Respiratory Effects of Obesity in Children
Conditions: Childhood Obesity
Sponsor: University of Texas Southwestern Medical Center

Title of Study: Respiratory Effects of Obesity in Children 
Document: Study Protocol and Statistical Analysis Plan 
Date of document: 11/22/2017 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Overall Strategy 
We will measure respiratory function at rest, exercise tolerance during graded cycle ergometry, 
and ratings of perceived breathlessness during constant load submaximal cycling in all subjects 
before and after 1 yr. We will study 72 prepubescent obese boys (n=36) and girls (n=36) 
including 12 boys and 12 girls misdiagnosed with asthma (BMI > 95th percentile, but less than 
150% of the 95th percentile), and 24 prepubescent normal weight boys (n=12) and girls (n=12) 
(BMI between 16th and 84th percentile). Recently, there has been a shift towards classifying child 
BMI over the 95th percentile as a percent of the 95% percentile because the statistical 
procedures used to generate percentile curves are not accurate at the extreme tails of BMI 
distribution 40. We have chosen 150% of the 95th percentile as a reasonable cut-off or upper-limit 
because it will exclude children with an average age and sex specific BMI of approximately > 35 
kg/m2 (BMI Range 33.2–36.3 in boys and 34.5–37.9 in girls), which roughly corresponds to 
Class II obesity in adults. Our approach will enable us to study and compare boys and girls 
while pubertal effects on lung function and exercise responses are minimized 76. Furthermore, 
we are not studying the effectiveness of the intervention stimulus, the dose response of diet and 
exercise, or the rate of weight loss but only the response to 1) weight loss and regular exercise 
or 2) continued weight gain.  
Specific Aim 1: Respiratory Function at Rest in Obese Children 
Aim 1a. Introduction: at Rest Seated Upright. The working hypothesis is that childhood obesity 
will alter pulmonary function and breathing mechanics while seated upright but to a greater 
extent in obese children with respiratory symptoms misdiagnosed as asthma. The rationale 
behind the proposed research centers on the fact that nonobese children already breathe at 
very low lung volumes 21 and have compliant chest walls 2,21,89 and excess fat on the chest will 
push FRC to lower levels 28,81 where obese children may experience breathing limitations, all 
because of a simple reduction in lung volume. Furthermore, we propose that obese children 
with respiratory symptoms misdiagnosed as asthma will have greater changes in lung volumes 
and/or differences in peripheral airways function (e.g., resistance or reactance or both) making 
them more susceptible to low lung volume breathing. 
Methodology, experimental protocol, and measurements. The strategy will be to measure body 
composition and respiratory function while seated upright. Height, weight, circumference 
measurements (chest, waist, hip, and neck), BMI, and body composition by DEXA (e.g., %body 
fat, fat mass, lean body mass, & distribution of chest wall fat) will be used to characterize 
differences in overall body size and general fat distribution (e.g., weight-to-height, waist-to-hip 
ratios, android/gynoid measures, & chest wall fat distribution by segmental analysis of the DEXA 
scan) among groups. Baseline respiratory function tests will include spirometry before and after 
bronchodilators (i.e., to assess airway hyperresponsiveness), airway resistance (including 
impulse oscillometry system to examine central & peripheral airway function), lung volumes by 
plethysmography, diffusing capacity, MVV, MIP, and MEP. Participants who show clinically 
significant airway hyperresponsiveness (i.e., to bronchodilator or bronchial challenge) will be 
referred for treatment and excluded from further study (~8-9% prevalence in children, CDC). 
The absence of asthma will be confirmed by a negative response to spirometry before and after 
bronchodilator and by a negative bronchial challenge test (i.e., methacholine) in obese children 
with a prior diagnosis of asthma without confirmation by lung function testing 1,45. 
Expected results. We expect that altered respiratory function and breathing mechanics will be 
both prevalent and significant in obese children, primarily a reduced FRC, which may be 
correlated with other obesity-related changes in body composition. Furthermore, we expect that 
obese children with respiratory symptoms misdiagnosed as asthma will have greater changes in 
obesity-related respiratory function and/or differences in peripheral airways function making 
them more susceptible to low lung volume breathing. We also expect to have a better 
understanding of the magnitude, mechanism, and importance of the respiratory effects in obese 
children and the differences (if any) between obese boys and girls. 

