Obstructive Sleep Apnea in WTC Responders: Role of Nasal Pathology
Phase: NA
Conditions: Obstructive Sleep Apnea
Sponsor: Rutgers, The State University of New Jersey

Study Protocol 
 
 
 
 
 
Obstructive Sleep Apnea in WTC responders: Role of nasal Pathology 
 
NCT01753999 
 
May 18, 2016 

 
 
Protocol Version 12: 05/18/16 
1 
 
 
 
 
Title of Project: 
Obstructive Sleep Apnea in WTC responders: Role of 
nasal Pathology 
 
 
 
Principal Investigator: 
Jag Sunderram 
 
 
 
 
Funding Source(s): 
Centers for Disease Control/ NIOSH 
 
1. Purpose/Specific Aims 
Following the World Trade Center (WTC) disaster, responders who worked in rescue, recovery 
and debris removal were initially exposed to greater than 100,000 µm/m3 total particles1. 63% of 
these responders examined in 2004 reported at least one new or worsened upper airway respiratory 
symptom since 911, and in June 2007, 50% of responders continued to have symptoms of chronic 
rhino-sinusitis or upper airway disease (UAD). In addition, about 50% of those with UAD referred 
to our sleep center reported new onset snoring on their questionnaires immediately following their 
exposure and had unusually high prevalence of obstructive sleep apnea (OSA)2. Usual risk factors 
for OSA include a high body mass index (BMI) and increasing severity of OSA as determined by 
the apnea+hypopnea index (AHI) correlates with increasing BMI. Unique to the WTC population 
was the fact that there was no correlation between AHI and BMI and those with new onset snoring 
had a lower BMI compared to habitual snorers. This suggests that mechanisms other than obesity 
may be important in the pathogenesis of OSA in these subjects and given their chronic nasal 
symptoms, provides a unique opportunity to examine the relationship between nasal pathology and 
OSA. Our hypothesis is that the nasal symptoms reported by the subjects in the WTC medical 
monitoring and treatment program (WTCMMTP) now termed WTC Health Program (WTCHP) 
are an indicator of increased nasal resistance due to nasal inflammation resulting from exposure to 
the WTC dust. In particular reversible nasal resistance may play an important role. Alternatively 
inflammation of the posterior pharynx without influencing nasal resistance may predispose to OSA 
in this population. Continuous Positive Airway Pressure (CPAP) is the standard therapy for OSA 
but despite its efficacy has poor adherence. Subjects with high nasal resistance may experience 
additional pressure during expiration at the upper airway due to high nasal resistance. This may 
result in greater difficulty in tolerating this therapy than those who do not have high nasal 
resistance. Reduction of excess expiratory positive pressure by the modality known as Cflex™ 
during CPAP therapy (CPAPFlex) has been suggested to improve comfort without compromising 
CPAP efficacy.  
SA1: Examine the relationships between post-9/11 OSA and upper airway disease. 
Subjects without evidence of pre-9/11OSA (no documented OSA or habitual snoring prior to 9/11 
based on questionnaire) will be recruited for home sleep studies and categorized by BMI and report 
of new or worsening UAD since 911. 
Hypothesis 1a: Onset of post-911OSA is positively associated with the occurrence of new or 
worsened UAD.  

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Hypothesis 1b: Among patients with post-911OSA, UAD is associated with lower BMI, compared 
to patients without UAD. In the WTC population with both UAD and OSA, BMI and AHI are not 
correlated. 
SA2: Determine the relationship between post-911 OSA, upper airway disease, nasal 
inflammation and nasal resistance. 
Nasal lavage will be used to measure markers of inflammation (leukocyte counts and soluble IL-
8, IL-6, TNFα) and rhinomanometry will be used to determine nasal resistance before and after 
decongestants  
In WTC patients, we will test:  
Hypothesis 2a: UAD is associated with both increased nasal resistance and inflammatory markers 
in nasal lavage. 
Hypothesis 2b: OSA is associated with both increased nasal resistance and inflammatory markers 
in nasal lavage. 
Hypothesis 2c: The association between UAD and OSA is attributed to both increased nasal 
resistance and inflammatory markers in nasal lavage.. 
SA3. Relate nasal resistance to CPAP adherence in patients with OSA and show that 
reduction of expiratory pressure using CPAPFlex will improve CPAP adherence. Patients with 
OSA will be randomized in a double blind cross over design to receive CPAP or CPAPFlex and 
adherence will be measured.  
In patients with OSA, we will test: 
Hypothesis 3a: Increased nasal resistance is associated with decreased adherence to CPAP. 
Hypothesis 3b: Use of CPAPFlex will improve adherence with CPAP in subjects with high nasal 
resistance, but not in those with low nasal resistance. 
Hypothesis 3c: The benefit of CPAPFlex on adherence will be greatest if it is offered at CPAP 
initiation rather than as a “rescue” therapy in subjects with high nasal resistance. 
 
