Down Syndrome, Trisomy 21
Conditions
Keywords
Down syndrome, Philadelphia, The Children's Hospital of Philadelphia, Body composition, Obesity, Cardiovascular
Brief summary
The purpose of this research study is to determine which measures best capture cardiovascular disease (CVD) risk and type 2 diabetes (T2DM) risk in children and adolescents with Down syndrome (DS). We hypothesize that DS is associated with worse cardiometabolic risk factors for a given body mass index compared to controls. This difference arises at least in part, from increased fat tissue.
Detailed description
DS 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. DS is associated with an increased risk for obesity, with an estimated prevalence of 47-48% in adults and 30-50% in children with DS. 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 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. Congenital heart disease (CHD) affects approximately 50% of individuals with DS; the National Institutes of Health Heart Lung and Blood Institute (NHLBI) Working Group on Obesity and Other Cardiovascular 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.
Interventions
None listed
Sponsors
National Institutes of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Children's Hospital of Philadelphia
Study design
Observational model
CASE_CONTROL
Time perspective
CROSS_SECTIONAL
Eligibility
Sex/Gender
ALL
Age
10 Years to 20 Years
Healthy volunteers
Yes
Inclusion criteria
* Both groups: Ages 10 - 20 * Both groups: Parental/guardian permission (informed consent) and if appropriate, child assent. * Down syndrome group only: diagnosis of Down syndrome
Exclusion criteria
(both groups): * Major organ system illness (such as leukemia), except for type 2 Diabetes * Cyanotic congenital heart disease and/or pulmonary hypertension * Medically unstable congenital heart disease * Pregnancy * Genetic syndrome known to affect glucose tolerance * Familial hypercholesterolemia * Currently treated with medications known to affect insulin sensitivity (other than diabetes agents in participants with type 2 diabetes)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pulse Wave Velocity | Study Visit 1 | Cardiac end organ injury assessed by Pulse Wave Velocity (PWV) |
| Body Mass Measures | Study Visit 1 | Adiposity measured by Dual-energy X-ray absorptiometry |
| Left Ventricular Mass | Study Visit 1 | Cardiac end organ injury assessed by echocardiography. Left Ventricular Mass (LVM) was measured by area/length method using the apical four-chamber and parasternal short-axis views. LVM was calculated as LV area × LV length × 1.05 × 5/6. |
| Non-HDL Cholesterol | Study Visit 1 | Non-HDL cholesterol measured via fasting blood draw |
| Lipid Subparticles | Study Visit 1 | Lipoprotein subclass particle analysis run on samples from fasting blood drawn Study Visit 1. |
| Lipid Subparticles (Size) | Study Visit 1 | Lipoprotein subclass particle analysis run on samples from fasting blood drawn Study Visit 1. |
| Insulin Resistance | Study Visit 1 | Insulin Resistance (HOMA-IR) was calculated as \[fasting insulin (uIU/mL) x fasting glycemia (mmol/L)\]/22.5 |
| Cardiometabolic Risk Biomarker Proteins | Study Visit 1 | hs-CRP, PAI-1, and IL-6 run on samples from fasting blood drawn Study Visit 1. |
| Abnormal Glucose Tolerance | Study Visit 1 | Impaired fasting glucose (IFG) was defined as fasting glucose ≥ 100 mg/dl. Impaired glucose tolerance (IGT) was defined as 2-hour glucose 140-199 mg/dl measured as part of an oral glucose tolerance test. |
| Visceral Fat | Study Visit 1 | Adiposity measured by Dual-energy X-ray absorptiometry |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Health Related Quality of Life - IWQOL | Study Visit 1 | Parent perception of the effects of weight on his/her child's QOL was assessed with a caregiver-proxy version of the Impact of Weight on Quality of Life - Kids (IWQOL-Kids) questionnaire. The IWQOL-Kids is a validated, 27-item, self-report measure of weight-related QOL for youth ages 11-19 years. It yields 4 subscales (Physical Comfort, Body Esteem, Social Life, and Family Relations) and a Total score, which have strong psychometric properties, discriminate among weight status groups, and are responsive to weight change. Scaled scores are standardized and range from 0 to 100, with greater scores representing better weight-related QOL. |
