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Comparisons of metabolic factors among gestational diabetes mellitus probands, siblings and cousins

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Comparisons of metabolic factors among gestational diabetes mellitus probands, siblings and cousins

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Content COMPARISONS OF METABOLIC FACTORS AMONG GESTATIONAL
DIABETES MELLITUS PROBANDS, SIBLINGS AND COUSINS
by
li Eun Kang
A Thesis Presented to the
FACULTY OF THE GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
MASTER OF SCIENCE
(APPLIED BIOSTATISTICS AND EPIDEMIOLOGY)
August 2005
Copyright 2005 Ji Eun Kang
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UMI Number: 1435111
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ACKNOWLEDGEMENTS
First, I would like to express my gratitude to my graduate advisor Dr. Xiang
for her guidance, support and generous commitment of time and her thorough insight
that led to cultivate my foundation of the knowledge of this field of study. 1 would
also like to extend my gratitude to Dr. Azen and Dr. Watanabe for their contribution
of time and comments. It has been an unforgettable and honorable experience to
work with this outstanding group of researchers.
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TABLE OF CONTENTS
ACKNOWLEDGEMENTS ii
LIST OF TABLES iv
ABSTRACT v
INTRODUCTION 1
METHODS 2
RESULTS 6
DISCUSSION 15
APPENDIX 19
REFERENCES 25
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Table 1.
Table 2.
Table 3.
Table 4.
Table 5.
Table 6.
iv
LIST OF TABLES
Comparison o f characteristics among probands, and their 19
siblings and cousins (n=273)
Intergroup Pairwise Comparisons of OGTT and IVGTT after 20
adjustment (n=273)
Comparison of characteristics among probands, and their 21
siblings and cousins (females only) (n=167)
Intergroup Pairwise Comparisons of OGTT and IVGTT after 22
adjustment (females only) (n=167)
Comparison of characteristics among probands, and their 23
siblings and cousins (n=123)
Comparison o f characteristics among probands, and their 24
sisters and female cousins excluding whom had ever been
diagnosed as diabetes (n=151)
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V
ABSTRACT
We examined metabolic characteristics in Latino women with gestational
diabetes mellitus (GDM) and their siblings and cousins to predict type 2 diabetes.
Proband group tended to be older, shorter, and obese than their sibling group or
cousin group. This group had higher OGTT glucose concentrations and total AUC
insulin concentrations than the other groups, but they had lower insulin sensitivity,
glucose disappearance rate, acute response to intravenous glucose at basal, and
disposition index. Regardless o f their similarity in demographic characteristics or
strong heritability in their metabolic B-cell activities in phenotypes between
probands and siblings, pairwise comparisons show probands and siblings were
significantly different in their metabolic characteristics, further indicating the
differences observed not solely depend on genetic factors. The present results lend
further credence to the notion that other behavioral risk factors such as physical
activity or dietary factors will further explain the differences among those groups in
developing type 2 diabetes.
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1
INTRODUCTION
According to the National Institute of Child Health & Human Development^,
11, and 12), approximately three to five percent of all pregnant women in the United
States with blood glucose levels are elevated above normal during pregnancy. Risk
factors that influence the incidence/prevalence of gestational diabetes include
increasing maternal age (> 30); maternal obesity (> 90 kg or 200 lbs); a family history
of either Type 1, Type 2, or gestational diabetes; and race/ethnicity (particularly
Latinos, Native Americans, Indians, and southeast Asians) (7). Longitudinal studies
indicate that there are 30-50% of those women with gestational diabetes mellitus
(GDM) will later develop diabetes in their lifetime, making GDM as an important risk
factor for diabetes, especially Type 2. Type 2 diabetes affect approximately 9.1
million or 8.9% of all women in the United States (1). Type 2 diabetes mellitus is
most prevalent among Hispanics (10.6%). Impairment of B-cell function during
pregnancy was reported as predictor of the persistence or development of diabetes
after GDM (4, 13). Previous studies show that women with GDM have multiple
defects in insulin action along with impaired B-cell function than women with normal
pregnancy. Insulin resistance and B-cell defect are closely linked. Chronic insulin
resistance causes or worsens the B-cell defect that characterizes GDM in Hispanics.
Administration of the insulin-sensitizing drug, troglitazone to Latino women with
prior GDM for 2-5 years reduced the diabetes incidence rate by 56% compared to
placebo group (5). A reduction in the secretory demands placed on B-cell by chronic
insulin resistance appeared to be responsible for the protection from diabetes. Thus,
identification of the fundamental causes of B-cell defect will be the key to
understanding and preventing Type 2 diabetes.
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Many mechanisms could explain the susceptibility of B-cells to fail in the
presence of chronic insulin resistance. Preliminary family study showed that both
insulin resistance and B-cell function are heritable in families with GDM proband. To
detail investigating the genetic determinants, a large family study has been initiated to
recruit 250 GDM proband families with detailed phenotype of metabolic
measurements and B-cell function for the GDM proband and their siblings and
cousins. Genome-wide scan and candidate genes approach are the primary methods
that will be used to identify the variants that responsible to B-cell function.
The question as to answer whether the women with GDM are different from
the rest of their family members in their metabolic characteristics has never been
addressed. It is also never been addressed whether the difference between the
probands and the rest of their family members in their metabolic characteristics is
