Cardiometabolic Risk and Obesity in Adolescents With Down Syndrome
Conditions: Down Syndrome, Trisomy 21
Sponsor: Children's Hospital of Philadelphia

 
10/8/2018 
Title: 
Cardiometabolic risk and obesity in adolescents with Down syndrome 
Short Title: Cardio risk factors in DS youth – Aim 1 
 
Sponsor: National Institutes of Health  
eIRB Number: 12-009233 
 
Protocol Date: July 9, 2012 
 
Amendment 1 Date: November 20, 
2012 
Amendment 4 Date: April 11, 2013 
Amendment 2 Date: November 29, 
2012 
Amendment 5 Date: July 1, 2013 
Amendment 3 Date: 2/14/2013 
Amendment 6 Date: April 14, 2014 
Amendment 7 Date: August 18, 2014 
Amendment 8 Date: August 31, 2015 
Amendment 44 Date: February 22, 
2017 
Amendment 45, May 23, 2017 
Amendment 46 Date: June 21st, 2017 
 
 
Site Principal Investigator 
Andrea Kelly, MD, MSCE  
The Children’s Hospital of Philadelphia 
11 NW 30 Main Building 
Philadelphia, PA, 19104 
Phone 215-590-1663 
email: kellya@email.chop.edu 
 

 
  
 
 
 
 
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TABLE OF CONTENTS 
Table of Contents ................................................................................................................... ii 
Abbreviations and Definitions of Terms............................................................................. iv 
Abstract ................................................................................................................................. vi 
Protocol Synopsis ................................................................................................................ viii 
Table 1: Schedule of Study Procedures ............................................................................. xii 
Figure 1: Study Diagram- Sample (exact procedure order may vary)................... xiv 
1 
BACKGROUND INFORMATION AND RATIONALE ....................................................................... 1 
1.1 
INTRODUCTION ..................................................................................................................................... 1 
1.2 
COMPLIANCE STATEMENT .................................................................................................................... 2 
2 
STUDY OBJECTIVES .............................................................................................................................. 2 
2.1 
PRIMARY AIM 1 .................................................................................................................................... 2 
2.2 
SECONDARY AIM.................................................................................................................................. 3 
3 
INVESTIGATIONAL PLAN .................................................................................................................... 3 
3.1 
GENERAL SCHEMA OF STUDY DESIGN ................................................................................................. 3 
3.2 
TOTAL NUMBER OF STUDY SITES/TOTAL NUMBER OF SUBJECTS PROJECTED ...................................... 3 
3.2.1 
Duration of Study Participation ...................................................................................................... 3 
3.2.2 
Total Number of Study Sites/Total Number of Subjects Projected .................................................. 3 
3.3 
STUDY POPULATION ............................................................................................................................. 4 
3.3.1 
Inclusion Criteria ............................................................................................................................ 4 
3.3.2 
Inclusion Criteria ............................................................................................................................ 4 
3.3.3 
Exclusion Criteria ........................................................................................................................... 4 
4 
STUDY PROCEDURES ............................................................................................................................ 5 
4.1 
STUDY VISIT ........................................................................................................................................ 5 
4.1.1 
Visit 1 .............................................................................................................................................. 5 
4.2 
FOLLOW-UP PHASE ............................................................................................................................... 7 
4.3 
SUBJECT COMPLETION/WITHDRAWAL ................................................................................................. 8 
5 
STUDY EVALUATIONS AND MEASUREMENTS .............................................................................. 8 
5.1SCREENING AND MONITORING EVALUATIONS AND MEASUREMENTS .......................................................... 8 
5.1.1 
Physical Examination ...................................................................................................................... 8 
5.1.2 
Vital Signs ....................................................................................................................................... 8 
5.1.3 
Laboratory Evaluations................................................................................................................... 8 
5.1.8 
Safety Evaluation .......................................................................................................................... 10 
6   STATISTICAL CONSIDERATIONS ........................................................................................................ 11 
6.1 DATA ANALYSIS ........................................................................................................................................ 11 
6.2    SAMPLE SIZE AND STATISTICAL POWER .................................................................................................. 12 
6.3   POTENTIAL PROBLEMS/FEASIBILITY ........................................................................................................ 13 
7 
SAFETY MANAGEMENT ..................................................................................................................... 13 
7.1 
CLINICAL ADVERSE EVENTS .............................................................................................................. 13 
7.2 
ADVERSE EVENT REPORTING ............................................................................................................. 13 
7.3 
MEDICAL EMERGENCIES (IF APPLICABLE) .......................................................................................... 14 
8 
STUDY ADMINISTRATION ................................................................................................................. 14 
8.1 
DATA COLLECTION AND MANAGEMENT ............................................................................................ 14 
8.2 
CONFIDENTIALITY .............................................................................................................................. 15 
8.3 
REGULATORY AND ETHICAL CONSIDERATIONS.................................................................................. 15 

 
  
 
 
 
 
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8.3.1 
Data and Safety Monitoring Plan ................................................................................................. 15 
8.3.2 
Incidental Findings ....................................................................................................................... 15 
8.3.3 
Risk Assessment ............................................................................................................................. 16 
8.3.4 
Potential Benefits of Study Participation ...................................................................................... 18 
8.3.5 
Risk-Benefit Assessment ................................................................................................................ 18 
8.4 
RECRUITMENT STRATEGY .................................................................................................................. 18 
8.5 
INFORMED CONSENT/ASSENT AND HIPAA AUTHORIZATION ............................................................ 19 
8.5.1 
Consent for Down syndrome subjects 18 – 20 years of age .......................................................... 19 
8.5.2 
Assent Procedures ......................................................................................................................... 20 
8.6 
PAYMENT TO SUBJECTS/FAMILIES ..................................................................................................... 21 
9 
PUBLICATION ........................................................................................................................................ 21 
10 
REFERENCES ......................................................................................................................................... 21 
 
 

 
  
 
 
 
 
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ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
 
AAP 
 
American Academy of Pediatrics 
ABAS-II 
 
Adaptive behavior assessment system-Second edition 
parent form 
AE 
 
Adverse events 
AH 
BES 
 
Abdominal height 
Body Esteem Scale for Children 
BF 
 
Body fat 
BG 
 
Blood glucose 
BP 
 
Blood pressure 
CEBQ 
 
Child eating behavior questionnaire 
CHOP 
 
The Children’s Hospital of Philadelphia 
CMR 
 
Cardiometabolic risk 
CNMC 
 
Children’s National Medical Center 
CPP 
 
Central pulse pressure 
CRP 
 
C-reactive protein 
CTRC 
 
Clinical and Translational Research Center 
DS 
 
Down syndrome 
DXA 
 
Dual energy x-ray absorptiometry 
EMR 
FRS 
 
Electronic medical record 
Stunkard Figure Rating Scale 
HbA1c   
 
Hemoglobin A1c 
HDL-C 
 
High-density lipoprotein cholesterol 
HFI 
 
Home food inventory 
HOMA-IR 
 
Homeostasis model assessment – insulin resistance 
HRQOL 
 
Health-related quality of life 
Hs-CRP 
 
High-sensitivity C-reactive protein 
IL-6 
 
Interleukin-6 
ISI 
 
Insulin sensitivity index 
IWQOL-Kids 
 
Impact of weight on quality of life-Kids 
LDL-C 
 
Low-density lipoprotein cholesterol 
LV 
 
Left ventricular 
MCV 
 
Mean corpuscular volume 
NMR 
 
Nuclear magnetic resonance 
OGTT 
 
Oral glucose tolerance test 

 
  
 
 
 
 
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PAI 1 
 
Plasminogen Activator Inhibitor 
PDAY 
 
Pathological Determinants of Atherosclerosis in Youth 
PedsQL 
 
Pediatric Quality of Life Inventory 
PeRC 
 
Pediatric Research Consortium 
PHI 
 
Protected Health Information 
PWA 
 
Pulse wave analysis 
PWV 
 
Pulse wave velocity 
QOL 
 
Quality of life 
RCT 
 
Randomized controlled trial 
REE 
 
Resting energy expenditure 
REC 
SD 
 
Research Enhancement Core 
Standard deviation 
T1DM 
 
Type 1 diabetes 
TC 
 
Total cholesterol 
TG 
 
Triglycerides 
VLDL-C 
 
Very low-density lipoprotein cholesterol 
WC 
 
Waist circumference 
WHR 
 
Waist hip ratio 
 
 
 
 
 
 

 
  
 
 
 
 
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ABSTRACT 
 
Context:  
Down syndrome affects 1 per 800 births and is one of the most common causes of 
developmental disability in the US. Life expectancy for Down syndrome has increased 
significantly: estimated median survival in the US in 1997 was 49 years. Down syndrome is 
associated with an increased risk for obesity, with an estimated prevalence of 47-48% in 
adults and 30-50% in children with Down syndrome. Adolescents with Down syndrome are 
more likely to have increased adiposity compared to unaffected peers and may be at 
increased risk for obesity-related co-morbidities, such as type 2 diabetes and cardiovascular 
disease. How one defines obesity in DS is not clear.  Individuals with DS have short stature 
and possibly increased adiposity, and the body mass index (BMI) used to define obesity for 
otherwise healthy populations may not accurately depict body fatness or capture 
cardiometabolic risk in DS. 
 