| Health Related Quality of Life - PedsQL | Study Visit 1 | Caregiver-perception of his/her child's health-related QOL was assessed with the use of the parent-proxy report of the Pediatric Quality of Life Inventory (PedsQL) Version 4.0. Sub-scale scores are converted to a 0-100 scale so that greater scores indicate better QOL. Scale scores are computed as the sum of the items divided by the number of items answered (this accounts for missing data). If more than 50% of the items in the scale are missing, the scale score is not computed. The Physical Health Summary Score (8 items) is the same as the Physical Functioning Scale. To create the Psychosocial Health Summary Score (15 items), the mean is computed as the sum of the items divided by the number of items answered in the Emotional, Social, and School Functioning Scales. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Down Syndrome Our goal is to enroll 155 subjects with Down syndrome, and to compare their data to our control group. | 154 |
| Control Our goal is to enroll 105 typically developing controls, who are matched to the Down syndrome group by age, sex, race, ethnicity, and BMI-z score. | 103 |
| Total | 257 |
Baseline characteristics
| Characteristic | Down Syndrome | Control | Total |
|---|---|---|---|
| Age, Continuous | 14.4 years STANDARD_DEVIATION 0.3 | 14.7 years STANDARD_DEVIATION 0.3 | 14.7 years STANDARD_DEVIATION 0.2 |
| BMI Percentile | 81.4 percentile STANDARD_DEVIATION 1.8 | 79.3 percentile STANDARD_DEVIATION 2.5 | 80.5 percentile STANDARD_DEVIATION 1.4 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 13 Participants | 6 Participants | 19 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 141 Participants | 97 Participants | 238 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 30 Participants | 24 Participants | 54 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants | 4 Participants | 7 Participants |
| Race (NIH/OMB) White | 117 Participants | 74 Participants | 191 Participants |
| Region of Enrollment United States | 154 participants | 103 participants | 257 participants |
| Sex: Female, Male Female | 87 Participants | 61 Participants | 148 Participants |
| Sex: Female, Male Male | 67 Participants | 42 Participants | 109 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 154 | 0 / 103 |
| other Total, other adverse events | 7 / 154 | 3 / 103 |
| serious Total, serious adverse events | 0 / 154 | 0 / 103 |
Outcome results
Primary
Abnormal Glucose Tolerance
Impaired fasting glucose (IFG) was defined as fasting glucose ≥ 100 mg/dl. Impaired glucose tolerance (IGT) was defined as 2-hour glucose 140-199 mg/dl measured as part of an oral glucose tolerance test.
Time frame: Study Visit 1
Population: Participants completed an oral glucose tolerance test if they were in the overweight or obese categories: DS n=96, Control n=64.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Down Syndrome | Abnormal Glucose Tolerance | Impaired Fasting Glucose | 12 Participants |
| Down Syndrome | Abnormal Glucose Tolerance | Abnormal Glucose Tolerance | 10 Participants |
| Control | Abnormal Glucose Tolerance | Impaired Fasting Glucose | 3 Participants |
| Control | Abnormal Glucose Tolerance | Abnormal Glucose Tolerance | 3 Participants |
Primary
Body Mass Measures
Adiposity measured by Dual-energy X-ray absorptiometry
Time frame: Study Visit 1
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Down Syndrome | Body Mass Measures | Whole Body Fat Mass | 18607.5 g |
| Down Syndrome | Body Mass Measures | Whole Body Lean Mass | 34927.16 g |
| Control | Body Mass Measures | Whole Body Fat Mass | 22372.1 g |
| Control | Body Mass Measures | Whole Body Lean Mass | 44108.3 g |
Primary
Cardiometabolic Risk Biomarker Proteins
hs-CRP, PAI-1, and IL-6 run on samples from fasting blood drawn Study Visit 1.