explained genetically or merely by chance alone or other factors such as behavioral or
dietary factors.
The objective of this report is to use current available data from the B-Gene
study to compare metabolic characteristics that are precursors to Type 2 diabetes in
three different groups comprised of GDM probands, their siblings and their cousins.
This study will further determine whether differences in metabolic characteristics
between patients with GDM and their family members could be explained by
differences in the GDM risk profiles or just by chance.
METHOD
Study design
The proband group consisted of Mexican American (both parents and at least
three of four grandparents from Mexico or of Mexican descent) women with age >18
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3
years and GDM in a singleton pregnancy in prior three years. Their fasting plasma
glucose during index pregnancy was >105 mg/dl and their fasting plasma glucose at
time of enrollment <126 mg/dl with negative serum anti-GAD antibodies. To qualify
for the genetic study, probands were required to have a minimum of three siblings or
two siblings with > 2 first cousins who are themselves siblings. The inclusion
criterion for siblings and cousins of the probands was age >18 years with fasting
plasma glucose < 126 mg/dl at time of phenotype. The exclusion criteria for all
subjects were chronic medical illness or medication known to alter glucose or insulin
metabolism, current pregnancy or breastfeeding, elicit drug or alcohol abuse, inability
or unwillingness to give informed consent. All study subjects gave written informed
consent for participation in the study and the study was approved by the Institutional
Review Board of the University of Southern California.
Statistical Analysis
Distributions of all continuous variables were tested for normality. Insulin,
insulin areas, insulin sensitivity, and ratios of insulin to other variables were log-
transformed before statistical analyses, due to skewness on the distribution. For
continuous variables, mean values were compared among the three groups and tested
for significance at 5% level. Statistical analyses were performed using SAS (SAS
Institute, Cary, NC). Means reported for all variables are in units of their original
scales. All p-values are 2-sided.
B-cell insulin release in response to glucose was assessed using incremental
area under the insulin curve during the first 10 min after the glucose injection and the
increase above basal in plasma insulin 30 min after the OGTT glucose ingestion.
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Insulin sensitivity (SI) and acute insulin response to intravenous glucose (AIRg)
were assessed by minimal model analysis (18) using MINMOD program. Disposition
index (DI), the product of insulin sensitivity (SI) and acute insulin response to
intravenous glucose (AIRg) was used to assess B-cell insulin release function in
relation to ambient insulin sensitivity. Total areas under the curves (AUCs) for
OGTT glucose and insulin were calculated by the trapezoid method. Glucose
tolerance status of each subject was determined as defined by the American Diabetes
Association criteria.
Mean values for all variables were compared between groups. Since subjects
from the same family might be correlated, demographic and clinical characteristics
were compared among probands, their siblings and cousins using generalized
estimating equations model (GEEs). OGTT measurements and IVGTT measurements
for each group were compared using generalized estimating equations (GEEs) model,
as well. The analysis strategy was to perform overall test with 2 degree of freedom to
examine whether there were any difference among the proband, siblings and cousins
group followed by pairwise comparison tests to see whether there were any significant
differences between each pair of groups (proband vs. sibling, proband vs. cousin, and
sibling vs. cousin). To ensure correct Type I error, Bonferroni multiple comparison
approach was used, that is, a p-value of less than 0.017(=0.05/3) was called
significant in the pairwise comparisons.
Metabolic measures of OGTT glucose and insulin, IVGTT insulin sensitivity,
acute insulin release and B-cell function were the primary interested outcomes to
compare. As for controlling for statistically significant differences in age, body mass
index (BMI) and percent body fat, the comparisons were further performed with the
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adjustment of age, age + sex, age + sex + BMI, and age + sex + percent body fat
respectively. Since probands were all females, the analyses were then performed
including females only. Same analysis approaches as above were adopted, that is
both unadjusted and adjusted analysis (except adjusting for sex) with pairwise
comparisons. Thirdly, to investigate how proband compared to their siblings and
cousins with the worst glucose tolerance, subjects who rank the highest OGTT
glucose area under the curve in each family in the sibling and cousin groups were
chosen to compare to the proband within the family. Both unadjusted and adjusted
analyses were performed as above with pairwise comparisons.
Lastly, we were interested in how diabetic subjects contributed to the results
of analysis in females since probands were females. Thereafter, only females were
included with females who had been diagnosed to have diabetes were excluded from
the analysis. Descriptive statistics in their demographic characteristics along with
pairwise comparisons in OGTT and IVGTT measurements were provided in the same
way as above.
RESULTS
From current on-going B-Gene study, we identified 273 subjects who have
complete OGTT and IVGTT data available for this report. The 273 study subjects
comprised of 41 families (41(15%) probands, 104(38%) siblings of the probands, and
128(47%) cousins of the probands). The distribution of the siblings was 1 to 5 per
family with median of 2 per family. The distribution of the cousins was 1 to 8 per
family with median of 3 per family. Sibling group consisted of 56 females (54%) and
48 males (46%). Cousin group consisted of 70 females (55%) and 58 males (45%).
General characteristics of proband group, sibling group, and cousin group are
