associated with
ambulatory disability. This allowed us to directly review medical records to confirm diagnoses
and disability levels. Both the entire population with a diagnosis of HTN and the subset with
objective evidence of stage II HTN, were approximately 3 times more likely to have an EDSS≥6
compared to those without HTN. Comparison of our findings with other studies is difficult due to
different techniques. A study evaluating time dependent disability showed a hazard ratio of 1.25
for reaching an EDSS of 6 and 1.17 for reaching an EDSS of 6.5 in a predominantly white
cohort
45
. Given the previously reported higher rates of disability and uncontrolled HTN, it is
possible that Hispanics have a larger association between HTN and disability than
whites
24,25,52,55
.
Limitations:
Our study is somewhat unique in associating HTN with disability level at time of entry
into a large database, which allowed us to directly review medical records to confirm diagnoses
and disability levels. Despite the strengths of our study including its large sample size and
granular blood pressure readings, our study does have some limitations. First, we attempted to
explain comorbidity and HTN using a retrospective design accessing a single site ARHMS
registry. Specifically, it does not allow us to infer the temporal relationship between HTN and
22

disease severity, for example it is unclear if MS was diagnosed before HTN or after. Secondly,
because we used preexisting data for the secondary analysis, we had missing data. However, the
baseline demographics of the individuals appeared representative of the larger group. Third, we
adjusted for multiple important factors associated with disability in MS and hypertension.
However, like in most epidemiologic studies, we cannot rule out the possibility of unmeasured or
residual confounding in these findings. Fourth, as a study based out of 2 tertiary academic
hospitals in one geographic location, it is possible that the prevalence of comorbidities in this
study is not representative of the larger population of Hispanics with MS. Specifically this study
is predominantly US born Hispanics and predominantly of Mexican ancestry. This population
may differ from Hispanics further East in the U.S. who have more Afro-Caribbean ancestry or
those with more direct roots to Spain. It is also possible for recruitment to result in unmeasured
selection bias however this registry approaches every Hispanic individual with MS at
participating sites and has a high rate of participation making selection bias less likely. Finally,
future studies will be needed to evaluate if HTN is associated with longitudinal disability
progression in Hispanic MS patients, and if disparities in HTN help explain disparities in
disability for Hispanics with MS. Additionally, the possibility of HTN interventions for these
patients should be explored.
Conclusions of these findings:
Hispanics with MS report a similar rate of HTN to previous studies, but there is evidence
of poor HTN awareness within this group as objective blood pressure readings revealed a
significant increase in the proportion of individuals with HTN compared to self-report and chart
review. The true prevalence of HTN in this group is between 22 and 32%. This range would
represent a number larger than what is reported in white cohorts with MS but slightly less than
23

estimations in the general Hispanic populations (25-30%)
33,55
. Hispanic MS patients with a
diagnosis of HTN are 3 times as likely to have severe ambulatory disability as those without.
This association appears to specifically affect those with blood pressure readings meeting criteria
for stage II HTN. Factors contributing to, or with potential to ameliorate this effect are not yet
fully understood. Hispanics are known to have disparities in the treatment and control of both
HTN and MS
24,25,52,55
. While we do not fully understand whether the observed variance in
disease severity is due to race/ethnicity or other factors associated with MS, race/ethnicity
remains an important surrogate on the pathway of the factors directly contributing to disease
outcomes. These shared pathways may help to explain the specific associations between HTN
and MS disparities in Hispanics. Social factors such as high sodium intake, obesity, cigarette
smoking, and physical inactivity all have either animal or human evidence of worse outcomes in
both HTN and MS
60-65
. Additionally, there are physiologic overlaps between HTN and MS. Pro-
inflammatory cytokines present in MS are also known to play a role in vascular fibrosis and
endothelial disfunction in HTN
66,67
. Alterations in the renin angiotensin aldosterone system
accepted in the HTN literature are now being found in individuals with MS
68-71
. Other
explanatory factors for disease severity could also include other unmeasured SES (family
income, access to prescription medications, or culturally competent care) which can also affect
both HTN and MS.
Significant barriers to effective hypertension and MS care also overlap in the Hispanic
community, with evidence of less awareness and delays in treatment for both MS and HTN
24,72
.
This suggests these outcomes may be the result of social factors. The multifactorial relationships
which likely result in the observed association between HTN and disability in MS patients
requires a greater look into the sources of ethnic disparities.
24

