Impact of Treatment of Mild Sleep-Disordered Breathing on Children's Health
Phase: NA
Conditions: Sleep-Disordered Breathing
Sponsor: Brigham and Women's Hospital

IMPACT OF TREATMENT OF MILD SLEEP-DISORDERED BREATHING ON 
CHILDREN’S HEALTH 
Abbreviated title: Pediatric Adenotonsillectomy for Snoring; PATS 
 
Clinical Coordinating Center 
Children’s Hospital of Philadelphia 
P.I.’s Susan Furth, MD Lead CCC, Ignacio Tapia, M.D., MS 
 
Data Coordinating Center 
Brigham and Women’s Hospital---- 
MPIs: Susan Redline, M.D., M.P.H., Rui Wang, Ph.D. 
Protocol Version: 26     December 19, 2022  
Incorporates: Amendment #1 
Dated November 17, 2015 
 
Amendment #2 
Dated February 5, 2016 
 
Amendment #3 
Dated April 21, 2016 
 
Amendment #4 
Dated August 23, 2016 
 
Amendment #5 
Dated July 20, 2016 (administrative change) 
 
Amendment #6 
Dated November 21, 2016 
 
Amendment #7 
Dated February 10, 2017 
 
Amendment #8 
Dated July 28, 2017 
 
Amendment #9 
Dated August 18, 2017 
 
Amendment #10 
Dated November 3, 2017 
 
Amendment #11 
Dated February 19, 2018 
 
Amendment #16 
Dated April 26, 2018 
 
Amendment #17 
Dated August 1, 2018 
 
Amendment #18 
Dated November 14, 2018 
 
Amendment #20 
Dated February 19, 2019 
 
Amendment #21 
Dated April 15, 2019 
 
Amendment #28 
Dated May 7, 2020 
 
Amendment #29 
Dated July 27, 2020 
 
Amendment #31 
Dated October 2,2020 
 
Amendment #32 
Dated June 23, 2021 
 
Amendment #33 
Dated October 12, 2021 
 
Amendment #34 
Dated March 15, 2022 
 
Amendment #35 
Dated April 25, 2022 
 
Amendment #36 
Submitted December 19, 2022 
 
 
 
 

 
 
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Table of Contents 
LIST OF ABBREVIATIONS ............................................................................................ 6 
STUDY SUMMARY......................................................................................................... 7 
Rationale for the PATS Study ....................................................................................... 8 
1. 
Study Objectives .............................................................................................. 14 
1.1. 
Primary Objectives ............................................................................... 14 
1.2. 
Secondary Objectives ........................................................................... 14 
2. 
Study Design ..................................................................................................... 15 
2.1. 
General Design .................................................................................... 15 
2.2. 
Study Schema ...................................................................................... 16 
2.3. 
Blinding and Maintaining the Blind ........................................................ 16 
2.4. 
Overview of Study Design .................................................................... 17 
2.4.1. Screening Visit ........................................................................... 17 
2.4.2. Baseline Visit ............................................................................. 17 
2.4.3. Follow-up Contacts .................................................................... 17 
2.5. 
Study Organization ............................................................................... 18 
3. 
Study Endpoints ............................................................................................... 19 
3.1. 
Primary Endpoint .................................................................................. 19 
3.2. 
Secondary Endpoints ........................................................................... 19 
3.3. 
Sample Descriptors and Potential Effect Modifiers ............................... 20 
4. 
Participant Criteria ............................................................................................ 22 
4.1. 
Study Population .................................................................................. 22 
4.2. 
Inclusion Criteria ................................................................................... 22 
4.3. 
Exclusion Criteria .................................................................................. 22 
4.4. 
Deferral Criteria .................................................................................... 23 
5. 
Participant Recruitment and Consent ............................................................. 24 
5.1. 
Participant Recruitment ........................................................................ 24 
5.2. 
Overview of Procedures ....................................................................... 25 
5.3. 
Informed Consent ................................................................................. 26 
5.3.1. HIPAA Authorization .................................................................. 28 
5.3.2. Patient Confidentiality ................................................................ 28 
6. 
Risks and Benefits to Participants .................................................................. 29 
6.1. 
General Statement about Risk versus Benefit ...................................... 29 

 
 
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6.2. 
Potential Risks ...................................................................................... 29 
6.3. 
PSG Risks ............................................................................................ 32 
6.4. 
Risks Identified in Behavioral Testing ................................................... 32 
6.5. 
Phlebotomy risks .................................................................................. 32 
6.5.1. Burden to participant .................................................................. 32 
6.6. 
Potential Benefits to Participants and Others ........................................ 32 
6.7. 
Alternatives ........................................................................................... 33 
7. 
Study Interventions .......................................................................................... 33 
7.1. 
Sleep and Healthy Lifestyle Education .................................................. 33 
7.2. 
Other Supportive Care .......................................................................... 33 
8. 
Procedures Specific to Treatment Arm Assignment ...................................... 33 
8.1. 
Surgical Treatment – Early Adenotonsillectomy (eAT) .......................... 34 
8.2. 
Participants Randomized to Watchful Waiting with Supportive Care ..... 34 
9. 
Study Procedures ............................................................................................. 34 
9.1. 
Polysomnography (PSG) ...................................................................... 34 
9.1.1. PSG Methods Overview ............................................................. 34 
9.1.2. Screening PSG .......................................................................... 35 
9.1.3. 12 Month Endpoint PSG ............................................................ 35 
9.1.4. Scheduling the PSG .................................................................. 35 
9.1.5. PSG Procedures ........................................................................ 35 
9.1.6. Montage..................................................................................... 35 
9.1.7. Central Transmission of PSG Data ............................................ 36 
9.2. 
Study procedures and details of the baseline visit ................................ 36 
9.2.1. Orientation ................................................................................. 37 
9.2.2. Urine collection for cotinine ........................................................ 37 
9.2.3. Morning blood pressure ............................................................. 37 
9.2.4. Anthropometry ........................................................................... 37 
9.2.5. Physical examination ................................................................. 37 
9.2.6. Breakfast/Snack and rest period ................................................ 37 
9.2.7. Behavioral performance testing and questionnaire completion .. 38 
9.2.8. Venipuncture for IgE .................................................................. 39 
9.2.9. Medical status ............................................................................ 39 
9.2.10. Sleep educational material is reviewed. ..................................... 39 

 
 
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9.3. 
Randomization ..................................................................................... 39 
9.4. 
Teacher report forms ................................................................. 40 
9.5. 
Monthly caregiver interviews ...................................................... 40 
9.6. 
Health care utilization (HCU) and electronic medical record (EMR) 
surveillance ............................................................................................ 41 
9.7. 
Study Visits (see Appendix A for Summary of Visit Schedule and 
Procedures) ................................................................................................................. 41 
9.7.1. Screening visit/PSG eligibility – Day -60 to -1 ............................ 41 
9.7.2. Baseline visit – Day 0 ................................................................. 41 
9.7.3. Monthly Check-In – Months 1, 2, 3, 4, 5, 7, 8, 9, 10, 11 ............. 42 
9.7.4. Remote Interim Visit – Month 6 .................................................. 42 
9.7.5. Endpoint PSG – Month 12 ......................................................... 42 
9.7.6. Endpoint daytime visit – Month 12 ............................................. 42 
9.7.1. Post-participation Surveys ......................................................... 42 
9.8. 
Potential Treatment Failures ................................................................. 42 
9.9. 
Adverse Event Definitions and Reports ................................................ 43 
9.9.1. Overview of Surveillance for Adverse Events and Safety Indices
 
43 
9.9.2. Urgent Medical Referral Criteria ................................................. 44 
9.9.3. Definitions .................................................................................. 44 
9.9.4. Adverse Event Reporting Period ................................................ 47 
9.9.5. Recording and Reporting Adverse Events ................................. 47 
9.9.6. Hospitalization, Prolonged Hospitalization or Surgery ................ 47 
9.9.7. Follow Up on Adverse Events .................................................... 48 
9.9.8. Post-Study Adverse Event Follow-Up ........................................ 48 
9.9.9. Treatment Failure ...................................................................... 48 
9.9.10. Reporting Serious Adverse Events ............................................ 49 
10. 
Medical Monitoring ........................................................................................... 50 
10.1. 
Medical Safety Monitor ......................................................................... 50 
10.2. 
Serious Adverse Event and Unblinding of Treatment Arm .................... 51 
10.3. 
Management of Associated Adverse Events and Discontinuation of 
Treatment .......................................................................................................... 51 
10.4. 
Other Study Medical Monitoring and Reporting .................................... 51 
10.4.1. Surgical Monitoring .................................................................... 51 

 
 
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10.4.2. Severe OSA on PSG ................................................................. 52 
10.4.3. Baseline ..................................................................................... 52 
10.4.4. Follow-Up .................................................................................. 52 
10.4.5. Behavioral testing ...................................................................... 52 
11. 
Participant Refusal ........................................................................................... 52 
12. 
Withdraw/Premature Termination .................................................................... 53 
13. 
Missed Appointments ...................................................................................... 53 
14. 
Quality Assurance ............................................................................................ 53 
14.1. 
Quality Control Procedures ................................................................... 53 
14.2. 
Centralized Training ............................................................................. 53 
14.3. 
Certification Processes ......................................................................... 54 
15. 
Administrative ................................................................................................... 54 
15.1. 
Institutional Review Board .................................................................... 54 
15.2. 
Record Keeping .................................................................................... 54 
15.2.1. Source Documents .................................................................... 55 
15.2.2. Case Report Forms (CRF) ......................................................... 55 
15.2.3. Record Retention ....................................................................... 55 
16. 
Data Management and Analysis ...................................................................... 55 
16.1. 
Study Monitoring, Auditing, and Inspecting ........................................... 55 
16.1.1. Recruitment and Retention Monitoring ....................................... 55 
16.1.2. Study Monitoring Plan/Site Visits ............................................... 55 
16.1.3. Site Visits ................................................................................... 56 
16.1.4. Recruitment and Retention Monitoring ....................................... 56 
16.1.5. Ongoing training ........................................................................ 57 
16.1.6. Auditing and Inspecting .............................................................. 57 
17. 
Data Safety and Monitoring Plan ..................................................................... 57 
18. 
Ethical Considerations ..................................................................................... 58 
19. 
Statistical Analysis Plan................................................................................... 58 
APPENDIX A: PATS VISIT SCHEDULE ...................................................................... 68 
APPENDIX B: PROJECT TIMETABLE ........................................................................ 70 
APPENDIX C: ROSTER OF DSMB MEMBERS ........................................................... 71 
  
 

 
 
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LIST OF ABBREVIATIONS 
 
ABAS 
Adaptive Behavior Assessment   
ADHD 
Attention deficit hyperactivity disorder 
AHI 
Apnea hypopnea index 
AT 
Adenotonsillectomy 
BRIEF 
Behavior Rating Inventory of Executive Function 
BMI 
Body mass index 
BP 
Blood pressure 
CBCL 
Child Behavior Checklist 
CHOP 
Children’s Hospital of Philadelphia 
CCC 
Clinical Coordinating Center 
CRF 
Case report form 
DCC 
Data Coordinating Center 
DMS 
Data Management System 
DSMB 
Data Safety and Monitoring Board 
eAT 
Early adenotonsillectomy 
EEG 
Electroencephalogram 
ECG 
Electrocardiogram 
EDC 
Electronic data capture 
EDF 
European data format 
EMG 
Electromyogram 
EMR 
Electronic medical record 
ENT 
Ear Nose Throat 
EOG 
Electrooculogram 
FTP 
File transport protocol 
GNG 
Go-No-Go 
HCU 
Health care utilization 
IRB 
Institutional Review Board 
ISAAC 
International Study Of Asthma And Allergies In Childhood 
MOP 
Manual of procedures 
MSDB 
Mild sleep disordered breathing 
NHLBI 
National Heart Lung Blood Institute 
OAI 
Obstructive apnea index 
OSA 
Obstructive sleep apnea 
PedsQL 
Pediatric Quality of Life Inventory 
PSQ 
Pediatric Sleep Questionnaire 
PSG 
Polysomnogram 
RCT 
Randomized controlled trial 
SDB 
Sleep-disordered breathing 
SES 
Socioeconomic status 
WWSC 
Watchful Waiting with Support Care 
 
 
 

 
 
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STUDY SUMMARY 
 
Title 
Impact of Treatment of Mild Sleep Disordered Breathing (MSDB) 
on Children’s Health 
Short Title  
PATS (Pediatric Adenotonsillectomy for Snoring) 
Special Population 
Children (male and female), ages 3.0 to 12.9  years of age 
Methodology 
Parallel, randomized, single blind, multi-center design 
Study Duration 
5 years 
Clinical Study Center(s) 
Multicenter (7) 
Objectives 
1. Determine the effect of early adenotonsillectomy (eAT) on 
behavior (primary outcome), sleep-disordered breathing (SDB) 
symptoms, and quality of life.   
2. Determine the effect of AT on health care utilization (HCU) in 
children with MSDB.  
3. Identify factors that moderate the response to surgery: age, 
socioeconomic status, asthma and atopy, second hand tobacco 
smoke exposure, family functioning, short sleep duration, 
obesity, minority status 
Number of Participants 
460 
Diagnosis and Main 
Inclusion Criteria 
Diagnosis of mild sleep-disordered breathing (MSDB) defined by 
an obstructive apnea index (OAI) <1/hr or an apnea hypopnea 
index (AHI) <or =3.0 /hr confirmed by nocturnal 
polysomnography (PSG); parental report of habitual snoring (on 
average occurring > 3 nights per week); tonsillar hypertrophy ≥2 
+; deemed to be a surgical candidate for adenotonsillectomy 
(AT) by ENT evaluation 
Study Intervention 
Early Adenotonsillectomy (eAT) 
Reference Intervention 
Watchful Waiting with Supportive Care (WWSC) 
Duration of Follow-Up 
12 months 
Statistical Methodology 
Primary analyses will follow the “intention-to-treat” principle; that 
is, individuals will be analyzed according to their assigned 
treatment group, whether or not they remain on the study 
treatment.  The co-primary outcomes will be the change in 
executive behavior relating to self-regulation and organizational 
skills (as measured by the Behavior Rating Inventory of 
Executive Function [BRIEF2/P] Global Composite Score) and 
vigilance (as measured on the Go-No-Go [GNG]) between the 
eAT and WWSC groups at 12 months.  Analyses addressing 
secondary aims will be considered exploratory.  Details of the 
statistical plan are outlined in the Data Coordinating Center 
application.    

 
 
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Rationale for the PATS Study 
 
Adenotonsillectomies are performed more than 500,000 times per year in the US1, and 
are the 2nd most common surgery performed under general anesthesia in children2.  The 
majority of surgeries are performed for obstructed breathing rather than for infection or 
other indications2.  We recently addressed the role of adenotonsillectomy (AT) in 
improving the 7-month neurocognitive, behavioral and health outcomes of children with 
frank obstructive sleep apnea (OSA). The results of this rigorous, multicenter, 
randomized controlled trial (Childhood Adenotonsillectomy Trial; [CHAT]) were published 
in the New England Journal of Medicine3 and provided critically important  data 
indicating that AT compared to watchful waiting resulted in improved behavior, quality of 
life, sleep-disordered breathing (SDB) symptoms and polysomnographic parameters. 
However, this study addressed the role of surgery in the minority of operative candidates 
who have frank OSA, only one form of SDB on a spectrum that includes a more common 
phenotype, namely primary snoring (also termed mild SDB [MSDB])4.  MSDB is 
characterized by snoring without frank obstruction or gas exchange abnormalities and 
has a population prevalence of about 10% in children5.  Since most surgeries for 
obstructed breathing are performed for MSDB rather than OSA6, the next logical 
question is whether surgery is also effective in improving symptoms and health 
outcomes in this large group of children.  
 
We propose to take advantage of a successful collaboration of leaders in sleep 
medicine, otolaryngology and clinical trials to efficiently leverage experiences from 
CHAT to evaluate the role of AT in children with MSDB. We aim to resolve uncertainties 
on management approaches for pediatric MSDB by addressing several critical issues: a) 
assess outcomes of importance to children and their families - in particular, the patient-
reported outcomes of behavior, quality of life, and sleep disturbances; b) examine 
differences in treatment responses among children who are at increased risk for MSDB, 
such as pre-school children, minorities, and children with asthma or obesity; c) evaluate 
health care utilization (HCU) as a unique and timely outcome; d) assess moderating 
influences of second hand smoke, insufficient sleep, socioeconomic status (SES)  and 
family functioning; e) examine longer term outcomes than were feasible in the CHAT 
study (12 months). 
 
These aims have substantial public health significance given the high morbidity of SDB 
in children7 and the  vulnerability of certain groups such as African Americans, who have 
a higher prevalence8 and increased severity of SDB compared to children of other 
races3.  Large health care costs arise from AT, which is also associated with surgical 
morbidity, including significant hemorrhage in 3% of patients, and death in 1 in 16 000 to 
35 0002.  Although the cumulative cost of AT is high, these costs must be balanced by 
the costs of untreated MSDB. Research from Israel suggests that children with OSA 
have increased HCU in the year prior to their diagnosis9, which declines by one third 
following AT10.  Given the rising health care costs in the US11, there is a critical need to 
address this question in the US and to evaluate children with MSDB who constitute the 
majority of children with SDB.  Finally, tremendous practice and geographic variability 
exists in the management of SDB due to the paucity of clear guidelines. For example, 
while the American Academy of Pediatrics and the American Academy of Sleep 
Medicine recommend polysomnography (PSG) prior to AT, with subsequent surgery only 
if PSG shows OSA12;13, other medical societies do not support this view2;14.  Indeed. the 
American Academy of Otolaryngology—Head and Neck Surgery Clinical Practice 
Guideline on Polysomnography for Sleep-Disordered Breathing Prior to 

 
 
9 
 
Tonsillectomy in Children recommends PSG in children with suspected sleep-
disordered breathing only if the child has complex medical conditions such as 
Down syndrome, or if the need for surgery is uncertain and there is a discrepancy 
between symptoms and clinical exam14.  In fact, PSG is performed prior to AT in only 
10% of children undergoing surgery for suspected OSA.6  Less than 50% of children 
scheduled for AT for suspected OSA actually have abnormal PSGs; the remainder have 
MSDB3;7. This study will provide evidence on whether children with “normal” PSGs 
benefit from surgery, by randomizing children to the two most common managements for 
MSDB: adenotonsillectomy and observation.  The findings will have key implications for 
disease management, including the need for pre-operative PSGs to establish the 
diagnosis of OSA. 
 
Significance 
 
Mild sleep-disordered breathing (MSDB; snoring without frank obstruction or gas 
exchange abnormalities on polysomnography15) is an extremely common disorder.  
Large studies of more than 1,000 children each have shown an MSDB prevalence of 
10.5-17.1% in young children in the USA5;16;17, and MSDB is one of the commonest 
indications for adenotonsillectomy (AT).  Given the high prevalence of the condition, the 
relevance of the study’s outcomes to patients and the health care system, the large 
geographical variations in care resulting from lack of data on the role of surgery and 
polysomnography (PSG) in this population, and the vulnerability of a young population 
(often minority) with the disorder, MSDB is of great clinical and public health relevance.  
The proposed study will address gaps in the literature by: a) enrolling very young 
children who are at greatest risk for MSDB and its potential neurobehavioral 
consequences; b) following children for a full year after intervention to obtain reliable 
estimates of changes in health care utilization and behavior that are not biased by 
seasonal effects18; c) analyzing the influence of both individual and family-level factors in 
modifying responses to treatment; d) enrolling children with MSDB, who are the largest 
group who undergo AT, an expensive procedure with significant morbidity. The proposed 
study (Pediatric Adenotonsillectomy Trial for Snoring; PATS) will provide data from a 
randomized controlled trial that for the first time will address the role of AT in children 
with MSDB, and define the subgroups most suitable for this procedure. 
 
Importance and Public Health Significance: Tonsillectomies are performed more than 
500,000 times per year in the US and are the second most common surgery under 
general anesthesia in children, resulting in $400 million annual costs. 
Adenotonsillectomy is most commonly performed for the treatment of pediatric 
obstructive sleep apnea or MSDB, often with the expectation that surgery will improve 
behavior, quality of life and cognition. The recently completed CHAT study demonstrated 
that surgery resulted in improved patient and family centered outcomes - behavior and 
quality of life - in children ages 5-9 years with polysomnographic evidence of OSA, 
although cognitive ability did not change3. This new information will assist with clinical 
decision making for children with OSA.  However, data are not available on the benefits 
of surgery for treatment of MSDB, or for treating younger children, who may be most 
sensitive to the effects of sleep problems due to developmental plasticity. There is a 
pressing need to address this question since young children with MSDB constitute the 
majority of children referred for AT19.  Lack of data has led to huge geographical 
variability in the management of this disorder, with the rate of AT per 10,000 children 
varying from 28.9 in the West to 125.1 in the South of the USA19. Inappropriate surgery 
may unnecessarily expose children to risk, and the health care system to considerable 

 
 
10 
 
costs. Conversely, withholding effective treatment from children likely to respond could 
result in substantial short and long-term health burdens to the child, their family, and 
society. This information is also needed due to the increased prevalence of SDB among 
vulnerable groups of children, such as racial minorities.  Filling these gaps in knowledge 
is critical for informing clinical guidelines and decision-making, and appropriate utilization 
of interventions in populations most likely to benefit.  
 
MSDB: Prevalence and Health Impact: Most tonsillectomies are performed for 
obstructed breathing (determined clinically by history and examination) rather than for 
infection or other indications. The vast majority of children undergoing AT for obstructed 
breathing do not undergo PSG: only 4% of pediatric otolaryngologists obtain 
polysomnograms “most of the time” to diagnose OSA prior to AT20.  Patients at major 
academic medical centers may be more likely to undergo polysomnography before AT, 
in part because more complex patients are evaluated at these centers (e.g., infants or 
patients with major comorbidities, unlike those eligible for the current study). However, 
even at academic centers, the majority of children undergoing AT for SDB do not have 
polysomnography.  For example, 977 children underwent AT at Children’s Hospital of 
Philadelphia between May 2012 to March 2013, of whom only 386 (39%) had a 
polysomnogram in the preceding 12 months.  Thus, 61% did not have 
polysomnographically proven OSA.  Although some of these surgeries may have been 
performed for infectious or other non-obstructive reasons such as tumor, the number far 
exceeds the percentage of AT performed at Children’s Hospital of Philadelphia for non-
obstructive reasons (~20%; personal communication from Lisa Elden, MD).  Thus, the 
majority of children undergoing AT for symptoms of SDB do not have polysomnography.   
 