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presented in the table 1. Probands were one year older than their siblings and both
probands and siblings were significantly older than their cousins (p<0.002). Probands
were significantly shorter than the sibling group and cousin group (p<0.0001) and
siblings and cousins had similar height. Probands weighed slightly less than their
siblings and weighed slightly more than their cousins. However, since probands were
generally short, probands tended to have higher BMI than both siblings and cousins
and both probands and siblings had higher BMI than their cousins (p<=0.007). The
proband group had significantly higher percentage of body fat compared to both
sibling group and cousin group (p<0.0001). The sibling group had slightly higher
percentage of body fat than the cousin group but the difference did not approach
statistical significance after multiple comparison adjustment. The proband group
includes 22% of diabetes, 49% of IGT and 29% of normal glucose tolerance. There
were 4% of diabetes, 32% of IGT, and 64% of normal patients in the sibling group.
There were 3% of diabetes, 23% of IGT, and 74% of normal patients in the cousin
group. There were more diabetes and IGTs in the proband group than in their sibling
and cousin group.
OGTTs revealed significantly higher plasma glucose concentrations in
probands at all time points than the other two groups. There were highly significant
differences in plasma glucose concentration at all different time points between
proband group and sibling group (Group 1-2), and between proband group and cousin
group (Group 1-3). There were no significant differences in plasma glucose
concentration at fasting, 30 min, and 2 hr level between siblings and cousins. The
differences in plasma glucose concentrations at 60 min, and 90 min level between
siblings and cousins (p=0.04,0.02, respectively) were not significant after multiple
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comparison adjustment of p-values. Proband group had the highest plasma glucose
AUC among all three groups (20.3±3.1 vs. 17.4±2.9, 16.3±3.4, p=<0.0001). There
were significant differences between probands and siblings, between probands and
cousins, for both total OGTT glucose AUC and incremental glucose AUC (p<0.0001).
The difference between siblings and cousins for total OGTT AUC and incremental
glucose AUC were not statistically significant after multiple comparison adjustment.
For OGTT insulin, in general probands had the highest OGTT plasma insulin
concentrations at all time points except 30 min. At 30 min time point, cousin group
had the highest plasma insulin concentration. At fasting, 90 min and 120 min, the
differences between probands and siblings and between probands and cousins were
statistically significant. Siblings and cousins did not differ significantly at all time
points in plasma insulin concentration. Total OGTT insulin AUC were slightly
higher in the proband group followed by sibling group and cousin group. The mean
of incremental insulin at 30 min after glucose ingestion was the lowest in the proband
group and there were no significant differences among groups (p=0.74).
IVGTT data revealed a significant difference for insulin sensitivity (SI) among
proband, sibling and cousin groups (2.37±1.2 vs. 2.73±1.5, 3.1±1.7, p=0.02).
Probands had the lowest insulin sensitivity followed by sibling and the cousin group
with sibling in-between proband and cousin groups. The difference between proband
and cousin were significant (p=0.01). Probands had lowest glucose disappearance
rate (Sg) than both sibling and cousins (p<0.001) with sibling and cousin had similar
Sg (p=0.22). For acute insulin responses (AIRg), probands tended to have
significantly lower responses than siblings and cousins and sibling and cousin had
similar response (AIRg: 484.6±594.5 vs. 662.7±721.5, 623.5±511.5, p=0.02).
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Disposition index (DI), the product of insulin sensitivity (SI) and acute insulin
response to intravenous glucose (AIRg) were significantly lower in the proband group
than in other groups and sibling and cousin group also had similar values. In general,
the results indicated that probands had significantly lower insulin sensitivity (SI),
glucose disappearance rate (Sg), acute insulin response (AIRg) and disposition index
(DI) than both their siblings and cousins.
Table 2 presents pairwise comparison p-values for OGTT glucose and insulin
and IVGTT measures after adjustments of age, sex, BMI and percent body fat. When
age was adjusted, probands and siblings did not differ in plasma glucose
concentration at fasting point but after adding adjustments for sex, BMI, and fat
percentage it retained its original significance level indicating that they were still
significantly different. There were significant differences between probands and
siblings and between probands and cousins in OGTT glucose concentration at 2 hour
point, in total OGTT glucose AUC and in incremental AUC glucose concentration.
After adjusting for age, there were significant differences in plasma insulin
concentrations at fasting point between proband and sibling group (p=0.0003) and
between proband and cousin group (p=0.0002). After adjusting for age and sex, there
were significant differences in plasma insulin concentrations at fasting point between
proband and sibling group (p=0.03) and between proband and cousin group (p=0.005).
However, after adding adjustment for BMI or fat percentage there were no more
significant differences between probands and siblings and between probands and
cousins in plasma insulin concentrations at fasting point. Similar patterns were
observed for plasma insulin at 2-hour point. Probands and siblings did not
significantly differ in OGTT insulin AUC throughout adjustments. There were no
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significant differences between each group in incremental 30-minute insulin as well.
Thus, adjustment for age, sex, BMI and percent body fat did not make a difference to
OGTT glucose, however, adjustment for BMI and percent body fat abated the
difference for fasting and 2-hour insulin between proband and siblings and between