Interpretation of results. We will interpret these results to suggest that obese children have 
significant obesity-related alterations in respiratory function, which predispose them to 
potentially clinical breathing limitations especially in obese children misdiagnosed with asthma, 
all through a common mechanism of low lung volume breathing. This is important knowledge for 
the healthcare provider who may assume obese children have mostly normal lung function and 
that any respiratory symptom in obese children is primarily related to asthma.  
Aim 1b. Introduction: at Rest Lying Supine. The working hypothesis is that childhood obesity 
will alter respiratory function and breathing mechanics when lying supine. Also, we propose that 
obese children with respiratory symptoms misdiagnosed as asthma will have greater changes in 
lung volumes when supine and/or differences in peripheral airways function making them more 
susceptible to low lung volume breathing. The rationale behind the proposed research centers 
on the fact that excess fat on the chest wall will push FRC to extremely low levels in the obese 
children especially when lying supine, thus creating the potential for significant breathing 
limitations especially in obese children misdiagnosed with asthma. To further test the 
hypothesis, we will add an external weight (2.5kg) between the xiphoid process and umbilicus of 
supine nonobese children and measure the change in FRC. This weight is lower than the 5kg 
that we used in preliminary testing, and is representative of the difference in chest wall fat 
observed between our obese and nonobese children. 
Methodology, experimental protocol and measurements. The strategy will be to measure 
respiratory function and breathing mechanics when lying supine at the cardiopulmonary 
exercise station. Baseline data will consist of 15 min of sitting upright in a chair. After obtaining a 
steady-state, we will measure HR, SpO2% (by pulse oximetry), PETCO2, ratings of perceived 
breathlessness (RPB; Borg 0-10 scale), respiratory function (FVC&IC by spirometry, FRC by 
helium dilution, & calculate TLC=IC+FRC) including breathing pattern and tidal flow-volume 
loops 8,9,15,47. Measurements will be made in duplicate, and averaged for analysis, which has 
worked well in preliminary studies in children. During 15 min of lying supine, we will measure the 
same variables in the same way as above. In nonobese children only, we will add a 2.5kg 
external weight between the xiphoid process and umbilicus to simulate the effects of abdominal 
fat on FRC and make the same measurements. 
Expected results. We expect that in comparison with nonobese children many obese children 
will have a marked reduction in FRC when lying supine, which may be correlated with other 
obesity-related measures of body composition. Furthermore, we expect that obese children with 
respiratory symptoms misdiagnosed as asthma will have greater changes in obesity-related 
respiratory function when lying supine. We anticipate a decrease in FRC with the external 
abdominal weight in the nonobese children. We expect this change will be qualitatively similar to 
that observed in obese children. We also expect to have a better understanding of the 
importance of changes in supine respiratory function in obese children, and the differences (if 
any) between obese boys and girls.  
Interpretation of results. We will interpret these results to suggest that obese children have 
significant obesity-related alterations in respiratory function when lying supine, which predispose 
them to potentially clinical breathing limitations, especially in obese children misdiagnosed with 
asthma, all through a common mechanism of low lung volume breathing. This is important 
knowledge for the healthcare provider who sees obese children with symptoms of orthopnea or 
sleep related complaints. These findings would stress the need for further clinical/physiological 
testing in obese children with symptoms when lying supine (i.e., more testing than simple 
seated spirometry). 
Specific Aim 2: Exercise Tolerance in Obese Children 
Introduction: Exercise Tolerance. The working hypothesis is that respiratory effects of obesity in 
children will decrease exercise tolerance (i.e., decreased peak V