Of children with clinically suspected SDB, numerous studies have shown that when PSG 
is performed, approximately 50% do not have frank airway occlusion or gas exchange 
abnormalities3;7, but have MSDB and are classified as “primary snorers.”  Thus, AT for 
MSDB is usual care. Snoring is due to vibration of upper airway tissues during sleep, 
secondary to upper airway narrowing and sleep-induced pharyngeal hypotonia, and 
results from increased upper airway resistance. The consequent airflow limitation may 
cause a variety of physiological responses, including sleep fragmentation, autonomic 
nervous system dysfunction, vagal neuroreceptor activation and gastroesophageal 
reflux.  Of note, snoring itself, in the absence of apnea, has been linked to 
hypertension21 and asthma exacerbations22;23 in adults, and to hypertension24, behavioral 
disturbances25 and poor asthma control26 in children.  Evidence exists that snoring is a 
mechanical stress and may  cause upper airway neuronal damage and myopathy 
secondary to vibrational damage (similar to hand-arm vibration syndrome caused by 
vibrating hand-held tools)27-29, neutrophilic airway inflammation (characteristic of severe 
and difficult to treat asthma)30;31,  and direct damage to carotid vessels32.  
 
Both OSA and MSDB have been shown to be associated with behavioral dysfunction in 
children (including attentional issues, hyperactivity, social withdrawal and anxiety), which 
has a significant potential to impair learning, academic performance, and quality of life, 
and thus to negatively impact childhood health and well-being as well as curtail future 
adult potential.  The CHAT study is the only large, randomized controlled trial of 
neurobehavioral outcomes in children with SDB3.  This study was limited to children with 

 
 
11 
 
polysomnographically-proven OSA.  We showed that children with OSA had significant 
improvements in the important areas of behavior, quality of life, SDB symptoms and 
polysomnographic parameters following AT compared to children randomized to 
watchful waiting with supportive care (WWSC), although no improvements were seen in 
cognition over a 7 month observation period3.  However, this study showed no 
correlation between the severity of polysomnographic abnormalities and behavioral 
deficits, or with the behavioral response to intervention. For example, although there was 
a significant improvement in the Child Behavior Checklist (CBCL) measure of behavior in 
the eAT group compared to the WWSC group (change over 6 months of -3.8 + 8.1 vs -
1.2 + 7.9, p<0.001), the baseline CBCL did not correlate with the baseline apnea 
hypopnea index (AHI; Figure 1) or other measures of PSG severity.  Similarly, studies in 
adults have failed to show a relationship between polysomnographic severity and 
daytime outcomes33.  Small, nonrandomized observational studies have shown impaired 
attention, social problems, anxiety and depressive symptoms in children with MSDB 
without OSA, as compared to controls34;35.  The importance of behavioral outcomes in 
children with MSDB is also supported by preliminary research by members of our team.  
Chervin studied 40 children with OSA, 38 children with MSDB and 26 controls25.  
Children with both OSA and MSDB had worse behavior and hyperactivity compared to 
controls, and in both groups, behavior improved 12 months after AT.  A comparison of 
the OSA and MSDB groups showed that they had similar behavioral scores at baseline, 
and also both showed similar levels of behavioral improvements after AT, suggesting 
that MSDB may have as important an effect on behavioral disturbances as OSA.  
Marcus studied 108 children presenting with symptoms of SDB and 72 controls36.  
Although patients with SDB had increased sleepiness (modified Epworth Sleepiness 
Scale 8.1+4.9 vs 5.3+3.9, p<0.001) and symptoms of attention deficit-hyperactivity 
disorder (ADHD)(Conners Abbreviated Symptom Questionnaire 12.8+7.6 vs. 9.0+6.2, 
p<0.001) compared to controls, there was no difference in sleepiness or ADHD 
symptoms in patients with MSDB vs OSA.  In the Cleveland Children’s Sleep and Health 
study, investigators Rosen and Redline evaluated 835 children from a community cohort 
which include a wide range of SDB37.  After adjusting for confounding variables, 
cognitive deficits were associated with parent-reported habitual snoring (i.e., MSDB), but 
not with polysomnographic parameters such as arterial oxygen saturation levels or the 
AHI.  Thus, these studies indicate that children with MSDB have poorer neurobehavioral 
outcomes than controls and suggest that these outcomes may be reversible with AT.  
However, these studies had limitations and confounding factors inherent to their 
nonrandomized design; thus the current 
proposed  randomized controlled trial is 
required for a definitive assessment of 
the potential benefits of AT on behavior in 
this large group of children with MSDB for 
whom there is a lack of research to 
inform clinical decision making. 
 
Health Care Utilization (HCU): 
Escalating health care costs highlight the 
need to use evidence such as data on the 
value of treatment to both patients and 
the health care system when making 
treatment decisions. Both untreated 
childhood SDB and its treatment, AT, are 
associated with large health care costs.  
Figure 1: Correlation between CBCL and AHI
Apnea hypopnea index (N/hr)
0
5
10
15
20
25
30
CBCL (Total T score)
0
20
40
60
80
100
r = 0.13
p = 0.79

 
 
12 
 
A European study estimated the total 
societal costs of an uncomplicated 
tonsillectomy to be 1,074 Euros41.  Thus, 
the economic impact of tonsillectomy is 
enormous considering the number of 
surgeries performed each year.  There is 
also significant morbidity associated with 
AT, including post-operative hemorrhage 
(~3% of patients), respiratory compromise 
and post-operative pulmonary edema, 
dehydration, nasopharyngeal stenosis, 
velopharyngeal incompetence2 and 
death42.  Although the cumulative cost of 
AT is high, these costs must be balanced 
by the economic and health costs of 
untreated SDB.  Research from Israel has shown that children with OSA have health 
system utilization that is 225% higher than controls in the year prior to their diagnosis, 
indicating that these children are a financial burden on the health care system. Notably, 
these uncontrolled data indicate that health care costs decline by one third following 
AT10;43.  Decreased costs were largest in the youngest children (whom we intend to 
study), and were attributable to changes in number of hospitalizations, emergency 
department visits, consultations (ENT, pulmonary and allergy) and medication use 
(primarily asthma, allergy and antimicrobial drugs). The Israeli studies were limited by 
the modest sample (with little power to detect differences due to obesity, asthma and 
other risk factors) and no data on other relevant risk factors and outcomes, such as 
behavior and quality of life, which may importantly modify by treatment response and 
complement data on HCU.  Although the Israeli data suggest that HCU is lower in 
children with milder SDB, their sample did not include African Americans and may not 
represent HCU patterns in the US.  Given that the majority of children undergoing AT in 
the US have MSDB, there is an urgent need to assess HCU in this population. Thus, a 
randomized controlled trial is required to determine whether the benefits from this 
frequently performed surgery outweigh the risks, as well as to better inform rational use 
of limited health care resources.  Changes in HCU will be evaluated in Aim 2. 
 
Effect of Age on Behavioral Response to AT: SDB has been shown to affect 
neurobehavioral and cognitive function across the age span.  However, only a handful of 
studies have evaluated young (preschool) children despite the fact that SDB is more 
common in preschool-aged children than older children.  Figure 2 shows the age 
distribution for the 2,732 children who underwent PSG at Children’s Hospital of 
Philadelphia in 2012; 757 (28%) were aged 3-5 years, and 579 (21%) were aged 6-9 
years.  Preschool children are likely the most at risk for neurocognitive impairment, due 
to the rapidly developing nervous system at that age, and the importance of sleep in 
preserving memory and learning44, although they may also be the most likely to show 
improvement if treated early, due to central nervous system plasticity.  By recruiting 
children as young as 3 years of age, we will fill an important knowledge gap in research 
in young children.  In Aim 3 of this proposal, we will examine the modifying effect of age 
on the response to surgery in children with MSDB.  
 
Racial Health Disparities, Socioeconomic Status (SES) and SDB: We8;45;46 and 
others47-49 have shown that African American adults and children have a higher 
prevalence of SDB than Whites, even when controlled for factors such as obesity and 
Fig. 2: Age distribution of patients with SDB
Age (yr)
1
2
3
4
6
7
8
9
11 12 13 14
16 17 18
0
5
10
15
No. of children
0
50
100
150
200
250
300
350

 
 
13 
 
SES; the prevalence of SDB in African American children is 3.5 to 6.0 fold higher than 
that of Whites.  The CHAT study showed that African American children with OSA had 
smaller relative improvements in behavior following AT compared to children of other 
races, even when controlling for obesity, baseline behavioral scores and parental  
income (Table 1).  Although African American children have a higher prevalence of SDB 
and more sequelae thereof, they are less likely to undergo AT50;51, with one study 
showing a threefold prevalence of AT in White compared to African American children50.  
Further, PI Marcus prospectively followed 329 high risk children undergoing AT for SDB, 
and found that African American race was a predictor of post-operative respiratory 
complications (35% of African Americans vs 24% of children of other races, p=0.036)52.  
Thus, African American children have a higher prevalence of SDB but are less likely to 
undergo AT, and if they do, they have an increased rate of complications and less 
behavioral improvement. The reasons for these racial differences are unclear but may 
include differences in craniofacial anatomy, adipose tissue distribution, ventilatory drive 
and inflammatory responses.  Racial differences in sleep quantity have also been found, 
with African American children reporting less nocturnal sleep, increased daytime 
napping and overall less sleep than children of other races53-55.  This is important, as 
even one hour less of sleep per night can affect neurocognitive and behavioral 
functioning56.  In addition, we have shown that SDB is associated with lower SES, 
independent of race and obesity57, a finding that may be partially explained by 
exposures to second hand smoke, environmental irritants and allergens.  Low SES 
parents also may have decreased medical literacy, which may impede their 
management of SDB-related co-morbidities (such as asthma) or influence sleep 
practices. 
 
Further data are needed to understand the response to surgery in African American 
children and in lower SES families, in order to optimize their management and reduce 
health disparities.  This will be evaluated in this study through a comprehensive 
consideration of factors that may modify treatment responses, including obesity, sleep  
duration, asthma/atopy and family functioning. 
 
Asthma: Asthma accounts for nearly $60 billion of total costs per year in the US58 and is 
the leading cause of hospitalizations and school absenteeism in children.  Asthma and 
SDB frequently co-aggregate, with evidence of bi-directional links between these two 
common conditions59.  Children with habitual snoring have an increased risk of asthma 
compared to non-snorers (odds ratio 1.48 to 3.27)60-64.  Investigators Redline and Ross 
demonstrated that children with asthma had a 27 - 43% prevalence of habitual 
snoring26;59, substantially higher than the 10% seen in the general pediatric population7.  
Further, they and others have shown that SDB is associated with severe or difficult to 
treat childhood asthma, independent of BMI and race26;65.  There are several biologically 
plausible mechanisms by which SDB could adversely influence asthma, including 
Table 1: Relative improvements in behavioral measures between races 
African American 
Other races 
 
eAT 
WWSC 
eAT 
WWSC 
P value 
Conners 
-1.06 + 10.85 
-0.98 + 9.53 
-4.84 + 9.49 
0.61 + 9.22 
*p<0.01 
BRIEF 
-1.82 +  8.86 
-0.30 + 9.27 
-4.98 + 7.69 
1.17 + 8.29 
*p<0.05 
PSQ-SRBD 
-0.24 + 0.19 
-0.04 + 0.19 
-0.32 + 0.16 
-0.02 + 0.18 
*p<0.01 
*P value for interaction between race and treatment 
 

 
 
14 
 
mechanical, inflammatory, metabolic, and autonomic nervous system effects.  Notably, 
the increased work of breathing associated with SDB can induce neutrophilic airway 
inflammation, which is a characteristic of severe and refractory asthma30;31.  We have 
shown that children with asthma and untreated SDB had a 3.7-fold greater one year rate 
of asthma exacerbations, as measured by medication use, symptoms and HCU, 
compared to children without SDB26.  An uncontrolled study indicated that asthma 
control may be improved by AT.  In this study of only 35 children, asthma exacerbations 
decreased from 4.1 ± 1.3 per year to 1.8 ± 1.4 per year after AT65.  Although untreated 
MSDB may exacerbate asthma, no prior research has addressed the role of AT in 
influencing asthma-related HCU in children with SDB and asthma.  Since asthma is one 
of the leading causes of HCU in children, it is critical to assess whether AT in asthmatic 
children with SDB is beneficial. Demonstrating improved HCU among asthmatic children 
with MSDB treated with AT would change asthma management paradigms.  In CHAT, 
143 (30.8%) of subjects had asthma, 107 (23%) had hay fever, and 123 (26.5%) had 
eczema.  This is much higher than the reported US prevalence of childhood asthma 
(10%), hay fever (7-10%) and eczema (12%)66.   
 
Secondhand Smoke: Multiple studies have shown that secondhand smoke is 
associated with snoring in children67;68. CHAT demonstrated that, among children 
referred for AT, the AHI was 20% higher in those exposed to second hand smoke than 
non-exposed children69. The proposed objective assessment of urinary cotinine levels 
will provide a unique opportunity to assess whether secondhand smoke modifies the 
response to AT. This information may help inform policies that target secondhand smoke 
during pre-operative planning of AT. 
 
1. Study Objectives 
 
1.1. Primary Objectives 
 
The primary co-objectives are to determine the effect of eAT versus WWSC on 
executive function (Behavior Rating Inventory of Executive Function [BRIEF2/P] Global 
Composite Score), and vigilance (Go-No-Go; GNG). 
 
1.2. Secondary Objectives 
 
To determine the effect of eAT versus WWSC on sleep-disordered breathing (SDB) 
symptoms, and quality of life health care utilization (HCU).  We will track and compare 
group changes in health care utilization: sick days/intercurrent illness, asthma 
exacerbations; prescriptions and over-the-counter medication use; ambulatory or 
hospital encounters.  Exploratory outcomes include change in anthropometry and blood 
pressure. 
 
To identify factors that moderate the response to surgery including age, socioeconomic 
status (SES), race, asthma/atopy, secondhand smoke exposure, short sleep duration 
and assessment of family function competency.  
   
As an exploratory aim, to determine whether quantitative snoring metrics from the 
Tascon DR-10L Snoring Microphone correlate with the above outcomes. 
 

 
 
15 
 
As an exploratory aim, to determine whether participants would be willing to be 
contacted with long-term follow-up questions to assess the feasibility of conducting a 
study to evaluate the long-term outcomes in children with mild sleep disordered 
breathing, and to exam the number of children that sought additional treatment for sleep 
disordered breathing after their one-year participation period. 
 
2. Study Design 
 
2.1. General Design 
 
This will be a randomized, single-blind 12-month intervention study that compares the 
impact of AT on measures of behavior, quality of life and HCU in children with MSDB. 
The proposed study will involve participation of children and their caregivers.  Children 
with symptoms of MSDB will be recruited from each site’s sleep clinics and laboratories, 
otolaryngology clinics, asthma clinics and general pediatric clinics.  Potentially eligible 
children who are reported to be snorers at each site will be identified through systematic 
screening of health records and parent interviews.  Children who meet study eligibility 
criteria will be randomized to having either eAT or WWSC for 12 months.  In addition to 
the enrollment PSG at baseline, participants will receive behavioral testing, assessment 
of SDB symptoms, sleepiness, quality of life, anthropometry, and blood pressure.  PSG 
and baseline measures will be repeated at 12-months. At 6 months caregivers will 
complete neurobehavioral assessments remotely, except for Virginia , where they will 
have an in person visit with child neuro behavior testing. Potential factors that may affect 
response to AT will also be assessed (asthma and atopy, secondhand smoke exposure, 
, family functioning).  Approximately 920 participants will undergo baseline screening 
PSG, and 460 participants will be randomized. Both genders and all racial and ethnic 
groups will be eligible for participation.  Participants failing baseline screening PSG will 
be referred for clinical care.  It is anticipated that ~50% of participants will be eligible 
after PSG.460 eligible children, 230 per treatment arm, will be randomized to one of two 
treatment groups, and followed for a 12-month period.   
 
Eligible participants will be randomized to one of two management groups:  
 
1. Early Adenotonsillectomy (eAT) performed by participating ENT surgeons within 
1-4 weeks of randomization. 
 
2. Watchful waiting with Supportive Care (WWSC) 
 
Participants in both groups will receive verbal and written information about healthy 
sleep habits guidance.  Participants will be referred for appropriate “usual care” for 
relevant co-morbidities (for example, poorly controlled asthma, allergies) identified by the 
study team as needing further optimization of management.   
 
Participants will undergo a standardized assessment of behavior, behavioral 
performance testing, and other health-related evaluations at baseline and 12 month 
follow-up time points. At 6 months caregivers will complete neurobehavioral 
assessments remotely. Virginia will have a 6 month visit in person and repeat baseline 
assessments.   Participants will receive monthly check-in by telephone, , email and/or 
text messaging in order to maximize retention and to collect additional symptom and 
HCU reports.  Text messaging will only be utilized with families who agree to receive text 
messages.  After 12 months, children who did not get surgery who have a 12-month 

 
 
16 
 
PSG showing obstructive sleep apnea (apnea hypopnea index >3 /hr or obstructive 
index > 1/hr) or whose parent reports ongoing symptoms/concerns will be referred back 
to ENT for further clinical management (such as adenotonsillectomy) as per standard 
clinical care.   
2.2. Study Schema 
 
6-month visit, remote collection of parent behavior assessments at all sites except Virginia 
 
 
 
2.3. Blinding and Maintaining the Blind 
 
The study will be single blinded since sham surgery, including use of general 
anesthesia, would not be ethical, and evidence of tonsillectomy is evident.  All members 
of the Clinical Coordinating Center, research personnel and Steering Committee 
members, including investigators, quality control personnel, scorers, data entry staff, 
polysomnologists, and staff performing anthropometry, behavioral testing, and blood 
pressure, will be blinded to the study arm.  Unblinded personnel include the research 
coordinator who will make the intervention appointments, the otolaryngologist performing 
the surgery, the research coordinator making monthly contact by telephone, email, 
and/or text messaging and assessing for adverse events, the study’s external Medical 
Safety Monitor, and selected DCC personnel.  The unblinded research coordinator will 
not be administering any tests or measurements that could be influenced by interview or 
administration technique.  If cases of unblinding are identified, a protocol deviation will 
be reported.   

 
 
17 
 
 
Each site will designate an unblinded research coordinator/assistant who will have 
knowledge of the treatment arm assignment.  The unblinded research coordinator  will be 
responsible for informing the parent/legal guardian of the treatment arm assignment, 
making follow-up contact by telephone, , email and/or text messaging, assessing for 
AE’s, scheduling AT within 1-4 weeks for the eAT group, and scheduling WWSC re-
evaluation after the Month 12 visit. 
 
 
2.4. Overview of Study Design 
 
See Appendix A for a summary of study visits and all study related procedures 
 
2.4.1. Screening Visit 
 
Screening of ENT, sleep clinic, general pediatric or other internal clinical practice patients 
(including electronic medical records [EMR] and existing PSG review) will be performed 
to identify potentially eligible participants to ascertain preliminary study eligibility.  
Outside referring physicians will be contacted for permission to approach external practice 
patients. All HIPAA requirements will be met. 
 
• 
Obtain informed consent and confirm further eligibility criteria with parent  
interview (at face-to-face encounter). 
• 
Refer for ENT evaluation (if not done within 3 months of randomization) to 
confirm surgical candidacy. 
• 
Arrange a research baseline PSG with central scoring. (If a standardized clinical 
PSG is available, this will be obtained and centrally scored to confirm final 
eligibility criteria.) 
• 
Perform the ABAS-III if possible (if time does not permit, this will be performed 
at the baseline visit). 
 
2.4.2. Baseline Visit 
 
• 
Perform baseline assessments and procedures: behavioral and performance 
testing and questionnaires including the parent-completed BRIEF2/P;  weight, 
height, anthropometry, and blood pressure  measures; lab tests (serum IgE, 
urinary cotinine); provide healthy sleep guidance;  ; mail teacher behavioral 
rating scales. To ensure that at least one of the primary co-outcomes is 
available, the parent version of the BRIEF2/P must be completed before a 
participant can be randomized. 
• 
Randomize to eAT versus WWSC  
 
2.4.3. Follow-up Contacts 
 
eAT arm only: AT surgery 1-4 weeks from randomization within Month 1 
 
WWSC arm only: ENT re-evaluation visit with 1-4 weeks after Endpoint Visit if indicated by 12-
month PSG revealing obstructive sleep apnea (AHI >3.0 /hr. or obstructive apnea index > 1/hr.) 
or parent  reporting concerning symptoms. 
 

 
 
18 
 
Both groups:  
• 
Monthly  contact by telephone, email and/or text messaging  , for health care 
utilization, medication, adverse event inquiries and to support study participation.  
• 
Check In questionnaires and surveys will be completed bi-monthly, at months 2, 
4, 6, 8, and 10.  
• 
Interim remote visit at 6 months for caregiver questionnaires and neuro 
behavioral assessments, adverse event and health care utilization inquiry, and 
teacher forms of behavior rating scales.   
o Virginia will have in person child neurobehavior testing in addition to 
assessments above.   
• 
Endpoint Visit at Month 12 for behavioral and performance testing; 
questionnaires;  anthropometry, and BP measures. Behavioral rating scales 
mailed to teachers. 
• 
Follow-up research PSG at Month 12 
• 
Follow up questionnaires after participation  ended to assess feasibility of 
conducting a study to evaluate long-term outcomes of mild SDB 
 
  
 
2.5. Study Organization 
 
The PATS Study Organization consists of the following 7 clinical sites that will recruit 
participants for this randomized study: 
 
1) Children’s Hospital of Philadelphia, Philadelphia, PA 
2) Rainbow Babies and Children’s Hospital, Case Medical Center, Cleveland, OH 
3) Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 
4) University of Michigan, Ann Arbor Hospital, Ann Arbor, MI 
5) UT Southwestern Medical Center, Dallas, TX 
6) Boston Children’s Hospital, Boston, MA 
7) East Virginia Medical Center, Norfolk, VA 
 
Study investigators will interact at annual Steering Committee meetings (in addition to an 
initial centralized training session) and during monthly conference calls.   
 