proband and cousins observed in the unadjusted analysis, suggesting obesity mediated
insulin secretion/clearance.
When age-adjusted, SI did not significantly differ between probands and
siblings but significantly differed between probands and cousins (p=0.17, 0.02,
respectively). After adding other adjustments, there were no significant differences
between probands and siblings and between probands and cousins in SI. Probands
and siblings were significantly different in their AIRg and DI throughout adjustments.
Probands and cousins were also significantly different in their AIRg throughout the
adjustments except when age and sex were adjusted. Both were also significantly
different in their DI throughout adjustments. Sg did not differ significantly between
probands and siblings and between probands and cousins (except when age and age +
sex adjusted). There were no significant differences between siblings and cousins in
the IVGTT measurements after adjustments. Thus, compared to unadjusted analysis,
adjustment of age and sex did not make much difference. However, adjustment of
BMI and percent of body fat reduced the differences in SI and Sg between probands
and siblings and between probands and cousins. No changes were observed after
adjustments for AIRg and DI.
Table 3 describes general characteristics of data including only females which
is comprised of 41 probands, 56 siblings, and 70 cousins. Again, probands tended to
be one year older than their sisters and four years older than female cousins, although
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statistically not significant with the reduced sample size (p=0.24). Cousins tended
to be taller than probands and siblings (p=0.01). Probands and siblings were similar
in their weight but both groups tended to be more obese than cousin group. Three
groups significantly differed in the mean of BMI and fat percentage (p=0.02, and
0.0004, respectively). BMIs in the proband group tended to be higher than those of
sibling or cousin group. Between probands and siblings (Group 1-2), there were no
significant differences in all demographic variables, indicating that these two groups
were similar in demographic characteristics. Between probands and cousins (Group
1-3), there were significant differences in all demographic variables. Siblings and
cousins (Group 2-3) were significantly different in their weight, BMI, and fat
percentage (p=0.03, 0.01, and <0.0001, respectively) but not significantly different in
their age, height. 25% of women in the sibling group and 13% of women in the
cousin group had experienced pregnancy, compared to 100% in the proband group.
Additionally, 6% in the sibling group and 10% in the cousin group had a history of
GDM compared to 100% in the proband group.
Overall, OGTT measurements revealed significantly higher plasma glucose
concentrations in women with GDM at all time points than women in the other two
groups, where there were no significant differences between siblings and cousin group.
This result was similar to the results using all subjects with the inclusion of males
[Table 1]. The mean of plasma insulin concentrations for females only were slightly
higher than the corresponding values when all subjects included for sibling and cousin
groups [Table 1]. Similarly OGTT insulin measurements were not statistically
different among the three groups except 90 and 120 minutes. At 90 min and 120 min
level, there were significant differences between probands and female cousins
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(p=0.0007, 0.0005, respectively) and between sisters and female cousins of GDM
women (p=0.002, 0.005, respectively), whereas there were no significant differences
between probands and their sisters. The mean of incremental 30-minute insulin did
not statistically differ across three groups (p=0.61), although probands had the lowest
mean.
IVGTT data revealed similarity in SI between proband and their sisters and
both group had lower SI than their female cousins. (SI: 2.37±1.2 vs. 2.37+1.36,
2.92±1.44). Probands had lower AIRg than their sisters and female cousins (AIRg:
484.6±594.5 vs. 781.8±901.2, 645.9+586.5). There was significant difference
between probands and their sisters (p=<0.0001) in AIRg. The mean of Sg was
significantly lower in the proband group (Sg: 1.37±0.34 vs. 1.53+0.5,1.75+0.7,
p=0.04). Probands and their female cousins were significantly different in their
glucose disappearance rate (p=0.007), however probands and sisters (Group 1 -2), and
sisters and female cousins (Group 2-3) were not significantly different in it. DI was
significantly lower in the GDM women (833.03±591.9 vs. 1388.3±835.5,
1532.3±929.3). DI significantly differed between probands and their sisters
(p=<0.0001) and between probands and their female cousins (p=0.0001). Compared
to Table I where all subjects included, females only revealed similar conclusion, that
is, probands were more insulin resistant and had less in acute insulin secretion and
they had lower DI than their sisters and female cousins.
Table 4 shows intergroup pairwise comparisons in OGTTs and IVGTTs after
adjustments of age, BMI and percent fat for females only. Compared to Table 3,
generally we see that the differences in OGTT glucoses between proband and sisters,
between proband and female cousins remained even after adjustment for age, BMI
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and percent body fat. Between proband and female cousins, insulin did generally
not differ after adjustment except 2-hour insulin. Differences in AIRg between
proband and sisters, in DI between proband and sisters and between proband and
female cousins remained to be significant even after all the adjustments
Table 5 presents characteristics of subjects who ranked the highest AUC for
OGTT glucose tolerance test in each family in each group. Since there were 41
families in each group, equally 41 subjects from each group were selected for this
analysis. Due to reduced sample size, attentions were paid to actual mean values
rather than p-values. Probands tended to be one year older than siblings and two
years older than cousins. Probands tended to be significantly shorter than siblings and
cousins (p=<0.0001). The mean of body fat composition of probands was the highest