Objectives:  
Primary: To compare the relationship between BMI-Z score and cardiometabolic risk 
(CMR) factors in youth with DS, and in age-, sex-, race-, ethnicity- and BMI-Z score- 
matched controls.  
Secondary: To examine the relationship between obesity, lifestyle (physical activity, 
nutrition), body image, and quality of life in DS, and to explore barriers to maintaining a 
healthy weight in children with DS. 
Study Design:  
Observational cohort study 
Setting/Participants: 
The Children’s Hospital of Philadelphia Clinical and Translational Research Center and 
Children’s National Medical Center. 
A total of 260 evaluable male and female subjects ages 10-20 years of any race or ethnic 
background will be recruited: 155 subjects with DS (with and without significant CHD) and 
105 non-DS controls, matched for age, sex, race, ethnicity, and BMI-Z. Approximately 600 
subjects will need to be screened in order to achieve this number of evaluable subjects.  
Study Measures:  
Anthropometrics (height, weight, BMI), DXA derived measures (lean body mass, fat mass),  
blood glucose, plasma insulin, oral glucose tolerance tests (glucose tolerance, insulin 
sensitivity index, insulin resistance (HOMA-IR)),  HbA1c, lipids, non-HDL cholesterol, 
lipoprotein subclass analysis, hs-CRP, IL-6, PAI 1, ,  adiponectin, leptin, TSH & T4, blood 

 
  
 
 
 
 
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pressure, pulse wave velocity, pulse wave analysis, left ventricular mass, quality of life, 
physical activity, body image, nutrition.

 
  
 
 
 
 
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PROTOCOL SYNOPSIS 
Study Title 
Cardiometabolic risk and obesity in adolescents with Down syndrome 
Funder 
National Institutes of Health (NIH) 
Study Rationale 
 
DS is associated with an increased risk for obesity. Adolescents with DS are 
more likely to have increased adiposity compared to unaffected peers and may 
be at increased risk for obesity-related co-morbidities, such as type 2 diabetes 
(T2DM) and cardiovascular disease (CVD). Congenital heart disease (CHD) 
affects approximately 50% of individuals with DS; the NHLBI Working Group 
on Obesity and Other Cardio-vascular Risk Factors in Congenital Heart Disease 
highlighted the high prevalence of obesity in the setting of CHD, and called for 
studies to identify obesity measures that are more sensitive than BMI as well as 
studies of CVD risk prevention. Unfortunately, clinicians caring for obese 
adolescents with DS with or without CHD have little scientific evidence upon 
which to base guidance regarding cardiometabolic risk (CMR): data regarding 
CVD risk and prevalence of pre-diabetes and T2DM in obese adolescents with 
DS are lacking.  
The measure of body fatness which best predicts CMR in DS is not known. We 
plan to compare BMI and other measures of body fatness in healthy controls 
and adolescents with DS to determine which measures best capture CVD and/or 
T2DM risk.  These data will equip medical providers with the tools to better 
assess risk, initiate prevention measures, and guide screening in adolescents 
with DS.  
Study Objective(s) 
Part 1: 
 
 
Primary  
To compare the relationship between BMI-Z score and 
cardiometabolic risk factors in youth with DS, and in age-, sex-, 
race-, ethnicity-, and BMI-Z score-matched controls. 
a) Compare cardiometabolic risk factors [non-HDL cholesterol, 
lipoprotein subclass particles, blood pressure, insulin resistance 
(measured by HOMA-IR), insulin sensitivity index (ISI), glucose 
tolerance, inflammatory markers, and adipokines)] in adolescents with 
DS and in matched controls.  
b) Determine the extent to which adiposity (fat mass by DXA) explains 
this relationship in DS vs. controls.  
c) Assess cardiac end organ injury (pulse wave velocity (PWV) and left 
ventricular mass) in relationship to BMI-Z score in adolescents with DS 
and controls. Determine whether BMI-Z or other measures of adiposity 
(skin-fold thickness, waist circumference) better discriminates 
adolescents with DS at increased cardiometabolic risk. 
Hypothesis: DS is associated with worse cardiometabolic risk factors for 
a given BMI-Z compared to controls. This difference arises at least in 
part, from increased adiposity. 

 
  
 
 
 
 
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 Secondary 
To examine the relationship between obesity, lifestyle (physical 
activity, nutrition), body image, and quality of life in DS, and to 
explore barriers to maintaining a healthy weight in children with 
DS.  
a) Compare the relationships between BMI-Z, and body image and 
quality of life in adolescents with DS with those of matched controls. 
b) Identify DS-specific barriers (i.e., nutrition, behavioral issues, body 
image, feeding behaviors, parental-and self-imposed activity restrictions) 
to maintaining a healthy lifestyle. 
Hypothesis: Obesity negatively impacts body image and quality of 
life in adolescents with DS. 
Obesity is associated with less physical activity. 
Psychological, behavioral, physical conditions unique to DS impede 
maintenance of healthy lifestyle and weight. 
 
Study Design 
 
This is cross sectional study of two groups of adolescents:  healthy 
controls and subjects with DS. 
Subject Population 
key criteria for 
Inclusion and 
Exclusion: 
Inclusion Criteria 
Control Group 
1. Males and females age 10 – 20 years 
2. Parental/guardian permission (informed consent) and if 
appropriate, child assent 
Down Syndrome Group 
1. Male and females age 10 – 20 years 
2. Diagnosis of Down syndrome  
3. Parental/guardian permission (informed consent) and if 
appropriate, child assent 
Exclusion Criteria (Both Groups) 
1. Major organ system illness (such as leukemia, for DS), except for 
T2DM 
2. Cyanotic congenital heart disease and/or pulmonary hypertension 
(as described by most recent echo report in subjects with CHD) 
3. Medically unstable congenital heart disease  
4. Pregnancy 
5. Genetic syndrome known to affect glucose tolerance 
6. Familial hypercholesterolemia  
7. Currently treated with medications known to affect insulin 
sensitivity other than diabetes agents in known T2DM subjects 
(e.g. oral glucocorticoids or high-dose inhaled steroids(>1000 

 
  
 
 
 
 
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mcg/day) in the last month) or lipid profiles (statins, high dose 
vitamin A), or atypical antipsychotics 
Number Of 
Subjects  
 
Total Number of Subjects Overall and at CHOP: Total n = 260. 155 with 
DS and 105 controls. At CHOP: Total n = 210 (130 with DS and 80 
controls).  
Total Number of Study Sites: Two – The Children’s Hospital of 
Philadelphia and Children’s National Medical Center 
Study Duration 
Each subject’s participation will last approximately 7-8 hours for those 
with BMI ≥ 85%ile for age and sex (undergoing OGTT), and 5-6 hours 
for those with BMI <85%ile; physical activity will be determined over 7 
days in the home setting; Three twenty-four hour dietary recall 
interviews of parents and children will be conducted research 
bionutritionists by telephone. 
 
Study Phases 
 
   
Screening & Recruitment: Potential participants (DS group and control 
group) will be identified through the ambulatory electronic medical 
record (EMR) and primary care clinics.  DS subjects may also be 
recruited from Endocrinology, Trisomy 21 and Cardiology clinics, DS 
community events, the DS Growing Up Study and local advertisements. 
Control subjects may also be identified through local advertisement. 
After potential subjects are identified, parents/guardians will be 
contacted to screen for eligibility. Eligible, willing subjects will be 
scheduled for a morning study visit after a 12 hour overnight fast. 
Phase 1: Parental/guardian permission and child assent (if applicable) 
will be obtained prior to any study related procedures being performed. 
Subjects will undergo the following: physical exam/pubertal assessment, 
anthropometric measurements, vital sign assessment, fasting blood draw, 
2-hour oral glucose tolerance test (OGTT), Pulse wave velocity (PWV) 
and Pulse Wave Analysis (PWA), echocardiography. 
Subjects and their parent/guardian will complete the following 
questionnaires: The Pediatric QOL inventory (PedsQLTM), Stunkard 
Figure Rating Scale (FRS), Body Esteem Scale for Children (BES), 
Adolescent Sedentary Activity Questionnaire (ASAQ), Child Eating 
Behavior Questionnaire (CEBQ), Child Feeding Questionnaire (CFQ),  
Adaptive Behavior Assessment System-Second Edition (ABAS-II) 
Parent Form, the Home Food Inventory (HFI), and family history of 
cardiometabolic conditions. Dietary history will be obtained by three 
twenty-four hour dietary recall interviews will be performed over the 
telephone. 
Physical activity will be assessed by accelerometry using SenseWear® 
Armbands.  Armbands are worn for 7 consecutive days.  
  
Efficacy 
N/A  in Aim 1  

 
  
 
 
 
 
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Evaluations 
Pharmacokinetic 
Evaluations 
N/A 
Safety Evaluations 
Adverse events are not anticipated. Any AEs and SAEs will be reported 
to the CTRC and the IRB within the allotted timeframe. 
Statistical And 
Analytic Plan 
. 
Data Analysis: Descriptive data analysis will summarize distributions of 
all risk factor measures Subjects with DS will be compared to age-, sex-, 
race-, and BMI-Z matched controls, first by comparison of risk factor 
distributions by DS status. Next, separate regression models will be fit 
for each risk factor, with DS as the exposure of interest, adjusted for 
potential confounders.  
 