2. Background and Significance 
 
From September 11, 2001 onward following the World Trade Center (WTC) disaster, an estimated 
40,000 individuals were exposed to significant amounts of dust while working in rescue, recovery 
and debris removal3. These workers included traditional first responders, such as firefighters and 
police, and a diverse population of construction, utility, and public sector workers. A medical 
screening program was developed to evaluate the health status of workers and volunteers who 
spent time at the WTC site and thus sustained exposure in the aftermath of September 11th. 
Standardized questionnaires were adapted for use in this unique population. These questionnaires 
underpin our exploration of the relationship between the new symptoms following the exposure 
and the presence of diseases such as OSA. The WTC Worker and Volunteer Medical Screening 
Program (MSP) and the follow up World Trade Center Medical Monitoring and Treatment 
program (WTCMMP) now called the World trade Center Health program (WTCHP) have 
successfully recruited more than 27,000 responders to assess and treat health effects from these 
exposures4. About 1700 of these responders are followed at the Environmental and Occupational 
Health Sciences Institute (EOHSI) of Rutgers Biomedical Health Sciences in Piscataway, New 
Jersey, about 2100 in the NYU School of Medicine Clinical Center of Excellence (NYUSOM 
CCE) at Bellevue Hospital in New York City and about 22,000 are followed at Mt. Sinai School 
of Medicine (MSSM CCE). 

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The collapse of the WTC towers resulted in a massive plume of building debris and particulates. 
Sources of associated pollutants varied over the months after the disaster,1,5 but included 
combustion products, evaporating gases, gaseous fine and supercoarse particles1. These were from 
dust, rubble and debris from breakdown of WTC buildings, gases, dust, soot and smoke formed as 
a result of fires at the WTC site and motor vehicle emissions from vehicles at the WTC site. The 
dust was highly alkaline and corrosive, capable of causing chemical irritation to the upper 
respiratory tract.6 It contained high levels of calcium sulfate (gypsum) and calcium carbonate 
(calcite)7known causes of irritation to mucus membranes (eyes, nose throat and large airways) as 
well as cough and sneezing and are likely to be among the major irritants of WTC dust.  
Consistent with this exposure persistent upper airway disease has been a prominent finding 
amongst WTC responders. Clinical evaluation of iron workers who were present at the site 
between September 11th and Sept 14th and who had worked there for at least 3 days revealed 
persistent rhinitis and sinusitis in 52% after 5 months8. Upper respiratory ailments were more 
prevalent than lower respiratory in other cohorts as well9,10. Amongst the responders who are 
currently in the WTCHP, approximately 40% of the participants arrived at the WTC site on 
September 11, 2001. Of those who arrived on September 11, 49% reported that they were in the 
dust cloud. Among workers who were previously asymptomatic, 44% reported developing new 
upper respiratory symptoms in the months prior to the clinical examination. By 2004, rates of new 
respiratory symptoms after 9/11 among WTC workers and volunteers were high and persistent, 
and there was a strong relationship between exposure intensity at the site and respiratory 
symptoms3. De La Hoz and colleagues reported on airway disease and atopy in WTCMMTP 
participants11,12: Upper airway disease (UAD) was physician diagnosed based on the presence of 
three symptoms of rhinitis, persistent symptoms for more than 8 weeks unrelated to an infection, 
and associated symptoms of sinusitis, pharyngitis, or laryngitis. More than three quarters of the 
subset studied (78.5%) was diagnosed with an UAD11. Atopy was present in more than half of the 
population studied and was significantly associated with WTC-related upper airway diagnoses. 
However, atopic patients were not more likely to have been diagnosed with a WTC-related upper 
or lower airway disease then non-atopic patients12. Cell counts and soluble markers of 
inflammation are readily quantified in the fluid obtained from washing the nasal cavity. Nasal 
lavage is a relatively noninvasive procedure that has been used extensively to assess acute and 
chronic inflammation in the nasal cavity, especially in response to inhaled air pollutants, including 
various forms of particulate matter13-16. In the only study of markers of inflammation in WTC 
responders, nasal lavage results were consistent with clinical findings of chronic nasal 
inflammation17. 
OSA is a chronic condition with recurrent episodes of partial or complete upper airway collapse 
during sleep. The main risk factors for OSA are obesity and male gender and it is highly prevalent 
in the general population, with estimates ranging from 5-10% to >25%18,19. Upper airway 
inflammation resulting in mucosal congestion could mimic these predisposing conditions and 
provide an alternate mechanism for development of compromised upper airway patency during 
sleep. Correspondingly, OSA has been associated with nasal congestion, seasonal allergic rhinitis, 
GERD, and occupational exposure to guar gum dust. Plausible physiological mechanisms that 
could explain the role of altered nasal function in the pathogenesis of OSA include: (i) The starling 
resistor model of the UA,20 predicts that elevated upstream (nasal) resistance and the associated 
increase in inspiratory negative pressures increase the tendency for upper airway collapse during 
inspiration.;(ii) nasal obstruction may cause reflex increased respiratory effort (iii) nasal 
obstruction may cause elevations in CO2 from hypoventilation21, increasing respiratory effort thus 