(39.6±5.6 vs. 32.7±10.3, 31.2±9.9, p=<0.0001). The gender distribution in this
selected sample was similar to all subjects (46% female in sibling group and 54% in
cousin group). There were 5% of diabetes, 46% of IGT, and 49% of normal subjects
in the sibling group (compared to 4% of diabetes, 32% of IGT, and 64% of normal
subjects in the all subject sibling group). There were 10% of diabetes, 36% of IGT,
and 54% of normal subjects in the cousin group (compared to 3% of diabetes, 23% of
IGT, and 74% of normal subjects in the all subject cousin group). Thus, as one
expected, more diabetic and IGT subjects were selected from the sibling and cousin
group. Even though all of the subjects ranked the highest OGTT measurements
within their family sibling and cousin group, probands were still shorter, more obese
and OGTT diabetes than the highest risk siblings and cousins.
OGTT measurements revealed no significant differences in plasma glucose
concentrations in women with GDM at all time points except 90 min and 2 hr time
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point. Probands and siblings differed significantly in plasma glucose concentration
at 90 min and 2-hr time point (p=0.001,0.002, respectively), and probands and
cousins also differed significantly (p=0.01, 0.01, respectively). Total area under the
curve for OGTT glucose showed no significant difference in this data (p=0.07).
Incremental AUC glucose concentration level tended to be significantly higher in the
probands than siblings and cousins (8.5±2.4 vs. 7.5±2.2, 6.9±3.0, p=0.016). The
three groups did not differ significantly in plasma insulin concentration at all time
points but at 120 min point. There were no significant differences between probands
and siblings and between siblings and cousins at 120 min point, however there was a
significant difference between probands and cousins (p=0.0008). Incremental 30-
minute insulin did not significantly differ among the three groups (p=0.55).
Compared to Table 1 all subjects analysis, we see that the significance of differences
in both OGTT glucose and insulin diminished in their mean in this selected sample
among the three groups.
Overall, all IVGTT data did not show significant difference among the three
groups with the smaller sample size. However, probands tended to have the lowest SI,
Sg, AIRg and DI among all three groups. Sibling and cousin groups were similar for
all IVGTT measurements. Compared to Table 1, this selected high risk sibling and
cousin group had slightly reduced SI, AIRg and DI. The pairwise comparisons after
adjustments showed same results as above, thereafter it is not meaningful to include
here.
Table 6 provides information after excluding those who have diabetes from
the data including only females. Similar to Table 3, proband and sisters had similar
height and obesity and both of them were shorter and more obese than their female
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cousins. 30% and 13% were pregnant in the sister and female cousin groups with
5% and 7% had GDM history respectively. There were still more IGTs in the
probands than their sisters and female cousins. Plasma glucose concentration at each
level and total glucose and incremental glucose AUC differ significantly among the
groups. There were significant differences between probands and siblings and
between probands and cousins at all time points. Different from Table 3 where
sibling and cousins were not different when all females were included, sibling and
cousin group when diabetes were excluded differed significantly for all glucose
except for fasting and 30 min time point. OGTT insulin results were similar as in
Table 3, that is, three groups significantly differed in plasma insulin concentration at
90 min and 120 min (p=0.001, both). All the results for IVGTT comparisons were
also similar to the results in Table 3 when all females were included. In another
words, GDM proband without diabetes were slightly more insulin resistance, had less
acute insulin secretion (AIRg) and less disposition index (DI) than their non-diabetic
sisters and female cousins
DISCUSSION
Overall, the results presented here show that in this population there were
significant differences among probands, siblings and cousins in their demographic
and metabolic characteristics. Probands tended to be older, shorter, and obese than
their siblings and cousins. They tended to have higher OGTT glucose concentrations
and slightly higher insulin concentrations. They tended to have lower insulin
sensitivity, lower glucose disappearance rate, lower acute response to intravenous
glucose at basal, and lower disposition index indicating their poor B-cell function.
Analysis limited to females only, females without diabetes drew similar conclusions.
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Adjustment for differences in age, gender and obesity did not change the results
either. Analysis limited to sibling and cousin with the highest OGTT glucose AUC
within family group reduced the differences, however, trend of GDM proband the
highest glucose and insulin, the lowest insulin sensitivity, acute insulin release and B-
cell function remained. These findings are consistent with the concept that GDM
probands have chronic insulin resistance with poor B-cell function which will place
them at an increased risk of developing diabetes.
Since proband consisted female only, it is logical to restrict the data analysis to
females only. The means of BMI and fat percentage of sibling group and cousin
group using female data were higher than those using all subject data. Compared to
all-subject data analysis, the means of OGTT insulin measurements at all time points
were higher in sisters and female cousins. Sisters and female cousins had lower SI
and AIRg than all siblings and all cousins. It is evident that male subjects contributed
to the change in the means. In fact, normal male subjects included in sibling group
and cousin group counts about half of all normal subjects, implying that the male
subjects included were healthier than female subjects included.
Compared to female data analysis, the means of OGTT glucose measurements
were lower in the females with no diabetes. Their BMI and fat percentage tended to