Time frame: Study Visit 1
Population: Participants excluded from analysis if they failed to complete blood draw or were diagnosed with Type 1 Diabetes: DS=7, Controls=0.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Down Syndrome | Cardiometabolic Risk Biomarker Proteins | IL-6 | 2.3 ng/dL |
| Down Syndrome | Cardiometabolic Risk Biomarker Proteins | PAI-1 | 0.0204 ng/dL |
| Down Syndrome | Cardiometabolic Risk Biomarker Proteins | hs-CRP | 2.5 ng/dL |
| Control | Cardiometabolic Risk Biomarker Proteins | IL-6 | 1.5 ng/dL |
| Control | Cardiometabolic Risk Biomarker Proteins | PAI-1 | 0.0254 ng/dL |
| Control | Cardiometabolic Risk Biomarker Proteins | hs-CRP | 1.0 ng/dL |
Primary
Insulin Resistance
Insulin Resistance (HOMA-IR) was calculated as \[fasting insulin (uIU/mL) x fasting glycemia (mmol/L)\]/22.5
Time frame: Study Visit 1
Population: Participants excluded from insulin resistance analysis if they failed to complete blood draw or were diagnosed with Type 1 Diabetes: DS=147, Controls=103.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Down Syndrome | Insulin Resistance | 1.8 HOMA-IR |
| Control | Insulin Resistance | 1.95 HOMA-IR |
Primary
Left Ventricular Mass
Cardiac end organ injury assessed by echocardiography. Left Ventricular Mass (LVM) was measured by area/length method using the apical four-chamber and parasternal short-axis views. LVM was calculated as LV area × LV length × 1.05 × 5/6.
Time frame: Study Visit 1
Population: LVM was available in 136 adolescents with DS (60M/76F) and 101nonDS controls (41M/60F).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Down Syndrome | Left Ventricular Mass | 68.3 g |
| Control | Left Ventricular Mass | 64 g |
Primary
Lipid Subparticles
Lipoprotein subclass particle analysis run on samples from fasting blood drawn Study Visit 1.
Time frame: Study Visit 1
Population: Participants excluded from lipid analysis if they failed to complete blood draw or were diagnosed with Type 1 Diabetes: DS=7, Controls=0.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Down Syndrome | Lipid Subparticles | Small HDL-P (nmol/L) | 9.8 nmol/L |
| Down Syndrome | Lipid Subparticles | Large VLDL-P (nmol/L) | 3.9 nmol/L |
| Down Syndrome | Lipid Subparticles | Small LDL-P (nmol/L) | 518 nmol/L |
| Down Syndrome | Lipid Subparticles | Total LDL-P (nmol/L) | 977 nmol/L |
| Control | Lipid Subparticles | Total LDL-P (nmol/L) | 850 nmol/L |
| Control | Lipid Subparticles | Small HDL-P (nmol/L) | 11.7 nmol/L |
| Control | Lipid Subparticles | Small LDL-P (nmol/L) | 420 nmol/L |
| Control | Lipid Subparticles | Large VLDL-P (nmol/L) | 2.4 nmol/L |
Primary
Lipid Subparticles (Size)
Lipoprotein subclass particle analysis run on samples from fasting blood drawn Study Visit 1.
Time frame: Study Visit 1
Population: Participants excluded from lipid analysis if they failed to complete blood draw or were diagnosed with Type 1 Diabetes: DS=7, Controls=0.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Down Syndrome | Lipid Subparticles (Size) | HDL-P size (nm) | 9.6 nm |
| Down Syndrome | Lipid Subparticles (Size) | VLDL-P size (nm) | 49.2 nm |
| Down Syndrome | Lipid Subparticles (Size) | LDL-P size (nm) | 20.7 nm |
| Control | Lipid Subparticles (Size) | HDL-P size (nm) | 9.6 nm |
| Control | Lipid Subparticles (Size) | VLDL-P size (nm) | 47.1 nm |
| Control | Lipid Subparticles (Size) | LDL-P size (nm) | 20.7 nm |
Primary
Non-HDL Cholesterol
Non-HDL cholesterol measured via fasting blood draw
Time frame: Study Visit 1
Population: Participants excluded from lipid analysis if they failed to complete blood draw or were diagnosed with Type 1 Diabetes: DS=7, Controls=0
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Down Syndrome | Non-HDL Cholesterol | 128 mg/dl |
| Control | Non-HDL Cholesterol | 107 mg/dl |
Primary
Pulse Wave Velocity
Cardiac end organ injury assessed by Pulse Wave Velocity (PWV)
Time frame: Study Visit 1
Population: PWV was available in 129 adolescents with DS and 97 controls
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Down Syndrome | Pulse Wave Velocity | 5 m/s |
| Control | Pulse Wave Velocity | 4.9 m/s |
Primary
Visceral Fat
Adiposity measured by Dual-energy X-ray absorptiometry
Time frame: Study Visit 1
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Down Syndrome | Visceral Fat | 54.5 cm^2 |
| Control | Visceral Fat | 55.9 cm^2 |
Secondary
Health Related Quality of Life - IWQOL
Parent perception of the effects of weight on his/her child's QOL was assessed with a caregiver-proxy version of the Impact of Weight on Quality of Life - Kids (IWQOL-Kids) questionnaire. The IWQOL-Kids is a validated, 27-item, self-report measure of weight-related QOL for youth ages 11-19 years. It yields 4 subscales (Physical Comfort, Body Esteem, Social Life, and Family Relations) and a Total score, which have strong psychometric properties, discriminate among weight status groups, and are responsive to weight change. Scaled scores are standardized and range from 0 to 100, with greater scores representing better weight-related QOL.