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favoring suction forces (iv) increased mouth breathing in the presence of elevated nasal resistance 
with forward shift of the tongue and mandible and increased resistance of oral breathing during 
sleep22 (v) activation of nasopulmonary reflexes (trigeminal nerve stimulation causing decreased 
respiratory effort)23 (v) Nasal–ventilator reflex: decreased nasal airflow results in decreased 
activation of nasal receptors with subsequent inhibition on muscle tone and ventilation  All these 
mechanisms assume inflammation resulting in increased nasal resistance is the key link of UAD 
to OSA but it is also possible that the same factors causing elevated nasal resistance may also 
directly affect the collapsible downstream UA segment. The resulting local swelling and edema 
could directly predispose to upper airway collapse independent of nasal resistance. 
Previous studies of the relationship between WTC-related conditions and OSA have reached 
differing conclusions on the association between GERD and and/or chronic rhino-sinusitis and 
increased risk for OSA2,24,25. In a pilot study of a small sample of WTC responders with aero-
digestive symptoms, snoring and daytime symptoms of sleep deprivation, we found that out of 50 
responders referred for sleep studies, 48 of them had OSA. In contrast to a comparison population 
who were referred to our sleep center for snoring and daytime symptoms where there was a strong 
association between body mass index (BMI) and AHI, there was no association between BMI and 
AHI in WTC responders, suggesting a possible role for an inflammatory etiology for OSA. 
Additionally, a subset of WTCHP responders who had developed habitual snoring after 911 had a 
significantly lower BMI than WTCHP responders who were habitual snorers prior to 911, despite 
having the same severity of OSA, indicating that the classic risk factor of obesity alone did not 
play a prominent role in their development of OSA2. The findings in our study differed 
significantly from a recent publication by de la Hoz et.al24. Those authors found that OSA was 
associated with BMI and male gender in their sample of 100 WTCHP responders. De la Hoz et.al, 
also did not find an association between OSA and UAD. In contrast, our study findings are similar 
to the results of Webber et.al who, based on questionnaire data, found that in 11,701 responders, 
16.9% of those not previously at high risk for OSA qualified as high risk for OSA following 91125. 
These contradictory findings call for a larger 
and more systematic study to examine 
risk factors that may play a role in the 
development of OSA in the WTC 
population. In specific aim 1 of this proposal we will examine the relationship between post-
9/11 OSA and new or worsened upper airway disease. 
Many patients with OSA have nasal symptoms and nasal pathology is associated with snoring.26 
Studies creating nasal obstruction have induced OSA in normal subjects,21 but there are limited 
and conflicting data in the literature on a causal relationship between nasal resistance, nasal 
symptoms and OSA in the clinical population, 27,28 because prior studies have not used objective 
measures of nasal resistance and many have not objectively documented OSA. In addition, some 
studies suggest that obesity may mask the independent effect of nasal obstruction28,29 in the 
pathophysiology of OSA. Despite this, two population studies suggest nasal symptoms contribute 
to risk of OSA. The Wisconsin Cohort study reported a 1.8 times higher AHI in subjects with 
allergic rhinitis compared to those without nasal symptoms.30 Other studies have reported an 
association between nasal congestion and OSA,31 and nasal decongestants may improve the 
AHI.26. However, to date there has been no large epidemiologic study relating objective nasal 
resistance and OSA, and a recent review summarizing the role of nasal obstruction in OSA by 
McNicholas32 emphasized the need for such data. The WTC cohort provides us with this 
opportunity to explore the relationship between upper airway inflammation and resultant upper 
airway disease, nasal resistance and OSA (See model). We hypothesize that WTC dust exposure 
 