O2 in ml/min/kg) but not 

cardiorespiratory fitness (i.e., normal peak V

O2 in percent predicted based on ideal body 
weight), except in those misdiagnosed with asthma. The rationale behind the proposed research 
centers on the fact that conventional thinking suggests that obese children are ‘out of shape’ or 
deconditioned, but when displayed appropriately, cardiorespiratory fitness will be within normal 
limits during graded cycle ergometry. However, in obese children misdiagnosed with asthma, 
cardiorespiratory fitness may be decreased also due to respiratory symptoms and/or avoidance 
of exercise. 
Methodology, experimental protocol and measurements. The strategy will be to measure HR, 
BP, SpO2%, PETCO2, gas exchange (V

E,V

O2,V

CO2, RER), RPB (Borg 0-10 scale), RPE (6-20 
scale), and breathing mechanics (IC,EELV,EILV) including breathing pattern and tidal flow-
volume loops continuously during maximal graded cycle ergometry (step increments of 
10W/min) using standard methods as required for participant safety. A maximal flow-volume 
loop will be measured before and immediately after the exercise to assess the possibility of 
bronchodilation or bronchoconstriction (i.e., exercise induced airway reactivity) during exercise. 
Peak exercise capacity will be evidenced by peak HR, peak work rate, peak V

O2, and peak 
RER obtained during graded cycle ergometry as well as by verification at 105% of maximal work 
rate to exhaustion 67. 
Expected results. We expect that in comparison with nonobese children, obese children will 
have decreased exercise tolerance due to increased body weight but normal cardiorespiratory 
fitness when peak V

O2 is properly evaluated, despite altered breathing mechanics (e.g., EELV, 
expiratory flow limitation) during peak exercise. However, we also expect cardiorespiratory 
fitness may be decreased in obese children misdiagnosed with asthma. We also expect to have 
a better understanding of obesity-related alterations in respiratory function during peak exercise 
in obese children and the differences (if any) between obese boys and girls.  
Interpretation of results. We will interpret these results to suggest that obese children are not 
deconditioned despite significant obesity-related alterations in breathing mechanics during peak 
exercise, except in obese children with respiratory symptoms misdiagnosed as asthma where 
cardiorespiratory fitness may be reduced also. This could be due to greater breathing alterations 
or an avoidance of exercise. These findings are extremely important for healthcare providers 
who examine fitness and associations with chronic disease in obese children, and prescribe 
weight loss and exercise programs.  
Specific Aim 3: Dyspnea on Exertion in Obese Children 
Introduction: DOE During Constant Load Submaximal Exercise. The working hypothesis is that 
childhood obesity will increase DOE and alter respiratory function during constant load 
submaximal cycling, but to a greater extent in obese children with respiratory symptoms 
misdiagnosed as asthma. The rationale behind the proposed research centers on the fact that 
exercising will force EELV to even lower levels in obese children creating the potential for 
significant breathing limitations. If low enough, obese children could experience tidal expiratory 
flow limitation, constrained expiratory tidal volume expansion, and decreased ventilatory 
capacity. It is unclear whether these respiratory effects or changes in body composition will be 
linked with DOE in obese children (i.e., increased RPB as it is in obese adults). Furthermore, we 
propose that obese children with respiratory symptoms misdiagnosed as asthma will have 
greater changes in EELV or differences in peripheral airways function making them more 
susceptible to the limitations of low lung volume breathing and/or increased ratings of dyspnea 
on exertion. 
Methodology, experimental protocol, and measurements. The strategy will be to determine 
respiratory function, breathing mechanics, and DOE during 6 minutes of constant load 
submaximal exercise cycling at 30W (8-9 yr olds) or 40W (10-12 yr olds) and during 6 minutes 
of constant load cycling at 50% of peak V