In addition to the clinical sites, the organization includes: 
 
• 
Clinical Coordinating Center (CCC) will be based at Children’s Hospital of 
Pennsylvania and led by Drs. Susan Furth and Lisa Young.  The CCC will be 
responsible for coordinating the clinical activities of each of the clinical sites.  The 
CCC will also provide central analysis of blood and urine samples. 
• 
Data Coordinating Center (DCC) and Sleep Reading Center will be co-directed 
by Drs. Redline and Rui Wang and will be located at Brigham and Women’s 
Hospital.  The DCC will be responsible for generating all case report forms, 
developing and maintaining the database and study web portal, data audits, 
conducting the statistical analyses, preparing DSMB reports, and supporting the 
study communications and quality control.  The Sleep Reading Center will 
provide central scoring of PSGs, confirm PSG eligibility, and provide 
standardized PSG training and monitoring.   
 

 
 
19 
 
• 
Additional analyses will be completed by Dr. Wang and staff from Harvard Pilgrim 
Health Care (HPHC) through a cede review to BWH IRB. To meet the goal of 
completing analyses for multiple manuscripts using data collected under the 
auspices of the Data Coordinating Center at BWH, Dr. Wang’s group at HPHC 
will be provided fully de-identified research data collected for this multi-center 
trial. Dr. Wang and her colleagues at HPHC will access this de-identified dataset 
through use of a secure FTP transfer. This activity (and data access) will be 
addressed in an updated subcontract from BWH to HPHC. 
• 
External Medical Safety Monitor (Dr. Heidi Connolly, University of Rochester) will 
provide safety monitoring and central adjudication of treatment failures and 
serious and unexpected adverse events.  Although all sites are responsible for 
local reporting of AEs, the Independent Medical Monitor will be responsible for 
adjudicating the status of potential Treatment Failures as used as a study 
outcome. 
• 
The NHLBI has established an external DSMB according to NHLBI policies. 
Members include experts in sleep medicine, biostatistics, pediatrics, 
neurocognition, surgery, and ethics (some overlapping). The DSMB has 
convened to review the final protocol and DSMB Charter before study initiation 
and will continue to meet periodically, and not less frequently than annually. The 
DSMB Chair and the Independent Medical Monitor will receive all reports of 
serious adverse and unexpected adverse events and treatment failures in real 
time. The DSMB has requested to receive interim reports on a quarterly basis 
sent electronically to all DSMB members. The DCC Project Manager  is 
responsible for assembling materials/reports for the DSMB and NIH and 
maintaining all regulatory files across the duration of the study. 
• 
The study will be  governed by a Steering Committee composed of each PI, 
and leaders of the Quality Control subcommittees.  
• 
Steering Committee subcommittees will be charged with tasks associated with 
specific operations and quality control activities and will include Protocol 
Development, Protocol Operations, Surgical Quality Control, Neurobehavioral 
Quality Control, Recruitment & Retention, and Publications & Presentations. An 
external Data Safety and Monitoring Board will be established by NHLBI. 
 
 
3. Study Endpoints 
 
3.1. Primary Endpoint 
 
The primary co-endpoints are the BRIEF2/P Global Composite Score and the GNG 
signal detection parameter ( d’ ). 
 
3.2. Secondary Endpoints 
 
Secondary measures include data from the following domains:  
• 
Objective performance testing 
o Vigilance/attentional skills: Go-No-Go test subtests 
o Fine motor coordination: NIH-Toolbox 9-Hole Pegboard Dexterity Test 
 
• 
Behavioral scales (note that several measures utilize a date stamp when 
questionnaires are entered electronically into the commercial scoring websites) 

 
 
20 
 
 
o Executive function: BRIEF2/P meta-cognition and emotional regulation 
summary scores  and subscales for parent and teacher reports; 
BRIEF2/P teacher report global composite score and subscores 
o Behavior: Child Behavior Checklist (CBCL) summary scale and 
subscores, parent and teacher responses 
o Attention: Conners 3 Short Form (caregiver and teacher versions) Global 
Index T score and subscales 
o Adaptive Behavior Measure System, 3rd Edition (ABAS-III), a measure of 
children’s everyday functioning (this measure is centrally scored, and 
date of birth as well as date of study and study ID is required to be 
entered into the WPSpublish website) 
 
• 
SDB symptoms 
o Pediatric Sleep Disordered Breathing Questionnaire (SRBD) total score 
o Sleepiness: Epworth Sleepiness Scale modified for children summary 
score and SRBD sleepiness scale 
o Snoring: The Tascam DLR-10L Microphone results as an exploratory aim 
 
• 
Quality of Life  
o Generic: Pediatric Quality of Life Inventory (PedsQL) total score and 
subscores 
o Disease specific: OSAS-18 total score 
 
• 
Physical exam 
o Measurements of weight; height; body mass index (BMI); waist, hip, neck 
circumferences 
o Systolic, diastolic, and mean blood pressure levels 
 
• 
Health Care Utilization  
o Medications, health care visits (scheduled, unscheduled), ascertained 
from caregiver reports, EMR surveillance, billing and pharmacy records, 
hospitalizations. 
 
 
3.3. Sample Descriptors and Potential Effect Modifiers 
 
• 
Demographics: race, SES (parent education, family income, financial stress 
rating scale, geocode data on neighborhood characteristics) 
 
• 
Asthma/atopy: IgE, International Study Of Asthma And Allergies In Childhood 
(ISAAC) questionnaire, review of EMR and parent interview (using NHLBI 
asthma definitions based on a history of asthma and use of asthma medications) 
 
• 
Second-hand smoke exposure: urinary cotinine 
 
• 
Family functioning cluster: family functioning (Family Assessment Device, short 
form); parenting style (Parenting Style Questionnaire); parent perception of 
stress (Parenting Stress Index 4th Ed., short form); medical literacy (Rapid 

 
 
21 
 
Estimate of Adult Literacy in Medicine, Revised); discrimination (Experiences of 
Discrimination)  
 
• 
COVID-19 Survey 
 
 

 
 
22 
 
4. Participant Criteria 
 
4.1. Study Population 
 
This study will involve participation of children with symptoms of MSDB and their 
caregivers.  Both genders and all racial and ethnic groups will be eligible for 
participation.  Dyads (child and one caregiver) will be included. The following inclusion 
and exclusion criteria refer to the child participant only.  There are no specific 
inclusion/exclusion criteria for the caregiver participant. The caregiver participant will be 
the parent/guardian providing informed consent or accompanying the child on the study 
visits. 
 
4.2. Inclusion Criteria 
 
1. Ages 3.0 to 12.9  years at the time of screening 
 
2. Diagnosed with MSDB defined as: 
 
a. Parent report of habitual snoring that occurs most of the night on at 
least 3 nights per week, and has been present for at least 3 months 
(on average occurring > 3 nights per week or more than one-half the 
sleep time) and 
b. Obstructive apnea index < 1/hr or obstructive apnea hypopnea index 
<3 /hr and no desaturation < 90% in conjunction with obstructive 
events, confirmed on nocturnal, laboratory-based PSG 
 
NOTE: Participants failing baseline screening PSG will be referred for 
clinical care.   
 
3. Tonsillar hypertrophy ≥ 2  based on a standardized scale of 0-5 
a. 0 = surgically absent 
b. 1 = taking up < 25% of the space between the tonsillar pillars 
c. 2 = taking up 25-50% of the space between the tonsillar pillars 
d. 3 = taking up 51-75% of the space between the tonsillar pillars 
e. 4 = taking up > 75% of the space between the tonsillar pillars  
 
4. Deemed to be a candidate for AT by ENT evaluation, i.e., no technical issues 
that would be a contraindication for surgery such as submucous cleft palate.  
 
5. Primary indication for AT is nocturnal obstructive symptoms (i.e., not 
recurrent infections or other indications) 
 
4.3. Exclusion Criteria 
 
1. Previous tonsillectomy (whether partial, i.e., tonsillotomy, or complete 
tonsillectomy). 
 
2. Recurrent tonsillitis that merits prompt AT per the American Academy of 
Otolaryngology-Head and Neck Surgery Clinical Practice Guidelines, i.e., ≥ 7 

 
 
23 
 
episodes/yr. in the past year; ≥ 5 episodes/year over the past 2 years or ≥ 3 
episodes/yr. over the past 3 years2.   
 
3. Severe obesity (BMI z-score ≥ 3)  
 
4. Severe chronic health conditions that might hamper participation or confound 
key variables under study.  These conditions include, but are not limited to: 
 
• 
severe cardiopulmonary disorders (e.g. cystic fibrosis, congenital heart 
disease) 
• 
bleeding disorders 
• 
sickle cell disease 
• 
epilepsy requiring medication 
• 
other severe chronic health problems such as diabetes or narcolepsy. 
• 
mental retardation or assigned to a self-contained classroom for all 
academic subjects 
• 
known genetic, craniofacial, neurological, or psychiatric conditions likely 
to affect the airway, cognition, or behavior 
• 
psychiatric or behavioral disorders requiring or likely to require initiation of 
new medication, therapy, or other specific treatment during the 12-month 
trial period (other than ADHD).  
 
5. Current use of psychotropic medication (other than medications for ADHD), 
hypnotics, antihypertensives or growth hormone.  Note that children with 
ADHD will be included as it is possible that some cases of ADHD are 
secondary to MSDB 
 
6. History of severe developmental disability or ABAS score < 60 
 
7. Parent/guardian unable to accompany the child on the night of the PSG 
 
8. Family planning to move out of the area within the year 
 
9. Family does not speak English or Spanish well enough to complete the 
behavioral and performance measures. 
 
10. Children in foster care. 
 
4.4. Deferral Criteria 
 
There may be some situations or conditions for which a participant will be 
deferred from entry into the study.  Once it is formally ascertained that the 
condition is not present or has subsided according to the time frame identified, 
the participant will be reconsidered for entry into the study.  The following list 
identifies some of the conditions for deferral: 
 
1. Participants currently enrolled in another intervention or longitudinal 
study.   

 
 
24 
 
2. Participants who have received an investigational drug or device within 30 
days prior to screening will be deferred until off study for a period of at 
least 30 days. 
3. Child and parent/guardian request additional time to consider treatment 
options. 
4. Changes in healthcare insurance that require clarification before 
additional testing/interventions are initiated. 
5. Children currently on a “burst” of oral corticosteroid therapy for asthma 
may be enrolled, but PSG and daytime measurements may not be done 
until after daily oral corticosteroids are no longer prescribed and 30 days 
have passed since the last dose. Children using chronic steroids for 
asthma do not need to be deferred. 
6. Children with a comorbidity that is considered to be contributing to MSDB 
(e.g., untreated allergic rhinitis) for which the otolaryngologist 
recommends treatment and re-evaluation.  
 
5. Participant Recruitment and Consent 
 
5.1. Participant Recruitment 
 
Children with MSDB will be recruited from the Sleep Clinics, Sleep Laboratories, 
Otolaryngology Clinics, Asthma Clinics and general pediatric clinics at each clinical 
site.    Where available, real-time alerts in the electronic health record will also be 
used. 
The sources of referral, approaches for recruitment, and recruitment procedures will 
differ somewhat among the sites based on local variation in referral patterns and the 
organizational working relationship between the principal investigators and other 
specialties.  At every site, recruitment procedures, including regular review of 
electronic medical records and upcoming clinic appointment schedules, will meet the 
local HIPAA and Institutional Review Board (IRB) requirements specific for that site.  
 
Recruitment sites will utilize local web sites, newsletter, organizational communication 
channels and EMR-based tools to assist with identifying potential study candidates. 
The Clinical Research Center will speak to patients and if interested will refer them to 
Research Coordinator on the PATS Study team weekly via email. The general 
procedures to be followed at all sites are: 
 
• 
Children referred to ENT, sleep clinics/labs or other clinics who are potentially 
eligible (i.e., by age range, referring diagnosis, lack of comorbidities) will be 
identified by review of EMR at least one week prior to the visit. 
 
• 
Prior to the scheduled clinical visit, referring physicians will be contacted to 
confirm appropriateness of study participation for each potential participant and 
to agree to allow study personnel to contact the family.  
 
• 
Where available, some children will be referred by their primary care provider 
using the electronic medical record real time alert. 
 
• 
Families of potentially eligible participants will be contacted (either in person at 
the time of their clinic appointment or by telephone with arrangements made for 

 
 
25 
 
a subsequent interview if needed).  The study will be described and written 
informed consent obtained.  Following consent, a standardized set of screening 
questions will be administered to further assess eligibility criteria as per the 
screening (Child Information Worksheet) case report form (CRF). 
 
• 
Children who meet initial study eligibility criteria who have not already had a 
standardized PSG within the previous 60 days (i.e., most of the children 
recruited from ENT clinics or general pediatric offices) will be invited to have a 
research PSG.  The PSGs performed as part of routine clinical care for the other 
children will be obtained and scored centrally to confirm that PSG eligibility 
criteria are met.   
 
 
 
5.2. Overview of Procedures 
 
Once potential participants are identified, the following general procedures will be used in 
preparation for the informed consent discussion: 
 
1. Families of potentially eligible participants will be contacted by telephone and/or 
during the clinic or sleep lab visit, if applicable to ascertain interest. Each site will 
utilize an IRB-approved telephone script to invite families and participants to 
consider enrollment into the study.   
 
2. A preliminary eligibility determination check list (Child Information Worksheet) will 
be utilized and completed for potentially eligible participants.   
 
3. A preliminary Screening and Prescreening Summary form will be completed at 
each site on a bi-monthly basis to tracking recruitment efforts and activity 
 
4. A screening visit to explain the study protocol in detail and obtain informed consent 
will be conducted. Note: This visit may coincide with the ENT, PSG or other clinical 
visit at the discretion of the family and research team.   
Procedures to confirm eligibility after the informed consent discussion 
1. Participants who have not been evaluated by ENT for surgical eligibility within the 
prior 90 days will be referred to the ENT clinic as a research visit for evaluation of 
surgical candidacy. During their surgical evaluation, children will be evaluated for 
concomitant ENT issues which could exacerbate their symptoms of obstructive 
sleep-disordered breathing.  If such conditions are identified, study enrollment will 
be deferred until the condition is treated per routine clinical practice.  The child will 
then be re-evaluated and a determination made at that time if study participation is 
appropriate. 
 
2. If initial eligibility criteria are met and informed consent is given, then : 
• 
Prior PSG data (performed for clinical purposes within 60 days of the 
baseline/randomization visit) will be transmitted to the Reading Center to 
ascertain PSG eligibility OR 

 
 
26 
 
• 
A research PSG will be scheduled to be performed locally and scored centrally 
by the Reading Center 
 
3. PSGs will not be scheduled or occur within 7 days from the time of:  
• 
a febrile illness 
• 
upper respiratory illness resulting in increased coughing 
• 
acute nasal problems  
• 
asthma exacerbation 
 
4. The centrally scored PSG report will be transmitted from the DCC/Reading Center 
to the clinical site where it will be imported into a study eligibility file.  Based on the 
PSG findings, ENT evaluation and initial eligibility criteria, preliminary eligibility will 
be determined.  Families will be contacted, consent will be re-affirmed, and the 
baseline visit will be scheduled.  Note: Children with PSG results that exceed the 
AHI or desaturation criteria after central review are ineligible for participation 
regardless of the local clinical interpretation of the PSG data.   
 
5. Baseline and follow up visits will aim to collect data representative of the child’s 
usual health status.  Thus, PSG, baseline and follow up visits will not occur earlier 
than 30 days from the time of an acute exacerbation of illness requiring 
hospitalization, or oral steroid medication “burst”. When a child has other symptoms 
such as a fever or nasal/respiratory illness, then the baseline and follow-up 
visits/exams excluding PSG (see stipulations above) will not be scheduled or occur 
within 14 days from the time of a febrile illness. 
 
 
5.3. Informed Consent 
 
Each clinical center will be responsible for ensuring that informed consent is obtained 
from each participant according to the guidelines of its IRB.  Informed consent must be 
obtained (signed and dated by the participant’s parent/guardian) prior to initiation of any 
study related activity.  At the time of screening, written consent for parental permission 
for the research will be obtained.  In addition, assent will be obtained from each 
participant 7 years of age or older in the presence of the parent/guardian when required 
by a clinical site’s local IRB.   
 
Clinical sites will prepare an informed consent form following the guidelines of the central 
IRB and all applicable local hospital and regulatory requirements for Informed Consent.  
The form will, at a minimum, contain a description of the purpose of the research, 
description of procedures at each study visit, expected and potential risks, benefits, 
burden, participants' rights and alternative treatments.   
 
Consent from the parent/guardian will be obtained at the time of study entry in the 
presence of one of the investigators; assent will be obtained from the child him/herself if 
required by the local IRB, in the presence of the parent/legal guardian. Prior to the 
signing of the informed consent, all aspects of the study will be explained in detail and 
the research team member will review the details of the consent form verbally with the 
parent/guardian and answer any questions they may have concerning participation in the 

 
 
27 
 
study.  They will be informed of the nature of this research, its potential benefits, and 
possible risks.  It is stressed that participation is voluntary.  The family will be informed 
that they are free to refuse participation or to withdraw from the study and that this will 
not affect any future medical care.  A physician-level member of the study team will be 
present to answer questions during the consent discussion, and members of the 
research team will be available to answer questions throughout the study.  The original 
signed IRB-approved consent form will be kept in the participant’s study file at the clinical 
center and a copy of the signed consent form will be given to the family.  
 
If parents of subjects are CHOP employees, they will be informed that their participation will 
not affect their performance evaluations or employment, and that the study data/questionnaire 
responses will not be shared with their supervisor.  
 
The following compensation plan pertains to participants enrolled at CHOP.  Each 
individual site’s compensation plan is provided in their reliance site survey.  
 
During the clinic visit, the research coordinator will explain the following compensation 
plan.   
• 
The parent/caregiver accompanying you to the visit will receive $50 
cash/check or ClinCard for each sleep study performed, as a reimbursement 
for transportation, parking, meals, and baby-sitting costs for siblings. 
• 
The parent/caregiver accompanying you to the baseline day visit will receive 
$25 cash/check or ClinCard as a reimbursement for transportation, parking, 
meals, and baby-sitting costs for siblings. 
• 
Your parent/caregiver will receive $25.00 cash/check/ClinCard for the remote 
6 month. 
• 
The parent/caregiver accompanying you to the visit will receive $74 in 
cash/check or ClinCard for the 12-month day visit as a reimbursement for 
transportation, parking, meals, baby- sitting costs for siblings and for the time 
involved in the phone calls. 
• 
Your parent/care giver will receive $50 cash/check or ClinCard in trust for you 
as compensation for your time and effort for every visit involving a sleep 
study, and the baseline day visit. 
• 
Your parent/caregiver will receive $100 cash/check or ClinCard in trust for 
you as compensation for your time and effort at the 12-month day visit. 
• 
You will also get small “prizes” (stickers, toys of < $ 10 value, etc.) during the 
visits. 
 
Education in the protection of human research participants is required for all research 
team members and includes certified completion of the research compliance course 
"The Collaborative Institutional Training Initiative (CITI) Course in Human Research 
Subject Protections” or equivalent local courses.   
 

 
 
28 
 
5.3.1. HIPAA Authorization 
Following mandated federal HIPAA regulations and according to local IRB guidelines, 
the use and disclosure of the subject’s protected health information will be explained and 
participant authorization will be obtained.  The consent and/or authorization forms will list 
those individuals and organizations that may have access to the participant’s research 
data.   
Other elements of authorization must include: the use of protected health information in 
future studies (for example, storage of blood samples for future analyses other than that 
which is listed in the protocol at the time the informed consent was obtained) and the 
participants’ right to withdraw permission and have the blood samples destroyed.  The 
consent and/or authorization forms must also state that investigators will have the right to 
reject participants from the research trial if written authorization is not provided.  At each 
clinical site, the process of participant recruitment must be reviewed and approved by the 
site’s local IRB to help assure that privacy protections are consistent with federal HIPAA 
regulations.   
The following information will be explained to families during the informed consent 
process: 
 
Some of the questionnaires are scored by commercial companies involved in 
developing these types of behavioral tests. The ratings you enter on these 
questionnaires will be sent electronically to the companies for scoring. The 
companies will not have information about your child other than your child’s age, 
sex, and the date that the questionnaire was sent. You child’s birth date will also 
be sent to the company that scores one of the questionnaires. However, no other 
personal information that could identify your child will be shared with these 
companies.  
Some companies may use summary information from these tests, such as 
helping them develop better tests or scoring procedures. However, individual 
information on your child will not be used for any commercial purpose. 
 
5.3.2. Patient Confidentiality 
 
All participants are recruited and followed at the participating clinical centers.  To 
maintain patient confidentiality, participants are identified to the DCC only by patient 
identification numbers and no personal information will be transmitted to the DCC.  
Furthermore, data for reports and publications will be provided in aggregate or blinded 
form without the identification of individual patients.   
Families will be informed during the informed consent process that the limited PHI noted 
in section 5.3.1 is submitted to online companies for the scoring of neurobehavioral 
measures. 
All information will be kept strictly confidential and used for research purposes only.  All 
research data will be collected on standardized research forms with participant 
identification numbers, but without personal identifiers.   