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results in upper airway and nasal inflammation, leading to nasal symptoms and increased nasal 
resistance that leads ultimately to OSA. It is conversely possible that nasal symptoms could be a 
predictor of OSA without producing increased nasal resistance if inflammation of the collapsible 
upper airway (UA) segment occurs in parallel to the inflammation of the nose and sinuses. Our 
data from specific aim 2 on the association of UAD with nasal inflammation and nasal 
resistance, the association of OSA with nasal inflammation and nasal resistance and the use 
of logistic regression analysis to determine if nasal inflammation and resistance both mediate 
the association of UAD with OSA should address this possibility. 
 
The health benefits of diagnosis and treatment of OSA are well recognized: untreated OSA is 
associated with daytime sleepiness, increase in motor vehicle accidents, increased hypertension, 
stroke, impaired glucose metabolism, and increase in all-cause mortality30,33. CPAP is the primary 
treatment for OSA.34 CPAP use normalizes sleep architecture, reduces daytime sleepiness, and 
reduces automobile accidents and decreases blood hypertension and cardiovascular events35-38. 
Despite its efficacy, 29-83% of patients are non-adherent to CPAP39 and no specific factors 
(demographic, disease specific) that predict CPAP adherence have been identified. In addition to 
problems with the mask and claustrophobia, pressure intolerance and “difficulty exhaling” are 
frequently cited by patients as limiting acceptance of CPAP therapy39. Nasal symptoms and side 
effects are also common and may account for 30-50% of cases of CPAP intolerance40. Thus, in 
addition to its role in causing OSA,30 elevated nasal resistance may impact on initial acceptance of 
CPAP27,41. Small studies40 have shown that nasal resistance was significantly higher in OSA 
patients who did not tolerate CPAP and reduction of nasal resistance by surgery42has been shown 
to increase CPAP use. CPAP adherence in WTC responders with UAD is unknown but in general 
has anecdotally been thought to be poor. High nasal resistance can play a potential role in their 
poor adherence. 
CPAP keeps the UA open and nasal resistance becomes the primary determinant of total UA 
resistance. Thus, during CPAP use, high nasal resistance may continue to cause a patient to 
experience discomfort while exhaling despite adequate relief of OSA and could contribute to 
intolerance of CPAP. In preliminary data we have shown that, as expected, increased nasal 
resistance results in higher expiratory pressure. By decreasing this excess pressure during the 
expiratory cycle, CPAPFlex (Philips Respironics) may improve CPAP adherence. Although 
prospective, randomized studies have demonstrated that CPAPFlex is not inferior to conventional 
fixed CPAP, increased adherence has not been uniformly demonstrated. Some studies have shown 
CPAPFlex reduces discomfort and improves adherence,43 but larger randomized studies44 have 
shown no difference in adherence between CPAP and CPAPFlex. However none of these studies 
have attempted to target therapy to patients based on elevated nasal resistance as we propose to 
do.In specific aim 3 of this proposal we will relate nasal resistance to CPAP adherence in 
patients with OSA and show that reduction of expiratory pressure using CPAPFlex will 
improve CPAP adherence. 
Additionally other studies have found an association of PTSD (Post-traumatic stress disorder) with 
OSA45 and an increased risk for OSA in those with PTSD (defined as a PCL (PTSD checklist) 
score of 44 or greater) in WTC exposed rescue and recovery workers46. The REM sleep 
abnormalities reported in PTSD and/or OSA could result in increased REM arousals and might 
predispose PTSD patients to increased nightmares. On the one hand, PTSD patients may benefit 
from treatment of OSA as it should reduce these arousals. However, treatment of OSA may result 
in REM rebound, and this may cause an increase in dreaming and/or nightmares in some subjects. 