Future Directions:
Proposed Hypotheses:
To further understand the association between HTN, cardiovascular risk factors and
disability in Hispanics with MS I have formed hypotheses that 1) uncontrolled HTN is associated
with long term disability progression in Hispanic MS patients, and 2) physiological changes in
the renin-angiotensin, aldosterone (RAAS) system are associated with HTN in Hispanics with
MS. The first hypothesis is an extension of the work described in my current research. The
second hypothesis comes from attempting to find evidence for a physiologic mechanism for the
association between HTN and MS disability.
Literature support of the proposed hypotheses:
Interestingly, alterations in the renin-angiotensin-aldosterone system (RAAS), which
functions to regulate blood pressure dynamics, have been separately described in both HTN and
MS
52,58,59,69,71-75
. Studies in HTN suggest that reduced renin levels and increased aldosterone
levels, with higher aldosterone to renin ratios, are associated with the presence of HTN
59
.
Increased aldosterone levels have been specifically associated with longitudinal increases in
blood pressure and the future development of HTN
73
. Additionally, racial and ethnic minorities,
such as AA and Hispanics, who have disproportionately high rates of uncontrolled HTN, have
been reported to have similarly reduced renin levels or increased aldosterone levels compared to
whites
52,58,59,72
. In studies of MS, CSF levels of the enzyme angiotensin converting enzyme II
(ACE II) and the active metabolite angiotensin II are reduced, and angiotensin converting
enzyme (ACE) is increased
71,74,75
. Additionally, the angiotensin II receptor, AT1R, has been
observed to be upregulated in infiltrative cells of MS plaques
70
.

In mouse models, AT1R is
upregulated in the spinal cords affected by experimental autoimmune encephalomyelitis
(EAE)
69
. There is overlap between the RAAS associated pathophysiology in HTN and MS as
25

highlighted in Figure 2. Angiotensin II leads to activation of AT1R and also leads to production
of aldosterone
68,71
. In humans, blocking angiotensin II or its receptor is therapeutic for
hypertension and in EAE mice, it ameliorates the disease course and upregulates FoxP3+
regulatory T cells
52,58,69,70
.

The evidence indicating the involvement of the RAAS system in the pathophysiology of
both HTN and MS raises the question if alterations in this system could play a role in the
observed associations between HTN and disability in MS patients. The question of alterations of
RAAS in MS patients with hypertension compared to MS patients without hypertension has not
previously been evaluated. It is possible that higher aldosterone and aldosterone to renin ratios,
as seen in hypertensive populations, may indicate a more active RAAS pathway which shares
pathophysiology with MS.
Proposed Study Design:
To examine the effect of HTN on MS disease severity and progression, we will collect
longitudinal measures of blood pressure, assess control of HTN and other risk factors associated
with HTN, and examine the risk of ambulatory disability over time using the EDSS
24
.
26