O2. We will measure HR, BP, SpO2%, PETCO2, gas 

exchange (V

E, V

O2, V

CO2, RER), RPB (Borg 0-10 scale), RPE (Borg 6-20 scale), and breathing 
mechanics (IC,EELV,EILV) including breathing pattern and tidal flow-volume loops continuously 
by standard methods used in prior studies 8,9,15,47. RPB and RPE will be measured every 2 min 
during the tests and the last values recorded will be used for analysis. We chose 30W and 40W 
to represent roughly ventilatory threshold where the exercise is not too easy or too difficult, and 
the participants can exercise continuously for 6–10 min as needed to get adequate assessment 
of RPB. We chose 50% to examine RPB and EELV at the same relative intensity. We selected 
cycling exercise because stationary cycling is affected less by body weight (and in a predictable 
manner) than treadmill exercise, we can impose smaller work rates more precisely, and we can 
compare the results in obese children to our previous findings in obese adults. 
Expected results. We expect to have shown that in comparison with nonobese children 
otherwise healthy obese children have an increase in RPB and altered respiratory function (i.e., 
reduced EELV and increased expiratory flow limitation) during submaximal cycling, which may 
be correlated with other obesity-related changes in body composition and resting respiratory 
function. However, we expect that obese children with respiratory symptoms misdiagnosed as 
asthma will have greater changes in EELV or airway function making them more susceptible to 
low lung volume breathing and/or greater DOE. We also expect to have a better understanding 
of the importance of obesity-related alterations in respiratory function and breathing mechanics 
in obese children during exercise, and the differences (if any) between obese boys and girls. 
Interpretation of results. We will interpret these results to suggest that obese children have 
significant obesity-related alterations in DOE and respiratory function during submaximal 
exercise, which predispose them to potentially clinical breathing limitations, especially in obese 
children misdiagnosed with asthma, all through a common mechanism of low lung volume 
breathing. This is important knowledge for the healthcare provider who sees obese children with 
symptoms on exertion. On the other hand, if obese children have RPB values similar to that in 
nonobese children during exercise, without association with other obesity-related changes, this 
would imply that increased chest wall fat and a lower EELV do not impair breathing during 
exercise as in obese adults, which would be important to document. 
Specific Aim 4: Effects of Weight Loss and Regular Exercise and Weight Gain in Obese 
Children 
Introduction. The working hypothesis is that weight loss (or an equivalent reduction in BMI 
percentile) and regular exercise will improve respiratory function, exercise tolerance, and DOE 
in obese children, including obese children misdiagnosed with asthma, while continued weight 
gain (or increase in BMI percentile) will worsen respiratory function, exercise tolerance, and 
DOE in obese children, including obese children misdiagnosed with asthma, as compared with 
normal weight children after 1 yr. The rationale behind the proposed research centers on the 
fact that FRC at rest, EELV during exercise, and peak V

O2 in ml/min/kg will be increased in 
obese children after weight loss and regular exercise but decreased by continued weight gain. 
The cumulative effect of the weight loss program would thereby reduce the potential for 
breathing limitations at rest and/or during exercise, increase exercise tolerance, and potentially 
reduce DOE in obese boys and girls, including those misdiagnosed with asthma, but weight 
gain would have the reverse effects. 
Methodology, experimental protocol and measurements. The strategy will be to repeat the 
measurements detailed in Aims 1-3 after 1 yr: 1) in 12 obese boys and 12 obese girls after 
weight loss (or an equivalent reduction in BMI percentile) and regular exercise, 2) in 12 obese 
boys and 12 obese girls after weight gain (or an increase in BMI percentile), 3) in 12 obese boys 
and 12 obese girls misdiagnosed with asthma regardless of weight changes or exercise 
participation, and 4) in 12 normal weight boys and 12 normal weight girls. We will test at 1 
yr because parents prefer to have testing done during summer vacation months only.  
Weight Loss and Regular Exercise will be prescribed by attending physicians at the COACH 