 
 
29 
 
Procedures to assure confidentiality will be strictly observed.  The clinical sites and 
participating centers will follow standard guidelines to assure that participant 
confidentiality is maintained.  All data will be:  
• 
kept in confidential locked files 
• 
identified by participant identification number only  
• 
kept separately from identifying information used for participant tracking and 
follow-up contacts.   
Computer files do not permit linking individual data with medical or other data collected 
for research purposes.  Identifying information will be kept in separate locked files.  No 
identifying information will be disclosed in reports, publications, or presentations. 
 
 
6. Risks and Benefits to Participants 
 
6.1. General Statement about Risk versus Benefit 
 
In most clinical trials evaluating a more intensive versus a less intensive intervention, one 
expects that the more intensive treatment (in this case AT) may have both greater 
efficacy and increased risk, which must be assured to be in a favorable balance.   
Participants will be closely monitored during the study and will be monitored by a Data 
Safety Monitoring Board (DSMB) and an external safety officer.   
 
 
6.2. Potential Risks 
 
Participants eligible to participate in the study are being clinically evaluated for habitual 
snoring, have MSDB confirmed by PSG, and are all potential candidates for AT from an 
experienced ENT surgeon as part of their usual clinical care.  Thus, the risks of having 
surgery and anesthesia as part of this study are the same as the risks of having these 
procedures outside of the study. However, participants are being randomized in this 
study, which is a departure from usual care that may expose participants to different 
risks." 
 
Note that potential participants with obstructive sleep apnea are excluded from 
participation.   
 
Risks of deferred treatment 
The potential consequences of untreated MSDB may include behavioral problems, sleep 
disturbances, impaired quality of life and hypertension. However, it is not known 
definitively whether these symptoms and signs are related to MSDB or not, and if they 
are cured by AT; hence the purpose of this study.  The 12 month wait, however, appears 
small relative to the average, 3.3 years (range, 6 months to 13 years) that elapse 
between the onset of significant OSAS symptoms and AT70.  Further, many children 
referred for clinical evaluation for MSDB may wait months for an ENT clinic appointment, 
have a further wait for a PSG if scheduled, or a further wait for surgery.  It is reassuring 
to note that the CHAT study, which evaluated children with a more severe form of SDB 

 
 
30 
 
(i.e., OSA), showed no cognitive or cardiovascular changes over 6 months of watchful 
waiting. In the CHAT study, which involved children with more severe SDB, only 9 of 464 
(1.9%) children were designated as treatment failures, i.e., having worsening of 
symptoms requiring a cross-over of study arms. No child in the CHAT study had any 
serious complications attributed to treatment delay, such as developing failure to thrive, 
respiratory distress or cardiac complication3. As described in the protocol, specific 
safeguards will be followed to ensure the participant’s safety, and the participant will 
have close follow-up by telephone, email and/or text messaging, and in-person visits. 
Regular monitoring for adverse events will provide a mechanism for referring the child 
for evaluation for earlier surgery, if so recommended by the external Medical Monitor. 
Risks of adenotonsillectomy 
AT is a commonly performed operation, with clear standardization of approaches. 
Although associated with a finite mortality and small morbidity, levels of risk are those 
which the participant would have been exposed to as part of usual care. Monitoring of 
surgical outcomes according to the Surgical Quality Control Manual of Procedures will 
be implemented by the University of Michigan.  
Surgical complications associated with the study can occur in the peri-operative period, 
or in the months following surgery. Most of the following risks are rare, as can be seen 
from the site-specific data presented below.  Older data (1970’s) indicated a mortality 
rate for tonsillectomy of 1:16,000 to 1:35,0002;42; the current mortality rate is likely lower, 
and even lower in otherwise healthy children ≥3 years of age without major 
comorbidities.   
Perioperative Risks (within 24 hours): damage to teeth, infection, trauma or burns to soft 
tissue, atlanto-axial subluxation with neurological deficit, foreign body aspiration, airway 
fire, excessive blood loss (> 7 ml/kg), need for blood transfusion, hemorrhage that 
requires transfusion or an intervention to control, airway obstruction, re-intubation 
requiring unanticipated ICU admission, death and other related perioperative 
complications. 
Post-operative Risks:  dehydration; which may require intravenous fluids or inpatient 
admission, hemorrhage; which may require in-patient observation admission or return to 
the operating room, nasal regurgitation requiring speech therapy or surgical 
intervention, hypernasality requiring speech therapy or surgical intervention, 
nasopharyngeal scarring or stenosis which may require surgical intervention, carotid 
pseudoaneurysm, cervical osteomyelitis, refractory torticollis, regrowth of tonsil or 
adenoid tissue and other related long-term surgical risks. 
Risks of Anesthesia:  Common side effects of general anesthesia include nausea, 
vomiting, and a sore or painful throat following surgery. Serious general anesthesia-
related complications, though rare, can include breathing difficulties, drug reactions, 
changes in blood pressure or heart rate or rhythm, heart attack, or stroke. Death or 
serious illness or injury due to anesthesia is very rare and is estimated to be 1:250,000 
in healthy children (data provided by the IRB Committee). 
The children at the highest risk for complications of AT are those less than 3 years, 
those with significant comorbidities and those with severe OSAS7. All those high-risk 

 
 
31 
 
groups will be excluded from this study. In the CHAT study, which was performed in a 
population similar to the current one (except with more severe SDB), 221 children 
underwent AT.  Of those, 11 (5%) returned to the Emergency Department after 
discharge due to fever, dehydration, or bleeding. 7 (3%) of these children were 
readmitted (4 with bleeding).  2 children (0.9%) returned to the operating room for 
cauterization and both were discharged the following day. 
The parent/legal guardian(s) of all study participants will be informed of the surgical 
risks at the time of consent for the study. The surgical team will also review surgical 
risks with the parent/legal guardian (s) at the time of consenting for surgery.   
Mortality and Morbidity of Adenotonsillectomy by Site 
At Children’s Hospital of Philadelphia, we prospectively followed 329 children who 
underwent AT at the Main Hospital following abnormal PSG from May 2012 to May 
2013 (IRB #12-009230). In contrast to the current study population, which is older and 
does not have major comorbidities, this was a very high-risk population, with 27% being 
< 3 years of age, 43% having comorbidities, and a mean apnea hypopnea index of 
19.5/hr.  Nevertheless, despite the complexity of the study population, there were no 
deaths, only 1 child (0.3%) required reintubation, and 2.4% had either early or late 
bleeding requiring surgical intervention. 
At University of Michigan Medical Center, the rate of post-operative bleeding 
averaged 2.0% over the past 5 years, with no reported instances of persistent 
velopharyngeal insufficiency, nasopharyngeal stenosis, or death during this time. 
At University of Texas Southwest Children’s Medical Center, based on over 2,000 
annual pediatric tonsillectomies in children < 12 years of age over the past 3 years, the 
rate of primary post-tonsillectomy hemorrhage was 0.2%, secondary post-tonsillectomy 
hemorrhage 2.3%, dehydration requiring admission 1% and other causes for 
readmission 0.2%, with no mortality.  
 
At Rainbow Babies and Children’s Hospital, Cleveland, statistics are available for 
the past year.  The rate of post-operative hemorrhage was 1.4%, with no mortality. 
 
At Boston Children’s Hospital, Boston, mortality is 0%. 
Morbidity overall rate for the past 2 years is 6.4% 
 
At Children's Hospital of The King's Daughters, Norfolk , mortality is 0%.Morbidity 
rate for bleeding post T&A necessitating return to OR or admission or ED observation 
was 2.2% 
 
 
At Cincinnati Children’s Hospital, Cincinnati: Mortality- 0% 
Morbidity- bleeding post tonsillectomy requiring ED visit or readmission – 1.7% 2017 
Morbidity- bleeding post tonsillectomy requiring ED visit or readmission – 1.2% 2016 
Morbidity- Admission for dehydration without bleeding 1 – 0.8% 2017 
Morbidity- Admission for dehydration without bleeding 1 – 1.2% 2016 
 

 
 
32 
 
6.3. PSG Risks 
 
No serious risks are encountered from polysomnography, which is a standard, 
noninvasive monitoring procedure.  Sleeping away from home may be unsettling.  To 
allay anxiety, the participant’s parents/guardians will be encouraged to stay overnight in 
the same room as the participant.  Sensors and tape may cause transient skin irritation.  
 
Physical examination and anthropometry risks 
 
There are no risks associated with physical examination or anthropometry, although 
blood pressure measurements may be transiently uncomfortable. 
 
Risks with urine collection  
 
There are no risks with urine collection.  As the specimen need not be sterile, the 
participant can urinate into a “hat” container placed over the toilet. 
 
6.4. Risks Identified in Behavioral Testing 
 
Completing these measures may be anxiety-producing; these risks will be addressed by 
providing an appealing and quiet private area to complete the measures.  All data will be 
kept confidential.  The surveys do include questions regarding suicidality.  If at any time 
during the assessment there is concern that a participant has suicidal ideation, the study 
team will immediately evaluate the participant.  If the participant is felt to be a danger to 
themselves or others (via specific questionnaire responses or spontaneous reports from 
participant or parent), a study team member will escort them to the emergency 
department for further evaluation and management.  Indications of child abuse will be 
followed up through notification of the hospital child abuse team and/or state authorities, 
as appropriate at each site.   
 
6.5. Phlebotomy risks 
 
Phlebotomy may result in transient pain, bruising or dizziness, as well as anxiety.  There 
is a theoretical risk of phlebitis or infection which is uncommon.  Phlebotomy will 
be performed by skilled pediatric research nurses, and a topical anesthetic will be 
offered to the participants.  Families refusing phlebotomy despite encouragement will be 
allowed to participate in the rest of the study.    
 
6.5.1. Burden to participant 
 
PSG visits and daytime study visits will be scheduled during a time when children are 
stable and free of acute illnesses.  Testing of neurocognitive/behavioral functioning is 
performed with regularly scheduled breaks during test administration to avoid excessive 
fatigue. 
   
6.6. Potential Benefits to Participants and Others 
 
There is prospect for direct benefit to participants, although it is possible that some or all 
participants will not receive direct benefits.  Based on the nonrandomized smaller 
studies in children with MSDB, and the CHAT study on children with OSA beginning with 
an apnea hypopnea index as low as 2/hr, participants randomized to eAT may show 

 
 
33 
 
improvements in behavior, sleepiness and quality of life.  It is also possible, based on 
adult data, that in children with MSDB, treatment will lower their cardiovascular risk 
profile21.  Please see the rationale and Significance sections for a detailed description of 
the rationale for AT in improving behavior, sleepiness and quality of life in children with 
MSDB. 
 
Participants randomized to WWSC may benefit by avoiding surgery if snoring and 
symptoms resolve without surgery or if the study shows that surgery does not improve 
behavioral outcomes.  
 
In addition, all participants will receive information about healthy sleep habits for 
children.  Children identified with obstructive sleep apnea during PSG may benefit from 
being screened for this study, but will ultimately be excluded from participation. Data 
collected for research purposes only (research PSGs, behavioral performance testing, 
behavioral rating scales and IgE level) will be made available to families, and the child’s 
physicians after the study ends and may provide beneficial baseline information for 
future health concerns.  Any data indicating a health risk will be made available to the 
child’s physician as soon as those data are reviewed.  The information obtained from 
this study will improve our understanding of the effects of MSDB on children’s health, 
and will lead to better management, which is important as currently the management of 
MSDB varies widely across the country.   
 
6.7. Alternatives 
 
A discussion of alternative treatments (non-participation, other treatments available, and 
AT at the discretion of the ENT surgeon) will be presented at the time of informed consent. 
 
 
7. Study Interventions 
 
All participants, regardless of treatment assignment (eAT or WWSC) will receive the 
following interventions throughout the course of the trial: 
 
7.1. Sleep and Healthy Lifestyle Education 
 
Educational material on healthy sleep habits will be provided to each participant at the 
baseline visit after research data are collected.  Standardized materials recommended 
by the National Institute of Health and pediatric professional sleep societies will be 
used to reinforce optimal sleep healthy and educational play will also be encouraged 
by providing take-home materials. 
 
7.2. Other Supportive Care 
 
At initial evaluation (and as needed throughout the course of the trial), participants 
identified by the site principal investigator as having suboptimal asthma or allergy 
control will be referred to their primary care physician for management and further 
treatment of these problems.   
 
8. Procedures Specific to Treatment Arm Assignment 
 

 
 
34 
 
8.1. Surgical Treatment – Early Adenotonsillectomy (eAT) 
 
Within 1 to 4 weeks of randomization, participants randomized to the eAT arm will 
undergo AT under general anesthesia, as occurs as part of usual care.  Surgery will be 
performed by board-certified otolaryngologists with or without the assistance of resident 
physicians in accredited otolaryngology training programs.   
 
Prior to the surgical procedure, tonsillar size will be graded using a standardized scale 
of 0-4 as described above. Extent of adenoid tissue will also be graded as mild (0-
33%), moderate (34-66%) or severely (67-100%) obstructing the posterior choanae. 
Complete bilateral tonsillectomy and removal of obstructing adenoid tissue will be 
performed by cold dissection, monopolar electrocautery or any other recognized 
surgical technique. Further details of surgical intervention and quality monitoring of 
surgical intervention will be outlined in the Surgical Quality Control Manual of 
Procedures.   
 
8.2. Participants Randomized to Watchful Waiting with Supportive Care 
 
After 12 months, children who did not get surgery who have a 12-month PSG showing 
obstructive sleep apnea (apnea hypopnea index >or =3.0 /hr or obstructive index > 1/hr) 
or whose parent  reports ongoing symptoms/concerns will be referred back to ENT for 
further clinical management (such as adenotonsillectomy) as per standard clinical care.   
 
 
9. Study Procedures 
 
A study visit schedule is provided in Appendix A. Visit time points, study procedures 
and assessments are listed in the order in which they occur. 
 
9.1. Polysomnography (PSG) 
 
All children will undergo standardized screening PSG at study entry to determine 
eligibility, and at the 12 month visit.  
 
9.1.1. PSG Methods Overview 
 
Each clinical site will use a standardized approach as established in training.  Existing 
laboratory equipment will be used, but data will be standardized by using the same 
montage and similar sensors, sampling rates and filters.  Sleep technicians who collect 
PSG data for this study will be supervised by a lead technician who was certified by 
central training for technical proficiency to collect research PSG data for this trial, or 
someone trained by a centrally certified technician.  Participants will report to the sleep 
laboratory 1 hour before their usual bedtime and remain at the sleep laboratory in a quiet 
dark room until the study ends the following morning at their spontaneous wake time.  
Children must be accompanied by at least one parent/guardian during the night.  
Weekend slots will be made available, as feasible, to families to facilitate recruitment. 
The completed PSG will be exported as a standardized European Data Format (EDF) 
file and electronically transmitted to an FTP server at the central Reading Center for 
standardized scoring.   
 

 
 
35 
 
9.1.2. Screening PSG 
 
All potential participants who meet the initial eligibility criteria will be evaluated through 
a standardized PSG prior to the baseline exam.  PSG results that do not meet 
AHI/saturation criteria after central review by the Reading Center are ineligible for 
participation regardless of the local clinical interpretation of the PSG data and the 
baseline visit will not be scheduled.  Baseline PSG data can be obtained in two ways: 
 
1.  A proportion of PSGs may have been performed as part of routine clinical 
care.   PSG data (performed for clinical purposes within 60 days prior to 
the baseline/randomization visit) will be transmitted to the Reading Center 
where they will be re-scored to ascertain PSG eligibility and entry into the 
study.  If a clinical PSG has been performed more than 60 days prior to 
baseline/randomization or was not performed using agreed upon research 
sensors and montages, then a research PSG must be performed. 
 
2.  Potential participants who have not undergone a PSG within 60 days prior to 
the baseline/randomization visit will undergo a research PSG.  Resulting 
PSG data will be transferred to the Reading Center within 48 hours to 
determine PSG eligibility and to collect research quality data.   
 
9.1.3. 12 Month Endpoint PSG 
 
2 weeks before or 2 weeks after the scheduled Month 12 daytime visit, all 
participants will undergo a research PSG. Data will be transmitted to the Reading 
Center and results will be scored (refer to the PSG Manual of Procedures).    
 
9.1.4. Scheduling the PSG 
 
One to two days prior to each scheduled PSG, families will be contacted to remind 
them of the visit and to ensure that intervening medical illnesses have not occurred, 
requiring the visit to be rescheduled.  These include any of the following within the 
previous 7 days:   
• 
febrile illness 
• 
upper respiratory illness resulting in increased coughing 
• 
acute nasal problems  
• 
asthma exacerbation 
 
9.1.5. PSG Procedures 
 
Children will be encouraged to maintain their usual daily routine prior to PSG. Lights off 
will be at approximately 2000 -2100 (depending on age) and lights on no earlier than 
0600.  Neither sedation nor sleep deprivation is used to induce sleep.   
 
9.1.6. Montage 
 
The following are monitored: Sleep architecture (6 EEG sites [F3/M2, F4/M1, C3/M2, 
C4/M1, O1/M2, O2/M1], bilateral electro-oculograms [EOG: ROC/A2, LOC/A1], 
submental electromyography [EMG]; airflow by oronasal thermocouple (Pro-tech); 

 
 
36 
 
nasal pressure cannula (Pro-tech); snoring sound (microphone by Pro-tech, a 
vibration flow sensor,  or a battery operated Tascam  microphone; respiratory effort 
(chest and abdominal wall inductive plethysmography); end-tidal CO2 (capnography 
waveform and numeric display); pulse oximetry (numeric and plethysmograph 
waveform in the 2 sec averaging mode); ECG with a standard 3-lead precordial 
placement; leg movements (bilateral tibial EMG); body position. 
 
 
• 
When possible, EEG, EMG, and EOG signals will be sampled at rates designated as 
“desirable” by The AASM Manual for the Scoring of Sleep and Associated Events 
Version 2.2 (EEG, EOG, EMG, ECG and snoring at 500 Hz, respiratory signals at 
100 Hz, and oximetry at 25 Hz).  
• 
When equipment precludes collecting data at “desirable” rates, all data must at least 
meet the AASM 2015 “minimal” sampling rate criteria (EEG, EOG, EMG, ECG and 
snoring at 200 Hz, respiratory signals at 25 Hz, and oximetry at 10 Hz).  
 
9.1.7. Central Transmission of PSG Data 
 
The PSG will be exported in EDF format and transmitted to a sFTP server at the Reading 
Center for standardized scoring within 2 business days. If PSG urgent referral criteria are 
identified (i.e., on baseline/screening PSG, severe levels of obstructive sleep apnea 
precluding randomization; or on follow-up PSG, levels that exceed adverse event 
thresholds), the data will be reviewed by the Reading Center Director.  An Urgent 
Referral Alert form will be completed and transmitted to the clinical site for follow-up. The 
clinical site will provide this information to appropriate physicians and family members for 
clinical follow up (refer to PSG Manual of Procedures).  
  
9.2. Study procedures and details of the baseline visit 
 
Following confirmation of initial eligibility including screening PSG, participants will be 
scheduled for a baseline morning visit with consideration for any intervening medical 
illnesses (30 days from the time of an acute exacerbation of illness requiring 
hospitalization or systemic steroids or 14 days from the time of a fever or an illness of 
sufficient severity that it required the child to miss 2 or more days of school/pre-school or 
be confined to bed for 2 or more days).   
 
Visits should aim to begin between 8:00-9:00 AM and no later than 11 AM. The evaluation 
will generally last no more than 4.5 hours.  Participants will be encouraged to follow their 
usual bedtime routine the night prior to testing.  Participants will undergo the following, in 
the order listed: 
• 
Brief orientation to testing facility  
• 
Urine collection for cotinine 
• 
Resting morning blood pressures in triplicate 
• 
Anthropometry 
• 
Brief physical examination by the study physician or designee 
• 
Breakfast/snack and rest period 
• 
Behavioral performance testing by child and questionnaire completion by parent 
• 
Brief rest period 

 
 
37 
 
• 
Venipuncture (note: fasting not required) 
• 
Randomization  
 
The Research Coordinator will also review and provide an appointment schedule and 
reaffirm the importance of maintaining the blind. 
 
 
9.2.1. Orientation 
 
On arrival to the research facility, participant and parent/legal guardian (s) will be 
introduced to the research staff and provided with a brief tour of the facilities, using child-
friendly approaches. 
 
9.2.2. Urine collection for cotinine  
 
The child (with the assistance of the parent) is instructed to void into a collection device 
(urinal, “hat”, or bedpan).  Study staff transfers the specimen to a non-sterile container.   
Following instructions outlined in the Laboratory MOP, the specimen is stored locally at -
80°C and shipped on dry ice to the central laboratory at Children’s Hospital of Philadelphia 
Clinical and Translational Research Center as per the schedule in the Manual of 
Procedures.   
 
9.2.3. Morning blood pressure 
 
After a 5 minute rest period, while the child is sitting, systolic and diastolic BP will be 
measured 3 times, at least 60 seconds apart, according to standardized guidelines. Cuff 
size will be determined by measuring the circumference of the upper arm, measured at 
the midpoint, and identifying the appropriate bladder size from a standard chart 
 
9.2.4. Anthropometry  
 
Parent/caregiver will be instructed to have the child wear loose clothing to the visit. 
Weight (to 0.1 kg) will be measured on a calibrated digital electronic scale. Standing 
height (to 0.1 cm) will be measured with a stadiometer, and neck, waist and hip 
circumferences will be obtained to determine regional fat distribution, as outlined in the 
Anthropometry MOP. Measurements will be repeated three times, and average values 
will be utilized, as defined in the MOP. 
    
9.2.5. Physical examination 
 
The Principal Investigator/designee will review the participant’s medical and sleep history 
and perform a brief standardized physical exam, including standardized assessment of 
tonsillar size, evaluation of the oropharynx using Friedman and Mallampati position 
scales, and identifying any abnormalities on heart, lung, neurological and ears, nose and 
throat assessments. 
9.2.6. Breakfast/Snack and rest period 
 
The child will be provided with a snack and a brief break. 
 