To determine whether alterations in the RAAS system exist in MS patients with HTN,
We will collect blood samples for measurements of renin and aldosterone, and calculate
aldosterone to renin ratios on 61 hypertensive patients and 61 non-hypertensive patients matched
by sex and age.
We propose to complete this study using The USC Hispanic MS Registry already used in
our current research. As of 2020, all subjects are estimated to have at least one year of follow up
and will have an expected average follow up of 5.7 years providing an ideal population for
longitudinal evaluations and decreasing start up time for this proposal.
Data Collection: clinical outcome measures will include EDSS at entry and at last follow
up, change in EDSS, and clinician documented relapse over the course of follow up. All visits
from 2013 onward have active electronic medical records. Vital signs, laboratory data,
neurologic exams, comorbidities, and prescribed medications will be abstracted. In addition,
exposure variables will include HTN diagnosis at baseline, HTN diagnosis during follow up,
mean blood pressure readings over the follow up period, and AHA hypertension category based
on mean blood pressure measurements. To better understand the impact of having HTN, AHA
cardiovascular risk scores using lipid levels, and the presence of diabetes, smoking, and use of
hypertensive medications will be calculated. Data on other factors that may confound our
analysis will be collected including age, sex, disease duration, education level, and medical
access site (public or private). We will measure serum aldosterone and plasma renin levels and
calculate aldosterone to renin ratios as part of standard of care in 50 hypertensive patients. A
group of age and sex matched controls with MS but without HTN will be recruited for the same
tests.
27

Statistical Analysis: Descriptive statistics will be used to examine the population.
logistic regression will be used to evaluate the associations between HTN and dichotomous
outcomes (ambulatory disability, presence of EDSS progression, presence of relapse), and linear
regression will be used to evaluate change in EDSS as a continuous outcome. The presence of
anti-hypertensive therapies will be tested for interaction or confounding of the regressions. Each
model will test, age, sex, disease, duration, and socioeconomic status as potential confounding
variables. To evaluate the differences in RAAS function, differences in mean renin levels,
aldosterone levels, and aldosterone/renin ratios between participants with and without
hypertension, will be analyzed using unpaired t-test for parametric data, and Wilcoxon rank-
sums test for non-parametric data. Renin levels, aldosterone levels, and aldosterone/renin ratios
will then be used as dependent variables in linear regression models to evaluate for associations
with participant blood pressures, and finally, they will be included as exposure variables in the
models evaluating participant disability.
Power Analysis: Approximately 7% of the 451 individuals from our current study have a
diagnosis of hypertension at baseline. Assuming an N of 451 and a mean EDSS progression and
standard deviation of less than 1 point as seen in clinical trials for relapsing MS, there will be
approximately 85% power to detect a difference in mean EDSS progression of 0.5 using an alpha
value of 0.5
25,26
. For evaluating differences in aldosterone, an increased risk of future
hypertension has previously been reported with a 3 ng/dl increase in aldosterone levels. A
sample of 122 individuals will be required to provide 80% power of finding this clinically
meaningful difference using an alpha of 0.5
11
.
Potential pitfalls and alternative strategies: Potential limitations of this longitudinal
assessment will be the risk associated with missing data and reliance on retrospective chart
28

review for labs related the longitudinal risk factors. Questionnaires will be used to supplement
any missing data from the medical records and those still active in the registry will be contacted.
Aim 2 is an initial exploratory evaluation of a possible physiologic difference between those with
and without hypertension in MS. However, our data will provide information on the degree of
difference and can be used as a base for future studies with a larger number of patients and
controls.
Final Conclusions:
Hispanics with MS have been documented to have worse outcomes than whites. The
etiologies of these disparities are not well understood. One potential explanation is that of
cardiovascular risk factors which have been shown to be more poorly controlled in Hispanics and
have been associated with disability in MS patients. Before our current research, the topic of
comorbidities or vascular risk factors had not been well described in the Hispanic MS population.
We performed a retrospective study of participants in the USC Hispanic MS Registry which
showed that just having diagnosis of HTN is associated with greater ambulatory disability. In
addition, using HTN as measured by the AHA, those in the Stage II HTN category also had 3 times
grater odds of severe ambulatory disability (EDSS≥6). To further understand this association, we
propose to perform a retrospective study with longitudinal outcomes evaluating the effects of HTN
and the control of average blood pressure readings on disability progression. To further understand
the possible physiology behind the association of HTN with disability in MS patients, we will
evaluate serum renin and aldosterone levels and compare hypertensives with non-hypertensives.
RAAS alterations have been documented in both hypertensive patients and MS patients separately
but have never been looked at in hypertensive MS patients compared to MS controls.