DATA AND SAFETY 
MONITORING PLAN 
 
The study team will be responsible for data management and collection 
and are responsible for the accuracy and completeness. Only 
investigators and study team members that have completed appropriate 
IRB training/approval are eligible to collect and work on information 
collected from this study. Data will be entered into REDCap. Using 
REDCap checking tools, the data manager will confirm completeness 
and valid values weekly and inform any errors or omissions to the 
investigative team for prompt resolution. Original data will be recorded 
directly onto Case Report Forms (CRF) by the study team. All CRFs will 
be locked in a file cabinet in a locked office.  In order to guard against 
disclosure of protected health information, each study participant will be 
assigned a unique 4 digit identification code. The code will be kept in a 
locked cabinet in the PI and/or study coordinator’s office.   
 

 
  
 
 
 
 
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 TABLE 1: SCHEDULE OF STUDY PROCEDURES  
Study Phase 
Screening 
Visit Number 
 
1 
 
Study Days 
 
1 
 
Verbal Consent 
X 
 
Will be done prior to screening 
Review Inclusion/Exclusion 
Criteria 
X 
 
 
HFI  
X 
 
Will be done at home, following screening 
but before study visit 
Informed Consent/Assent 
 
X 
 
Demographics/Medical History 
 
X 
 
Physical Examination 
 
X 
 
Vital Signs: BP, HR, RR 
 
X 
 
Height and Weight 
 
X 
 
Pregnancy Test (If applicable) 
 
X 
 
Fasting Blood Glucose & Insulin 
Levels 
 
X 
 
Fasting Lipid Panel: TG, TC, 
HDL-C, LDL-C  
 
X 
 
Lipoprotein subclass analysis 
 
X 
 
OGTT (only in subjects with 
BMI≥85%ile, not known to have 
diabetes) 
 
X 
 
HbA1c 
 
X 
 
Hs-CRP 
 
X 
 
PAI 1 
 
X 
 
Adiponectin (total and HMW)& 
Leptin 
 
X 
 
TSH & T4  
 
X 
 
PWV & PWA 
 
X 
 
DXA 
 
X 
 
Echocardiography 
 
X 
 
Pubertal status 
 
X 
 
Smoking status 
 
X 
 
Family history of CVD, 
dyslipidemia, T2DM 
 
X 
 
Physical activity  
 
X 
Worn for 7 days after study visit 
Body image 
questionnaires:(PedsQL, 
IWQOL-Kids, IWQOL-Parents, 
CEBQ, CFQ, ABAS-II, FRS, 
ASAQ, BES, Body satisfaction 
scales, Physical activity/armband 
diary) 
 
X 
Physical activity/armband diary will be 
completed at home after study visit. All 
other questionnaires will be completed 
during the study visit. 
Dietary Intake (24 hour dietary 
 
 
X X X 

 
  
 
 
 
 
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recall done 3 times) 

 
  
 
 
 
 
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FIGURE 1: STUDY DIAGRAM- Sample (exact procedure order may vary) 
 
 

 
  
 
 
 
 
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1 
BACKGROUND INFORMATION AND RATIONALE 
1.1 Introduction 
Understanding the role of obesity and body composition in cardiometabolic (CMR) factors in 
Down syndrome (DS). DS affects 1 per 800 births12 and is one of the most common causes of 
developmental disability in the U.S. Life expectancy for DS has increased significantly; 
estimated median survival in the US was 49 years in 199713. DS is associated with an increased 
risk for obesity14, with an estimated prevalence of 47-48%15 in adults and 30-50%16 in children 
with DS. Concurrent with the physiologic increase in insulin resistance that accompanies 
puberty, adolescents with DS are more likely to have increased adiposity compared to 
unaffected peers, and may be at increased risk for obesity-related comorbidities, such as type 2 
diabetes (T2DM)17 and cardiovascular disease (CVD). Moreover, congenital heart disease 
(CHD) affects approximately 50% of individuals with DS5; the NHLBI Working Group on 
Obesity and Other Cardio-vascular Risk Factors in Congenital Heart Disease highlighted the 
high prevalence of obesity in the setting of CHD, and called for studies to identify obesity 
measures that are more sensitive than BMI as well as studies of CVD risk prevention.6 
Unfortunately, clinicians caring for obese adolescents with DS with or without CHD have little 
scientific evidence upon which to base guidance regarding CMR: data regarding CVD risk and 
prevalence of pre-diabetes and T2DM in obese adolescents with DS are lacking.  
 
In 1977, DS was proposed to be an atheroma-free model; atheroma was completely absent at 
autopsy in five institutionalized adults with DS, while atheroma was present in institutionalized 
adults without DS18. Individuals with DS were hypothesized to be protected from 
atherosclerotic disease. Subsequent studies both supported19, 20, and contradicted21, 22 this 
conclusion. Group differences in lipid profiles were not found in the original study, but others 
identified a more atherosclerotic lipid profile in DS 23-26. Recently, after excluding deaths 
caused by CHD, three large cohort studies reported increased mortality due to CVD in DS 27-29. 
Hill et al28 found a standardized mortality ratio of 6.2 for cardiovascular deaths, with a ratio of 
3.9 for ischemic heart disease specifically. Mortality due to diabetes mellitus is also increased, 
with a standardized mortality ratio of 11.4 28, however T1DM and T2DM were not 
differentiated. These data suggest increased CVD risk in DS, but the relative contributions of 
obesity versus factor(s) intrinsic to DS have yet to be delineated. Increased life expectancy in 
DS demands that we better understand obesity, characterize CMR, and identify the best 
screening measures for this risk, with the goal of minimizing health disparities for this at-risk 
population. This study will examine the association of obesity with CMR in DS during 
adolescence, a critical period marked by pubertal insulin resistance and transition to potential 
independence. Our study has direct implications for daily medical care of individuals with DS. 
The marker which best predicts CMR in DS is not known. We plan to evaluate which measure 
of adiposity best captures CVD and/or T2DM risk in DS to equip medical providers with the 
tools to better assess risk, initiate prevention measures, and guide screening in adolescents with 
DS. 
Understanding the relationship of obesity to body image, QOL, and physical activity, and 
explore barriers to healthy weight in adolescents with DS. Childhood obesity may contribute to 
significant psychosocial complications30. In general, obese children report poorer QOL.31 
Children and adults with DS have low levels of physical activity 32, 33. Children with CHD also 

 
 
 
 
 
 
 
 
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tend to be less physically active than peers34, 35, and self-concept may limit engagement in 
physical activity; 36 thus, a cycle of poor self-esteem may feed physical inactivity and obesity. 
Among children with DS, factors such as competing family responsibilities, reduced skills; and 
paucity of accessible programs likely contribute to low physical activity37. Body image, QOL, 
and physical activity in relation to BMI have not been explored in adolescents with DS. 
Cognitive and physical complications of DS, as well as parental perceptions, can make 
traditional community-based weight loss programs difficult to access and utilize effectively. 
Identification of barriers to obesity prevention and management is crucial if effective programs 
are to be developed. This study will explore body image, QOL, physical activity patterns, 
eating behaviors, and parental perception of activity risk and tolerance in adolescents with DS, 
both with and without CHD. 
Thus, we will characterize the relationship between obesity and CMR in DS, fill a critical 
knowledge gap regarding CVD and T2DM risk, and clarify screening measures for these risks. 
We will also explore psychosocial implications of increased weight and barriers to healthy 
weight in adolescents with DS, to establish the foundation for future studies addressing these 
important aspects of obesity prevention and treatment. 
1.2 Compliance Statement 
This study will be conducted in full accordance with all applicable Children’s Hospital of 
Philadelphia and Children’s National Medical Center Research Policies and Procedures and all 
applicable Federal and state laws and regulations including 45 CFR 46. All episodes of 
noncompliance will be documented. 
The investigators will perform the study in accordance with this protocol, will obtain consent 
and assent, and will report unanticipated problems involving risks to subjects or others in 
accordance with The Children’s Hospital of Philadelphia and Children’s National Medical 
Center IRB Policies and Procedures and all federal requirements. Collection, recording, and 
reporting of data will be accurate and will ensure the privacy, health, and welfare of research 
subjects during and after the study. 
2 
STUDY OBJECTIVES 
This study will examine the association of BMI and body composition as measured by DXA 
with CMR in adolescents with DS. 
2.1 Primary Aim 1  
The primary objective is to compare the relationship between BMI-Z score and 
cardiometabolic risk factors in youth with DS, and in age-, sex-, race-, ethnicity- and BMI-Z 
score- matched controls.  
a) Compare cardiometabolic risk factors [non-HDL cholesterol, lipoprotein subclass particles, 
blood pressure, insulin resistance (measured by HOMA-IR), insulin sensitivity index (ISI), 
glucose tolerance, inflammatory markers, and adipokines)] in adolescents with DS and in 
matched controls. 
b) Determine the extent to which adiposity (fat mass by DXA) explains this relationship in DS 
vs. controls. 