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This potential increase in nightmares could reduce CPAP adherence, particularly in PTSD, as was 
demonstrated in a study by El-Solh et al.47.  
The present proposal should have broad impact on the diagnosis and management of OSA 
potentially caused by upper airway pathology resulting from toxic inhalation of WTC dust. 
Although the relationship between UAD and OSA appears to be strong in the WTC cohort, only a 
small numbers of subjects have had objective evaluation of sleep with nocturnal polysomnography 
(NPSG), in part due to the high cost and patient burden. We will use a validated portable monitor 
in Specific Aim 1 to evaluate large numbers of subjects specifically for the presence of OSA. Our 
first specific aim addresses the need to examine the relationship of UAD to OSA in this population. 
Our second specific aim will examine the role of nasal pathology in the etiology of sleep apnea, 
important in the WTC population but these results also extends to the general population with 
UAD from allergies and other causes. In specific aim three, we will also address the important 
specific question of whether nasal pathology negatively impacts on the ability to use CPAP, with 
the potential that addressing this with modified CPAP will improve the therapeutic approach to 
OSA. The proposed research will be performed in collaboration with the NYUSOM CCE for 
Responders (PI Denise Harrison, MD)which follows 2100 subjects, MSSM CCE (PI Michael 
Crane, MD, MPH) for Responders which follows 22,000 responders, and EOHSI, RWJMS, 
Piscataway (PI Iris Udasin, MD) which follows 1700 responders.  
The present proposal is in keeping with the mission of NIOSH and will address several areas of 
current need listed in PAR-12-126. It will generate new knowledge about conditions common in 
WTC exposed individuals, including nasal pathology and OSA. By using a less costly but equally 
effective evaluation of sleep disordered breathing (limited channel portable monitoring) and 
automated CPAP initiation48-50 it will improve access to care for individuals exposed to WTC dust. 
The objective measures of nasal inflammation and nasal resistance measurements will help answer 
whether the OSA is attributable to nasal consequences of WTC exposure. Adherence and efficacy 
of different therapies will be evaluated providing guidelines to physicians caring for these patients. 
The growing, but anecdotal, awareness of the large number of patients in the WTC population who 
present with OSA has prompted much internal discussion as to possible mechanisms and 
implications. A well-attended day-long symposium on this topic was organized by the WTC 
working group at the request of NIOSH in August 2009, and concluded that further investigation 
into the relationships between WTC exposure, nasal pathology and OSA was warranted. 
A particular strength of the WTC databases is the potential for future analyses. For OSA, there is 
particular interest in the evaluation of systemic markers of inflammation that may play a role in 
cardiovascular outcomes. As all the sleep data collected will be merged with the central database 
and blood has been banked on all subjects, multiple future research directions can be supported by 
the data we will collect. . 
This proposal capitalizes on the complimentary academic fields of the investigators including 
epidemiology, clinical pulmonary and sleep medicine, physiology, inflammation and biostatistics. 
The investigators have extensive experience in clinical medicine, and research in the epidemiology 
of diseases including OSA, in both laboratory and human physiology models of OSA, expertise in 
measuring nasal inflammation, nasal resistance and its effects on OSA, as well as longstanding 
experience in laboratory and portable sleep monitoring. Finally, they have been involved in the 
use, modification and monitoring of CPAP since its inception. 
 

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3. Research Design and Methods  
 
Specific Aim 1: Examine the relationships between post-9/11 OSA and UA Disease. 
Specific Aim 2: Determine the relationship between post-911 OSA, upper airway disease, 
nasal inflammation and nasal resistance. 
 