 
 
38 
 
9.2.7. Behavioral performance testing and questionnaire completion 
 
Behavioral performance testing will take approximately 20 minutes for the child and 
questionnaire completion will take approximately 90 minutes for the caregiver.  Testing 
will be administered by a Research Coordinator who is centrally trained, certified by the 
Neurobehavioral Quality Control Committee, and blinded to the treatment arm.  Tests 
will be performed in the same order. Testing will be performed in a private, quiet room 
with adequate lighting and table space.  Breaks are built into the testing sequence to 
avoid excess fatigue.  The parent will complete the questionnaires in a separate room 
while their child is being tested, on a computerized system.  The child will be supervised 
in a hospital play room, with a Child Life therapist, or other appropriate site and 
personnel, while the parent completes the surveys.  All tests will be performed as 
outlined in the Behavioral Testing MOP.  The Research Coordinator will be available for 
assistance, and will ensure completion of all tests at the end of the session. 
 
 
We will provide families with paper forms that can be mailed or emailed back to the 
study coordinator. Blinded coordinators will instruct the parent not to provide any 
personal identifiers on paper forms and the RC will check the forms for PHI and remove 
any if found. Families will also be given the opportunity to complete these questionnaires 
electronically. An email link to the SLICE data management system will be sent to 
parents for remote completion of neuro-behavioral forms, SLICE is managed by the 
DCC. The SLICE Data Management system has a safeguard that will not allow parents 
to enter PHI directly into the system.  CBCL for children 6 years and older, the only 
measure that assess for suicidal ideation, will be completed during an in person visit only 
with a blinded RC. These alternatives meet CHOP IT standards and are critical to have a 
complete dataset in all participants.  
 
 
Child Performance Testing 
• 
NIH Toolbox 9-Hole Pegboard Dexterity Test (a test of fine motor coordination) 
• 
Go-No-Go Continuous Performance Task (GNG), a test of sustained attention 
(vigilance).  
• 
PedsQL: Children > 5 years of age also complete the child version of the 
PedsQL, a generic measure of global quality of life 
 
Parent  Questionnaires (note that several measures utilize a date stamp when 
questionnaires are entered electronically into the commercial scoring websites) 
• 
Behavior Rating Inventory of Executive Function (BRIEF2/P), a measure of 
executive function (the global score a co-primary outcome). The BRIEF-P is for 
use in pre-school children. 
• 
Child Behavior Checklist (CBCL), a measure of behavior 
• 
Conners Third Edition Short Form, a measure of attention-deficit/hyperactivity 
disorder symptoms (parents of children >6 years of age only) 
• 
Adaptive Behavior Measure System, 3rd Edition (ABAS-III), a measure of 
children’s everyday functioning (this measure is centrally scored, and date of 
birth as well as date of study and study ID is required to be entered into the 
WPSpublish website) 

 
 
39 
 
• 
Epworth Sleepiness Scale modified for children, a measure of daytime 
sleepiness 
• 
Pediatric Quality of Life Inventory (PedsQL; parent form), a generic measure of 
global quality of life 
• 
OSAS-18, a measure of disease-specific quality of life  
• 
Pediatric Sleep Questionnaire Sleep-Related Breathing Disorder Scale (PSQ-
SRBD scale), a measure of symptoms of SDB, including nighttime and daytime 
symptoms. 
• 
Family Assessment Device, a measure of family functioning 
• 
Parenting Style Questionnaire, a survey of the type of parenting style 
• 
Parenting Stress Index 4th Ed., Short Form, a measure of parents’ perception of 
stress 
• 
Rapid Estimate of Adult Literacy in Medicine, Revised, a measure of patient 
(caregiver) health literacy (only at baseline visit) 
• 
Experiences of Discrimination, a measure of experiences with racism  
• 
International Study Of Asthma And Allergies In Childhood (ISAAC), a survey to 
determine the presence of asthma, rhinitis and eczema  
• 
Asthma Severity Survey, a measure of asthma exacerbations and controller 
therapy based on items from the Composite Asthma Severity Index (only for 
children with ISAAC Global Wheezing Score >5) 
• 
COVID-19 Survey 
 
9.2.8. Venipuncture for IgE 
 
Approximately 5 cc of blood will be obtained by venipuncture (and no more than 3 cc/kg 
body weight) and after preparing the skin with a local anesthetic, per participant 
preference.  Within one hour of collection, the specimen is centrifuged and serum and 
plasma aliquoted, with removal and storage of the buffy coat if applicable.  Following 
instructions outlined in the Laboratory MOP, the specimen is stored locally at -80°C and 
shipped on dry ice in batches as per the MOP to the central laboratory at Children’s 
Hospital of Philadelphia Clinical and Translational Research Center.  This sample does 
not require fasting and may be collected at another time point within 30 days of the 
baseline visit, per participant preference.   
 
9.2.9. Medical status 
 
The Research Coordinator will obtain baseline information regarding health status and 
medication according to a standardized script, and enter responses into the CRF. 
 
9.2.10. Sleep educational material is reviewed. 
 
9.3. Randomization  
 
Participants meeting all eligibility criteria will be randomized at the end of the Baseline 
Visit to either the eAT group or to WWSC.  The unblinded coordinator will complete this 
step in a customized electronic data capture (EDC) system using a standard internet 

 
 
40 
 
connection that communicates with the secure study portal.  After entering key fields 
(e.g., stratification variables) and submitting the web-based forms, eligibility will be 
electronically ascertained.  Upon confirmation, the site staff will be presented with the 
randomization assignment for that participant.  
 
The randomization schema will be setup per the DCC protocol and stored/maintained by 
the Brigham and Women’s Hospital Program in Sleep Medicine Epidemiology.  The 
randomization distributions and system will be re-assessed on a quarterly basis to 
ensure that it is working as expected.  To minimize problems with connectivity, staff will 
be asked to confirm internet connectivity and EDC system availability at the beginning of 
the baseline visit to avoid any potential problems accessing the randomization module.  
If problems arise with connectivity during a given baseline visit, site staff will be asked to 
immediately contact the Brigham and Women’s Hospital Program in Sleep Medicine 
Epidemiology to resolve these; a manually generated randomization assignment would 
then be generated based upon the subject criteria.  The DCC will be responsible for 
providing and documenting appropriate user access to the database, preventing against 
unauthorized entry into the randomization system. 
 
Participants will be assigned randomly to either eAT or WWSC.  For those participants 
assigned to the eAT arm, arrangements will be made by the unblinded coordinator to 
schedule surgery within 4 weeks of randomization.  
 
 
9.4. Teacher report forms 
 
BRIEF2/P, Conners 3 Short Form and Teacher Report Form (teacher version of the 
CBCL) will be mailed to pre-school and schoolteachers.  The teacher (or for summer 
months, the teacher from the preceding semester) will be mailed the forms along with a 
background letter on the study, written permission to contact them signed by the parent 
and a gift card as an incentive.  Repeat mailings, and if needed phone calls, will be 
made if forms are not returned within 2 weeks.  At each subsequent visit, caregivers will 
also be asked to bring in the child’s most recent report card so that school absences and 
grades can be recorded and used for exploratory analyses.  The teacher ratings will be 
obtained at baseline, Month 6 and Month 12.  Permission to contact the child’s primary or 
homeroom teacher will be obtained from parents at the time of consent, and again at the 
time each follow-up visit is scheduled.   
 
9.5. Monthly caregiver interviews 
 
 As part of ongoing contact with participants (see Appendix A Visit Schedule), caregivers 
will be contacted on a bi-monthly basis for completion of check in questionnaires and 
surveys. Centrally trained research coordinators will administer these questionnaires by 
telephone, email and/or text messaging at months 2, 4, 6, 8, 10 and in person visit at 12 
months. A structured interview that will identify adverse events and HCU, including 
hospitalizations (reason, place and number of days), emergency room visits (reason, 
place), unscheduled and scheduled medical outpatient visits, and medication 
prescriptions.  The coordinator will use a script with follow-up questions and record all 
information in the CRF. 
 
If parents cannot be reached by phone for monthly calls, we will provide parents direct 
links to The SLICE data management system provided by The DCC. However, adverse 

 
 
41 
 
events and healthcare utilization will be followed up by phone calls as there are many 
nuances that need direct communication with the coordinators. 
 
On alternate months of check in questionnaires, caregivers will be contacted to assess 
for adverse events and health care utilization only.   
 
9.6. Health care utilization (HCU) and electronic medical record (EMR) surveillance 
 
EMR will be tracked by both monthly manual review of EMR by the Research 
Coordinator after each reported adverse event or HCU event, and by automated 
surveillance of billing records and pharmacy records using query systems co-developed 
by Dr. Linden, conducted approximately bi-annually.  At each monthly check-in by 
telephone, email and/or text messaging, or in-person visit, the research coordinator will 
conduct a structured interview that will identify adverse events and HCU, including 
hospitalizations (reason, place and number of days), emergency room visits (reason, 
place), unscheduled and scheduled medical outpatient visits, and medication 
prescriptions.  Data will be entered into a CRF. In addition, each health system’s billing 
system informatics analytics team will extract relevant information from inpatient, 
outpatient and pharmacy records as outlined in the DCC application. Query results will 
be returned monthly to the research coordinator who will extract the information to the 
CRF and compare these data to the parent-reported data. When discrepancies are 
identified, the research coordinator will attempt to resolve differences by further 
interviews with the caregiver, requests to other health institutions for medical record 
release, or by consulting with the DCC. Healthcare utilization data will be collected 
prospectively through ongoing surveillance of electronic medical records (EMR) for up 
24 months following randomization of subjects. We will utilize a query structure to be 
used by the EMR informatics analytics team for ongoing EMR surveillance for extracting 
relevant information from inpatient, outpatient and pharmacy records. 
 
 
9.7. Study Visits (see Appendix A for Summary of Visit Schedule and Procedures) 
 
The details of the specific study procedures at each study visit are summarized in the 
previous section.  This section lists the study visits and summarizes the procedures at 
each visit.   
 
9.7.1. Screening visit/PSG eligibility – Day -60 to -1 
 
At this visit, preliminary study eligibility is confirmed and informed consent obtained.  If 
the participant had a clinical PSG, then these data are sent to the DCC/ Reading Center 
to confirm eligibility.  If the participant has not had a PSG, then a research PSG is 
performed.   
 
 
9.7.2. Baseline visit – Day 0 
 
After PSG eligibility for MSDB is confirmed, this visit includes anthropometry, BP 
measurement and physical examination.  The child completes behavioral performance 
measures and the parent completes questionnaires about behavior & attention, SDB 
symptoms, sleepiness, quality of life and family functioning.  Children ≥ 5 years of age 
also complete the child version of the PedsQL. Urine is collected for cotinine and serum 

 
 
42 
 
IgE is collected by venipuncture.  The research coordinator inquiries about adverse 
events, changes in health status or medication, and HCU.  Eligibility is confirmed and the 
participant is randomized.    Behavioral rating scales are mailed to teachers.  
 
9.7.3. Monthly Check-In – Months 1, 2, 3, 4, 5, 7, 8, 9, 10, 11  
 
Between each face-to-face visit, study staff will make contact by telephone, email and/or 
text messaging, with families in both groups for inquiries about adverse events, 
medications, and changes in health status using a study CRF.  HCU is assessed and 
EMR surveillance completed.  Participants are reminded about upcoming study visits 
and study participation is reinforced. 
 
9.7.4. Remote Interim Visit – Month 6 
 
The parent completes questionnaires about behavior, SDB symptoms, sleepiness, 
quality of life and family functioning.  Study staff inquire about adverse events, changes 
in health status or medication, and HCU.  EMR surveillance is completed.  Behavioral 
rating scales are mailed to teachers.  Note that with the Covid-19 pandemic, 6 month 
visits can be held virtually if in-person visits are not possible, focusing on parent-related 
questionnaires. 
 
9.7.5. Endpoint PSG – Month 12 
 
Participant completes overnight PSG using the same protocol as for baseline PSG.     
 
9.7.6. Endpoint daytime visit – Month 12 
 
This visit includes measurement of anthropometry, BP and behavioral performance 
testing.  Parent completes questionnaires about behavior and attention, SDB symptoms, 
sleepiness, quality of life and family functioning.  Participants ≥ 5 years also complete 
the child version of the PedsQL.  Study staff inquire about adverse events, changes in 
health status or medication, and HCU.  Behavioral rating scales are mailed to teachers. 
Participants in the WWSC arm are scheduled for re-evaluation with their ENT surgeon 
within 1-4 weeks if indicated. 
 
9.7.1. Post-participation Surveys 
The research coordinator will ask and verbally consent all participants to complete 3 
follow up questionnaires after completion of the study via email, mail or phone. 
 
 
9.8. Potential Treatment Failures 
 
During the trial, the research coordinator may discover signs and/or symptoms that could 
potentially indicate treatment failure regardless of the arm assignment. “Treatment 
failure” is generally defined as a condition or situation that is observed during either 
routine interim follow-up phone calls or any study visits or clinical visits discovered in EMR 
surveillance, or from parent or physician contact, and indicates a potential need to change 
treatment.  See Adverse Events section.   
 
The research coordinator has the responsibility to:  
 

 
 
43 
 
• 
Identify and record these events utilizing the Treatment Stop [TSTOP] case report 
form (at this stage they are “potential” Treatment Failures). 
• 
The research coordinator will notify the PI, who will make any decisions required 
for the participant’s clinical safety.  The study team will make appropriate 
arrangements for further follow-up/referral (e.g., back to the referring physician).   
• 
Follow the general procedures for reporting SAEs (i.e., notify the DCC Project 
Manager within 24 hours of first knowledge of the event) and Complete the 
SAE/Treatment Failure report within 48 hours of first knowledge of the event. It 
will be submitted to the DCC who will forward the AE report and all supporting 
documents to the Medical Monitor via the data management system (Slice). 
Instructions for completing and submitting this information will be listed on the form 
and details provided in the Master Manual of procedures.  Diagnostic information 
that will assist in the understanding of the event may b e requested and follow up 
reports may be necessary. Significant new information on ongoing serious 
adverse events should be provided promptly to the DCC. 
• 
The Medical Monitor will determine if the event meets Treatment Failure criteria.  
This information, including specific reasons for failure including why a physician 
involved in the child’s care determined alternative therapy and which alternative 
therapy was recommended, will be documented on the [TSTOP] CRF and entered 
into the data management system.  If there is discordance between the PI and 
the external Medical Monitor, then the Medical Monitor’s decision will be used for 
data analytical purposes.  All reports of Treatment Failures will be tabulated as 
aggregate data and summarized monthly for review by the Steering Committee (in 
blinded format) and quarterly to the DSMB (or more frequently based on the 
trends and the Steering Committee’s recommendations). 
 
 
9.9. Adverse Event Definitions and Reports 
 
9.9.1. Overview of Surveillance for Adverse Events and Safety Indices  
 
Adverse events are monitored through several means of surveillance, as described 
below: 
 
1. Families will be in contact with study staff monthly by either electronic media 
(telephone, email and/or text messaging) or face-to-face visits to ascertain if a 
new medical or behavioral condition requiring therapy or causing interference 
with daily activities has occurred or been diagnosed, or if any emergency 
room visit or hospitalization has occurred.  EMR surveillance is also used to 
support these efforts.   
2. At each visit (day 0, months 6, and 12), and during monthly check-in, data will 
be collected that includes changes in health status, medications, SDB symptoms 
including sleepiness.  Also, height, weight and blood pressure data are 
collected during the in-person visits and can alert study staff to the need for further 
investigation if problem changes are discovered.   
3. Surgical adverse events will be captured by an intraoperative CRF completed 
by the surgeon and by questionnaires completed via a telephone interview 
post-operatively, and by ongoing monthly contact and EMR surveillance.  
Refer to the Surgical MOP for details. 

 
 
44 
 
4. Research data will be interrogated to identify questionnaire data exceeding 
values that indicate an abnormality warranting further investigation. 
5. All treatment failures will be reviewed by the study’s Medical Safety Monitor in 
real time and reported to the DSMB on a quarterly basis 
 
9.9.2. Urgent Medical Referral Criteria 
 
Conditions that will generate an Urgent Medical Referral Alert are those laboratory, 
physiological or behavioral findings that are believed to represent conditions that 
may require additional evaluation by the participant’s health care providers in a 
timely manner.  Because the participants in this study are pre-screened to be 
“otherwise healthy” children, most participants who meet Urgent Medical Referral 
Criteria are likely to be encountered at the time of their screening PSG and will no 
longer be eligible to participate and will exit the study to routine or urgent health 
care, as appropriate.   
 
NOTE: At the baseline visit, one of the behavioral questions asks about suicidal 
ideation.  A positive endorsement of that symptom will lead the study team to 
prompt assessment, deferred participation and possibly exclusion from the study, 
as appropriate for the participant’s welfare. CBCL for children 6 years and older, 
the only measure that assesses for suicidal ideation, will be completed during an in 
person visit by the blinded RC only.  
 
If the following conditions are identified during the course of the study, their 
occurrence will generate an Urgent Medical Referral by the Site PI who will 
communicate with the participant’s parent or guardian, and with permission, contact 
the child’s health care provider.  Some of these conditions (abnormalities of blood 
pressure) will be noted as usually needing confirmation with repeat testing before 
clinical decision making. 
 
• 
Stage 2 hypertension (> 99% for age and gender) 
• 
PSG: Desaturation to < 90% for > 2% of total sleep time OAI >20/hr. or AHI 
> 30/hr. 
• 
ABAS-3 score of <60 
• 
Suicidal ideation 
 
It should be noted that if any of these conditions occur after enrollment (i.e., not 
during a screening visit that disqualifies the child from enrolling in the study), these 
conditions will also be reported as Adverse Events.   
 
An Urgent Medical Referral Alert should be completed and the site PI notified within 
24 hours of first knowledge of the event. 
 
 
9.9.3. Definitions 
 
9.9.3.1. 
Pre-existing condition 
 
A preexisting condition is one that is present at the start of the study.  A 
preexisting condition should be recorded as an adverse event if the frequency, 

 
 
45 
 
intensity, or the character of the condition worsens during the study period.  At 
screening, any clinically significant abnormality should be recorded as a 
preexisting condition.  At the end of the study, any new clinically significant 
findings or abnormalities that meet the definition of an adverse event must also be 
recorded and documented as an adverse event.   
 
9.9.3.2. 
Adverse Event (AE) 
 
An AE is any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease that occurs during a participant’s enrollment period 
in the study including the clinically significant worsening of an already existing 
symptom, physical sign and abnormal laboratory value, whether or not the event 
is considered to be related to the study or the intervention under investigation.   
 
Preexisting diseases or conditions present or detected at the start of a study that 
do not worsen including any day-to-day fluctuations or anticipated day-to-day 
fluctuations will not be captured as Adverse Events (AE), including those 
identified as expected to occur in high frequency. 
 
9.9.3.3. 
Expected (Anticipated) Adverse Event 
 
Adverse events that are expected and are identified in the protocol and for 
the purpose of this study have been identified as: 
 
• 
Foreseeable (expected) mild adverse events that may not warrant reporting 
• 
Foreseeable (expected) adverse events that exceed threshold definitions 
and warrant reporting 
 
The Office of Human Research Protection distinguishes between risks and 
discomforts that are related to research compared to clinical intervention and 
have defined new reporting guidelines as of January 17, 2007.   
 
Since the surgical procedure (AT) is being performed as part of usual clinical 
care (e.g., it is not paid for as a study procedure and is performed as part of 
routine clinical care), all foreseeable mild AEs that are expected to occur at 
high frequencies as part of routine clinical care (like PSG or phlebotomy) 
including those associated with surgery (AT) that do not exceed threshold 
definitions will not be considered adverse events and will not warrant reporting, 
such as the following:   
 
Associated with PSG 
• 
Skin irritation from removal of adhesives (lasting < 2 days) 
• 
Temporary depigmentation under area of sensor attachment (lasting < 1 
month) 
• 
Poor sleep during PSG 
Associated with AT 
• 
Post-op throat pain lasting < 21 days and not requiring intravenous hydration 
or unscheduled medical evaluation or treatment. 

 
 
46 
 
• 
Post-op hoarseness or difficulty swallowing lasting < 21 days and not 
requiring intravenous hydration or unscheduled medical evaluation or 
treatment. 
• 
Intra-operative blood loss <7 ml/kg 
• 
Post-op blood-tinged oral or nasal secretions, lasting < 72 hours 
• 
Velopharyngeal Insufficiency (nasal regurgitation or hypernasality) lasting < 2 
months and not requiring specific evaluation or intervention 
Associated with Phlebotomy 
• 
Temporary pain, lasting < 48 hours 
• 
Bleeding or bruising at the blood draw site not needing medical attention 
 
Other 
• 
Anxiety surrounding behavioral testing not requiring psychiatric attention and 
not interfering with completion of the protocol 
 
9.9.3.4. 
Unexpected Adverse Events 
 
Adverse events that are not expected and not identified in the protocol or 
consent form. Adverse Events in this category will be reported. 
 
Abnormal laboratory value 
 
A laboratory abnormality should be documented as an adverse event if:  
• 
The abnormality suggests a disease and/or organ toxicity, OR 
• 
The abnormality is of a degree that requires active management; (e.g., 
specific treatment, more frequent follow-up assessments, further diagnostic 
investigation, etc.) AND 
• 
The laboratory abnormality is not otherwise refuted by a repeat test to 
confirm the abnormality. 
 
NOTE: Participants and their parent/legal guardian (s) will not be informed of 
any of the results collected and processed in the future for research purposes.  
These are research data only and not meant for the purpose of diagnostic 
evaluation. The results will not become part of the participant’s medical 
record.   
 
9.9.3.5. 
Unanticipated Problem Involving Risk to Participants or 
Others 
 
Any incident, experience, or outcome that meets all of the following criteria: 
 
• 
Unexpected (in terms of nature, severity, or frequency) given (a) the research 
procedures that are described in the protocol-related documents, such as the 
IRB-approved research protocol and informed consent document; and (b) the 
characteristics of the subject population being studied 
 
• 
Related or possibly related to a participant’s involvement in the research 

 
 
47 
 
 
• 
Suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) related to the 
research than was previously known or recognized. 
 