 
 
 
 
 
 
 
 
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3
c) Assess cardiac end organ injury (pulse wave velocity (PWV) and left ventricular mass) in 
relationship to BMI-Z score in adolescents with DS and controls. Determine whether BMI-Z or 
other measures of adiposity (skin-fold thickness, waist circumference) better discriminates 
adolescents with DS at increased cardiometabolic risk.  
2.2 Secondary Aim  
The secondary objective is to examine the relationship between obesity, lifestyle (physical 
activity, nutrition), body image, and quality of life in DS, and to explore barriers to maintaining 
a healthy weight in children with DS.  
a) Compare the relationships between BMI-Z, and body image and quality of life in 
adolescents with DS with those of matched controls. 
b) Identify DS-specific barriers (i.e., nutrition, behavioral issues, body image, feeding 
behaviors, parental and self-imposed activity restrictions) to maintaining a healthy lifestyle. 
3 
INVESTIGATIONAL PLAN 
3.1 General Schema of Study Design 
This observational  cross-sectional study will involve one study visit for all groups. All 
participants will be consented before any procedures. During the study visit both groups will 
receive: urine pregnancy test (for female subjects), fasting blood sample, OGTT (if BMI≥85% 
percentile), DXA scan, anthropometric measurements, pubertal status exam, PWV and PWA, 
echocardiography, family history of CVD/dyslipidemia/T2DM,  QOL, body image, eating 
behaviors and other questionnaires. Three twenty-four hour dietary recall interviews of parents 
and children will be conducted by research bionutritionists by telephone, using the multi-pass 
method.  Accelerometers will be distributed for home use. 
 
3.2 Total Number of Study Sites/Total Number of Subjects Projected 
3.2.1 Duration of Study Participation 
The study duration for both the DS and control group will be approximately 5-8 hours for the 
1-day visit. The dietary intake phone interview will be approximately 30 minutes each time, 
totaling approximately 1.5 hours. SenseWear armbands will be worn in the home environment 
for seven consecutive days. 
3.2.2 Total Number of Study Sites/Total Number of Subjects Projected 
The study will be conducted at 2 investigative sites in the United States: The CTRC at CHOP 
and the CSR at CNMC. 
Recruitment will stop when approximately 260 evaluable subjects are enrolled (155 DS 
subjects and 105 control subjects). It is expected that CHOP will enroll 130 subjects and 
CNMC will enroll 25 subjects into the Down syndrome group, and that CHOP will enroll 80 
subjects and CNMC will enroll 25 subjects into the control group. Approximately 600 subjects 

 
 
 
 
 
 
 
 
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overall (450 at CHOP and 150 at CNMC) will be screened, or “enrolled,” to produce 260 
evaluable subjects.  
3.3 Study Population 
3.3.1 Inclusion Criteria  
The study plans to recruit approximately equal numbers of females and males, and is open to 
participants regardless of their race or ethnic background. We will not restrict enrollment based 
on gender, race or ethnicity, and will actively recruit members of minority groups. We 
anticipate that the sample will be predominantly Caucasian and African American with smaller 
numbers of Hispanic and Asian minority groups since these are not well-represented in the 
CHOP and CNMC catchment areas.. We anticipate recruiting a number of participants who 
self-identify as mixed race. Very few families of American Indian/Alaska Native and Native 
Hawaiian or Other Pacific Islander groups reside in the Philadelphia area and are not likely to 
be represented in this study. 
In the event that a non-English speaking participant wishes to enroll in the study, we will use 
the Hospital Interpreter Services to locate an interpreter that can assist the study and the family 
to achieve this goal. 
3.3.2 Inclusion Criteria 
DS Group 
1) Males and females age 10 to 20 years.   
2) Diagnosis of DS  
3) Parental/guardian permission (informed consent) and if appropriate, child assent 
Control Group 
1) Males and females age 10 to 20 years 
2) Parental/guardian permission (informed consent) and if appropriate, child assent 
3.3.3 Exclusion Criteria 
Both DS and Control Group 
1) Major organ system illness (such as leukemia, for DS) except T2DM 
2) Cyanotic congenital heart disease pulmonary hypertension (as described by last echo report 
in subjects with CHD), or congenital heart disease considered medically unstable by the 
study cardiologists 
3) Pregnancy  
4) Genetic syndrome known to affect glucose tolerance 
5) Familial hypercholesterolemia 

 
 
 
 
 
 
 
 
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5
6) Currently treated with medications known to affect insulin sensitivity other than diabetes 
agents in known T2DM subjects (e.g. oral glucocorticoids or high-dose inhaled steroids 
(>1000mcg/day) in the last month) or lipid profiles (statins, high dose vitamin A), or 
atypical antipsychotics 
Subjects that do not meet all of the enrollment criteria may not be enrolled. Any violations of 
these criteria must be reported in accordance with IRB Policies and Procedures.  
4 
STUDY PROCEDURES 
4.1 Study Visit 
 Informed Consent: 30 minutes/as long as needed for parent/guardian/participant to fully 
comprehend the study involvement 
 Fasting blood draw: 15 minutes 
 Pubertal Status Exam: 5 minutes 
 OGTT (Only done in subjects with BMI ≥85%ile, not known to have diabetes): 2 hours 
 Vital Signs: 10 minutes 
 DXA scan: 10 minutes 
 Anthropometric measurements: 15 minutes 
 PWV and PWA: 30 minutes 
 Echocardiography: 45 minutes 
 Family history of CVD, dyslipidemia, T2DM: 10 minutes 
 QOL, body image, and other questionnaires: 1 hour 
 
4.1.1 Visit 1 
 Fasting Blood Sample: Will be completed by nursing staff. A total of approximately 
12.5 mL (approximately 2½ teaspoons) of blood will be obtained from all participants. 
Subjects who do not undergo OGTT will be allowed to eat after the fasting blood 
sample. 
 
 OGTT: A 2 hour OGTT will be done only in subjects with BMI≥85%tile, not known to 
have diabetes. A total of approximately 7.5 mL (1½ teaspoons) of blood will be 
obtained. The OGTT will be performed by nursing staff. A blood drawing IV will be 
placed.  Baseline BG and insulin will be obtained. Subjects will ingest glucose solution 
(1.75 g/kg; maximum of 75 g) over 2 minutes. BG and insulin will be draw at 30, 60, 
90, and 120 minutes via a blood drawing IV. For subjects refusing a blood drawing IV, 
BG and insulin will be drawn fasting and at 120 minutes. If a subject refuses the OGTT, 
only fasting labs will be obtained. Subjects who undergo OGTT will be allowed to eat 
after the OGTT is completed. 
 
 Anthropometric Measurements: Performed by trained research anthropometrists, in 
order to assess body composition. 
 

 
 
 
 
 
 
 
 
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6
 DXA Scan: The scan measures body composition and will be conducted and analyzed 
by trained staff. 
 Pubertal Status: Tanner staging of puberty will be performed by a pediatric 
endocrinologist team member. This exam will take place in a private exam room. 
 
 
Pulse Wave Velocity (PWV) and Pulse Wave Analysis (PWA): The PWV and PWA 
will be performed by a trained technician123 
 
 Echocardiography: Left ventricular mass will be measured by a trained sonographer and 
analyzed by the study cardiologist. 
 
 Family History of CVD, Dyslipidemia, T2DM: The study coordinator or appropriate 
member of the investigative team will administer a CRF to collect relevant patient 
medical history, family history of CVD/dyslipidemia/T2DM, sedentary and physical 
activity for each participant. Each question will be verbally communicated to the 
parent/participant, and the team member will show the questions as they are read, as 
appropriate. 
 
 Questionnaire Assessment: The following questionnaires (PedsQL, IWQOL, BES, 
FRS, ASAQ, CEBQ, CFQ, ABAS-II, Body Satisfaction Scales) will be administered by 
the study coordinator or appropriate member of the investigative team. Each 
questionnaire will be verbally communicated to the parent/participant, and the team 
member will show the questions as they are read, as appropriate. The HFI and physical 
activity/armband diary will be self-administered at home. 
 
 PedsQL - The Pediatric Quality of Life Inventory uses a modular approach 
to measuring health related QOL in healthy children, adolescents, and those 
with acute and chronic health conditions. Scales include: 1) physical 
functioning, 2) emotional functioning, 3) social functioning, and 4) school 
functioning, which yield summary scores of a total scale score, a 
psychosocial health summary score, and the physical health summary score. 
 IWQOL-Kids - The Impact of Weight on Quality of Life – Kids (IWQOL-
Kids) © is a validated self-report measure of weight-related quality of life 
for youth ages 11-19. This condition-specific QOL assessment is a 27 item 
questionnaire that yields a total score and 4 domain scores, including 
physical comfort, body esteem, social life, and family relations. It has been 
used in children, adolescents, and in special populations. 
 IWQOL-Kids – Parent Form - The Impact of Weight on Quality of Life 
Kids – Parent Form (IWQOL-Parents) is a measure of the parent perception 
of weight-related quality of life. This condition-specific QOL assessment is 
a 27 item questionnaire that yields a total score and 4 domain scores, 
including physical comfort, body esteem, social life, and family relations. 
 BES – the Body Esteem Scale for Children is a 20-item, yes/no 
questionnaire designed to assess children’s attitudes and feelings about their 
body and appearance.  