Study Protocol: The first two specific aims will be addressed through a cross-sectional design. 
Study subjects will be evaluated  for: 1) nasal signs and symptoms, 2) clinical interview to confirm 
onset of or worsening of symptoms post 9/11, 3) medication review including nasal steroids, use 
of Neti pots, and CPAP therapy, 4) review of symptoms of OSA and measures of sleepiness, 5) 
nasal resistance measurement (rhinomanometry) in the upright and supine positions, 6) nasal 
lavage and 7) home sleep study to determine presence or absence of OSA. Medical records will be 
reviewed for a history of snoring and development of nasal symptoms. Changes in weight will also 
be recorded. 
Procedures for SA1 and SA2: 
Medical Chart Review: As part of the WTCHP, participants are asked to complete several 
questionnaires during their monitoring visits. Data from Visit 1 questionnaires (Mail Home 
Snoring and Interview Administered Medical Questionnaire (IAMQ)) will be abstracted for the 
research. The abstracted data will focus on upper respiratory symptoms, snoring and sleepiness. 
The participant’s height, weight, and blood pressure at Visit 1 will also be recorded. Within the 
WTC patient database, an aggregate exposure measurement (Exposure Ranking Index) has been 
calculated for each patient. The index is based on patient responses to an Exposure Assessment 
Questionnaire (EAQ) completed at Visit 1. Responses to individual questions will also be 
abstracted from the EAQ. The questions concern the following areas of their WTC work/volunteer 
experience: dates, hours, locations, and conditions as well as experience with respiratory 
protection. Additionally, diagnoses of GERD and PTSD will be abstracted from the periodic 
IAMQs which are completed at each monitoring visit in the WTCHP. In order to assess the severity 
of PTSD, the PCL score from the periodic WTCHP Mental Health Questionnaire from the most 
recent monitoring visit will be recorded. 
Subjective Assessment of nasal symptoms: Participants will complete a nasal symptom 
questionnaire. Presence of at least 3 symptoms of rhinitis with onset or worsening after 9/11 will 
classify a subject as positive for nasal symptoms (UAD).51 The symptoms must have been present 
for >8 weeks and be unrelated to an infection, with or without associated symptoms of sinusitis, 
pharyngitis or laryngitis. This definition was used previously in evaluating UAD in the WTC 
population11 Current medication use for chronic symptoms including nasal steroid use or use of 
Neti pots etc. will be documented. 
Subjective Assessment for sleep disorders: We will evaluate excessive daytime sleepiness with a 
sleep questionnaire to evaluate for sleep disorders (insomnia, RLS, circadian rhythm disorders) 
and the Epworth Sleep Scale (ESS), a well-validated questionnaire that asks the subject to rate the 
likelihood of falling asleep in 8 commonly encountered situations.52 Possible scores range from 0 
(the least sleepy) to 24 (the most sleepy) with a score of ≥ 10 indicative of excessive daytime 
somnolence. ESS correlates with the severity of OSA and with objectively measured sleepiness in 
patients with OSA52. Current snoring will be ascertained using responses to the following 
questions, developed for use in the Sleep Heart Health study:53 "Have you ever snored?" and "How 

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often do you snore?" Snoring will be considered to be present (positive) if it is reported to occur 
more than three nights/wk and will be used to compare to previous snoring. 
Objective Assessment of nasal pathology:  
Clinical Examination: An investigator (a study physician, a research assistant, or the research 
coordinator) will perform a visual inspection of the inside of the nose to identify redness, swelling, 
polyps or polypoid swelling, crusting, mucus, and or frank pus. An oral exam will also be done to 
evaluate characteristics of the mouth (including tongue position, tonsillar size, and uvula size and 
a score will be given for each Dr. Sunderram will train all study investigators to perform the visual 
exams. 
 