9.9.3.6. 
Serious Adverse Events (SAE) 
 
Any event that is life threatening or fatal; results in significant or persistent 
disability; requires hospitalization or represents other significant hazards or 
potentially serious harm to research subjects or others, in the opinion of the 
investigators.  The appropriate case report form must be completed for all 
events in this category according to the guidelines listed in the Manual of 
Procedures. 
 
9.9.4. Adverse Event Reporting Period 
 
The study period during which adverse events must be reported is normally defined 
as the period from the initiation of any study procedures to the end of the study 
follow-up.  For this study, the study treatment follow-up is defined as the last 
scheduled visit.   
 
9.9.5. Recording and Reporting Adverse Events 
 
At each contact with the subject, the investigator must seek information on AEs by 
specific questioning and, as appropriate, by examination.  Information on all 
adverse events should be recorded immediately in the source document, and also 
in the appropriate AE module of the case report form (CRF). 
   
All adverse events occurring during the study period must be recorded.  The clinical 
course of each event should be followed until resolution, stabilization, or until it has 
been determined that the study treatment or participation is not the cause.  The 
following data will be recorded:   
 
• 
Any event reported by the participant or parent/legal guardian, other than 
those expected and identified as detailed in the MOP will be immediately 
reported to the site PI.   
 
• 
Signs and symptoms will be graded by the Unblinded Research Coordinator 
utilizing a 5-grade scale as listed in the manual of procedures.   
 
• 
Each event will be assessed by the Principal Investigator (PI) for its 
relationship to study participation according to the guidelines listed in the 
Manual of Procedures. 
 
9.9.6. Hospitalization, Prolonged Hospitalization or Surgery  
 
Any adverse event that results in hospitalization (refer to manual of procedures for 
definition) surgery or prolonged hospitalization, should be documented and 
reported as a Serious Adverse Event (SAE) unless it is AT surgery occurring as a 

 
 
48 
 
treatment arm.  Any condition responsible for surgery should be documented as an 
adverse event if the condition meets the criteria for an adverse event.   
 
Neither the condition, hospitalization, prolonged hospitalization, nor surgery are 
reported as an adverse event if it occurred for a diagnostic or elective surgical 
procedures for a preexisting condition. Surgery should not be reported as an 
outcome of an adverse event if the purpose of the surgery was elective or 
diagnostic and the outcome was uneventful.   
 
9.9.7. Follow Up on Adverse Events 
 
The clinical investigator will follow every AE to a satisfactory outcome or 
stabilization of the event, even when this requires a time period beyond the scope 
of the study. The clinical investigator will record each AE outcome on the CRF 
according to the instructions outlined in the MOP.SAEs that are ongoing at the end 
of the study period must be followed to determine the final outcome.  Any SAE that 
occurs after the study period and is considered to be possibly related to the study 
treatment or study participation should be recorded and reported immediately.   
 
9.9.8. Post-Study Adverse Event Follow-Up 
 
All unresolved adverse events should be followed until the events are resolved, the 
subject is lost to follow-up, or the adverse event is otherwise explained. At the last 
scheduled visit, the investigator should instruct each participant and parent/legal 
guardian (s) to report any subsequent event(s) that they believe may be related to 
participation in this study 
 
9.9.9. Treatment Failure 
 
This will be defined as a change in clinical status interpreted by the Medical Safety 
Monitor as requiring an immediate change to established clinical therapy for SDB.  
Operationally, potential treatment failures will be identified by the research 
coordinator based on interim telephone calls, emails and/or text messaging and 
research visits, or contacts initiated by the participant or their referring physician.  
Information will be submitted to the Medical Safety Monitor who will make an 
adjudication of the status of the participant and notify the PI who will arrange 
medical follow-up as indicated.  Data will be subsequently reviewed by the DSMB.  
Note that, as the study will utilize an intent to treat paradigm, every effort will be 
made to continue the participant in the study, regardless of whether the participant 
receives clinical treatment or not.   
 
 
Examples of treatment failures include worsening symptoms of SDB such as: 
 
1) sleepiness interfering with schoolwork.   
 
2) new academic or behavioral problems resulting in a recommendation for grade 
retention, special education, or counseling 
 
3) placement on new medications for behavioral or emotional problems 
 
4) recurrent bacterial tonsillitis defined as 3 or more episodes of streptococcal 

 
 
49 
 
culture positive infection occurring over a 3-month time interval.  Children who 
have medical record documentation of 3 culture positive infections are asked to 
undergo a repeat throat culture after completion of the third course of antibiotics 
to exclude a chronic carrier state.  If this test is not ordered for routine clinical 
purposes, it will be arranged by the study staff and paid for by the study. 
 
Parent/legal guardian (s) who decide that they no longer want to wait 12 months 
for their child to be re-evaluated for AT surgery, but whose children do not meet 
any of the criteria for treatment failures, are not considered treatment failures. 
These children will be reevaluated by the ENT physician who initially evaluated 
them, unless they prefer to seek other medical consultation, and will be classifies 
as crossovers. 
 
9.9.10. Reporting Serious Adverse Events 
 
The clinical site is responsible for reporting SAEs to the DCC within 48 hours of first 
knowledge of the event by creating an Adverse Event Report in the data 
management system (Slice) listing participant ID, description of the event and 
adverse event date.  Creation of this initial report will automatically notify the DCC 
and provide summary data for the adverse event. SAEs will be reported to the Data 
Coordinating Center Project Manager, the Children’s Hospital of Philadelphia IRB, 
the DSMB Chair, and the NHLBI Program Scientist within 7 days of its occurrence. 
The DCC will also provide follow up reports. 
 
After the initial summary data are entered, the Research Coordinator and DCC will 
complete the full Adverse Event Report, including the following information: 
• 
Study identifier (PATS) 
• 
Study Center ID/Research Coordinator ID 
• 
Participant Identification Number 
• 
A description of the event in the form of a written narrative, including 
relevant medical history and/or co-morbidities 
• 
Date of onset 
• 
Date of resolution 
• 
Study time point during which event occurred 
• 
Randomization arm 
• 
Whether study treatment was altered 
• 
Description of actions taken by PATS staff, and follow-up required 
• 
If the event is expected and non-mild, or unexpected 
 
The research coordinator will provide further information on the AE in the form of a 
written narrative. This should include a copy of de-identified diagnostic tests or 
information that will assist in the understanding of the event. Significant new 
information on ongoing serious adverse events should be provided promptly to the 
DCC. 
 

 
 
50 
 
For all unexpected events and all events that are expected and serious the 
Medical Monitor will be notified and provided the Adverse Event Report.  
Using this report the Medical Monitor will complete an Adverse Event 
Adjudication form that will be available to the DCC and clinical site once 
completed, including the following information: 
• 
Expectedness 
• 
Relatedness 
• 
Severity 
• 
Whether the event constitutes a Treatment Failure 
• 
If the event suggests a greater risk of harm than previously recognized 
• 
Comments and recommendations for follow-up 
 
In addition, the site must promptly report all SAEs and unexpected, related events 
to their IRB via written, dated notification in accordance with the IRB’s reporting 
requirements. Copies of all such correspondence must be maintained in the clinical 
site’s regulatory binder. 
 
Upon notification from the clinical site, any serious adverse event that might 
reasonably be due to the study intervention will be reported to the monitoring 
bodies. 
 
 
10. Medical Monitoring 
 
It is the responsibility of the Principal Investigator to oversee the safety of the study at 
his/her site.  However, since the PI at each site is blinded to the treatment arm 
assignment, initial screening of adverse events will be performed by the unblinded 
research coordinator. If the adverse event appears related to surgery, the coordinator 
will contact the otolaryngologic surgical co-investigator or other unblinded investigator at 
the site to ascertain the preliminary relationship to study participation, and coordinate 
follow up when applicable.  The surgical co-investigator will contact the PI whenever 
he/she considers it medically necessary.  Note that every site has a primary surgical co-
investigator. If the adverse event appears not to be related to surgery, then the research 
coordinator will discuss the event with the PI or other unblinded co-investigator. When 
necessary, the DCC will notify the independent Medical Monitor for adjudication of all 
severe or related unexpected events for study purposes.  The PI, IRB, Steering 
Committee, DSMB, and NIH Program Officer will be notified of all AEs, unanticipated 
problems, and Treatment Failures according to the reporting timeframe specified in the 
MOP. The PI’s responsibility will include assuring that appropriate study data are 
communicated to the participant’s family and physicians and that appropriate referrals or 
interventions are initiated.   
 
Medical Monitoring will also include oversight by the Data Coordinating Center 
generating reports through regular assessment of the number and type of SAEs.  
 
10.1. Medical Safety Monitor 
 

 
 
51 
 
A pediatrician who is board-certified in pediatric intensive care, pediatric 
pulmonology, and sleep medicine (Dr. Connolly, University of Rochester), 
unassociated with any clinical site, will serve as the independent Medical Safety 
Monitor.  The Medical Safety Monitor will provide independent adjudication of 
unexpected and serious AEs and potential treatment failures.  The Medical Safety 
Monitor will have access to randomization codes to make an informed decision 
about a particular participant.  In addition to aggregate data, the Medical Safety 
Monitor will receive reports of all AEs that are: 
 
• 
Expected and exceed thresholds 
• 
Unexpected and Serious 
• 
Unanticipated Problems that fit the reporting criteria  
 
If a medical or psychological adverse event occurs that requires immediate 
intervention, it will be evaluated on an individual basis and study termination or 
recommendation regarding immediate AT surgery will be made.  The Medical 
Safety Monitor will also evaluate both trends in AEs and Treatment Failures 
across the study and within each arm, as well as to confirm or refute the 
occurrence of specific treatment failures. 
 
10.2. Serious Adverse Event and Unblinding of Treatment Arm 
 
If there is an SAE, which is thought to be possibly or probably related to the coded 
intervention, the clinical site, when necessary for the safety of the participant, will 
unmask the treatment arm assignment.  An explanation of the need for unblinding 
the treatment arm assignment must be provided to the DCC, who will disseminate 
the information to the various regulatory groups (DSMB, NIH) and external site PIs. 
Unblinding of the treatment arm assignment is anticipated to be an uncommon 
occurrence and is highly discouraged.  An exception is made for any information 
identified that may pose acute health risks or would influence immediate treatment, 
in which case the PI will be notified immediately. 
 
10.3. Management of Associated Adverse Events and Discontinuation of 
Treatment 
 
The administration of the intervention may be discontinued at the subject’s request 
or by the investigator, based on clinical judgment.  If the subject is withdrawn from 
the study and participation terminated, the Study Stop CRF must be completed 
documenting the date study participation ended and identifying the reason. 
Parent/legal guardian (s) of participants who are discontinued will be instructed to 
report any AE experienced after treatment without delay. 
 
10.4. Other Study Medical Monitoring and Reporting 
 
10.4.1. Surgical Monitoring 
 
Complications resulting from surgery will be documented at each site with use of an 
intra-operative data sheet and by reports obtained from the family during routine interim 
follow-up, supplemented by medical records, as appropriate. Major unanticipated 
adverse events and unanticipated problems that fit the reporting criteria will be reported 
(as required by institutional IRBs). The DCC will report complications from surgery to 

 
 
52 
 
the Surgical Quality Control Committee, the Independent Medical Monitor and to the 
DSMB and NHLBI. Periodically, these results will be tabulated and any significant 
deviations from reported national rates will be investigated. If any surgical complication 
is noted that exceeds expectation of usual care, or any site experiences excessive 
problems (as defined by the Surgical Quality Control Committee or the DSMB), Dr. 
Garetz, Director of the Surgical Quality Control Committee, will initiate an investigation. 
Actions may include ongoing monitoring, retraining, excluding the participation of 
specific surgeons, or excluding specific sites. 
 
10.4.2. Severe OSA on PSG 
 
10.4.3. Baseline 
 
Any OSA is an exclusion for the study, so the participant with severe OSA will exit the 
study and the study team will facilitate appropriate clinical management.  
 
10.4.4. Follow-Up 
 
Data from follow-up PSGs will be available at a time when all 12 month follow up data 
have been collected to minimize influencing study outcomes, an approach that is 
standard for research data.  However, an exception will occur for any information that 
meets the Urgent Medical Referral Criteria. Data will be shared earlier, as described 
above relative to baseline data. 
 
10.4.5. Behavioral testing 
 
If at any time during the assessment there is concern that a participant is reported by 
his/her parent/caregiver to have suicidal ideation, the study team will immediately 
evaluate the participant.  The Neurobehavioral Subcommittee has developed a plan for 
suicidal ideation and suspected child abuse. Each site has modified this to specify local 
individuals and mechanisms for referral. All site-specific plans identify the primary 
professionals who will be contacted in the event of suicidal ideation or suspected child 
abuse, as well as backups when the primary is unavailable. These professionals will be 
responsible for contacting and working with local mental health staff.  All sites also 
identify the local department that participants will be escorted to by PATS staff if the 
primary and backup professionals cannot be contacted. The CBCL for children 6 years 
old and older, the only measure that assesses suicidal ideation, will be completed in the 
presence of a blinded RC only.  
 
 
Participant Refusals, Screen Failure, Withdraws, Discontinuation, and Missed 
Appointments   
 
11. Participant Refusal 
 
A record will be kept of all participants and parent/legal guardian (s) who are 
approached but refuse to participate in the study prior to signing the Informed 
Consent.  For tracking purposes, the reason for refusal will be documented on the 
Screening Log. 
 

 
 
53 
 
12. Withdraw/Premature Termination 
 
If a participant withdraws/terminates from the study prior to the 12-month visit, 
every effort should be made to obtain follow-up safety data which includes 
information on adverse events and current health status including sleep habits and 
surgical AEs (if applicable).  The clinical site must also complete the Study Stop 
CRF [SSTOP] indicating the reason for termination. 
 
 
 
13. Missed Appointments 
 
If a participant does not keep a scheduled appointment, the missed visit (testing) 
must be rescheduled within two weeks.   
To minimize the occurrence of missed appointments the parent/legal guardian will 
be provided with the following reminders when appropriate:  
 
• 
Written schedule of visits during the baseline exam 
• 
Printed card with date of next visit or contact (when appropriate) 
• 
Phone notification within 1 to 2 days prior to the scheduled visit 
• 
Letter via postal mail if other methods of communication fail 
 
 
14. Quality Assurance 
 
14.1. Quality Control Procedures 
 
Quality control measures will be implemented at several levels to ensure that all 
centers and personnel meet and maintain comparable and high levels of technical 
performance.  Quality Control will be optimized by multiple levels of training, 
monitoring and feedback activities, including central training, certification of 
research personnel for all specialized testing procedures. All clinical site personnel 
will be centrally trained and certified by DCC, Reading Center and CCC staff. The 
Quality Control Procedures are detailed in the MOP for each specialty group. 
 
 
14.2. Centralized Training 
 
After protocol development and printing of a final MOP, a training session will be 
held at the CCC in Philadelphia.  Attendees will include: all key study investigators 
and staff (coordinators, research assistants) and leaders of quality control 
committees.  Joint introductory sessions will be held that include review of the 
entire protocol and study organization and allow study personnel to become 
acquainted. Specifically, but not exclusively, this training will ensure that clinical 
personnel understand the study’s goals and objectives, data collection process, all 
CRFs, MOPs, database software, and all applicable Standard Operating 
Procedures to attest that the study is conducted in a proper manner.   
 

 
 
54 
 
Breakout sessions will focus on specific aspects of data collection and database 
management: polysomnography; anthropometry; behavioral performance testing; 
safety monitoring; health care utilization ascertainment; recruitment; follow-up and 
retention strategies; surgical intervention; data entry and data queries; ethical 
issues; and special procedures for studies of children.  Specific sessions will be 
videotaped for future references by staff.  Time also will be allotted to document 
proficiency in specific procedures (e.g., data entry), which may require 
combinations of observation by the trainer and written exams. 
 
 
 
14.3. Certification Processes 
 
All procedures (behavioral performance testing, anthropometry, data entry, 
polysomnography,) will require certification of staff prior to their performance on 
study participants.  Requirements differ per procedure, but generally include 
documentation of successful performance during central training and observation, 
possible completion of a written exam, and submission of successfully completed 
studies during pilot studies (meeting standards for quality and completeness when 
evaluated by the relevant Quality Control group or DCC). In addition, after initial 
certification, each technician’s performance will be monitored on an ongoing basis.  
If a minimal number of studies are not performed in any given study period, or if 
studies submitted fall below threshold levels for quality, the PI will be notified and 
procedures for remediation be implemented (e.g.  completion of additional practice 
studies, re-training or removal from the study).   
 
15. Administrative 
 
15.1. Institutional Review Board 
 
It is the responsibility of the Principal Investigator at each clinical site to provide their 
IRB with all pertinent material, including a copy of the informed consent.  Approval 
from the reviewing IRB of the informed consent form must be obtained and forwarded 
to the Data Coordinating Center prior to screening or enrolling any participants.  The 
clinical site’s Principal Investigator also maintains the responsibility of coordinating 
with the DCC and CCC in initiating protocol re-approval, notification of protocol 
and/or consent form changes, adverse events, and termination of the study 
according to the appropriate IRB requirements. A central IRB will be used (CHOP). 
 
Direct Access to Source Documents 
Investigators will maintain, on-site, in an orderly fashion, and make available to the 
DCC and quality assurance personnel, the following documents: the signed study 
protocol, amendments, informed consent documents, and approval letters from the 
IRB, CRFs, all primary source documentations, and all letters of correspondence. 
 
15.2. Record Keeping 
 

 
 
55 
 
15.2.1. Source Documents 
 
Source data are all information, original records of clinical findings, observations, or 
other activities in a clinical trial necessary for the reconstruction and evaluation of the 
trial.  Source data are contained in source documents.  Examples of these original 
documents, and data records include: hospital records, clinical and office charts, 
laboratory notes, memoranda, subjects’ diaries or evaluation checklists, recorded data 
from automated instruments, copies or transcriptions certified after verification as 
being accurate and complete, microfiches, photographic negatives, digital pictures, 
microfilm or magnetic media, x-rays, subject files, and records kept at the pharmacy, 
at the laboratories, and at medico-technical departments involved in the clinical trial. 
 
15.2.2. Case Report Forms (CRF) 
 
The CRF is the primary data collection instrument for the study and all data requested 
on the CRF must be recorded. Samples of each form are provided online with direct 
“point of care” data entry via the Data Management System (Slice), as well as PDF 
copies available for print at the PATS study portal (patstrial.org). Study-designated 
personnel from each site will be trained in Case Report Form completion and entry 
into the Data Management System. 
 
15.2.3. Record Retention 
 
It is the investigator’s responsibility to retain study essential documents for at least 7 
years after the study is discontinued. 
 
16. Data Management and Analysis 
 
Details of data management and quality assurance are outlined in the DCC application.  
The DCC will coordinate all PATS data management activities including CRF collection, 
entry, verification, validation and query resolution of data.  The DCC will develop and 
maintain a computerized Data Management System for this protocol that will be deployed 
within each of the clinical sites. CRFs will be available to be printed locally at the clinical 
site from Portable Data Files (PDFs). Originals of these forms will be retained by the 
clinical sites. Single data entry will be performed at the clinical sites utilizing the Data 
Management System tools available on the workstation. A sample of data will be double data 
entered by the DCC for verification. Validation checks will be performed at the centralized 
database to verify data accuracy and identify missing, unclear, illogical, or problematic 
responses. Queries will be generated to resolve discrepancies. 
 
16.1. Study Monitoring, Auditing, and Inspecting 
 
16.1.1. Recruitment and Retention Monitoring 
 
The DCC and the Recruitment and Retention Sub Committee will monitor recruitment 
activities, develop recruitment brochures, tools and incentives that will enhance 
retention. Recruitment activities will be monitored on a regular basis utilizing the 
Recruitment Tracking Form listed in the Manual of Procedures. 
 
16.1.2. Study Monitoring Plan/Site Visits 
 

 
 
56 
 
A dedicated DCC Project Manager, reporting to Drs. Redline and Wang, will oversee 
the coordination of key activities across the DCC, CCC and field sites. S/he will oversee 
the development of the protocol, training materials, IRB templates and will coordinate a 
central training session that will be held at the beginning of the study.  S/he will oversee 
the certification of staff on all procedures prior to their performance on study 
participants.  S/he will conduct ongoing monitoring of site-specific activities and support 
each site’s coordinator, including holding weekly to monthly conference calls that 
include Operations and Recruitment and Retention subcommittee calls.  S/he will 
coordinate communications across study members and study entities using video 
conference calls (GoToMeeting) and ensure the web site is kept updated with 
appropriate study documents and reports.  With the support provided by a web-portal 
and data reporting system developed by the DCC Informatics Core, s/he will monitor 
site and individual technician performance, share results with key study members 
(including the Steering Committee), and provide additional support to individual sites or 
study members as needed, including retraining or recommendations for remediation.  
Recruitment and retention benchmarks and data integrity will be closely monitored and 
if milestones are not met, the site PI and Steering Committee will be notified and 
procedures for remediation will be implemented.  Formal site visits will occur as 
described below.  Additional site visits will be scheduled if problems are identified or if 
subsequent performance problems occur. All Quality Assurance and Regulatory 
Compliance measures will be explicitly detailed in a Data and Safety Monitoring Plan 
specifically developed for this project.  This plan will be filed with the NHLBI and study 
Data and Safety Monitoring Board (DSMB). This plan will identify the frequency and 
manner with which these activities will be conducted.   
 
16.1.3. Site Visits 
 
Within approximately 3 months of initiating data collection, each site will undergo a 
formal site visit by a team that will include members from the DCC and CCC.  One 
member from an alternative clinical site may also participate. Site visits will generally last 
two days (including one night observing the polysomnography hook-up) and are 
designed to identify early in the study any departures from procedure, as well as to 
provide positive reinforcement to the staff and further improve the bonding among staff 
from across the study.  Activities include; review of staff performance during a typical 
recruitment and data collection encounter, review of supply inventories, study 
documents, equipment cleaning procedures, and data audits.  A formal site visit report is 
produced within one week of the visit, which is shared with the site, Steering Committee 
and DSMB.  Additional site visits will be scheduled if problems are identified in the initial 
visit, or if subsequent performance problems are identified at the site.  
 