29

References

1. Wallin MT, Culpepper WJ, Campbell JD, et al. The prevalence of MS in the United
States: A population-based estimate using health claims data. Neurology.
2019;92(10):e1029-e1040.

2. Evans C, Beland SG, Kulaga S, et al. Incidence and prevalence of multiple sclerosis in
the Americas: a systematic review. Neuroepidemiology. 2013;40(3):195-210.

3. Collaborators GN. Global, regional, and national burden of neurological disorders, 1990-
2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol.
2019;18(5):459-480.

4. Scalfari A, Knappertz V, Cutter G, Goodin DS, Ashton R, Ebers GC. Mortality in
patients with multiple sclerosis. Neurology. 2013;81(2):184-192.

5. Leray E, Moreau T, Fromont A, Edan G. Epidemiology of multiple sclerosis. Rev Neurol
(Paris). 2016;172(1):3-13.

6. Kingwell E, van der Kop M, Zhao Y, et al. Relative mortality and survival in multiple
sclerosis: findings from British Columbia, Canada. J Neurol Neurosurg Psychiatry.
2012;83(1):61-66.

7. Confavreux C, Vukusic S. Natural history of multiple sclerosis: a unifying concept.
Brain. 2006;129(Pt 3):606-616.

8. Landfeldt E, Castelo-Branco A, Svedbom A, Löfroth E, Kavaliunas A, Hillert J. Sick
leave and disability pension before and after diagnosis of multiple sclerosis. Mult Scler.
2016;22(14):1859-1866.

9. Chen AY, Chonghasawat AO, Leadholm KL. Multiple sclerosis: Frequency, cost, and
economic burden in the United States. J Clin Neurosci. 2017;45:180-186.

10. Naci H, Fleurence R, Birt J, Duhig A. Economic burden of multiple sclerosis: a
systematic review of the literature. Pharmacoeconomics. 2010;28(5):363-379.

11. Lad SP, Chapman CH, Vaninetti M, Steinman L, Green A, Boakye M. Socioeconomic
trends in hospitalization for multiple sclerosis. Neuroepidemiology. 2010;35(2):93-99.

12. Cree BA, Gourraud PA, Oksenberg JR, et al. Long-term evolution of multiple sclerosis
disability in the treatment era. Ann Neurol. 2016;80(4):499-510.

13. Lunde HMB, Assmus J, Myhr KM, Bø L, Grytten N. Survival and cause of death in
multiple sclerosis: a 60-year longitudinal population study. J Neurol Neurosurg
Psychiatry. 2017;88(8):621-625.
30

14. Nortvedt MW, Riise T, Myhr KM, Nyland HI. Quality of life in multiple sclerosis:
measuring the disease effects more broadly. Neurology. 1999;53(5):1098-1103.

15. Reynders T, D'haeseleer M, De Keyser J, Nagels G, D'hooghe MB. Definition,
prevalence and predictive factors of benign multiple sclerosis. eNeurologicalSci.
2017;7:37-43.

16. Scalfari A, Neuhaus A, Degenhardt A, et al. The natural history of multiple sclerosis: a
geographically based study 10: relapses and long-term disability. Brain. 2010;133(Pt
7):1914-1929.

17. Langer-Gould A, Popat RA, Huang SM, et al. Clinical and demographic predictors of
long-term disability in patients with relapsing-remitting multiple sclerosis: a systematic
review. Arch Neurol. 2006;63(12):1686-1691.

18. Gajofatto A, Calabrese M, Benedetti MD, Monaco S. Clinical, MRI, and CSF markers of
disability progression in multiple sclerosis. Dis Markers. 2013;35(6):687-699.

19. Louapre C, Bodini B, Lubetzki C, Freeman L, Stankoff B. Imaging markers of multiple
sclerosis prognosis. Curr Opin Neurol. 2017;30(3):231-236.