be lower. The means of OGTT insulin measurements were lower in the females with
no diabetes. The means of SI, Sg, AIRg and DI were lower in all female probands
[Table 6]. It is evident that female subjects who had diabetes influenced in the
magnitudes of the OGTT and IVGTT measurements. Nonetheless, overall we
observed similarity in both data analyses in that the proband group was significantly
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different from the sibling or cousin group in their metabolic characteristics
although they seemed to have similarity in their demographic characteristics [Table 3
and 6].
Compared to all siblings and cousins, siblings and cousins who had the worst
glucose tolerance had generally higher OGTT measurements at each time point.
These siblings and cousins were more insulin resistance than all siblings and cousins
and they had slower glucose disappearance rate. These siblings were more acute in
insulin secretion whereas these cousins were less acute in insulin secretion. However,
DI in these siblings and cousins were lower than all siblings and cousins. Although
there were no significant differences among groups in this data due to smaller sample
size, probands were significantly different from their siblings in AIRg and DI same as
in the all subject analysis. Clearly these high risk subjects were similar in their
demographic and metabolic characteristics; nevertheless probands were more insulin
resistance, slower in glucose disappearance rate, less acute in insulin response to
glucose and thus had the lowest DI indicating that they were still on the highest risk of
all three groups.
Previous studies have indicated at least 30-50% of women who have high
glucose tolerance during routine glucose tolerance testing for gestational diabetes
mellitus (GDM) during pregnancy will develop diabetes compared to those who have
normal glucose tolerance (1-6). It is widely understood that gestational diabetes
mellitus (GDM) is a significant risk factor for type 2 diabetes. However, there were
no studies that examined the differences in their metabolic characteristics as important
precursors to type 2 diabetes comparing GDM patients to their family members. This
study has strength in that it was the first relatively large-scale assessment of glucose
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
17
tolerance, insulin sensitivity, pancreatic beta-cell function, and body composition
for not only women with prior GDM but also their siblings and cousins. Not only
substantiating previous findings on risk factors such as older age, shorter height,
higher BMI, and higher body fat composition, we studied pancreatic B-cell functions
as precursors of type 2 diabetes in GDM patients and their family members.
There are some limitations to this analysis that should be addressed. Probands
include only females by definition. It may seem to be not correspondent to compare
this group to their siblings and cousins where males were included in the sibling and
cousin groups. However, this study is focused virtually on GDM group where only
women can have GDM. It can be considered rather a different perspective than a
weakness. To assess this drawback, in any case, we compared GDM probands to
their sisters and female cousins only. The results were consistent with the original
analysis with all subjects suggesting both results can be applied to the general
population.
After adjusting for age, sex, BMI, fat percentage to control for significant
differences in those variables among the groups, the results decreased significance
level due to less degree of testing null hypothesis with less power to detect errors by
adding more adjusting terms. Even though adjusted analysis resulted in less
significance level, the magnitude of the results did not change much and the results
indicated that there were significant differences between groups [Table 2, 4].
Previous studies indicated strong heritability for measures of B-cell activities
in phenotypes of probands and siblings (15,16). However, in all three analyses in this
study, both crude and adjusted results indicated that there were significant differences
between probands and siblings. Probands and siblings share more in genetic
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
18
components than probands and first degree cousins do, nonetheless our results here
revealed that probands and siblings were much more different than probands and
cousins in their metabolic characteristics, further indicating the differences observed
not solely depend on genetic factors. In another words, this study suggests behavioral
or dietary factors to the cause of the B-cell defects unexplained in this data alone.
The findings here highlight the need as to study why GDM probands differ
significantly in developing type 2 diabetes from their siblings and cousins which will
be explained by studying other factors such as physical behavior or dietaiy behavior
of subjects. Such data is under collection currently and will be used to for further
analysis when available.
Since probands have more pregnancy history and previous GDM history than
their sisters and female cousins, one may suspect the history of pregnancy or history
of GDM may explain the differences observed. Our next interesting analysis will be
to limit to women who have been pregnant or have prior history of GDM only and
assess whether female obstetrical history such as number of pregnancy can explain the
differences. However, we only have 17 sisters and 9 female cousins who had
pregnancy history and 3 sisters and 5 female cousins had prior GDM, the sample sizes
are too small to allow for any meaningful comparisons. Preliminary adjusted analysis
to adjust for pregnancy status (yes/no) and GDM status did not reveal any change
(data not shown). Detailed obstetrical history data is under collection and will be
used to for further analysis when available.
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
19
Table 1
Comparison of characteristics anions probanda* and their siblings and cousins for ail subjects1
1
1
1
Proband(l)
n=41
Sibling(2)
n=104
Cousin(3)
n=128
overall
p-values
1 vs. 2
pairwise
1 vs. 3
2 vs. 3
age (year) 36.1 (6.2) 35.1 (9.34) 31.7(9.02) 0.002 0.13 0.002 0.02