 
 
 
 
 
 
 
 
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 FRS  – The Stunkard Figure Rating Scale depicts 9 male and 9 female 
figures, ranging in size from very thin to very overweight. It is used to 
assess perceptions of current and ideal body size.  
 ASAQ -   The Adolescent Sedentary Activity Questionnaire is a reliable 
assessment of a comprehensive range of sedentary behaviors that occur in 
school-aged young people. In this measure, the parent will estimate the 
amount of time spent engaging in various sedentary activities during each 
day of a typical school week and weekend. 
 CEBQ – The Child Eating Behavior Questionnaire157 is a reliable and valid, 
35 item questionnaire measuring appetite and eating style (satiety 
responsiveness, food enjoyment, food responsiveness, slowness in eating, 
food fussiness, desire to drink, emotional over-eating and emotional under-
eating). 
 CFQ – The Child Feeding Questionnaire measures parental feeding 
practices, assessing parental beliefs, attitudes, and practices regarding child 
feeding. It is designed for parents of children in the age range of 2-11 years 
of age. 
 ABAS-II – The Adaptive Behavior Assessment System-Second Edition is 
widely used to evaluate individuals with intellectual and developmental 
disabilities measuring daily living skills (what people actually do, or can do, 
without the assistance of others). It assesses adaptive behavior in individuals 
5-21 years of age. 
 Body Satisfaction Scales – The body satisfaction scales measure the level of 
satisfaction with body size, shape and weight. 
 HFI – The Home Food Inventory is a valid assessment of the home food 
environment. Families will be mailed the HFI prior to the study appointment 
and will be asked to bring the completed survey to the study appointment. 
 Physical activity/armband diary – Participants will be asked to keep a record 
of the times that they did not wear the physical activity armband and of their 
activities on the days that they wore the armband. The diary packet will be 
sent home with each participant, along with a postage-paid envelope to 
return the diary.  
 
 SenseWear® Armbands (Body Media, Inc.). Participants will be asked to wear armband 
accelerometers for 7 days, 24 hours per day, for 1 week with the exception of when they 
are bathing/showering or if participating in water activities, such as swimming. 
Information collected will include amount and intensity of physical activities, sedentary 
activities, and sleep. There are no direct benefits to participants of this assessment, but 
the data gleaned from these assessments will provide valuable information about the 
lifestyle habits of children and adolescents with Down syndrome. 
 
4.2 Follow-up Phase   
Dietary Intake Assessment: The twenty-four hour dietary recall will be completed by the 
research bionutritionists in the two to three weeks following the study visit. Three phone calls 

 
 
 
 
 
 
 
 
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(to gather information on two weekdays, one weekday) will be averaged to complete a single 
report. 
 
4.3 Subject Completion/Withdrawal 
Subjects may withdraw from the study at any time without prejudice to their care.  They may 
also be discontinued from the study at the discretion of the investigators for lack of adherence 
to study treatment or visit schedules, AEs, and/or pregnancy.  The investigators may also 
withdraw subjects who violate the study plan, or to protect the subject for reasons of safety or 
for administrative reasons.  It will be documented whether or not each subject completes the 
clinical study. If the Investigators become aware of any serious, related adverse events after the 
subject completes or withdraws from the study, they will be recorded in the source documents 
and on the CRF. 
5 
  STUDY EVALUATIONS AND MEASUREMENTS 
5.1Screening and Monitoring Evaluations and Measurements 
5.1.1 Physical Examination 
Evaluations obtained during the study visit include Tanner staging of puberty by a pediatric 
endocrinologist.  
5.1.2 Vital Signs 
Vital signs will be recorded while the subject is sitting down by the nursing staff. BP will be 
measured by auscultation three times, after a five minute rest in a quiet area with the subject in 
a seated position; the average of the 2nd and 3rd measurements will be used. 
5.1.3 Laboratory Evaluations 
A fasting blood sample will be performed for the following laboratory evaluations. For those 
individuals undergoing the OGTT, this will be done with insertion of the intravenous (IV) line 
before glucose has been ingested. For individuals not requiring an OGTT, the fasting blood 
samples will be obtained by a routine needle stick. When necessary, commercial kits for the 
individual lab tests will be purchased by the investigators. Blood sampling will be performed 
for the following laboratory evaluations. 
1. Lipid panel (TG, TC, HDL-C, LDL-C) 
2. Lipoprotein subclass analysis 
3. Blood glucose (BG) 
4. Plasma insulin 
5. High sensitivity C-reactive protein (hs-CRP)  
6. Interleukin 6 (IL-6)  

 
 
 
 
 
 
 
 
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7. Plasminogen Activator Inhibitor 1 (PAI 1) 
8. Adiponectin (total and HMW) & Leptin 
9. TSH and T4 
10. HbA1c 
5.1.4 Glucose Tolerance Test 
Glucose Tolerance (2-hour oral glucose tolerance test (OGTT)) will be performed by 
nursing staff. Subjects will be told to eat a high carbohydrate diet for 3 days before the 
study. Topical anesthetic ointment at the phlebotomy sites will be offered the morning of 
the visit. Baseline BG and insulin will be obtained. Subjects will ingest glucose solution 
(1.75 g/kg; maximum of 75 g) over 2 minutes. BG and insulin will be drawn at 30, 60, 90, 
and 120 min via a blood-drawing IV. However, the investigators realize that not all subjects 
will tolerate placement of the blood drawing IV, particularly given that children with Down 
syndrome may have developmental delays. For these subjects, BG and insulin will be 
drawn fasting, subjects will ingest glucose solution as described above, and a second blood 
draw will occur at 120 minutes. OGTT will be interpreted based on American Diabetes 
Association criteria98: Fasting BG: <100 mg/dl= normal, 100-125mg/dl = impaired fasting 
glucose (IFG), ≥126 mg/dl = diabetes; 2-hour BG <140 mg/dL = normal, 140-199 mg/dL = 
impaired glucose tolerance (IGT), ≥200 mg/dL = diabetes.  
5.1.5 Pulse Wave Velocity (PWV) and Pulse Wave Analysis (PWA) 
Pulse Wave Velocity (PWV) and Pulse Wave Analysis (PWA) will be performed in the by 
a trained professional. . Aortic PWV measurements are performed in the supine position 
after at least 5 minutes rest using the right carotid and right femoral arteries, with a 
Sphygmocor PVx System (AtCor Medical, West Ryde, Australia) device. PWA will 
provide novel, supplemental data about central pulse pressure (CPP) in our subjects. The 
same software and equipment as for PWV are used, on the right radial artery. CPP is 
measured using radial artery tonometry.99  
5.1.6  Anthropometry 
Weight measured by digital electronic scale (Scaletronix) and stature on a stadiometer 
(Holtain). Age- and sex-specific Z-scores generated based on CDC 2000 growth charts100 
so that DS and non-DS groups will be compared by the same reference. Body proportions 
and fat distribution measurements (sitting height, arm,waist and hip circumference, and 
skin fold thickness at triceps, biceps, subscapular, and suprailiac sites) will be measured. 
5.1.7  Left Ventricular (LV) Mass 
LV mass will be measured by echocardiography, as described by the American Society of 
Echocardiography’s guidelines101. Per these guidelines the equation of Devereux et al will 
be used102. LV Mass Index (LV mass/height2.7), has been used to normalize LV mass to 
body size103. However, this index increases with decreasing height, which is not ideal for 
children with DS. Use of centile curves and z-scores104 is another strategy to account for 

 
 
 
 
 
 
 
 
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lean mass (LM), which may also be different in children with DS. We will measure LM by 
DXA and can thus normalize LV mass directly. 
5.1.7.1Pregnancy Testing 
A urine pregnancy test will be performed for female subjects.  A positive pregnancy result will 
be disclosed to the participant only. Pregnancy results will be disclosed to the parent/guardian 
if the subject gives the investigators permission. Subjects found to be pregnant during the visit 
will not be able to enroll in this study. The investigators will counsel the subject and guide 
them to seek the appropriate care. 
5.1.8 Safety Evaluation 
The study investigators will be responsible for safety monitoring. A routine needle stick or an 
IV line used for drawing blood may cause some discomfort (topical anesthetic cream will be 
available), bruising, and rarely fainting. Use of the anesthetic cream may cause an allergic 
reaction. Although high adiposity is possible in participants with BMI<85%ile and might 
contribute to abnormal glucose tolerance, we will limit the subjects undergoing OGTT 1) to 
minimize participant burden in this cohort of children with developmental disabilities, and 2) 
on the likelihood of finding cardiometabolic abnormalities. We confined our IR assessment to 
HOMA-IR rather than IVGTT or clamp studies--considered the gold standard for IR 
assessment-- in the spirit of sensitivity to these children with intellectual disabilities and their 
families. We will obtain interim time points within the OGTT to calculate ISI, a measure of 
whole body insulin sensitivity. This requires a minimum of 5 time points, necessitating the 
placement of a blood-drawing IV. Given the children’s developmental disabilities, some 
children may not tolerate this procedure—in this subset only time points 0 and 120 will be 
drawn and ISI omitted from their analyses.  
Participants will be fasting 12 hours prior to their study visit. This may cause hunger pangs, 
upset stomach, headache, or light-headedness. If the participant shows any signs of clinical 
instability or definitively decides to discontinue participation, the study visit will be ended. 
Possible side effects of the OGTT include temporary high or low blood sugar. A risk of the 
OGTT includes an upset stomach. Participants will be monitored by a nurse or doctor during 
the study procedures. Episodes of low blood glucose will be treated with oral or IV glucose 
when indicated. 
During the study visit, if a participant is found to have any previously unknown medical 
conditions, they will be referred to their pediatrician for care. 
This protocol also involves exposure to radiation from the DXA scans. However, this involves 
a very small radiation exposure, which is unlikely to cause any untoward effects to the 
participant. Being that the protocol may be unsafe to an unborn child, pregnancy is an 
exclusion criterion of the study.   
The noninvasive measures of arterial stiffness and central pulse pressure are done via Pulse 
Wave Velocity and Pulse Wave Analysis. This poses little risk to the patient. 
The patient will be notified of any clinically relevant abnormal test result(s) performed by 
CLIA certified labs,  by mail and or by phone. Because of batching of samples, there may be a 