20. Alla S, Pearson JF, Taylor BV, et al. Disability profile of multiple sclerosis in New
Zealand. J Clin Neurosci. 2016;28:97-101.

21. Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability
status scale (EDSS). Neurology. 1983;33(11):1444-1452.

22. Tomassini V, Fanelli F, Prosperini L, Cerqua R, Cavalla P, Pozzilli C. Predicting the
profile of increasing disability in multiple sclerosis. Mult Scler. 2019;25(9):1306-1315.

23. Amezcua L, Rivas E, Joseph S, Zhang J, Liu L. Multiple Sclerosis Mortality by
Race/Ethnicity, Age, Sex, and Time Period in the United States, 1999-2015.
Neuroepidemiology. 2018;50(1-2):35-40.

24. Amezcua L, Lund BT, Weiner LP, Islam T. Multiple sclerosis in Hispanics: a study of
clinical disease expression. Mult Scler. 2011;17(8):1010-1016.

25. Ventura RE, Antezana AO, Bacon T, Kister I. Hispanic Americans and African
Americans with multiple sclerosis have more severe disease course than Caucasian
Americans. Mult Scler. 2017;23(11):1554-1557.

26. Weinstock-Guttman B, Jacobs LD, Brownscheidle CM, et al. Multiple sclerosis
characteristics in African American patients in the New York State Multiple Sclerosis
Consortium. Mult Scler. 2003;9(3):293-298.
31

27. Chitnis T, Glanz B, Jaffin S, Healy B. Demographics of pediatric-onset multiple sclerosis
in an MS center population from the Northeastern United States. Mult Scler.
2009;15(5):627-631.

28. Amezcua L, McCauley JL. Race and ethnicity on MS presentation and disease course.
Mult Scler. 2020;26(5):561-567.

29. Amezcua L, Beecham AH, Delgado SR, et al. Native ancestry is associated with optic
neuritis and age of onset in hispanics with multiple sclerosis. Ann Clin Transl Neurol.
2018;5(11):1362-1371.

30. Amezcua L, Conti DV, Liu L, Ledezma K, Langer-Goulda AM. Place of birth,age of
immigration,and disability in Hispanics with multiple sclerosis. Mult Scler Relat Disord.
2015;4(1):25-30.

31. Robers MV, Soneji D, Amezcua L. Multiple Sclerosis Treatment In Racial and Ethnic
Minorities. Practical Neurology. 2020(February):49-54.

32. Rae-Grant A, Day GS, Marrie RA, et al. Comprehensive systematic review summary:
Disease-modifying therapies for adults with multiple sclerosis: Report of the Guideline
Development, Dissemination, and Implementation Subcommittee of the American
Academy of Neurology. Neurology. 2018;90(17):789-800.

33. Marrie RA, Horwitz RI, Cutter G, Tyry T, Vollmer T. Association between comorbidity
and clinical characteristics of MS. Acta Neurol Scand. 2011;124(2):135-141.

34. Marrie RA, Elliott L, Marriott J, Cossoy M, Tennakoon A, Yu N. Comorbidity increases
the risk of hospitalizations in multiple sclerosis. Neurology. 2015;84(4):350-358.

35. Marrie R, Horwitz R, Cutter G, Tyry T, Campagnolo D, Vollmer T. Comorbidity,
socioeconomic status and multiple sclerosis. Mult Scler. 2008;14(8):1091-1098.

36. Marrie RA, Kosowan L, Singer A. Management of diabetes and hypertension in people
with multiple sclerosis. Mult Scler Relat Disord. 2020;40:101987.

37. Marrie RA, Horwitz R, Cutter G, Tyry T. Cumulative impact of comorbidity on quality
of life in MS. Acta Neurol Scand. 2012;125(3):180-186.

38. Conway DS, Thompson NR, Cohen JA. Influence of hypertension, diabetes,
hyperlipidemia, and obstructive lung disease on multiple sclerosis disease course. Mult
Scler. 2017;23(2):277-285.