height 156.2 (5.9) 163.3 (9.3) 164.5 (9.3) <0.0001 <0.0001 <0.0001 0.39
weight 80.6(18.2) 82.9(21.0) 75.8 (20.4) 0.025 0.28 0.09 0.003
BMI 33.04 (7.2) 30.9 (6.6) 28.7 (6.7) 0.0007 0.03 0.001 0.007
fet (%) 39.6 (5.6) 33.2 (9.6) 30.3 (9.04) <0.0001 <0.0001 <0.0001 0.025
female 41(100) 56(53.9) 70(54.7)
male 0(0) 48(46.1) 58(45.3)
OGTT
DM 9(21.9) 4(3.9) 4(3.1)
IGT 20(48.8) 33(31.7) 29(22.7)
Normal 12(29.3) 67(64.4) 95(74.2)
Glucose
fasting 98.7(11.5) 94.3 (8.6) 93.1 (10.1) 0.006 0.02 0.004 0.26
30-minute 159.7(21.4) 149.4 (26.4) 145.8 (25.6) 0.01 0.008 0.001 0.3
60-minute 194.4 (29.8) 164.9 (33.8) 152.9 (40.8) <0.0001 <0.0001 <0.0001 0.04
90-minute 190.3 (37.9) 151.6(33.6) 136.8 (41.5) <0.0001 <0.0001 <0.0001 0.02
120-minute 168.2 (41.1) 132.0 (33.5) 123.3 (37.5) <0.0001 <0.0001 <0.0001 0.17
totalAUC2 20.3 (3.1) 17.4(2.9) 16.3 (3.4) <0.0001 <0.0001 <0.0001 0.03
incAUC3 8.5 (2.4) 6.05 (2.4) 5.14(2.9) <0.0001 <0.0001 <0.0001 0.04
Insulin
fasting 12.4 (8.3) 9.28 (7.23) 8.8 (7.2) 0.004 0.0004 0.0002 0.31
30-minute 76.7(61.03) 74.14(48.7) 77.6 (48.2) 0.88 0.79 0.89 0.63
60-minute 106.9 (79.4) 97.3 (88.8) 83.4 (54.5) 0.16 0.37 0.08 0.16
90-minute 112.5(72.3) 89.9 (72.7) 73.9 (53.8) 0.0004 0.003 0.0001 0.04
120-minute 107.04(74.4) 78.3 (66.2) 63.7 (53.5) 0.0002 0.002 <0.0001 0.08
totalAUC 10672 (6787) 8799 (5246) 8134(4848) 0.049 0.09 0.03 0.28
30dINS4 64.3 (46.4) 65.2 (45.1) 68.8 (44.7) 0.74 0.91 0.63 0.64
IVGTT
SI 2.37(1.23) 2.73(1.50) 3.06(1.73) 0.024 0.16 0.01 0.11
Sg*100 1.37(0.34) 1.65 (0.62) 1.78 (0.73) 0.02 0.001 <0.0001 0.22
Airg 484.6 (594.5) 662.7(721.5) 624(511.5) 0.02 0.004 0.03 0.72
DI(SI*Airg) 833(592) 1434 (902) 1561 (993) <0.0001 <0.0001 <0.0001 0.54
1 Data are means - SD or n(%)
2 Total AUC denotes area under OGTT curves in millimoles per liter x minute
3 incAUC denotes incremental AUC
4 30dINS denotes 30-minute incremental insulin response from the OGTT
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
Reproduced w ith permission o f th e copyright owner. Further reproduction prohibited without permission.
Table 2
Intergroup Pairwise Comparisons of OGTT and IVGTi after adjustment for all subjects1
adjusted for
pairwise comparisons
age. sex
pairwise comparisons
OGTT 1 vs. 2 1 vs. 3 2 vs. 3 1 vs. 2 1 vs. 3 2 vs. 3 1 vs. 2 1 vs. 3 2 vs. 3 1 vs. 2 1 vs. 3 2 vs. 3
Glucose
fasting 0.25 0.01 0.61 0.008 0.004 0.65 0,007 0.017 0.62 0.01 0.04 0.57
2-hour <0.0001 <0.0001 0.4 <0.0001 <0.0001 0.38 <0.0001 0.0001 0.65 <0.0001 <0.0001 0.84
totAUC2 <0.0001 <0.0001 0.11 <0.0001 <0.0001 0.12 <0.0001 <0.0001 0.19 <0.0001 <0.0001 0.28
incAUC3 <0.0001 <0.0001 0.09 <0.0001 <0.0001 0.09 <0.0001 <0.0001 0.11 <0.0001 <0.0001 0.15
Insulin
fasting 0.0003 0.0002 0.27 0.03 0.005 0.26 0.07 0.13 0.98 0.034 0.095 0.69
2-hour 0.002 <0.0001 0.09 0.17 0.005 0.074 0.27 0.03 0.13 0.27 0.05 0.29
totAUC4 0.082 0.02 0.19 0.45 0.09 0.17 0.61 0.28 0.33 0.42 0.25 0.52
30dINS5 0.97 0.85 0.85 0.52 0.67 0.82 0.39 0.39 0.86 0.57 0.48 0.81
IVGTT
SI 0.17 0.02 0.12 0.07 0.11 0.12 0.88 0.76 0.47 0.78 0.64 0.74
Sg*100 0.01 0.001 0.65 0.08 0.03 0.63 0.09 0.097 0.87 0.08 0.09 0.89
Airg <0.0001 <0.0001 <0.0001 0.002 0.47 0.36 0.002 0.026 0.56 0.006 0.03 0.71
DI(SI*Airg) <0.0001 <0.0001 0.97 0.0002 0.004 0.97 0.0001 0.001 0.58 0.0002 0.002 0.59
age, sex.
BUI
pairwise comparisons
age, sex.
Mm
pairwise comparisons
1 data values given in p-values
2 totAUC denotes area under OGTT glucose curves in millimoles per liter x minute
3 incAUC denotes incremental AUC
4 totAUC denotes area under OGTT insulin curves in millimoles per liter x minute O
5 30dINS denotes 30-minute incremental insulin response from the OGTT
21
Table 3
Comparison of characteristics among probands, and their siblings and cousins for females only1
Demographic
Proband(l)
n=41
Sibling(2)
n=56
Consin(3)
n=70
overall
p-values
lv & 2
nairwise
1 vs. 3 2 vs. 3
age (year) 36.1 (6.2) 35.1(9.9) 32.1 (10.3) 0.05 0.24 0.01 0.11
height 156.2 (5.9) 156.9(6.1) 159.7(6.8) 0.01 0.24 0.01 0.15
weight 80.6 (18.2) 79.1(19.4) 72.5(22.2) 0.07 0.92 0.03 0.03
BMI 33.04(7.2) 31.9(6.7) 29.1(8.2) 0.02 0.49 0.01 0.01
fat (%) 39.6 (5.6) 39.9 (5.5) 35.8(7.1) 0.0004 0.54 0.005 <0.0001
pregnancy 41(100) 17(25.3) 9(13.4)
GDM 41(100) 3(6.1) 5(10.2)
OGTT
DM 9(21.9) 3(5.4) 4(5.7)
IGT 20(48.8) 18(32.1) 16(22.9)
Normal 12(29.3) 35(62.5) 50(71.4)
Glucose
fasting 98.7(11.5) 92.5 (8.5) 92.4(11.2) 0.005 0.002 0.006 0.99
30-minute 159.7(21.4) 142.4 (20.8) 142.6 (24.7) 0.0002 <0.0001 0.0002 0.69
60-minute 194.4 (29.8) 161.3(29.6) 149.3 (43.9) <0.0001 <0.0001 <0.0001 0.07
90-minute 190.3 (37.9) 152.5(31.7) 136.9(45.3) <0.0001 <0.0001 <0.0001 0.45
120-minute 168.2(41.1) 134.5(29.5) 127.1 (42.3) <0.0001 <0.0001 <0.0001 0.29
totalAUC2 20.3(3.1) 17.1(2.7) 16.2 (3.9) 0.15 <0.0001 <0.0001 0.15
incAUC5 8.5 (2.4) 6.0 (2.1) 5.1 (3.1) <0.0001 <0.0001 <0.0001 0.09
Insulin
Fasting 12.4 (8.3) 10.8 (8.7) 10.0 (8.5) 0.08 0.09 0.005 0.31
30-minute 76.7(61.03) 81.4(50.8) 82.9 (53.5) 0.82 0.39 0.53 0.95
60-minute 106.9 (79.4) 114.8(110.5) 85.6 (52.9) 0.1 0.62 0.11 0.02
90-minute 112.5 (72.3) 109.9(87.2) 77.6 (53.9) 0.001 0.58 0.0007 0.002
120-minute 107.04(74.4) 97.1(77.8) 68.9 (52.7) 0.0007 0.46 0.0005 0.005
totalAUC 10672 (6787) 10161(5978) 8569(5058) 0.12 0.82 0.07 0.08
30dINS4 64.3 (46.4) 71.2(46.1) 72.9 (49.3) 0.61 0.32 0.31 0.89
IVGTT
SI 2.37(1.23) 2.37(1.36) 2.92(1.44) 0.02 0.72 0.02 0.011
Sg*100 1.37(0.34) 1.53 (0.48) 1.75 (0.7) 0.04 0.13 0.007 0.19
Airg 484.6 (594.5) 781.8(901.2) 645.9(586.5) 0.007 <0.0001 0.05 0.16
DI(SI*Airg) 833 (592) 1388(835) 1532(929) 0.0001 <0.0001 0.0001 0.54
1 Data are means ± SD or n(%)
2 Total AUC denotes area under OGTT curves in millimoles per liter x minute
3 incAUC denotes incremental AUC
4 30dINS denotes 30-minute incremental insulin response from the OGTT
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
Reproduced w ith permission o f th e copyright owner. Further reproduction prohibited without permission.
Table 4
Intergroup Pairwise Comparisons of OGTT and IVGTT after adjustment for females only (n=167)’
adjusted for
OGTT
age
pairwise comparisons
1 vs. 2 1 vs. 3 2 vs. 3
0.003 0.01
< 0.0001 < 0.0001
< 0.0001 < 0.0001
< 0.0001 < 0.0001
0.06
0.43
0.75
0.43
0.003
0.0007
0.05
0.72
0.02
0.02
0.14
<0.0001 0.0008
< 0.0001
0.76
0.5
0.27
0.15
0.23
0.004