Program at Children’s Medical Center (Director Dr. Olga Gupta is co-investigator, see Facilities 
& Letter of Support). However, all obese children will receive standard of care information 
regarding weight loss and physical activity if they elect not to enter COACH. At COACH, the 
participant and parents will meet with a registered dietician who will perform a diet assessment 
and offer a meal plan for an initial weight reduction of ≈10% of body weight or an equivalent 
reduction in BMI percentile (e.g., growth of 2.5 cm would lower BMI percentile by ≈1 based on 
CDC growth charts). This change in weight or in BMI should yield significant changes in 
respiratory function based upon our prior adult data 9 and our preliminary data. Participants will 
then meet with nurses, and physical therapists in the COACH behavior modification class where 
they will be encouraged to participate in 60-min of moderate intensity physical activity per day 3. 
Finally, they will meet with the physician who will discuss clinical test results (i.e., blood work to 
eliminate diabetes, impaired glucose tolerance, impaired fasting glucose, dyslipidemia, liver 
enzyme elevation, vitamin D deficiency or insufficiency), and review the overall diet and physical 
activity plan. We will schedule retesting after 1 yr. 
To increase the likelihood of success of the weight loss and regular exercise, we will establish a 
biweekly phone-contact schedule with COACH participants. We will not interfere with the dietary 
and medical recommendations set forth by COACH faculty, but we will act as liaisons and 
supporters. Specifically, we will be available to answer any questions that might arise regarding 
diet and physical activity recommendations. The results of the constant load and incremental 
exercise tests will be used to provide a guide of appropriate physical activity intensities (e.g., 
based on VTh, peak HR, peak V

O2, & ACSM guidelines). We will invite the participants and 
parents to meet with us and we can demonstrate these physical activity intensities on multiple 
exercise devices depending on the preferences of the patient (e.g., stationary cycle, treadmill, 
etc.). Our goal will be to encourage regular exercise (i.e., increase energy expenditure), not to 
design an exercise training program for improvement of cardiorespiratory fitness. Consequently, 
activity levels will not be quantified (i.e., controlled & supervised exercise intensity, duration, & 
frequency). We will note biweekly whether the children have been active as recommended and 
we will administer the Physical Activity Questionnaire-Children (PAQ-C) before and after 1 yr.  
All children who completed Aims 1-3 will be tested at 1 yr whether they lose weight or gain 
weight. The retesting in nonobese children will be used as control data to document the effect of 
age and growth on respiratory function, exercise tolerance, and DOE. 
Expected results. We expect that a program of weight loss (or an equivalent reduction in BMI 
percentile) and regular exercise will increase FRC at rest and EELV during exercise while 
weight gain will decrease these. The change in FRC and EELV may be correlated with changes 
in body composition (if any). These improvements in respiratory function and breathing 
mechanics may also be associated with decreased DOE as well, while weight gain would have 
the reverse effects. Exercise tolerance will be increased in ml/min/kg but we expect no change 
in cardiorespiratory fitness (i.e., Peak V

O2 as percent predicted based on ideal body weight), 
which may actually be slightly decreased, including those misdiagnosed with asthma. With 
weight gain, exercise tolerance will be decreased but cardiorespiratory fitness would be 
unchanged as well. We also expect to have a better understanding of the importance of weight 
loss and regular exercise and weight gain on respiratory function and breathing mechanics in 
obese children, and the differences (if any) between obese boys and girls. 
Interpretation of results. We will interpret these results to suggest that weight loss (or an 
equivalent reduction in BMI percentile) and regular exercise will have a significant improvement 
on respiratory function, exercise tolerance, and DOE, while weight gain will worsen respiratory 
function, exercise tolerance, and DOE in obese children all through a common mechanism of 
increasing or decreasing EELV. Weight loss may also reduce potential clinical breathing 
limitations at rest and during exercise (e.g., expiratory flow limitation) but weight gain would 
increase limitations. This would be important knowledge for healthcare providers who may not 
appreciate the obesity-related respiratory effects in obese children, and who may assume that 