39. Al-Sakran L, Marrie RA, Blackburn D, Knox K, Evans C. Impact of comorbidity on
hospitalizations in individuals newly diagnosed with multiple sclerosis: A longitudinal
population-based study. Mult Scler Relat Disord. 2020;40:101955.
32

40. Thormann A, Sørensen PS, Koch-Henriksen N, Laursen B, Magyari M. Comorbidity in
multiple sclerosis is associated with diagnostic delays and increased mortality.
Neurology. 2017;89(16):1668-1675.

41. Marrie RA, Horwitz R, Cutter G, Tyry T, Campagnolo D, Vollmer T. Comorbidity
delays diagnosis and increases disability at diagnosis in MS. Neurology. 2009;72(2):117-
124.

42. Kowalec K, McKay KA, Patten SB, et al. Comorbidity increases the risk of relapse in
multiple sclerosis: A prospective study. Neurology. 2017;89(24):2455-2461.

43. Thormann A, Sørensen PS, Koch-Henriksen N, Thygesen LC, Laursen B, Magyari M.
Chronic comorbidity in multiple sclerosis is associated with lower incomes and dissolved
intimate relationships. Eur J Neurol. 2017;24(6):825-834.

44. Goldman MD, Min S, Lobo JM, Sohn MW. Retrospective cohort study of the
relationship between systolic blood pressure variability and multiple sclerosis disability.
BMJ Open. 2020;10(2):e034355.

45. Marrie RA, Rudick R, Horwitz R, et al. Vascular comorbidity is associated with more
rapid disability progression in multiple sclerosis. Neurology. 2010;74(13):1041-1047.

46. Marrie RA, Cutter G, Tyry T. Substantial adverse association of visual and vascular
comorbidities on visual disability in multiple sclerosis. Mult Scler. 2011;17(12):1464-
1471.

47. Jakimovski D, Gandhi S, Paunkoski I, et al. Hypertension and heart disease are
associated with development of brain atrophy in multiple sclerosis: a 5-year longitudinal
study. Eur J Neurol. 2019;26(1):87-e88.

48. Geraldes R, Juryńczyk M, Dos Passos G, et al. Distinct influence of different vascular
risk factors on white matter brain lesions in multiple sclerosis. J Neurol Neurosurg
Psychiatry. 2020.

49. Marrie RA, Yu BN, Leung S, et al. Rising prevalence of vascular comorbidities in
multiple sclerosis: validation of administrative definitions for diabetes, hypertension, and
hyperlipidemia. Mult Scler. 2012;18(9):1310-1319.

50. Whelton PK, Carey RM, Aronow WS, et al. 2017
ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the
Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults:
Executive Summary: A Report of the American College of Cardiology/American Heart
Association Task Force on Clinical Practice Guidelines. Circulation. 2018;138(17):e426-
e483.

33

51. Cheng YJ, Kanaya AM, Araneta MRG, et al. Prevalence of Diabetes by Race and
Ethnicity in the United States, 2011-2016. JAMA. 2019;322(24):2389-2398.

52. Bennett A, Parto P, Krim SR. Hypertension and ethnicity. Curr Opin Cardiol.
2016;31(4):381-386.

53. Redmond N, Baer HJ, Hicks LS. Health behaviors and racial disparity in blood pressure
control in the national health and nutrition examination survey. Hypertension.
2011;57(3):383-389.

54. Egan BM, Zhao Y, Axon RN. US trends in prevalence, awareness, treatment, and control
of hypertension, 1988-2008. JAMA. 2010;303(20):2043-2050.

55. Daviglus ML, Pirzada A, Talavera GA. Cardiovascular disease risk factors in the
Hispanic/Latino population: lessons from the Hispanic Community Health Study/Study
of Latinos (HCHS/SOL). Prog Cardiovasc Dis. 2014;57(3):230-236.