0.05
0.76
0.01
0.34
0.09
0.87
aee. BMl
pairwise comparisons
1 vs. 2 1 vs. 3 2 vs. 3
0.001
< 0.0001
0.07
0.54
0.94
0.34
0.51
0.19
<0.0001
< 0.0001
0.08
0.0005
<0.0001 <0.0001
< 0.0001 < 0.0001
0.07
0.002
0.12
0,55
0.31
0.08
0.14
0.007
0.22
0.84
0.47
0.2
0.79
0.003
0.06
0.92
0.06
0.42
0.11
0.64
age. fat(%)
pairwise comparisons
1 vs. 2 1 vs. 3 2 vs. 3
0.001
<0.0001
0.18
0.0007
< 0.0001 < 0.0001
< 0.0001 < 0.0001
0.03
0.43
0.72
0.43
0.89
0.13
0.0003
< 0.0001
0.09
0.006
0.11
0.64
0.29
0.11
0.16
0.009
0.06
0.68
0.95
0.52
0.67
0.05
0.15
0.86
0.22
0.78
0.13
0.47
' data values given in p-values
2 totAUC denotes area under OGTT glucose curves in millimoles per liter x minute
3 incAUC denotes incremental AUC
4 totAUC denotes area under OGTT insulin curves in millimoles per liter x minute
3 30dINS denotes 30-minute incremental insulin response from the OGTT
to
to
23
Table 5
Comparison of characteristics among probands, and their siblings and cousins for who had the highest OGTT
glucose AUC1 ___________________________________________
Demographic
Proband(l)
n=41
Sibling(2)
n=41
Cousin(3)
n=41
overall
p-values
1 vs. 2
pairwise
1 vs, ? 2 vs. 3
age (year) 36.1 (6.2) 35.3 (9.3) 34.0 (9.6) 0.55 0.43 0.19 0.48
height 156.2 (5.9) 164.3 (8.9) 164.6(10.4) <0.0001 <0.0001 <0.0001 0.88
weight 80.6 (18.2) 85.8(21.2) 77.7 (24.2) 0.25 0.09 0.52 0.08
BMI 33.04 (7.2) 31.7(6.9) 30.0 (7.5) 0.17 0.21 0.09 0.32
fat (%) 39.6 (5.6) 32.7(10.3) 31.2(9.9) <0.0001 <0.0001 <0.0001 0.5
female 41(100) 19(46.3) 22(53.7)
male 0(0) 22(53.7) 19(46.3)
OGTT
DM 9(21.9) 2(4.9) 4(9.8)
IGT 20(48.8) 19(46.3) 15(36.6)
Normal 12(29.3) 20(48.8) 22(53.7)
Glucose
fasting 98.7(11.5) 98.2 (9.1) 98.6 (13.6) 0.99 0.8 0.97 0.86
30-minute 159.7(21.4) 165.4 (26.3) 158.7 (26.3) 0.41 0.24 0.84 0.23
60-minute 194.4 (29.8) 188.1 (31.0) 180.0(42.8) 0.17 0.31 0.11 0.32
90-minute 190.3 (37.9) 168.5 (35.3) 164.4 (49.3) 0.01 0.001 0.013 0.67
120-minute 168.2(41.1) 145.9 (32.6) 192.5(48.0) 0.009 0.002 0.01 0.71
totalAUC2 20.3 (3.1) 19.3 (2.7) 18.7 (3.9) 0.074 0.06 0.05 0.39
incAUC3 8.5 (2.4) 7.5 (2.2) 6.9 (3.0) 0.016 0.03 0.02 0.25
Insulin
fasting 12.4 (8.3) 11.3(9.1) 10.8 (7.9) 0.37 0.15 0.17 0.79
30-minute 76.7 (61.03) 81.6 (51.0) 71.4 (33.4) 0.86 0.69 0.99 0.62
60-minute 106.9 (79.4) 118.1 (121.7) 92.9(59.1) 0.61 0.73 0.54 0.39
90-minute 112.5(72.3) 114.7(94.5) 88.1(60.9) 0.12 0.61 0.08 0.19
120-minute 107.04(74.4) 98,9 (83.7) 71.6 (50.6) 0.02 0.39 0.008 0.12
totalAUC 10672(6787) 10211(5807) 8807(4707) 0.45 0.83 0.31 0.35
30dINS* 64.3 (46.4) 71.1 (46.8) 60.7(32.3) 0.55 0.49 0.73 0.23
IVGTT
SI 2.37(1.23) 2.57(1.6) 3.02(1.7) 0.202 0.73 0.15 0.27
Sg*100 1.37(0.34) 1.55(0.56) 1.6(0.72) 0.68 0.27 0.32 0.99
Airg 484.6 (594) 681.0(987) 529.6(426) 0.27 0.04 0.52 0.38
DI(SI*Airg) 833.0(591.9) 1282.5(957.6) 1199.3(837.7) 0.49 0.008 0.08 0.57
1 Data are means ± SD or n(%)
2 Total AUC denotes area under OGTT curves in millimoles per liter x minute
3 incAUC denotes incremental AUC
4 30dINS denotes 30-minute incremental insulin response from the OGTT
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
24
Table 6
Comparison of characteristics among probands, and their siblings and cousins for females without diabetes1
Demographh
Proband(l)
n=32
Sibling(2)
n=53
Cousin(3)
n=66
overall
p-values
1 vs. 2
pairwise
1 vs. 3 2 vs. 3
age (year) 36.7(6.4) 34.5(9.7) 31.4(10.1) 0.02 0.1 0.002 0.08
height 156.6(5.5) 156.9(6.1) 160.1(6.7) 0.008 0.19 0.006 0.12
weight 78.7(17.1) 79.1(19.7) 72.5(22.1) 0.15 0.65 0.09 0.04
BMI 32.1(6.7) 31.9(6.8) 28.7(8.2) 0.03 0.99 0.02 0.005
fat (%) 38.7(5.4) 39.7(5.4) 35.5(7.1) 0.0007 0.16 0.01 <0.0001
OGTT
IGT
Normal
20(48.8)
12(29.3)
18(32.1)
35(62.5)
16(22.9)
50(71.4)
Glucose
fasting 96.3(9.9) 91.6(6.8) 90.7(8.3) 0.006 0.01 0.01 0.52
30-minute 155.5(20.4) 141.2(19.8) 139.8(21.9) 0.002 0.0001 0.0001 0.89
60-minute 187.5(26.1) 158.9(27.9) 143.5(37.9) <0.0001 <0.0001 <0.0001 0.007
90-minute 176.7(27.7) 149.2(28.9) 129.6(34.6) <0.0001 <0.0001 <0.0001 0.0009
120-minute 151.3(25.7) 130.9(26.0) 119.8(29.2) <0.0001 <0.0001 <0.0001 0.02
totalAUC2 19.3(2.4) 16.8(2.4) 15.5(2.9) <0.0001 <0.0001 <0.0001 0.009
incAUC3 7.8(19) 5.8(2.1) 4.7(2.7) <0.0001 <0.0001 <0.0001 0.009
Insulin
fasting 11.5(6.6) 10.6(8.6) 9.5(8.1) 0.11 0.2 0.004 0.25
30-minute 81.5(53.3) 82.7(51.9) 85.3(54.1) 0.9 0.74 0.59 0.8
60-minute 114.3(81.6) 116.4(113.2) 86.7(53.9) 0.08 0.91 0.05 0.03
90-minute 116.5(70.1) 110.7(89.3) 77.5(54.7) 0.001 0.39 0.0004 0.003
120-minute 106.7(71.5) 96.5(79.5) 68.3(53.6) 0.001 0.39 0.0008 0.007
totalAUC 11141(6784) 10222(6104) 8650(5145) 0.1 0.52 0.04 0.12
30dINS4 70.0(48.9) 72.7(47.0) 75.8(49.3) 0.82 0.67 0.41 0.71
IVGTT
SI 2.3(1.1) 2.4(1.4) 2.8(1.4) 0.03 0.74 0.04 0.02
Sg*100 1.4(0.37) 1.6(0.49) 1.8(0.7) 0.04 0.22 0.005 0.09
Airg 568.6(642) 818.1(913) 682.8(584) 0.05 0.0007 0.08 0.13
DI(SI*Airg) 958.2(589.2) 1445(821) 1622(877) 0.0004 0.0003 0.0001 0.23
1 Data are means ± SD or n(%)
2 Total AUC denotes area under OGTT curves in millimoles per liter x minute
3 incAUC denotes incremental AUC
4 30dINS denotes 30-minute incremental insulin response from the OGTT
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
25
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Asset Metadata

Creator Kang, Ji Eun (author)

Core Title Comparisons of metabolic factors among gestational diabetes mellitus probands, siblings and cousins

School Graduate School

Degree Master of Science

Degree Program Applied Biostatistics and Epidemiology

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

Tag biology, biostatistics,health sciences, pathology,OAI-PMH Harvest

Language English

Contributor Digitized by ProQuest (provenance)

Advisor Xiang, Dr. (committee chair), Azen, Stanley (committee member), Watanabe, Richard M. (committee member)

Permanent Link (DOI) https://doi.org/10.25549/usctheses-c16-50202

Unique identifier UC11338020

Identifier 1435111.pdf (filename),usctheses-c16-50202 (legacy record id)

Legacy Identifier 1435111.pdf

Dmrecord 50202

Document Type Thesis

Rights Kang, Ji Eun

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 au...

Repository Name University of Southern California Digital Library

Repository Location USC Digital Library, University of Southern California, University Park Campus, Los Angeles, California 90089, USA