 
 
 
 
 
 
 
 
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11
significant time delay between the study visit and result notification. It will be recommended 
that results, especially abnormal results, be discussed by the guardian with the participant’s 
primary care physician. In the case of study referrals by the primary care provider, the 
investigators may send study results via email, phone, and/or mail to the primary care physician 
directly. Studies performed by non CLIA labs will not be disclosed. 
Any adverse events will be reported as per the study site policies. 
6   STATISTICAL CONSIDERATIONS 
6.1 Data Analysis 
We will screen approximately 200 children with DS to enroll 155 evaluable children with DS. 
Approximately 50% will have CHD, which will be hemodynamically significant in 
approximately 50-75%.  Subjects with minor, hemodynamically insignificant lesions (such as a 
small PDA) will be grouped with subjects without CHD.  
Primary Aim: The primary aim is to compare the relationship between BMI-Z and 
cardiometabolic risk factors in youth with DS and matched controls.  This relationship may be 
different in children with DS with and without CHD.  In order to model the analyses 
appropriately, the primary outcome variables will be compared between children with DS with 
and without hemodynamically significant CHD. If the groups differ, subsequent analyses will 
include a dummy variable indicating presence/absence of hemodynamically significant CHD. 
Descriptive data analysis will summarize distributions of all risk factor measures (age, weight, 
BMI-Z, non-HDL-C, lipid levels, lipoprotein subclass particles, BP, HOMA-IR, ISI, 
inflammatory markers, adipokines, CPP, PWV, LV mass, gender, race, ethnicity, pubertal 
stage, pre-diabetes and diabetes status, physical activity). Subjects with DS will be compared to 
age-, sex-, race-, and BMI-Z matched controls, first by comparison of risk factor distributions 
by DS status. Next, we will fit separate regression models for each risk factor, with DS as the 
exposure of interest, adjusted for potential confounders, including pubertal stage, family history 
of CVD, dietary fat intake, and smoking history. Interaction terms among confounders will be 
used when data frequencies permit. Initial regressions will confirm the size and sign of 
associations of subject characteristics and CVD risk factors. Complementary analyses will 
implement propensity scores, using logistic regression to model DS as a function of observed 
covariates, and then will compare DS and non-DS children for each endpoint using weighted 
analyses. Weights will be calculated by the inverse of the fitted probability of DS106. This 
method will standardize the comparisons of CVD risk factors by differences in observed 
characteristics of DS and non- DS children and thus will permit statements such as ―If a 
sample of children otherwise comparable were alternatively DS and non-DS, what would be 
the differences in CVD risk factors? Finally, we will perform sensitivity analyses as to the 
potential impact on our results from unobserved potential confounders. Initial analyses will 
determine whether children with DS differ from their non-DS counterparts in terms of CVD 
risk factors and will become the basis for addressing the questions in the four sub-aims. 
 
 
6.1.1  Aim 1a) BMI-Z scores and DS – CMR factors  
 

 
 
 
 
 
 
 
 
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12
To analyze this aim, the statistical model noted above will be modified to include an interaction 
term between DS and BMI-Z score for each CVD risk factor. An important interaction term 
will reflect varying association of BMI-Z by disease status. Based on preliminary data we 
estimate 50% of subjects with DS will have BMI≥85%ile and undergo an OGTT. We will 
compare prevalence of IGT or IFG and T2DM between groups. (Although DS is associated 
with increased risk for T1DM, this would most likely present acutely and have already been 
diagnosed if present.)  
 
6.1.2  Aim 1b) DXA-measured FM This sub aim will make use of the model in Aim 1a. 
Inclusion of FM in explaining CMR factors in the model should offset any statistical 
interaction between BMI-Z and DS status.  
Aim 1c) PWV [and LV Mass] Using the model outlined previously, we will add PWV as an 
indicator of end organ damage to assess additional information provided by PWV, especially 
with regard to the interaction of BMI-Z and CVD risk factor levels. This approach will be used 
for CPP and LV mass as well.  
 
6.1.3  Aim 1d) Discrimination ability of BMI-Z and other screening measures This 
analysis will be confined to children with DS, and will require for each CVD risk factor the 
determination before analysis of a threshold of high versus low, in order to evaluate 
discrimination. With BMI-Z, and each risk factor taken individually, we shall estimate the c-
statistic, a measure of discrimination representing the area under the ROC curve of the tradeoff 
of sensitivity and specificity, for each screening measure as a predictor of high vs. low risk. 
Finally, we shall compare the additional discriminatory power of adding one screening measure 
to an existing screening measure, such as WC to BMI-Z to determine whether an additional 
screen is worth the expense and time. These contrasts will be implemented using the methods 
outlined by Pepe and colleagues122.  
 
6.1.4  Secondary Aim 
Initial data analysis will be descriptive to examine distributions of QOL, body image and other 
measures in this AIM.  Models for QOL and body image, with DS and BMI-Z as the exposure 
of interest, adjusted for potential confounders (e.g., sex, ethnicity) will be linear regressions 
and alternatively ordinal regressions depending on the measure distributions. The latter 
regression model assumes only ordered rather than continuous dependent variables. Estimates 
of interest will be the main effects (association of BMI-Z on QOL and body image), and the 
interaction of DS and these factors (does the presence of DS modify associations of interest?).      
 
Stata software (version 11.1 or later; Stata Corp., College Station, Texas), supplemented with 
SAS v 9.2 (SAS Institute, Cary NC) and R (The R Foundation for Statistical Computing, 
Vienna, Austria) will be used for statistical analysis. Methods outlined by Pepe and colleagues 
are now implemented in Stata v 11. 
6.2    Sample Size and Statistical Power 
Primary Aim: Assuming 155 evaluable children with DS and 105 evaluable children without 
DS for analysis and conservatively using nonparametric methods for comparison of CVD risk 
factors, power exceeds 0.85 to detect a between-group difference of 0.35 standard deviation 
(SD). For example, non-HDL-C is our primary CMR outcome measure, and 0.35 SD 

 
 
 
 
 
 
 
 
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13
corresponds to a difference of 7 mg/dl. A difference of 10 mg/dl is considered clinically 
relevant by pediatric cardiologists. 
Secondary Aim: Power for the paired design can be assessed by assuming paired comparisons 
of residuals of a regression of BMI-Z on QOL and body image measures. Assuming that the 
outcomes, and thus residuals, will be  continuous, power = 0.86 to detect as significant as little 
as 0.25 SD in  differences between DS children and controls using nonparametric tests 
(Wilcoxon) that would suitable for both continuous and ordered data. Thus, the sample should 
have substantial power to demonstrate even small differences between DS and matched 
controls.     
6.3   Potential Problems/Feasibility 
If we find no differences in CMR factors between youth with DS and controls, the resulting 
estimates (and confidence bounds) will still generate crucial information, given the literature 
claims of decreased CVD risk in DS, and scarcity of data on T2DM risk. Confidence bounds on 
estimates will allow us to rule out clinically important differences. We might find that DS 
children are at decreased CVD risk compared to unaffected controls. Such information would 
help guide clinicians caring for children with DS, and prevent unnecessary screening. Although 
high adiposity is possible in participants with BMI<85%ile and might contribute to abnormal 
glucose tolerance, we will limit the subjects undergoing OGTT 1) to minimize participant 
burden in this cohort of children with developmental disabilities, and 2) on the likelihood of 
finding cardiometabolic abnormalities. We confined our IR assessment to HOMA-IR rather 
than IVGTT or clamp studies--considered the gold standard for IR assessment-- in the spirit of 
sensitivity to these children with intellectual disabilities and their families. We will obtain 
interim time points within the OGTT to calculate ISI, a measure of whole body insulin 
sensitivity. This requires a minimum of 5 time points, necessitating the placement of a blood-
drawing IV. Given the children’s developmental disabilities, some children may not tolerate 
this procedure—in this subset only time points 0 and 120 will be drawn and ISI omitted from 
their analyses. Measures of LV mass may still be confounded by mild valve regurgitation or 
EKG conduction abnormalities. We are aware of this issue, and will interpret de-identified 
results with the expertise of the study cardiologist(s). They advocate acquiring this data, given 
the cardiometabolic implications of LV mass. The technique has not been used previously in 
this population and will generate novel data. 
 
7 
SAFETY MANAGEMENT 
7.1 Clinical Adverse Events 
Clinical adverse events (AEs) will be monitored throughout the study.  
7.2 Adverse Event Reporting 
The Investigator is responsible for recording and reporting unanticipated problems related to 
research that occur during and after study treatment.  The plan for Adverse Event reporting 
should be consistent with the study siteIRB Guidelines. Since the study procedures are not 
greater than minimal risk, SAEs are not expected. If any unanticipated problems related to the 
research involving risks to subjects or others happen during the course of this study (including 

 
 
 
 
 
 
 
 
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SAEs) these will be reported to the IRB in accordance with the study site policies. AEs that are 
not serious but that are notable and could involve risks to subjects will be summarized in 
narrative or other format and submitted to the IRB at the time of continuing review.  
 