16.1.4. Recruitment and Retention Monitoring 
 
A Recruitment and Retention Subcommittee will be established with representation by 
the Study Coordinators from each clinical site, the DCC, one study otolaryngologist, and 
an investigator with experience in multicenter clinical trials.  The committee will generate 
recruitment brochures, oversee the development of newsletters, nondenominational 
holiday cards and web sites targeting participants, and oversee the use of incentives 
(monetary and small gifts).  Recruitment and retention statistics will be posted on a study 
web site monthly, along with graphs that show deviations from projections.  Sites which 
fail to meet projections for 2 consecutive months will be asked to provide a report, with 
an analysis and action plan, to the Steering Committee. If continued lags are observed, 

 
 
57 
 
the study PIs (Furth; Redline), in consultation with the DSMB and NHLBI, will determine 
further actions, which may include replacement of the site or reallocation of funds.  
 
16.1.5. Ongoing training 
 
In addition to the initial central training, on-going training of project personnel will be 
conducted.  This training, in the form of telephone conferences, is designed to maintain 
a current level of project knowledge regarding developments post initial training.  
 
16.1.6. Auditing and Inspecting 
 
The investigator will permit study-related monitoring, audits, and inspections by the 
DSMB/IRB, the sponsor, government regulatory bodies, and University compliance and 
quality assurance groups of all study related documents (e.g. source documents, 
regulatory documents, data collection instruments, study data etc.). The investigator will 
ensure the capability for inspections of applicable study-related facilities (e.g. Clinical 
and Translational Science Award, Sleep Lab/Clinic, ENT clinic, diagnostic laboratory, 
and surgical suite, if appropriate).   
 
Participation as an investigator in this study implies acceptance of potential inspection by 
government regulatory authorities and applicable University compliance and quality 
assurance offices. 
 
17. Data Safety and Monitoring Plan 
 
The Data Safety and Monitoring Plan is outlined in the DCC application. 
 
 

 
 
58 
 
18. Ethical Considerations 
 
This study is to be conducted according to US and international standards of Good 
Clinical Practice (FDA Title 21 part 312 and International Conference on Harmonization 
guidelines), applicable government regulations and Institutional research policies and 
procedures.  This protocol and any amendments will be submitted to a properly 
constituted independent Ethics Committee (EC) or Institutional Review Board (IRB), in 
agreement with local legal prescriptions, for formal approval of the study conduct.  The 
decision of the EC/IRB concerning the conduct of the study will be made in writing to the 
investigator and a copy of this decision will be provided to the sponsor before 
commencement of this study. 
 
All subjects will be provided with a consent form describing the study and providing 
sufficient information to make an informed decision prior to entering.  The consent form 
template may be modified slightly from site-to-site depending upon local IRB 
requirements and will be submitted with the protocol for review.  Formal consent of a 
subject, using the IRB- approved consent form, must be obtained before that subject is 
submitted to any study procedure. The consent form must be signed by the subject or 
legally acceptable surrogate, and the investigator-designated research professional 
obtaining the consent. 
 
19. Statistical Analysis Plan 
 
Description of study 
 
We propose to conduct a randomized, single-blinded, controlled 12-month intervention 
study that evaluates the impact of early adenotonsillectomy [eAT] on measures of 
behavior, quality of life, and health care utilization (HCU) in children with mild sleep 
disordered breathing (MSDB). The study’s co-primary outcomes are a well-validated and 
clinically informative measure of behavior associated with executive function (Behavioral 
Rating Inventory of Executive Function [BRIEF2/P] Global Composite Score [GEC]), 
assessing self-regulation and organizational skills, and an age-appropriate, validated 
measure of attentional vigilance, the Go-No-Go [GNG] continuous performance test 
(signal detection parameter, d’).  Additional secondary outcomes will provide information 
relevant to patients, their caregivers, and the health care system. These include: other 
behavior measures, sleep disordered breathing (SDB) symptoms, generic and disease-
specific measures of quality of life, indices of HCU, and polysomnographic indices of 
SDB and sleep quality.  Analyses investigating effect modification by factors such as 
age, asthma, obesity, secondhand smoke exposure, sleep duration, and race will be 
conducted to explore subgroup variation in treatment response.  
 
Children aged 3 to 12 years, with habitual snoring without frank obstructive sleep apnea 
(OSA), who meet study eligibility criteria, will be recruited from 5 well-established 
pediatric sleep centers, and further screened with polysomnography to exclude frank 
OSA and other sleep disorders. It is anticipated, based on the literature and our 
experience conducting similar screening in CHAT, that ~50% of participants will be 
eligible after screening PSG. 460 eligible participants will be randomized to either eAT or 
to watchful waiting with supportive care (WWSC) for 12 months. All participants will 
receive information about healthy sleep habits for children, and appropriate clinical 
referrals for management of co-morbidities such as asthma. Participants will undergo 

 
 
59 
 
standardized assessments including behavioral, performance, and health evaluations at 
baseline and at 6- and 12-month follow-up time points. Monthly check in visits will be 
conducted by telephone, email and/or text messaging to maintain participant contact and 
enthusiasm, and to collect additional symptom and health care utilization reports. 
Following 12 months, participants in the WWSC group will be referred to ENT for a 
clinical visit, if their 12-month PSG shows an AHI> 3 /hr or obstructive apnea index > 
1/hr. or if the parent/caregiver reports  concerns or symptoms.  The 12-month end point 
was chosen to enable assessment of long-term therapeutic effects. However, data from 
the 6-month visit will be used to improve the study’s statistical efficiency; help identify the 
time-course and trajectory of treatment response; and provide information for imputing 
missing 12-month data. In addition to the efficacy analyses described below, adverse 
events will be summarized and presented by treatment groups.  
 
Aims, Hypotheses and Endpoints  
 
Aim 1: To determine the effect of eAT on behavior, attention, SDB symptoms, sleep 
quality, and quality of life in children with MSDB. 
 
Aim 2: To determine the effects of eAT on health care utilization (HCU) in children with 
MSDB.  
 
Aim 3: To identify factors that moderate the response to AT, including age, 
asthma/atopy, obesity, secondhand smoke exposure, sleep duration, family functioning 
socioeconomic status, and race.  
 
Endpoint for Primary Efficacy Hypotheses 
The co-primary outcome of the randomized controlled trial will be the GEC Score from 
the BRIEF2/P and the GNG. Please see the CCC application for details on its reliability, 
responsiveness, and psychometric properties.    
  
 
Primary Null Hypothesis  
The primary null hypothesis is that the mean change at 12 months in the BRIEF2/P GEC 
Score and GNG sustained attention d’ will be the same for children who were 
randomized to eAT or to WWSC.   
 
 
Secondary Null Hypotheses 
a) There will be no difference between treatment groups in the expected mean change 
at 12 months in other behavior/performance measures, SDB symptoms, and quality of 
life. 
 
b) There will be no difference between groups in expected HCU (illness or injury 
requiring hospitalizations; emergency department visits; inpatient procedures; 
outpatient procedures; scheduled office visits; unscheduled office visits or urgent care 
visits; medication use)  during the 12-month study period. 
 
c) Any differences in outcomes (BRIEF2/P, GNG, HCU) between children randomized to 
eAT or to WWSC will not vary by age, baseline overweight/obesity, atopy/asthma status, 
secondhand smoke exposure, family and neighborhood socioeconomic status, family 
functioning, baseline symptom severity (i.e., Sleep Disordered Breathing Scale) or race 
(African American vs other; Minority vs. non-minority).  

 
 
60 
 
 
 
Exploratory Analyses 
Analyses addressing secondary hypotheses will be considered exploratory.  These 
include mediation and moderation analyses. 
 
As snoring is the focus of this study, we will assess the association between quantitative 
estimates of snoring with study outcomes at baseline, evaluate the treatment effect on 
these snoring measurements, and whether changes in snoring correlates with changes 
in study outcomes,  as an exploratory analysis.  
 
Variables Used to Stratify Randomization 
 
Randomization will be stratified by the following factors within site: age (< 5 years vs > 5 
years); overweight status (body mass index [BMI] >85%ile); and race (African American 
vs other). These represent key groups likely to influence treatment responses. 
Stratification by these factors will provide greater assurance that the comparison groups 
will be similar with respect to these and related variables. Given an overall sample size 
of 460 and a relative large number of strata (8 strata within each of the 5 sites), we will 
use a dynamic randomization method, Pocock and Simon’s minimization method71, 
implemented in the Data Management System (Slice), to ensure treatment arms are 
balanced with respect to these factors as well as for the number of subjects in each 
group.  Because the minimization method is more complex than stratified permuted 
blocks, Dr. Wang will monitor the randomization assignment closely to ensure the 
integrity of randomization. 
 
Estimated Power and Sample Size 
 
The study plans to randomize 460 subjects into one of the two arms in a 1:1 ratio. Based 
on the experience in the CHAT study, we assume a dropout rate of 15% at 6 months, 
and an additional 5% attrition at 12 months, resulting in 390 and 368 evaluable subjects 
at 6 and 12 months, respectively. As described below, this sample size was chosen so 
that the study will have ample power to detect moderate to large moderation effects and 
a range of mediation effects when the exposure-moderator and moderator-outcome 
associations are moderate or large. 
 
The primary endpoints of the study are changes from baseline to 12 months in the 
BRIEF2 GEC score and the GNG d’ score. The primary alternative hypotheses are that 
children randomized to the eAT group in comparison to WWSC will have a significant 
improvement in behavior as measured by the BRIEF2/P GEC score and GNG 
continuous performance d’ score at the end of 12 months. To maintain a study-wise 
significance level of 5% for analysis of co-primary endpoints, the Holm method72;73 will 
be used. The Holm method has been shown to be uniformly more powerful than the 
Bonferroni procedure. The Holm method is a sequentially rejective method for 
performing multiple tests. In the case of two tests using an overall alpha of 0.05, the 
comparison with the largest difference will be tested at the 0.05/2=0.025 level. If it is 
rejected, the comparison with the second difference will be tested at the 0.05 level. 
 
We anticipate that 12-month changes in the BRIEF2/P GEC score in a sample of young 
children with MSDB will be comparable if not larger to that observed in the sample of 
children with OSA studied over 6 months in the CHAT study. In CHAT, the estimated 

 
 
61 
 
difference in change score from baseline to 6-month in the BRIEF GEC score in the eAT 
group compared to the WWSC group was 3.7 points. The standard deviation at baseline 
in the WWSC group was 11.5 and the correlation between the baseline and the follow-
up GEC score was 0.73. For the GNG score, the anticipated treatment difference is 
0.33, based on a published study that found a difference between 5-year-old with vs 
without SDB on an objective attention test74.  In a study of 105 5-year old children 
studied with the GNG test at baseline and then 12 months later75, Co-I Taylor observed 
the baseline GNG score to have a standard deviation of 0.77 and to correlate with the 
12-month follow-up score with an r=0.48. Using these estimates and methods described 
in Hedeker et al for sample size estimation for longitudinal designs with attrition, our 
sample size with the assumed attrition rate has 98% power to detect a difference of 3.7 
points in the BREIF2/P GEC change score and 98% power to detect a difference of 0.33 
points in the GNG change score between treatment groups at a significance level of 
2.5% and 5% respectively (the comparison for the BRIEF2/P GEC change score 
corresponds to a larger standardized effect and therefore is tested at a lower 
significance level of 0.025). The minimal effect size the study has 80% power to detect is 
0.22 (0.24) for the GNG change score, and 2.4 (2.6) for the GEC change score at 5% 
(2.5%) significance level.  
 
To detect the effect of eAT on health care utilization, in Aim 2 we will compare between 
group rates of hospital admissions, emergency department/unscheduled office visits, 
specialty consultations and medication use during the year following randomization. We 
estimate power based on the report by Tarasiuk et al who analyzed administrative health 
records in Israeli children with OSA10. Among children who underwent AT compared to 
those who did not, the number of new hospitalizations per child per year was 0.06 and 
0.25, the number of emergency department visits per child per year was 0.35 and 0.37, 
and the number of specialist consultations per child per year was 1.9 and 3.5, for the 
treated and untreated groups, respectively. Assuming that the rates of these events in 
the eAT and the WWSC group are similar to those observed in the treated and untreated 
groups in Tarasiuk et al, our study will provide ample power to detect the differences in 
number of hospitalizations or the number of specialist consultations. Specifically, a 
sample size of 368 (184 in each group) provides >99% power to detect the difference 
between the two distributions of number of hospitalizations at the 5% significance level 
using a two-sided Wilcoxon rank-sum Test, based on 2000 Monte Carlo samples from 
the alternative distributions: Poisson(.06) and Poisson(.25). Similarly, our sample size 
provides >99% power to detect the difference between the two distributions of number of 
consultations at the 5% significance level using a two-sided Wilcoxon rank-sum test, 
based on 2000 Monte Carlo samples from the alternative distributions: Poisson(1.9) and 
Poisson(3.5). We will have limited power to detect differences in the patterns of 
emergency department visits if our emergency visits mirror those in the Israeli study. 
However, due to the high prevalence of asthma projected in our sample and the 
emergency room patterns in the U.S., we expect to see larger changes in this outcome.  
 
Aim 3 is to identify factors that moderate the behavior and health care utilization 
changes in response to surgery (AT). As described in the CCC application, we anticipate 
that 50% of children will be age less than 5 years; 47% will be overweight/obese; 40% 
will be African American (AA), 30% will have asthma, and 20% will be exposed to 
secondhand smoke. The study will have 80% power to detect a treatment effect 
difference of 0.58, 0.59, 0.60, 0.64, and 0.74 standard deviations for interactions 
between treatment and age, overweight/obese, race, asthma, and secondhand smoke, 
respectively.  In the CHAT study, the estimated difference in treatment effect on BRIEF 

 
 
62 
 
GEC score between AAs and non-AAs was 4.63 and the estimated standard deviations 
in the 4 subgroups defined by treatment and race ranged from 7.69 to 9.27. Assuming 
that the difference in treatment effect between AAs and non-AAs is 4.63 and a standard 
deviation of 9, a sample size of 184 per treatment group with 40% AAs provides 67% 
power to detect this difference (a 0.51 standard deviation of treatment effect difference) 
based on normal approximation at the 5% significance level.  
 
Due to the considerable morbidity and HCU among children with asthma, it is of 
particular interest to assess changes in HCU with surgery within this group of children. 
National data demonstrate that asthma exacerbations occur in 57.2%, emergency 
room/unscheduled visits in 32.5%, and hospitalizations in 8% of children with asthma 
annually75.  Further, we and others have shown that SDB is associated with severe or 
difficult to treat asthma22,26,62,76.  SDB symptoms alone appear to predict asthma 
exacerbations as shown in the prior research22,26,76 and a secondary analysis of data 
reported in Ross et al26 which showed that 25% of children with habitual snoring had ≥ 3 
asthma exacerbations over one year in contrast to 6.8% of those without snoring 
(p<0.01)26. Within our asthma subgroup, we will analyze an aggregate measure of HCU, 
“asthma exacerbations”, defined according to NIH guidelines77 as use of oral or systemic 
corticosteroids, unscheduled or emergency visits during which the child was treated with 
a short acting bronchodilator, or hospitalizations for asthma/wheezing. Using effect sizes 
observed in an uncontrolled study that reported that AT was associated with a reduction 
in asthma exacerbations from 4.1 ±1.3 per person per year to 1.8 ± 1.4 per person per 
year62, we estimate that in our sample of  children with asthma (110 evaluable 12-month 
endpoints), we will have >99% power to detect the difference between the two 
distributions of number of asthma exacerbations at the 5% significance level using a 2-
sided Wilcoxon rank-sum test, based on 2000 Monte Carlo samples from the alternative 
distributions: Poisson(1.3) and Poisson(4.1). We have 80% power to detect a 27% 
reduction in exacerbation rate from a baseline rate of 4.1 per person per year.   
 
The power to detect potential mediation effects (see below) depends on not only the 
mediation effect, but also on the magnitude of the association between exposure (X) and 
mediator (M) and the association between outcome (Y) and mediator controlling for 
exposure. As determined in simulation studies by Fritz and MacKinnon76, a sample size 
of 368 achieves greater than 80% power to detect mediation effects ranging from small, 
to medium, to large (corresponding to a path coefficient of 0.14, 0.39 or 0.59) for the 
settings with moderate to large X-M and M-Y associations using various resampling 
methods including the PRODCLINC program77, the percentile bootstrap, and bias-
corrected bootstrap methods78. For the settings where one of the X-M and M-Y 
associations is small, a sample size of 368 achieves close to 80% power if the other 
association is moderate or large using the bias-corrected bootstrap method.  
 
 
Approaches to the Analysis  
 
Primary analyses will follow the “intention-to-treat” principle; that is, individuals will be 
analyzed according to their assigned treatment group, whether or not they receive the 
study treatment as assigned. This approach avoids bias if individuals drop out of the two 
arms for different reasons. Every effort will be made to obtain follow-up data on all 
children randomized, whether or not they follow their assigned treatment. Although every 
effort will be made to minimize missing data, some missing data will be inevitable, and 
therefore a variety of methods that accommodate missing data in analyses will be 

 
 
63 
 
considered, including inverse probability weighting and multiple imputation. For example, 
missing covariates may be imputed through the multiple imputation through chained 
equations (MICE) approach79 and missing outcomes may be handled through the use of 
mixed effects modeling or inverse probability weighting80 81. We will make explicit the 
assumptions for the methods employed and perform sensitivity analyses to assess the 
robustness of results to plausible violations of these assumptions. Sensitivity analyses 
will be conducted excluding children on ADHD medications. 
 
Preliminary Analyses 
 
Our approach will involve close collaboration between clinical experts and 
biostatisticians while ensuring appropriate blinding. Interim analyses of baseline 
variables (aggregated across intervention groups) will be conducted early in the study to 
ensure that the collected and derived data follow the assumed distributions, and that 
appropriate methods for identifying outliers and for computing clinical scores are 
implemented. Reports will provide a full description of the distributions of each study 
variable, along with indices of associated data quality, and include graphic displays. The 
amount and patterns of missing data, if any, will be characterized. Measures that are not 
normally distributed may be transformed to meet model assumptions. In some instances, 
such as symptom summaries for related outcomes, outcomes may be derived by 
combining several variables into a small set. Before conducting final analyses, 
descriptive statistics will be generated using the total data set, ensuring that outliers or 
potential discrepancies in the data are resolved. 
 
Descriptive Comparisons between Treatment Groups, Baseline and Over Time 
 
Descriptive analyses will be performed to characterize the treatment groups, and to 
confirm that the randomization resulted in no important group differences at baseline. 
Summary statistics such as means, medians, standard deviations, and ranges also will 
be used to describe changes from baseline to Month 6, and from baseline to Month 12, 
for all primary and secondary outcome variables within each treatment group, as well as 
to describe dropout rates, treatment failures/cross-over rates, and patterns of missing 
data. Graphical methods such as stem-and-leaf diagrams, box plots, and scatter plots, 
will be used to examine distributions, and guide the choice of transformations.  Two-
group comparisons will generally employ Wilcoxon rank-sum tests to protect against 
violations of normality assumptions. Categorical variables, including dichotomous 
factors, will be summarized by proportions, and compared among groups using Fisher's 
exact test.   
 
 
Statistical Approaches to Testing for Treatment Differences 
 
To compare changes in the BRIEF2/P GEC score and GNG score at 6 and 12 months in 
the eAT and WWSC groups, we will perform a longitudinal analysis with time (0, 6, and 
12 months) as a categorical variable, and with the assumption of equal means at 
baseline to reflect the randomized design. Both visit and treatment group will be treated 
as categorical variables to allow separate comparisons of intervention groups at 6 and 
12 months. This analysis will also permit testing of the null hypothesis that the means of 
changes in BRIEF2/P scores and GNG scores at 6 and 12 months  are the same in the 
eAT and WWSC groups. The model and testing procedure are: 
 

 
 
64 
 
Let X1 and X2 be indicator variables for time = 6 months and time = 12 months, and 
let X3 be the indicator variable for treatment group. We will fit a mixed effects model 
for repeated measures that includes the main effects of X1 and X2, and the 
interactions between X3 and the two indicator variables for time, X1 and X2. Let β3 
and β4 denote the coefficients of the interaction terms X1*X3 and X2*X3, 
respectively. β3 and β4 represent the treatment effects at 6 and 12 months and the 
average treatment effect is given by (β3 + β4)/2. Standard methods will be used to 
estimate and test the null primary hypothesis of β4 =0.  
 
Comparisons will be adjusted for stratification factors, and as appropriate, adjusted for 
potential covariates found to differ between groups at baseline and for baseline levels of 
other relevant covariates. Because the GnG test versions were developed for three 
broad age groups (with increasing difficult with higher age) we will address statistical 
adjustments that may be needed to accommodate heterogeneity in test difficulty across 
versions. 
 
 
 
 
 
Secondary Analyses 
 
Aim 1: We will use the Wilcox rank-sum test to compare group changes in secondary 
behavior/performance measures including the GNG inhibitory control d'-prime and the 
average of the sustained attention d-prime and inhibitory control d-prime, SDB 
symptoms and quality of life endpoints over the 12-month study period. Generalized 
linear regression models will be used to model treatment effects adjusting for covariates. 
All outcomes other than PSG indices will be available at 6 months and 12 months and 
thereby can be analyzed using the mixed effects model outlined for the primary analysis, 
which does not assume a linear trajectory over time. For continuous outcomes which 
appear to have a linear trajectory over time, we will also estimate the rate of change in 
each treatment group and test the null hypothesis that the rates of change are equal for 
the eAT group and the WWSC group using the following mixed effects model:  
 
Let T denote time and T=0, 1, 2 refer to baseline, month 6 and month 12. Let X3 
denote the treatment indicator as before. The model will have each of the outcomes as 
response and include the main effects of T and the interaction effect of T*X3. The 
coefficient for T*X3 represents the treatment effect on linear trajectories.  
 