Rhinomanometry: The study technician will perform rhinomanometry which is a measurement of 
airflow through the nose. We will assess nasal resistance using the 4-phase-rhinomanometer 
(RhinoLab GmbH, Rendsburg, Germany) following the detailed technical, practical methodology, 
and referenced normative data published in the literature.54 Briefly, during the rhinomanometry 
procedure, a small tube is held in place using tape over one nostril and a mask is placed on the 
subject’s nose. The subject will be asked to take a few breaths with his/her mouth closed. The 
procedure will be repeated with the other nostril.  Initially, the subject will be seated during 
measurement and measurements will be performed twice, before and 10 minutes after 
decongestion with 0.05% Xylometazoline solution. The procedure will be repeated while the 
subject is lying down. We have previously collected data using active anterior rhinomanometry 
(RhinoStream, Rhinometrics A/S, Lynge, Denmark) and published supine and sitting nasal 
resistances in subjects in patients coming to NYU sleep laboratory55. For the present study, we 
will change to the newer technology to bring it into accord with the more recent standardization 
recommendations. 
Nasal Lavage: The nasal lavage will be performed using a spray technique 56. Using a disposable 
metered-dose inhaler (100 µl per spray), room temperature saline will be sprayed in one nostril 
while the other nostril is closed. After 5 sprays, the subject will gently exhale through the lavaged 
nostril and the fluid will be collected in a specimen cup. The procedure will be repeated at least 8 
times in each nostril. The subject may be asked to repeat the procedure until 3 ml of lavage fluid 
are collected. The maximum number of repetitions will be 16. After collection, the sample will be 
placed on ice and processed within 2 hours. 
Home monitoring for OSA: Subjects will be given an ARESTM 
Unicorder (pictured) or a similar device (such as Embletta) and a 
separate wrist pulse oximeter (Nonin WristOx2 Model 3150) to take 
home and wear for 2 nights, with a pre-addressed mailer to return the 
devices to the sleep lab. The ARES Unicorder is routinely used in 
clinical practice for home monitoring of OSA. The ARES Unicorder 
is worn on the forehead and does not require additional wires to 
external devices. It measures oxygen saturation and pulse rate from 
reflectance oximetry, airflow from a nasal cannula/pressure 
transducer, snoring via acoustic microphone and head movement actigraphy and head position 
from accelerometers. The device also provides audible alerts during the study if poor quality 
airflow or SpO2 is detected so the subject can reposition the device. The wrist pulse oximeter 

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will be used to correct for the drift in oxygen saturation found in previous studies with the 
ARESTM Unicorder. 
 
Analysis of Respiratory Data from ARES: Data from the monitor will be autoscored and then 
manually reviewed by a single trained sleep technician at NYU SOM. Data from ARES will be 
de-identified; only the study ID will be used in monitoring. Apneas will be scored when there is a 
reduction in airflow to less than 10% of baseline. We have extensive experience using the ARES 
device and have validated it against NPSG (Noctornal Polysomnography) in over 300 subjects in 
multiple research studies57,58.  
SA3. Relate nasal resistance to CPAP adherence in patients with OSA and show that 
reduction of expiratory pressure using Cflex will improve CPAP adherence. Patients with 
OSA will be randomized in a double blind cross over design to receive CPAP or CPAPFlex 
and adherence will be measured as average hours of use over 2 weeks.  
Protocol for SA3 1. From the ARES studies, we expect to identify ~500 subjects with OSA. We 
expect about 10% to refuse to even try CPAP. All others would be recruited to be randomly 
assigned to CPAP or CPAPFlex as a first treatment, and crossed over to the other after completing 
the first arm of the protocol.  
2. Initially, the subject will be treated using the AutoCPAP program which varies the pressure, 
generally between 5 and 15 cm water, depending on the obstruction. If used regularly (for at least 
4 hours a night for 2 nights), a fixed pressure will be automatically assigned. If the subject does 
not regularly use CPAP, treatment will continue using the autotitrate program. The technician will 
monitor CPAP treatment to ensure adequate treatment when the subject uses CPAP. The 
automated AHI is monitored to ensure efficacy of therapy (AHI of <10 events per hour of sleep). 
If the AHI is >10 events per hour of sleep the data is reviewed by a designated sleep physician and 
the pressure is modified or the patient is recommended for an in laboratory sleep study if indicated. 
3. Adherence monitoring will be made from the CPAP machine for 1 month with first intervention, 
then switched to the alternate intervention and adherence monitored for another month. Data from 
last 2 weeks of each period will be used for objective adherence comparisons between 
interventions. Periods of reported non-use by the subject due to illness or travel will not be included 
in the treatment periods. The trial periods may be extended for up to 1 month due to instrument 
(CPAP machine or modem) failure. Instrument failure is not expected to exceed 10% of the users. 
At the end of the trial, subjects will be asked to return the modem either by mail or in person. If 
the subject returns the modem in person, he/she will be asked to repeat the nasal lavage sample. 
The subject will be informed that the purpose of this sample is to collect preliminary data. The 
pre-CPAP and post-CPAP samples will be compared to determine if CPAP use has any effect on 
markers in the lavage sample. 
4. Subjective assessment of sleepiness, quality of life and satisfaction with therapy will be obtained 
using questionnaires administered at the start and end of each period. 
Procedures for SA3 
Initiation of Therapy: Within 6 months of the home monitoring identify OSA, subjects will return 
to the clinic for CPAP therapy and will undergo mask fitting and desensitization and CPAP 
education during this visit. CPAP education will follow a written protocol common to both sites. 
During the first two weeks of therapy, the research co-coordinator will call the patients each week 
to discuss any mask or CPAP related issues. If the subject experiences any problems, he/she may 