7.3 Medical Emergencies (if applicable) 
The investigators do not anticipate any medical emergencies with this minimal risk study. 
However, there is a possibility that study participants may have low or high blood glucose or 
side effects resulting from the OGTT. The study participants will be monitored throughout 
testing. The study coordinator, a nurse or physician will be present during these procedures. If 
necessary, episodes of significant hypoglycemia will be treated immediately with oral or IV 
glucose (although unlikely).  
8 
STUDY ADMINISTRATION 
8.1 Data Collection and Management 
Data Management CHOP CTRC Informatics Core will create case report forms (CRF) and 
REDCap database for data capture. REDCap is an NIH-supported web-based data management 
software designed by Vanderbilt University investigators. Of special benefit to the proposed 
investigation is the interface between EPIC (the EMR) and the research database that allows for 
use of clinical information for research purposes. For data not already incorporated in EPIC, 
once the investigative team confirms complete and accurate data, it will be entered into 
REDCap. Using REDCap checking tools, the data manager confirms completeness and valid 
values weekly and informs any errors or omissions to the investigative team for prompt 
resolution. Real-time data checking ensures prompt creation of an analysis dataset upon data 
acquisition completion. Tables generated by REDCap will be exported and merged for use with 
Stata and SAS statistical packages as needed for immediate access to the research team.   
The PI is responsible for the accuracy and completeness of data collection and management. 
The PI may designate qualified individual(s) to collect data and manage data. Only 
investigators and research staff that have completed appropriate IRB training and approval and 
are listed on the IRB approved protocol are eligible to collect and work on information from 
the study. Future studies that may use patients or data collected from this study must have 
separate approved IRB protocols and consent forms, if applicable. 
Recruitment data will be recorded onto the screening questionnaire after the verbal consent is 
recorded. Original data will be recorded directly onto CRFs by the study coordinator or a study 
investigator. Copies of laboratory, physical exam, anthropometric, DXA, PWV, and PWA 
results will be received through inter-office mailing, picked up directly, and sometimes through 
email. This information also will be recorded onto CRFs while the originals may be kept at the 
testing site.CRFs will be kept in a locked filing cabinet in a locked room at all times. All 
information will be transferred to REDCap, a secure, web-based application supported by the 
CHOP Research Institute. The password to log onto the database will be unique to each 
member of the study team. CNMC study staff will be assigned to a REDcap user group that 
will restrict their access so they may view and edit solely the information of subjects enrolled at 
CNMC. The CNMC Principle Investigator will have access to view/edit data of all subjects. 

 
 
 
 
 
 
 
 
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Note that only limited PHI (date of visit, date of birth) is included in the REDcap database. 
CHOP will have read-write access for data collected at both sites. CHOP will require access to 
edit records for both sites because several evaluations will be analyzed at CHOP, and reports 
including data from both CHOP and CNMC sites will be forwarded to the CHOP team, who 
will then import or enter the data into REDCap. Written informed consent granting permission 
for other site(s) to access PHI will be obtained from all subjects.The CRF and REDCap 
database will be designed by the CTRC Informatics Services. 
All data and records generated during this study will be kept confidential in accordance with 
institutional policies and on HIPPA subject privacy. The investigators/study team members/site 
personnel will not use such data and records for any purpose other than for conducting the 
study. 
As a way to minimize the chance of PHI (protected health information) from being disclosed, a 
unique identification code will be used for each participant. The key to this code will be kept in 
a locked file in the PI/Study Coordinator’s office.  
If any publications result from this research, the participant will not be identified by name/PHI. 
The information collected as part of this study will be kept for 6 years or until the completion 
of the study (whichever is longer). At that time, the information collected will be destroyed or 
all identifiable information will be removed. All keys will be destroyed at this time, as well. 
8.2 Confidentiality 
All data and records generated during this study will be kept confidential in accordance with  
institutional policies and HIPPA’s guidelines on subject privacy. The investigators/study 
personnel will not use such data and records for any purpose other than conducting the study.  
8.3 Regulatory and Ethical Considerations 
8.3.1 Data and Safety Monitoring Plan 
Study progress and safety will be reviewed quarterly (and for frequently if needed) by the PI. 
Review of the rate of subject accrual, adherence to inclusion/exclusion criteria will occur 
quarterly to assure that participants meet the eligibility criteria. There will be ongoing 
collection of data on adverse events and compliance to the treatment protocol throughout the 
study by research staff, which will be reviewed monthly by the study team and PI. If there is an 
incidental finding deemed by the PI to be clinically relevant, the primary care provider will be 
notified. The parent/guardian will be notified and asked to follow up with the subject’s primary 
care provider if during the visit; a subject is noted to have blood pressure that is ≥ the 95th 
percentile for age, gender, and height. We will notify the parent/guardian/primary care provider 
with clinically relevant abnormal labs. Specifically, lipid levels/insulin levels/blood glucose 
levels/OGTT results/TSH and T4.  Note that some labs, such as lipids and insulin, are run in 
batches and reporting of results may be delayed. 
8.3.2 Incidental Findings 
Participants will have the option to consent for any incidental findings to be shared with their 
primary care provider. If there is an incidental finding deemed by the PI to be clinically 

 
 
 
 
 
 
 
 
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relevant, the primary care provider will be notified. The parent/guardian will be notified and 
asked to follow up with the subject’s primary care provider if during the visit; a subject is noted 
to have blood pressure that is ≥ the 95th percentile for age, gender, and height. We will notify 
the parent/guardian/primary care provider with clinically relevant abnormal labs. Specifically, 
lipid levels/insulin levels/blood glucose levels/OGTT results/TSH and T4.  Note that some 
labs, such as lipids and insulin, are run in batches and reporting of results may be delayed. 
 
8.3.3 Risk Assessment 
The risks of participating in this study are relatively small and the investigators believe the 
overall study is of minimal risk to the participants. An OGTT will only be administered to 
subjects that have BMIs ≥ 85th percentile, not known to have diabetes.  
Expected risks to the subject are as follows: 
 Blood draw may result in temporary discomfort from the needle stick, bruising, 
fainting, weakness, and rarely an infection at the site 
 Possible side effects of the OGTT include temporary high or low blood sugar and upset 
stomach 
 Anthropometric measurements and pubertal status exam poses minimal risks 
 Exposure to radiation during DXA scan 
 Sharing of private health information (PHI) including dietary intake, demographic 
information, health history and medical information 
 Pulse wave velocity and pulse wave analysis poses minimal risks 
 12 hour overnight fasting may cause hunger pangs, upset stomach, headache, or light-
headedness 
 Blood pressure measurement by auscultation may cause temporary numbness/tingling 
in the arm 
 SenseWear® Armbands worn for 7 consecutive days may cause skin irritability  
 Sensitive psychosocial issues may arise during questionnaire assessment 
A small amount of blood (about 3 teaspoons) will be drawn at major assessment points. 
Adolescents may experience some degree of discomfort, bruising, or lightheadedness with 
fasting blood draws. There is also a risk of infection when blood is drawn. These 
occurrences are rare, generally mild, and respond to conservative treatment. 
The OGTT is frequently used to screen for diabetes and impairments in glucose regulation 
in children both within the confines of a study and in routine clinical practice; additional 
intermediate blood draws will be performed for glucose and insulin in order to assess 
insulin sensitivity.  Because of these intermediate time points for blood collection, an 
intravenous line will be placed, which can be associated with discomfort and a small risk of 
infection.  The use of EMLA cream is optional to minimize discomfort to the study 
participant. Experienced pediatric research nurses will perform the OGTT; OGTT are 
routinely performed in this setting.  Seven blood samples are required and the volumes of 
blood will be minimized to reduce the risk of anemia.  The concern with OGTT is 
hypoglycemia occurring 2-3 hours after consumption of the dextrose load.  If hypoglycemic 

 
 
 
 
 
 
 
 