Time frame: Study Visit 1
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Down Syndrome | Health Related Quality of Life - IWQOL | Family Relationships (IWQOL-Kids) | 93.8 score on a scale | Standard Deviation 13.5 |
| Down Syndrome | Health Related Quality of Life - IWQOL | Body Esteem (IWQOL-Kids) | 91.4 score on a scale | Standard Deviation 11.1 |
| Down Syndrome | Health Related Quality of Life - IWQOL | Total (IWQOL-Kids) | 89.8 score on a scale | Standard Deviation 11.7 |
| Down Syndrome | Health Related Quality of Life - IWQOL | Social Life (IWQOL-Kids) | 89.7 score on a scale | Standard Deviation 17.6 |
| Down Syndrome | Health Related Quality of Life - IWQOL | Physical Comfort (IWQOL-Kids) | 83.3 score on a scale | Standard Deviation 18.6 |
| Control | Health Related Quality of Life - IWQOL | Social Life (IWQOL-Kids) | 98.4 score on a scale | Standard Deviation 5.9 |
| Control | Health Related Quality of Life - IWQOL | Family Relationships (IWQOL-Kids) | 98.6 score on a scale | Standard Deviation 5.3 |
| Control | Health Related Quality of Life - IWQOL | Total (IWQOL-Kids) | 98.0 score on a scale | Standard Deviation 5.1 |
| Control | Health Related Quality of Life - IWQOL | Body Esteem (IWQOL-Kids) | 98.0 score on a scale | Standard Deviation 5.4 |
| Control | Health Related Quality of Life - IWQOL | Physical Comfort (IWQOL-Kids) | 97.1 score on a scale | Standard Deviation 7.5 |
| Control, Obese | Health Related Quality of Life - IWQOL | Social Life (IWQOL-Kids) | 80.7 score on a scale | Standard Deviation 21 |
| Control, Obese | Health Related Quality of Life - IWQOL | Physical Comfort (IWQOL-Kids) | 86.0 score on a scale | Standard Deviation 16.6 |
| Control, Obese | Health Related Quality of Life - IWQOL | Body Esteem (IWQOL-Kids) | 73.9 score on a scale | Standard Deviation 25.7 |
| Control, Obese | Health Related Quality of Life - IWQOL | Family Relationships (IWQOL-Kids) | 93.2 score on a scale | Standard Deviation 11.2 |
| Control, Obese | Health Related Quality of Life - IWQOL | Total (IWQOL-Kids) | 82.4 score on a scale | Standard Deviation 16.7 |
| Control, Not Obese | Health Related Quality of Life - IWQOL | Family Relationships (IWQOL-Kids) | 97.5 score on a scale | Standard Deviation 8.9 |
| Control, Not Obese | Health Related Quality of Life - IWQOL | Body Esteem (IWQOL-Kids) | 93.9 score on a scale | Standard Deviation 12.8 |
| Control, Not Obese | Health Related Quality of Life - IWQOL | Physical Comfort (IWQOL-Kids) | 98.2 score on a scale | Standard Deviation 7.9 |
| Control, Not Obese | Health Related Quality of Life - IWQOL | Social Life (IWQOL-Kids) | 95.0 score on a scale | Standard Deviation 14 |
| Control, Not Obese | Health Related Quality of Life - IWQOL | Total (IWQOL-Kids) | 95.9 score on a scale | Standard Deviation 10.5 |
Secondary
Health Related Quality of Life - PedsQL
Caregiver-perception of his/her child's health-related QOL was assessed with the use of the parent-proxy report of the Pediatric Quality of Life Inventory (PedsQL) Version 4.0. Sub-scale scores are converted to a 0-100 scale so that greater scores indicate better QOL. Scale scores are computed as the sum of the items divided by the number of items answered (this accounts for missing data). If more than 50% of the items in the scale are missing, the scale score is not computed. The Physical Health Summary Score (8 items) is the same as the Physical Functioning Scale. To create the Psychosocial Health Summary Score (15 items), the mean is computed as the sum of the items divided by the number of items answered in the Emotional, Social, and School Functioning Scales.