Total 
n=96 
Obese 
Obese 
misdiagnosed 
with asthma 
Non-
obese 
Boys 
n=24 
n=12 
n=12 
Girls 
n=24 
n=12 
n=12 
symptoms such as breathlessness are just due to cardiovascular deconditioning and/or asthma. 
In contrast, if obese children have a simple increase in EELV with weight loss without 
association with other changes in respiratory function, exercise tolerance, and DOE, this would 
be clinically important to document as well. The same would be true if there were no negative 
effects of weight gain. These findings, while very unlikely, would suggest that chest wall fat and 
changes in respiratory function are not the lone sources of obesity-related breathing limitations 
and bring to question what effects weight loss and regular exercise, and weight gain might have 
on respiratory function, exercise tolerance, and DOE.  
Subject Selection 
Prepubescence. We have elected to study the effects of obesity in otherwise healthy 
prepubescent children for three reasons. One, this level of obesity is very prevalent in 
prepubescent children. Two, they may benefit the most from early intervention to prevent the 
development of further obesity, increased cardiovascular risk factors, and/or comorbidities like 
type-2 diabetes, which usually manifest after puberty. Three, boys and girls should have very 
similar predicted respiratory function values 64 and pubertal effects on exercise responses 
should be minimal 76.  
Matching of groups. Nonobese children will have age and sex specific BMI between 16th and 
84th percentile in order to exclude children who are overweight and/or possibly underweight. 
Both the groups will be otherwise healthy since most obesity-related metabolic issues occur 
after puberty. 
Recruitment of subjects. We will recruit participants by BMI percentile, age, and gender only. 
We will recruit participants from large pediatric practices, Children’s clinics (My Children’s 
Clinics), emails throughout Texas Health Hospital System, paid sites such as Center Watch and 
Sunshine Day, community programs (e.g., 7 Day Fitness Academy, Parkland Hospital Health 
Camps, Get UP and Go programs), advertisements in local newspapers, and ads in other media 
sources). Also, approximately 1250 patients enter the COACH program per year with an 
average age of 11.6±2.9 yr. Males make up 42% of the population and race/ethnic background 
is approximately 55/25/4/16 (W/AA/H/O). We are very confident in our ability to recruit and 
retain participants. Our preliminary retention numbers are quite good (14 of 16). Also, based 
upon our preliminary data, 50% of the obese children we tested last summer lost weight and 
50% gained weight, and we had no contact with these children since last summer. We will 
recruit heavily before and during summer. We will recruit, and search COACH and medical 
practice records for children diagnosed with asthma who have not had pulmonary function tests 
to confirm the presence of asthma. 
Subjects. A total of 96 prepubescent children, 48 boys (36 obese) and 48 girls (36 obese), who 
are otherwise healthy, will complete all four aims. 24 of these obese children (12 girls & 12 
boys) may have respiratory symptoms, which were misdiagnosed as asthma (i.e., not confirmed 
by lung function tests). We will confirm the absence of asthma by spirometry before and after 
bronchodilator, and by bronchial challenge test with methacholine 1,45.  We will include children 
between 8-12 years old as long as they have a Tanner stage ≤ 3 and can successfully perform 
pulmonary function tests, exercise tests, and ratings of breathlessness. We anticipate that 
children less than 8 yr old could have difficulty performing accurate pulmonary function and 
exercise tests and will be excluded from participation 45. Including children within 8-12 years old 
should increase the likelihood of meeting our recruitment goals. In future studies we anticipate 
studying older children and adolescents (also see Subject criteria Human Subjects Section).  
Statistical Considerations 
Co-investigator Beverley Huet (UT Southwestern Division of Biostatistics) is the statistical co-
investigator on this project and has assisted in the 
development of the statistical plan; she will also 