Standard methods can be used to estimate this effect and test the null hypothesis of a 
zero effect.   
 
For PSG indices (e.g., metrics of overnight hypoxemia, hypercapnia, sleep architecture, 
and breathing patterns) that are only available at baseline and 12 months, similar models 
can be used except that the variables corresponding to 6 months will be removed from the 
model. All participants enrolling in PATS entered the trial with an apnea-hypopnea index 
(AHI) under 3, i.e., without any evidence of obstructive sleep apnea syndrome (OSA). 
Estimating the proportion of participants who went on to develop OSA during the trial is 
thus of particular interest. We will also evaluate treatment effects on the proportion of 
participants with emergence of OSA (as defined by an AHI ≥ 3) and 5 (indicating 
emergence of moderate or more severe OSA) at 12 months, and whether treatment 
effects differ by subgroups specified in Aim 3.   
 

 
 
65 
 
 
If we observe differences in behavior and vigilance between groups, we will determine 
whether improvements in vigilance explain a significant portion of the improvement in 
behavior, using the steps to establish mediation outlined by Baron and Kenny84, which 
consist of fitting a series of regression models and testing relations among variable 
corresponding to significance tests of the regression coefficients.  Specifically, we will 
construct regression models with change from baseline to 12 month BRIEF2/P GEC score 
as the outcome, including a treatment indicator as an independent variable, with and 
without including the change in the Go-No-Go performance test as a covariate. We will 
compare the coefficients for the treatment indicator to examine how much of treatment 
effect on the BRIEF2/P is explained by changes in the GNG test. Point and interval 
estimates for the reduction in the coefficients will be provided. Similarly, if sleep duration 
(by actigraphy and parent report) and sleep-quality (by PSG and parent report) 
demonstrate treatment effects, we will explore these factors as potential mediators for 
changes in behavior and vigilance (if these outcomes show treatment effects).  
 
Aim 2: For endpoints related to HCU (illness or injury requiring hospitalizations; 
emergency department visits; inpatient procedures; outpatient procedures; scheduled 
office visits; unscheduled office visit or urgent care visits; medication use), incidence rate  
per person will be calculated. Recognizing that these count data are likely to be non-
normal and skewed, we will use Wilcoxon rank-sum tests to compare study groups. To 
better model the underlying distribution of the count data and take into account potential 
data dispersion and possible preponderance of zeros, we will use goodness of fit statistics 
(e.g., AIC/BIC), likelihood ratio tests or the Vuong test82 to choose among the zero-inflated 
negative binomial models, zero-inflated Poisson models or regular negative binomial 
models. The models that best fit the data will be used to model treatment effect adjusting 
for covariates. Incidence rate ratios comparing treatment groups will also be reported. We 
also will describe distributions of medication classes (e.g., antibiotics, nasal anti-
inflammatory medications, asthma medications) and reasons for hospitalizations, etc. by 
group to identify reasons for HCU differences (e.g., infection; respiratory illness). Analyses 
will be performed both including and excluding events associated with the intervention 
(surgery  and pre- and post-operative care, but not include the polysomnography). 
 
Aim 3: Whether treatment effects pertain to some subgroups and not to others are of great 
clinical significance.  Statistical tests of treatment by covariate interaction will be performed 
to assess whether treatment effect varies by age, baseline weight, atopy/asthma status, 
secondhand smoke, socioeconomic status, family functioning, baseline symptom severity 
(e.g., Sleep Disordered Breathing Scale) or race. Within the group of children with asthma, 
we will assess whether asthma exacerbations differ by treatment group, using similar 
approach for count data as described in the analysis for HCU indices.  
 
If we identify race differences in treatment effects, we will explore whether those 
differences are explained by the measured social and environmental factors, such as 
measures of family functioning or secondhand smoke exposure. To address this question, 
we will use models similar to the mediated baseline by treatment interaction models 
proposed by Baron and Kenny84 and MacKinnon86, except that the mediators under 
consideration will be those measured social and environmental factors mentioned above. 
More specifically, we will fit the following models: (1) Y=𝑖𝑖1+ 𝑐𝑐1𝑋𝑋+𝑐𝑐2𝑍𝑍+𝑐𝑐3𝑋𝑋𝑋𝑋+𝑒𝑒1; (2) 
Y=𝑖𝑖2+𝑐𝑐1
′ 𝑋𝑋+ 𝑐𝑐2 
′ 𝑍𝑍 + 𝑐𝑐3
 
′  𝑋𝑋𝑋𝑋 + 𝑏𝑏𝑏𝑏 + 𝑒𝑒2; (3) M=𝑖𝑖3+ 𝑎𝑎1𝑋𝑋+𝑎𝑎2𝑍𝑍+𝑎𝑎3𝑋𝑋𝑋𝑋+𝑒𝑒3, where Y denotes the 
outcome (e.g., BRIEF2/P GEC change score or GNG change score), X denotes the 

 
 
66 
 
treatment indicator, Z denotes race, and M denotes the potential mediator (measured 
social and environmental factor under consideration) for the racial differences in treatment 
effects (𝑐𝑐3).  Our interest here is to explore the potential mediation effects corresponding 
to the effect of XZ to M to Y, through evaluating the significance tests for 𝑐𝑐3ෝ, 𝑎𝑎3
ෞ, 𝑏𝑏෠, and 𝑐𝑐3
′෡ 
(or 𝑎𝑎3
ෞ𝑏𝑏෠), the estimates of corresponding regression coefficients. 
 
One gap in the CHAT study was lack of objective data on nightly sleep duration, which 
may significantly influence behavior and cognition. In this study, we will evaluate whether 
baseline average nightly sleep duration and continuity obtained from in-home actigraphy 
are associated with: a) baseline behavior and performance measures; b) whether there is 
an interaction between sleep duration and treatment. Models will be similar to those 
described above.  We also will evaluate whether changes in sleep duration and continuity 
are associated with changes in behavior and performance outcomes. 
  
 
 
 
Impact of Coronavirus Disease 2019 (COVID-19) Pandemic 
 
We will summarize data quality and missingness by whether the relevant visit (at 
baseline, 6 months, or 12 months) occurred (or was scheduled to occur) prior to or 
following 03/11/2020, the date on which the World Health Organization declared COVID-
19 to be a global pandemic.  
 
As a sensitivity analysis, we will examine the robustness of the co-primary efficacy 
analyses to the mid-trial onset of the COVID-19 pandemic. To do so, we will incorporate 
an indicator of pandemic onset as an additional covariate and consider its interaction 
with the visit and treatment group by visit interaction factors. Specifically:  
 
Let 𝐵𝐵𝑖𝑖𝑖𝑖 be the 𝑗𝑗th recorded BRIEF GEC score for the 𝑖𝑖th participant, let 𝑋𝑋1 and 𝑋𝑋2 be 
indicators of the 6-month and 12-month visit, respectively, and let 𝑋𝑋3𝑖𝑖 be an indicator of 
randomization to the eAT arm.  Let 𝐶𝐶𝑖𝑖𝑖𝑖 be an indicator of whether the 𝑗𝑗th measurement 
for the 𝑖𝑖th participant was recorded following the onset of the COVID-19 pandemic 
(dated on 03/11/2020). We will fit the model  
𝐵𝐵𝑖𝑖𝑖𝑖= 𝛽𝛽0 + 𝛽𝛽1𝑋𝑋1𝑖𝑖𝑖𝑖+ 𝛽𝛽2𝑋𝑋2𝑖𝑖𝑖𝑖+ 𝛽𝛽3𝑋𝑋1𝑖𝑖𝑖𝑖∗𝑋𝑋3𝑖𝑖+ 𝛽𝛽4𝑋𝑋2𝑖𝑖𝑖𝑖∗𝑋𝑋3𝑖𝑖+ 𝛽𝛽5𝐶𝐶𝑖𝑖𝑖𝑖+ 𝛽𝛽6𝑋𝑋1𝑖𝑖𝑖𝑖∗𝐶𝐶𝑖𝑖𝑖𝑖
+ 𝛽𝛽7𝑋𝑋2𝑖𝑖𝑖𝑖∗𝐶𝐶𝑖𝑖𝑖𝑖+ 𝛽𝛽8𝑋𝑋1𝑖𝑖𝑖𝑖∗𝑋𝑋3𝑖𝑖∗𝐶𝐶𝑖𝑖𝑖𝑖+ 𝛽𝛽9𝑋𝑋2𝑖𝑖𝑖𝑖∗𝑋𝑋3𝑖𝑖∗𝐶𝐶𝑖𝑖𝑖𝑖+ 𝑏𝑏𝑖𝑖+ 𝜖𝜖𝑖𝑖𝑖𝑖 
 
from which we will calculate the estimated mean baseline BRIEF GEC scores (or GNG 
sustained attention d’ measures), as well as the changes in those scores from baseline 
to 6 months and from baseline to 12 months in each randomization arm, both before and 
during the COVID-19 pandemic: 
• 
Estimated mean baseline score pre-pandemic: 𝛽𝛽̂0 
• 
Estimated mean baseline score during the pandemic: 𝛽𝛽̂0 + 𝛽𝛽̂5 
• 
Estimated mean change at 6 months (WWSC arm) pre-pandemic:  𝛽𝛽̂1 
• 
Estimated mean change at 6 months (WWSC arm) during the pandemic: 𝛽𝛽̂1 + 𝛽𝛽̂6  
• 
Estimated mean change at 12 months (WWSC arm) pre-pandemic: 𝛽𝛽̂2  
• 
Estimated mean change at 12 months (WWSC arm) during the pandemic: 𝛽𝛽̂2 +
𝛽𝛽̂7 
• 
Estimated mean change at 6 months (eAT arm) pre-pandemic: 𝛽𝛽̂1 + 𝛽𝛽̂3   

 
 
67 
 
• 
Estimated mean change at 6 months (eAT arm) during the pandemic: (𝛽𝛽̂1 + 𝛽𝛽̂6) +
(𝛽𝛽̂3 + 𝛽𝛽̂8) 
• 
Estimated mean change at 12 months (eAT arm) pre-pandemic: 𝛽𝛽̂2 + 𝛽𝛽̂4 
• 
Estimated mean change at 12 months (eAT arm) during the pandemic: (𝛽𝛽̂2 +
𝛽𝛽̂7) + (𝛽𝛽̂4 + 𝛽𝛽̂9) 
We will then assess the pandemic’s impact on the randomized treatment effects by 
using standard methods to test the null hypothesis of 𝛽𝛽9 = 0, and will assess its impact 
on children’s BRIEF global composite scores (or GNG sustained attention d’ measures) 
overall by testing the null hypothesis of 𝛽𝛽5 = 𝛽𝛽6 = 𝛽𝛽7 = 𝛽𝛽8 = 𝛽𝛽9 = 0.  
 
 
 
 
Data Quality Monitoring and Interim Monitoring 
 
The study will be monitored routinely for issues of data quality, study conduct (including 
recruitment and follow-up rates), data quality and adverse events. Of particular concern 
will be attrition and cross-over rates which, if excessive, could jeopardize the integrity of 
the study.  Monthly reports addressing these issues of study conduct, data quality and 
adverse events will be provided to the Steering Committee (aggregate data), and 
periodically to the DSMB and NIH.  Given that the patient population consists of children 
who are otherwise healthy, who have mild SDB, and that the intervention is considered a 
standard clinical intervention, we do not anticipate that the interim analysis will yield 
efficacy data compelling enough to require early termination. However, we will propose 
to monitor the BRIEF2/P GEC score and GNG score, our primary outcomes, in planned 
interim analyses of efficacy and safety. We plan to perform one interim analysis after half 
of the study population has completed their 12-month evaluations. Based on our 
recruitment projections, most of the accrual will be complete at this time and therefore 
early stopping may not be relevant. To create a formal framework for assessment of 
interim results, the Haybittle-Peto boundary85 will be used. That is, interim results for 
comparisons of the BRIEF2/P score and GNG score  between treatment groups will be 
considered sufficient to consider early termination only if at least one of the between-
group differences are statistically significant using a family-wide significance level of 
0.001. The Haybittle-Peto stopping rule allows the final analysis to be evaluated at a 5% 
level of significance85;86.  Concurrence with the monitoring plan by the PI’s, the DSMB 
and the NIH will be required prior to implementation of the plan.  
 
Interim comparative data will be considered confidential and will be available only to the 
DSMB members and to the DCC statistician analyzing the interim data and preparing the 
DSMB report. 
 
Statistical Software 
 
The software of choice for most of the analyses will be SAS 9.4, which has a wide range 
of statistical methods, and provides the routines for the multiple linear regression as well 
all other statistical methods planned for this trial. Where necessary, SAS may be 
supplemented with procedures from other software packages such as STATA or R. 
 

 
APPENDIX A: PATS VISIT SCHEDULE 
 
 
Preliminary 
Screen 
Confirm 
Final 
Eligibility 
eAT 
Only 
Visits for Both Arms 
WWSC 
Only 
Procedures and 
Assessments 
ENT 
V1 
PSG 
V2 
Baseline 
V3 
Randomiz
e V47 
Surgery 
V5 
Phone12 
 
Interim 
V6  
PSG 
V7  
Endpoint 
V 8  
ENT 
Re-eval 
 
Visit 
Screen 
Baseline 
Day 0 
eAT 
Only 
Phone 
Clinic 
PSG 
Clinic 
WWSC 
Only 
Time 
Day -60 to -
1 
At baseline 
or within 48 
hrs of 
baseline 
M1 
W/in 1-4 
wk 
randomiz
ed 
,M2, 
M4 
,M8, 
M10, 
M6 
M12 
M12 
1-4 wks 
after M12 
Preliminary 
eligibility 
review; 
informed 
consent1 
X 
X 
 
 
 
 
 
 
 
ENT evaluation2 
X 
 
 
 
 
 
 
 
 
PSG3 
 
X 
 
 
 
 
X 
 
 
Randomize 
 
 
X 
 
 
 
 
 
 
Surgery 
 
 
 
X 
 
 
 
 
 
Re-evaluation 
for surgery 
(WWSC only) 
 
 
 
 
 
  
 
WWSC 
Remind 
family 
X 
If 
indicated  
Urine cotinine4 
 
 
x 
 
 
  
 
 
 
Resting BP 
 
 
X 
 
 
X 
 
X 
 
Anthropometry 
 
 
X 
 
 
X 
 
X 
 
Physical exam 
 
 
x 
 
 
 
 
 
 
Behavioral 
performance 
testing5 
 
 
X 
 
 
X 
 
X 
 
Parent 
questionnaires6 
 
 
X 
 
 
X 
 
X 
 
Serum IgE4 
 
 
X 
 
 
 
 
 
 
Healthy sleep 
education 8 
 
 
X 
 
 
 
 
 
 
Sleep Diary 
 
 
X 
 
 
X 
 
X 
 
Behavioral 
rating scales: 
teacher10 
 
 
X 
 
 
X 
 
X 
 
Adverse event, 
medication, and 
HCU inquiry11 
 
X 
X 
 
X 
X 
 
X 
 
 
 
 

 
 
NOTES 
1. Preliminary screening/ascertainment of eligibility and the face-to-face consent 
discussion will occur at slightly different points of participant interaction, 
depending on the local site’s recruitment strategies (sources: ENT, sleep 
laboratory, other clinics) 
2. Existing ENT evaluations (within 90 days prior to randomization) can be utilized 
to establish primary eligibility for adenotonsillectomy surgical candidacy.  WWSC 
group will be re-evaluated for surgery after month 12 (within 1-4 weeks of the 
month 12 visits). 
3. An overnight PSG must be performed (with 60 days) and approved by the study’s 
reading center prior to randomization.  Another PSG is completed at the month 
12 endpoint visits for those who are eligible and enrolled in the study.   
4. Samples will be processed and stored locally for shipment to the CCC central 
repository monthly.   
5. Child completes 2 behavioral performance tests (coordination, vigilance). 
6. Parent  completes behavioral rating scales and other questionnaires.   
7. Not an actual visit.  Listed in the database as Visit 4 for tracking purposes.  
Randomization is an administrative process that can easily be completed at the 
end of the baseline visit before the family leave the clinic (ideal).   
8. Health sleep habits guidance Actigraph device initialized, verbal and written 
instructions provided at the baseline, interim, and endpoint visits to be returned in 
a pre-paid mailer after 1 week of recording at home.   
9. Teacher completes 3 behavioral rating scales (BRIEF2/P, Conners, CBCL-TRF) 
at 3 time points: baseline, month 6 and month 12.  Forms are sent (mailed by 
study staff) immediately after the visit. 
10. Adverse event, medication, health care utilization (HCU) inquiries occur at all 
participant visits (verbally for phone visit; face-to-face for other visit types).   
11. Monthly contact by telephone, email and/or text messaging at Months 1,2,3, 
4,5,7,8,9, 10,11 
 
 

 
APPENDIX B: PROJECT TIMETABLE 
 
 
Yr. 1 
Yr. 2 
Yr. 3 
Yr. 4 
Yr. 5 
 
Q  
1 
Q
2 
Q
3 
Q
4 
Q
1 
Q
2 
Q
3 
Q
4 
Q
1 
Q
2 
Q
3 
Q
4 
Q
1 
Q
2 
Q
3 
Q
4 
Q
1 
Q
2 
Q
3 
Q
4 
Finalize 
Protocol 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Local sites 
IRB 
Approval 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Central 
Training; 
Certification 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pilot Studies 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Enrollment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6 Month 
Follow Up 
Visits 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-Month 
Follow-Up 
Visits 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DSMB 
Meetings 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Interim 
Analyses 
/Data Query 
Resolution 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lock Data 
Base 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Primary MS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Secondary 
MS 
(baseline 
data, etc) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Deposit In 
BioLinnc 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Deposit in 
NSRR 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
APPENDIX C: ROSTER OF DSMB MEMBERS 
 
Kristen H. Archbold, PhD, RN 
Associate Professor, College of Nursing 
University of Tennessee Health Science Center 
2088 Allenby Rd. 
Germantown, TN 38139 
Phone: 901 800-1302 
Email: karchbold@azimuthsleepsolutions.com 
 
Meyer Kattan, MD 
Director, Division of Pediatric Pulmonology 
Columbia University Medical Center 
Division of Pulmonary 
3959 Broadway, CHC 7-701 
New York, NY 10032 
Phone: 212 305-8120 
Fax: 212 305-6103 
Email: mk2833@columbia.edu 
 
James S. Kemp, MD 
Co-Director, Sleep Laboratory 
St. Louis Children’s Hospital 
Division of Pediatric Allergy, Immunology & Pulmonary 
Medicine 
1 Children’s Place 
Suite 2C, 2nd Floor 
Saint Louis, MO 63110 
Phone: 314 454-2694 
Email: kemp_j@kids.wustl.edu 
 
Tonya S. King, PhD 
Professor of Biostatistics 
Department of Public Health Sciences 
Penn State University College of Medicine 
90 Hope Drive 
Suite 2200/A210 
Hershey, PA 17033 
Email: tking@phs.psu.edu 
 
Cynthia D. Morris, PhD 
Assistant Dean OHSU Professor of Medical Information 
Oregon Health Sciences University 
3181 S.W. Sam Jackson Park Road 
Portland, OR 97239 
Phone: 503-494-3262 
Fax: 503-494-5128 
Email: morrisc@ohsu.edu 
 
 
 

 
David E. Tunkel, MD 
Director Pediatric Otolaryngology 
Johns Hopkins Outpatient Center 
601 N Caroline Street 
6th Floor, 6232 
Baltimore, MD 21287 
Phone: 410 955-1559 
Fax: 410 955-0035 
Email: dtunkel@jhmi.edu 
 
Kathryn L. Weise, MD, MA 
Program Director, Cleveland Fellowship in Advanced Bioethics  
Cleveland Clinic Main Campus, Mail Code: JJ60, 9500 Euclid Avenue 
Cleveland, OH 44195 
Phone: 216-548-2655 
Email: k.weise@sbcglobal.net 
 
 
Roster of NHLBI members (Non-Voting Members)  
 
NHLBI Executive Secretary 
 
Aruna Natarajan, MD, PhD 
Program Director, Pediatric Lung Disease and Critical Care 
The National Heart, Lung, and Blood Institute (NHLBI) 
Two Rockledge Centre, Suite 10042 
6701 Rockledge Drive MSC 7952 
Bethesda, MD 20892-7952  
Tel: (301) 827-1880 
Email: michelle.freemer@nih.gov 
 
NHLBI Project Officer  
 
Marishka K. Brown, Ph.D. 
Program Director, Sleep Medicine  
National Center on Sleep Disorders Research 
Division of Lung Diseases 
National Heart, Lung, and Blood Institute 
National Institutes of Health 
Bethesda, MD 20817 
Phone: 301-435-0199 
Email: marishka.brown@nih.gov 
 
 
Other NHLBI Staff 
 
Peyvand Ghofrani 
Clinical Trials Specialist, National Center on Sleep Disorders Research (NCSDR) 
The National Heart, Lung, and Blood Institute (NHLBI) 

 
Two Rockledge Centre, Suite 10042  
6701 Rockledge Drive, MSC 7952  
Bethesda, Maryland 20892-7952  
Tel: (301) 435-0199  
Email: ghofranip@nhlbi.nih.gov 
 
Lora Reineck, MD, MS 
Medical Officer, Division of Lung Diseases 
The National Heart, Lung, and Blood Institute (NHLBI) 
Two Rockledge Centre, Suite 10042  
6701 Rockledge Drive MSC 7952 
Bethesda, Maryland 20892-7952  
Tel: (301) 435-0222 
E-mail: lora.reineck@nih.gov 
 
Colin Wu, PhD 
 
Biostatistician, Office of Biostatistics Research 
National Heart, Lung and Blood Institute (NHLBI) 
6701 Rockledge Drive, Room 9212 
Bethesda, Maryland 20892-7913 
Tel: (301) 435-0434 
Email: wuc@nhlbi.nih.gov 
 
 

 
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