Time frame: Study Visit 1
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Down Syndrome | Health Related Quality of Life - PedsQL | Total Score (PedsQL) | 66.2 score on a scale | Standard Deviation 13.2 |
| Down Syndrome | Health Related Quality of Life - PedsQL | Psychosocial (PedsQL) | 65.1 score on a scale | Standard Deviation 14.3 |
| Down Syndrome | Health Related Quality of Life - PedsQL | Social (PedsQL) | 60.7 score on a scale | Standard Deviation 20.9 |
| Down Syndrome | Health Related Quality of Life - PedsQL | School (PedsQL) | 65.1 score on a scale | Standard Deviation 18.2 |
| Down Syndrome | Health Related Quality of Life - PedsQL | Emotional (PedsQL) | 73.3 score on a scale | Standard Deviation 76 |
| Down Syndrome | Health Related Quality of Life - PedsQL | Physical Functioning (PedsQL) | 68.3 score on a scale | Standard Deviation 18.5 |
| Control | Health Related Quality of Life - PedsQL | School (PedsQL) | 64.0 score on a scale | Standard Deviation 17.2 |
| Control | Health Related Quality of Life - PedsQL | Physical Functioning (PedsQL) | 73.2 score on a scale | Standard Deviation 21.4 |
| Control | Health Related Quality of Life - PedsQL | Emotional (PedsQL) | 76.0 score on a scale | Standard Deviation 14.9 |
| Control | Health Related Quality of Life - PedsQL | Psychosocial (PedsQL) | 67.8 score on a scale | Standard Deviation 13.8 |
| Control | Health Related Quality of Life - PedsQL | Total Score (PedsQL) | 69.6 score on a scale | Standard Deviation 14.2 |
| Control | Health Related Quality of Life - PedsQL | Social (PedsQL) | 63.3 score on a scale | Standard Deviation 19.2 |
| Control, Obese | Health Related Quality of Life - PedsQL | Emotional (PedsQL) | 75.6 score on a scale | Standard Deviation 19.5 |
| Control, Obese | Health Related Quality of Life - PedsQL | Physical Functioning (PedsQL) | 78.9 score on a scale | Standard Deviation 18.8 |
| Control, Obese | Health Related Quality of Life - PedsQL | Social (PedsQL) | 80.4 score on a scale | Standard Deviation 16.4 |
| Control, Obese | Health Related Quality of Life - PedsQL | School (PedsQL) | 75.6 score on a scale | Standard Deviation 18.5 |
| Control, Obese | Health Related Quality of Life - PedsQL | Psychosocial (PedsQL) | 77.2 score on a scale | Standard Deviation 15.4 |
| Control, Obese | Health Related Quality of Life - PedsQL | Total Score (PedsQL) | 77.8 score on a scale | Standard Deviation 14 |
| Control, Not Obese | Health Related Quality of Life - PedsQL | Emotional (PedsQL) | 77.2 score on a scale | Standard Deviation 25.1 |
| Control, Not Obese | Health Related Quality of Life - PedsQL | Psychosocial (PedsQL) | 80.7 score on a scale | Standard Deviation 22.4 |
| Control, Not Obese | Health Related Quality of Life - PedsQL | Physical Functioning (PedsQL) | 89.7 score on a scale | Standard Deviation 19.7 |
| Control, Not Obese | Health Related Quality of Life - PedsQL | Total Score (PedsQL) | 83.9 score on a scale | Standard Deviation 21 |
| Control, Not Obese | Health Related Quality of Life - PedsQL | School (PedsQL) | 80.0 score on a scale | Standard Deviation 24 |
| Control, Not Obese | Health Related Quality of Life - PedsQL | Social (PedsQL) | 85.0 score on a scale | Standard Deviation 22.3 |