direct the data analysis on an on-going basis.  
Statistical Plan. Our plan is to complete testing in nonobese and two obese groups, boys and 
girls separately but concurrently. Thus, sample size calculations are based upon within-gender 
comparisons per allocation in table at right. In Aims 1-3, comparisons will be made between 
nonobese, obese, and obese children misdiagnosed with asthma within the same gender with 
analysis of variance models (ANOVA). Pairwise group comparisons will be made using least 
squares means contrasts derived from the linear models. Data transformations or 
nonparametric tests will be utilized as needed to meet analysis assumptions. At baseline, 
ISSAC and ECRHS asthma screening questionnaire scores will be compared among groups 
with the Kruskal-Wallis test. Comparisons for Aim 4 will be made similarly, but with the addition 
of repeated measurements to assess the two obese groups and the nonobese children of the 
same gender at baseline and at 1 year of follow-up. Additional assessments of gender effects 
will be performed as part of a secondary analysis, but we are not powering the study to detect 
interaction by gender. Alpha is set at 0.05 for ANOVA and planned contrast power (PASS 11, 
NCSS, LLC, Kaysville, UT), described below 75. Data will be analyzed using SAS version 9.4 
(SAS Institute, Inc., Cary, NC). 
Aim 1. Our primary variable is FRC measured while seated upright (Aim 1a) and when lying 
supine (Aim 1b). Based upon our preliminary data for seated FRC (%TLC) in nonobese boys 
(mean± SD, 42.4±2.5) and obese boys (36.5±6.2), it is calculated that a mean difference in FRC 
(%TLC) of 5.1 can be detected with statistical power of 81%, alpha=0.05, pooled SD of 5.0, 
comparing 24 obese to 12 nonobese children or to 12 obese children misdiagnosed with 
asthma. Our data also show that the differences may be larger for girls than boys, so power for 
a test between obese girls and obese girls misdiagnosed with asthma will be at least 80%. 
Similarly, for children lying supine, nonobese boys have an FRC (%TLC) of 34.4±8.8 vs. 
23.1±3.4 obese, a more conservative difference of 6.0 %TLC is detectable with 80% power. In 
our formal protocol, we anticipate being able to make precise and reproducible measurements, 
and have confidence that we can meet our goals with the sample size proposed. Preliminary 
data demonstrate that these measures and effect sizes are feasible. 
Aim 2. Our primary variable is peak V

O2. From our preliminary peak V

O2 (ml/min/kg) for 
nonobese (41.9±4.9) and obese boys (26.3±3.9), it is calculated that our study will yield power 
of 80% to detect a clinically relevant mean difference of 4.7 ml/min/kg for obese versus 
nonobese children or obese children misdiagnosed with asthma, anticipating smaller differences 
than the 16 ml/min/kg mean difference observed from our data in obese versus nonobese. 
Effect size estimates for girls are anticipated to be similar.  
Aim 3. Our primary variable for Aim 3 is RPB during constant load exercise. Preliminary data 
from children in our lab show that RPB at constant load is very similar between nonobese and 
obese children of both genders (e.g., girls, 3.4±0.6 vs. 3.3±1.5), which would not be detectable 
with a reasonable sample size. This is in contrast with our previous studies of RPB in nonobese 
(2.1±1.3) 46 and obese women with DOE (4.7±1.2) 8, where only 6 subjects would have been 
necessary per group to detect significant differences. At this time our preliminary sample of 
children is small, and we anticipate that future experience could be more like that in the adults, 
but we need to carry out the designed studies at a feasible sample size (96 total including 
nonobese controls) to find out. These effects contrast with another important variable for Aim 3; 
the EELV during constant load exercise. Based upon EELV (%TLC) data from obese girls 
(28±3) during exercise, we would be able to detect differences of 3.2%TLC between the 3 
groups at greater than 80% power (also note how low the EELV is in the obese children during 
exercise). We expect similar differences and power in studies with boys. 