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symptoms develop, blood glucose will be checked. In the event of hypoglycemia (blood 
glucose<60 mg/dL), the study will be terminated and carbohydrates consumed by the 
subject.  Blood glucose will be monitored until normalization is assured.  To minimize 
subject burden, particularly in this cohort of children with developmental disabilities, we 
will perform OGTT only in subjects with BMI≥85%.  While the aim of the study is to 
uncover cardiometabolic risk factors in children with DS and to uncover whether 
adolescents with DS have greater risk for a given BMI z-score, glucose intolerance is 
unlikely in children with BMI<85% and the yield of doing OGTT in this subgroup is 
relatively low. Our team felt that it was crucial to be sensitive to the burden of participation 
placed on these children with intellectual and developmental disabilities and their families. 
Participation in the study involves risks associated with the small amount of radiation 
exposure associated with the DXA whole body scan for body composition assessment; the 
total radiation EDE from DXA scans is less than 3 μSv (or 1 mrem). This total amount of 
radiation is less than the exposure to daily background radiation at sea level (3,000 μSv 
per year) and is therefore considered minimal risk. Females of childbearing potential 
undergo a urine pregnancy test prior to the DXA scans. Pregnant females do not have 
DXA scans performed in order to protect the unborn fetus. 
The anthropometric assessment involves measurements of height, weight, circumferences 
and skinfold thickness. There is a very minor possibility of bruising from the skinfold 
thickness measurements. The exam will be performed by trained anthropometrists 
experienced in obtaining measurements in children at all levels of cognitive ability. The 
measurements are obtained in a private room. The parent is permitted to stay with the child 
if it increases their comfort with the exam. 
The puberty assessment will be performed by pediatric endocrinologists in a private 
setting. The procedure will be explained to the child in advance, and the parent is 
permitted to be present if preferred by the child. The exam is performed by highly 
experienced personnel who are familiar with minimizing distress associated with the 
exam. 
SenseWear® Armbands (Body Media, Inc.). There is little to no risk associated with 
measuring physical activity, sedentary behavior, and sleep with armband accelerometers. 
These accelerometers fit comfortably on the participant’s arm and can easily be removed 
should he/she become uncomfortable. Some patients may experience skin irritation, 
particularly when sweating, with the devices in which case they can adjust them or in rare 
instances, remove them if necessary. To prevent irritation, parents will be instructed to 
clean the armband with mild soap and water when the child removes it to bathe or shower. 
If irritation does occur, parents will be instructed to use Aquaphor or Vaseline where the 
fabric of the band is to treat and prevent further irritation. If a child is allergic to metal they 
will not be required to complete this assessment. 
A licensed clinical psychologist with expertise in working with children and adolescents, 
will meet with families concerning sensitive psychosocial issues that may arise during 
assessments or intervention. Any emotional upset will be handled with appropriate support 
to the participants and their caregivers. Further, if a behavioral health concern arises 

 
 
 
 
 
 
 
 
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during the study needing further evaluation and treatment, the clinical psychologist will 
assist with a referral. 
If a subject shows any signs of clinical instability or definitively decides to discontinue 
participation, the study visit will end. 
 
8.3.4 Potential Benefits of Study Participation 
There may be no direct benefit and benefits will be to future patients, Science and society. 
Participants may directly benefit from identification of abnormalities such as diabetes from the 
OGTT. Participants may indirectly benefit from identification of abnormalities such as 
dyslipidemia and hypothyroidism from the fasting blood draw. If clinically relevant 
abnormalities are found, the family will be notified. With the consent from the family, 
clinically relevant tests results will be shared with the subject’s primary care physician. Only 
studies performed by CLIA certified labs will be disclosed. Participants found to have an 
impaired fasting glucose or impaired glucose tolerance will be referred appropriately for further 
management and treatment.  
The physical activity questionnaires and dietary recall may potentially lead the 
participants/parents/guardians into awareness about making healthy lifestyle options in diet and 
exercise.  
There is also a potential indirect benefit in helping scientists and health providers further 
understand the relationship between obesity and Cardiometabolic risk in Down syndrome 
youth.  
8.3.5 Risk-Benefit Assessment 
The benefits to participation in this trial outweigh the potential risks. Clinicians caring for 
obese adolescents with Down syndrome with or without CHD have very little scientific 
evidence upon which to base guidance regarding Cardiometabolic risk. Data regarding 
prevalence of pre-diabetes and T2D and on CVD risk in obese adolescents with Down 
syndrome are lacking. This study will have direct implications for the daily medical care of 
individuals with Down syndrome. Currently, we do not know whether BMI is the best marker 
of cardiometabolic risk in Down syndrome. We plan to determine which measure of adiposity 
best captures CVD and or diabetes risk in Down syndrome, so that primary care providers will 
know what measure to use to assess risk in adolescents with Down syndrome (i.e. BMI, waist 
circumference, or skin fold thickness). Medical providers will then be able to use the 
appropriate measure for prevention, and to guide screening. 
8.4 Recruitment Strategy 
Potential subjects will be identified using the protocol inclusion and exclusion criteria. Subjects 
will be recruited from multiple sources, including local primary care, Endocrinology, 
Cardiology and Trisomy 21 clinics, local advertisements, previous studies (if they gave 
permission to be contacted), and DS community events. The DS Connect recruitment registry 
will e-mail registry participants the IRB-approved recruitment flyer.  

 
 
 
 
 
 
 
 
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A study website will also be used as a source of information for potential DS and control 
subjects.  
The Recruitment Enhancement Core (REC) will e-mail or postal mail potential control subjects 
using the IRB-approved REC letter for control subjects. This letter will contain opt-out 
language that allows study staff to contact participants via one phone call who have not opted-
out 2 weeks following the letter being sent. 
After the initial telephone screening, subjects that agree to participate and qualify for the study 
will be scheduled for an appointment. Verbal consent will be obtained by the study team prior 
to the screening. 
8.5 Informed Consent/Assent and HIPAA Authorization 
Prior to conducting the screening interview and prior to mailing the family the HFI 
questionnaire, verbal consent from the subject (if 18 years or older)/parent/guardian/legal 
authorized representative will be obtained and documented by the study coordinator/study 
investigator. A description of the procedures involved in the study, as well as the risks/benefits 
will be provided verbally as part of this process. Additionally, it will be stressed that any 
questions are appropriate and that all aspects of the study are voluntary. 
Prior to conducting the study visit procedures, the study coordinator will obtain consent and if 
appropriate assent from the participant. A waiver of minor assent by the study coordinator will 
be obtained for participants not capable of assenting. The consent/assent process will take place 
in a private room. It will be stressed again that participation in the study is voluntary and that 
any questions can and should be raised. Consent and assent will be documented by the 
parent/guardian/participant’s signatures on the approved consent documents. A description of 
the procedures involved in the study, as well as the risks and benefits, will be provided verbally 
as part of the consent process.  
Consent/assent documents will be maintained in the participant’s study file and documented. 
The parent/guardian will receive a copy of the signed document(s). 
8.5.1 Consent for Down syndrome subjects 18 – 20 years of age 
Ability to provide consent will be ascertained by the study team. Initially, the team will assess 
the participants’ ability by engaging them in conversation to obtain a brief, general sense of 
their ability to comprehend and communicate. If ability to provide consent seems likely, the 
team will then explain the following to confirm that the study participant understands all of the 
essential elements of the consent form: 
a. The purpose of the research study. We will explain that the study is trying to 
find out which tests and measurements will best capture the risks of heart 
disease and type 2 diabetes in children and adolescents with DS. We will ask 
them to explain in their own words what the study is about. 

 
 
 
 
 
 
 
 
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b. Study procedures will be explained with the aid of a picture book that depicts 
the study visit and at-home procedures. We will then ask them to explain in their 
own words what each procedure will be like. 
c. The staff will clearly explain that the study participant does not have to 
participate in the study, that they can change their mind about being in the study 
at any time, and that no one will be disappointed, upset or consider it a failure if 
they decide they do not want to continue with the study. Subjects will be asked 
to explain in their own words that they understand that they do not have to 
participate in the study and that there are no consequences if they choose not to.  
d. We will explain that their information will be kept private to the best of our 
ability. We will explain the risks of each procedure. We will also explain that 
they may learn more about their health from the study, and that their health may 
improve from taking the thyroid hormone pills, but that it is also possible that 
they may not benefit from the study. Participants will be asked to explain in 
their own words what they understand about the risks and benefits of the study. 
If it is deemed by the study team at any of the above points that the subject is unable to consent 
for themselves, the subject’s legally authorized representative/health care representative will 
provide the written informed consent on the subject’s behalf. 
8.5.2 Assent Procedures 
Assent will be obtained and documented on the consent form for children capable of 
assenting.  DS subjects age 18-20 years of age that are not capable of consenting for 
themselves will have assent documented in the consent form. If the capability of some of the 
participants is limited in comprehending the study and that they cannot reasonably be 
consulted, assent will not be obtained. In these cases, the investigators will document it on 
the consent form. Investigators will obtain assent whenever possible. 
8.5.3 Waiver of Documentation of Consent 
Waiver of documentation of consent is being sought for screening procedures, as the 
subject over age 18/parent/guardian/legal authorized representative will be contacted by 
telephone and obtaining a signature will not be feasible. As described in (8.5), verbal 
consent/HIPAA authorization will be obtained and documented by the study 
coordinator/study investigator prior to conducting the screening interview and prior to 
mailing the family the HFI.  
 
8.5.4 Waiver of Assent 
Waiver of assent is being sought for screening procedures, as subjects may not be 
present when parents/guardians/legally authorized representatives are contacted 

 
 
 
 
 
 
 
 
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8.6 Payment to Subjects/Families 
All study procedures and expenses will not be billed to the participant. The total reimbursement 
for the study visit is $150. The parent/guardian will receive a total of $100 to offset the burdens 
of transportation/parking/time off work/babysitting fees/meals. The parent/guardian will 
receive $50 immediately after the study visit and an additional $50 once all post-visit 
procedures are complete.  The participant will receive a $50 gift card for their efforts toward 
the study.  
In the event that any study procedure cannot be completed on the date of the study visit and the 
participant returns on another date to complete any pending study procedure(s), the 
parent/guardian will be reimbursed with $50 to offset the burdens of the time and effort needed 
to come in for the visit. 
 
9 
PUBLICATION 
The results of this study may be submitted for consideration for presentations at national 
meetings and/or publication in academic journals. At no time will any PHI from this study be 
disclosed for any presentation(s) or journal article(s). 
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