56. NIH policy on reporting race and ethnicity data: subjects in clinical research. 2001.

57. Marrie RA, Reider N, Cohen J, et al. A systematic review of the incidence and
prevalence of cardiac, cerebrovascular, and peripheral vascular disease in multiple
sclerosis. Mult Scler. 2015;21(3):318-331.

58. Guzman NJ. Epidemiology and management of hypertension in the Hispanic population:
a review of the available literature. Am J Cardiovasc Drugs. 2012;12(3):165-178.

59. Grim CE, Cowley AW, Hamet P, et al. Hyperaldosteronism and hypertension: ethnic
differences. Hypertension. 2005;45(4):766-772.

60. Probst Y, Mowbray E, Svensen E, Thompson K. A Systematic Review of the Impact of
Dietary Sodium on Autoimmunity and Inflammation Related to Multiple Sclerosis. Adv
Nutr. 2019;10(5):902-910.

61. Castro I, Waclawovsky G, Marcadenti A. Nutrition and physical activity on hypertension:
implication of current evidence and guidelines. Curr Hypertens Rev. 2015;11(2):91-99.

62. Charron S, McKay KA, Tremlett H. Physical activity and disability outcomes in multiple
sclerosis: A systematic review (2011-2016). Mult Scler Relat Disord. 2018;20:169-177.

63. Seravalle G, Grassi G. Obesity and hypertension. Pharmacol Res. 2017;122:1-7.

64. Thompson AJ, Baranzini SE, Geurts J, Hemmer B, Ciccarelli O. Multiple sclerosis.
Lancet. 2018;391(10130):1622-1636.

65. Virdis A, Giannarelli C, Neves MF, Taddei S, Ghiadoni L. Cigarette smoking and
hypertension. Curr Pharm Des. 2010;16(23):2518-2525.
34

66. Wang K, Song F, Fernandez-Escobar A, Luo G, Wang JH, Sun Y. The Properties of
Cytokines in Multiple Sclerosis: Pros and Cons. Am J Med Sci. 2018;356(6):552-560.

67. Guzik TJ, Touyz RM. Oxidative Stress, Inflammation, and Vascular Aging in
Hypertension. Hypertension. 2017;70(4):660-667.

68. Xanthakis V, Vasan RS. Aldosterone and the risk of hypertension. Curr Hypertens Rep.
2013;15(2):102-107.

69. Stegbauer J, Lee DH, Seubert S, et al. Role of the renin-angiotensin system in
autoimmune inflammation of the central nervous system. Proc Natl Acad Sci U S A.
2009;106(35):14942-14947.

70. Platten M, Youssef S, Hur EM, et al. Blocking angiotensin-converting enzyme induces
potent regulatory T cells and modulates TH1- and TH17-mediated autoimmunity. Proc
Natl Acad Sci U S A. 2009;106(35):14948-14953.

71. Kawajiri M, Mogi M, Higaki N, et al. Angiotensin-converting enzyme (ACE) and ACE2
levels in the cerebrospinal fluid of patients with multiple sclerosis. Mult Scler.
2009;15(2):262-265.

72. Sorlie PD, Allison MA, Avilés-Santa ML, et al. Prevalence of hypertension, awareness,
treatment, and control in the Hispanic Community Health Study/Study of Latinos. Am J
Hypertens. 2014;27(6):793-800.

73. Vasan RS, Evans JC, Larson MG, et al. Serum aldosterone and the incidence of
hypertension in nonhypertensive persons. N Engl J Med. 2004;351(1):33-41.

74. Kawajiri M, Mogi M, Osoegawa M, et al. Reduction of angiotensin II in the
cerebrospinal fluid of patients with multiple sclerosis. Mult Scler. 2008;14(4):557-560.

75. Constantinescu CS, Goodman DB, Grossman RI, Mannon LJ, Cohen JA. Serum
angiotensin-converting enzyme in multiple sclerosis. Arch Neurol. 1997;54(8):1012-
1015.