Aim 4. Primary variables for Aim 4 are change in FRC at rest, peak V

O2, RPB, and EELV during 
constant load exercise from before to after 1 year of follow-up. We are gaining experience with 
studies in children; current preliminary data from n=7 obese children yield similar mean 
differences and standard deviations as in adults. Therefore, based upon the change in EELV 
during constant load exercise in obese men before (35±5) and after (39±3) a loss of 13% of 
body fat 9, and the change in RPB during constant load exercise in obese women before 
(4.7±1.1) and after (3.2±1.6) weight loss, our sample will have sufficient power (.80, alpha=0.05) 
to detect meaningful paired differences (e.g., 1.5 in RPB) with weight loss and regular exercise. 
We will retest all children after ~1 yr. We expect less than 10% attrition and repeated data on 
nearly all children will be available for this Aim. Combining the two obese groups (with and with 
asthma misdiagnosis), the children will be divided into obese who lost weight, obese who 
gained weight, and control normal weight children and respiratory changes will be compared 
between groups with ANOVA as described for Aims 1-3. While these categorized weight 
changes have clinical appeal, weight change analyzed as a continuous variable may be more 
powerful and informative. Hence, change at 1year minus baseline will also be evaluated with 
Spearman or Pearson correlations to quantify the association between 1-year weight change 
and the change for respiratory function, exercise tolerance, and DOE variables and, with the 36 
obese participants analyzed (by gender), a correlation of 0.45 can be detected with 80% power. 
To evaluate gender effects, baseline and follow-up measurements for FRC, peakV

O2, RPB, and 
EELV will be analyzed in mixed-effects repeated measures models with the study participant 
included as a random effect. Interactions between gender, study group (obese, obese 
misdiagnosed with asthma, nonobese), and time can be assessed as fixed effects; weight 
change effect will be modeled as a covariate. PAQ-C score changes will also be assessed with 
repeated measures models. 
Anticipated problems and potential solutions 
The anticipated changes in respiratory function (particularly FRC) should be apparent at this 
level of obesity. A 10.5 yr old boy at 4’ 8 ½” or 143.3 cm at the 95th percentile will have a body 
mass of 103-105 lb. The upper limit for that same child at 150% of the 95th BMI percentile is 155 
lbs. Thus, the range for this example child is ~50 lbs (22.7 kg). This increase in weight is 
significant and should produce the type of effects we expect as confirmed in our preliminary 
data. However, if this does not hold true, we do not believe increasing the range of obesity to 
include those with BMI scores > 150% of the 95th percentile would yield a subject population 
that is representative of the majority of obese children. We intend to perform testing for Aims 1a 
and 1b in two sessions (≈2.5 hr each). This approach has been very attractive to the children 
and parents without complaint and the children have performed upright and supine respiratory 
function tests without difficulty. Also, if the weight placed on the abdomen is not tolerable, we 
will investigate other methods like a weighted vest or broader distribution of the weight over the 
chest wall. We have not found our standard graded cycle ergometry protocol to be a problem 
when testing peak performance in obese or nonobese children, especially when confirmed at 
supra-maximal work rates. However, if we find the protocol difficult for them, we can try different 
stage increments, or try a non-continuous exercise test to determine peak exercise capacity. 
Also, we believe that the level of obesity planned for this study will not preclude the obese 
children from completing exercise testing at 30 or 40W as in the nonobese children or with our 
ability to examine respiratory function, breathing mechanics, and DOE during exercise at 30 or 
40W. Nevertheless, we will complete a second exercise session at 50% of peak V

O2 just to be 
sure. So far all procedures and testing has been very well-tolerated and without complaint. 
Weight loss success is always a concern that involves many personal and family-related issues. 

However, all of the investigators are aware of these difficulties and have the insight and 
flexibility to try different techniques to overcome obstacles that may arise. However, by testing 
the participants who are not successful with weight loss but actually gain weight, we believe we 
have dramatically increased the value of Aim 4. However, some subjects may have no change 
in body composition or %body fat. We anticipate this will not occur very often since all children 
will gain weight, fat weight, and/or fat free weight over the course of 1 yr. 
Tentative Timetable 
It will take ≈5 yr to complete the proposed studies. Roughly 30 to 60 children will be studied 
each year. Starting in year two, half will be repeat studies and half will be new participants. The 
last year will be devoted mostly to repeat studies. All projects will run concurrently but most of 
the data collection will take place in the summers with the exception of the obese children with 
respiratory symptoms misdiagnosed with asthma. These children may be able to complete 
testing throughout the year. We are highly confident that we can successfully complete this 
extremely important but ambitious project in 5 yr as planned.