Abstract (if available)

Linked assets

University of Southern California Dissertations and Theses

Conceptually similar

PDF

Hispanic ethnicity in multiple sclerosis

PDF

A genome wide association study of multiple sclerosis (MS) in Hispanics

PDF

Risk factors for unanticipated hospitalizations in children and youth with spina bifida at an urban children’s hospital: a cross-sectional study

PDF

Simulation-based training is associated with lower risk-adjusted mortality in ACS Pediatric TQIP centers

PDF

Clinical outcomes of allogeneic hematopoietic stem cell transplant in acute lymphoblastic leukemia patients: a quality improvement project and systematic review meta-analysis

PDF

The cost of opioid use in high-risk hospitalized infants

PDF

Understanding anti-depressant treatment failure in an underserved vulnerable population

PDF

Association of chronic obstructive pulmonary disease and mortality following thoracic and complex endovascular aortic repair: a retrospective cohort study

PDF

Association between cardiovascular risk factors and coronary CT measures of coronary atherosclerosis in healthy postmenopausal women

PDF

The association between sun exposure and multiple sclerosis

PDF

Predictors of thrombosis in hospitalized children with central venous catheters: a multi-center predictive study from the CHAT Consortium

PDF

Cryopreserved umbilical cord mesenchymal stem cells therapy for the treatment of knee osteoarthritis: in-vitro evaluation and phase I clinical trial protocol

PDF

Preeclampsia and occurrence of neurological outcomes in the child: a meta-analysis

PDF

A cross-sectional study of the association of PTH on bone quality across levels of propionic acid among adult patients with uremia

PDF

Radical prostatectomy or external beam radiation therapy versus no local therapy for survival benefit in metastatic prostate cancer: a SEER-Medicare analysis

PDF

Potential of aqueous humor as a liquid biopsy for uveal melanoma

PDF

Cardiac function in children and young adults treated with MEK inhibitors: a retrospective cohort study of routinely collected health data

PDF

The effect of cytomegalovirus on gene expression of pediatric acute lymphoblastic leukemia

PDF

The Filipino family initiative: preliminary effects of an evidence-based parenting intervention offered in churches on parent and child outcomes

PDF

The effect of vitamin D supplementation on the progression of carotid intima-media thickness and arterial stiffness in elderly African American women: Results of a randomized placebo-controlled trial

Asset Metadata

Creator Robers, Michael Vincent (author)

Core Title Medical comorbidities and multiple sclerosis in the Hispanic population: linking healthcare disparities

School Keck School of Medicine

Degree Master of Science

Degree Program Clinical, Biomedical and Translational Investigations

Publication Date 07/29/2020

Defense Date 06/23/2020

Publisher University of Southern California (original), University of Southern California. Libraries (digital)

Tag health disparities,Hispanic,hypertension,multiple sclerosis,OAI-PMH Harvest

Language English

Contributor Electronically uploaded by the author (provenance)

Advisor Amezcua, Lilyana (committee chair), Patino-Sutton, Cecilia (committee member), Wilson, Melissa (committee member)

Creator Email mrobers@usc.edu,mvrobers@gmail.com

Permanent Link (DOI) https://doi.org/10.25549/usctheses-c89-353904

Unique identifier UC11663927

Identifier etd-RobersMich-8822.pdf (filename),usctheses-c89-353904 (legacy record id)

Legacy Identifier etd-RobersMich-8822.pdf

Dmrecord 353904

Document Type Thesis

Rights Robers, Michael Vincent

Type texts

Source University of Southern California (contributing entity), University of Southern California Dissertations and Theses (collection)

Access Conditions The author retains rights to his/her dissertation, thesis or other graduate work according to U.S. copyright law. Electronic access is being provided by the USC Libraries in agreement with the a...

Repository Name University of Southern California Digital Library

Repository Location USC Digital Library, University of Southern California, University Park Campus MC 2810, 3434 South Grand Avenue, 2nd Floor, Los Angeles, California 90089-2810, USA