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return to the clinic for additional support or mask replacement. If more than 6 months elapse after 
the home monitoring and the subject wishes to participate in the CPAP trial, the subject will be 
asked to repeat the initial assessment including questionnaires, rhinomanometry, nasal lavage, and 
home sleep testing. 
Randomization and Blinding: OSA patients will be randomly allocated to CPAP or CPAPFlex 
stratified by site and low (log[Reff]≤1.0) and high (log[Reff]>1.0) resistance by the statistician. 
This will be accomplished by generating an allocation table of randomly permuted blocks of 
assignments to study condition (CPAP vs CPAPFlex) for each site. Outcome of the randomized 
choice of treatment will be provided to an unblinded individual (one at each site) who is not part 
of the analysis of the study data, and who will set the allocated CPAP device at the start of each 
treatment period. Devices will be tracked by serial number. Although subjects will be blinded to 
the therapy type, they may be able to perceive a difference in the mask pressure during expiration. 
CPAP and CPAPFlex machines are identical otherwise and no feedback will be provided to subjects 
regarding the type of treatment. The unblinded individual (not the PI) will maintain a master file 
containing numbered sealed envelopes containing the serial number, patient ID and designation 
code for each treatment period and subject. Except in an emergency situation these envelopes will 
not be opened until the study has been completed and all data have been entered/cleaned. The 
unblinded individual will document any premature unblinding that may occur. All data review 
relevant to adherence/titration scoring will be presented to the scorer as a flow signal alone, 
keeping the pressure data unvisualized so as not to reveal the presence of CPAPFlex. The automated 
report will indicate if there are significant deviations from prescribed pressure. 
Monitoring of CPAP Efficacy and Adherence: Efficacy will be evaluated by (i) reviewing residual 
AHI and inspiratory flow limitation at optimal pressure as recorded on the device and (ii) review 
of raw airflow signal. Nightly adherence at the optimal pressure is recorded on the device and also 
transmitted to the sleep center. 
Cross over to alternate therapy: Four weeks after the first intervention (ie CPAP or CPAPFlex), the 
device will be switched to the alternate mode by remote modem connection. The switch will take 
place after the subject has completed the telephone satisfaction questionnaire.  
Subjective Assessment: At the end of each intervention period subjects will fill out ESS, 
Functional Outcomes of Sleep Questionnaire (FOSQ) and a satisfaction questionnaire.59 At the 
second clinic visit (for the CPAP training and mask fitting), subjects will be given two stamped 
envelopes, addressed to the research coordinator.  The envelopes will each contain one copy of the 
ESS and FOSQ. After approximately 3 weeks of the first therapy mode, the subject will be called 
by a member of the study team. The investigator will interview the subject to complete the 
satisfaction questionnaire by phone. The satisfaction questionnaire must be completed prior to the 
switch to the alternate treatment period. The investigator will also remind the subject to complete 
the ESS and FOSQ and return it by mail. This will be repeated for the second therapy mode. The 
satisfaction questionnaire must be completed to conclude the CPAP trial. At the end of each the 
end of each treatment period, a study investigator will attempt to reach the subject at least 3 times 
to complete the satisfaction questionnaire. If the subject cannot be contacted, a letter will be sent 
requesting the subject to contact the investigator. During this contact period, the treatment period 
will be extended. If the subject does not respond within two weeks, he/she will be considered lost 
to follow-up. 
Exploratory Mechanistic Pilot Follow-Up Study at NYU: 

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An exploratory mechanistic follow-up study is being done at NYU. The follow-up study has 
been approved by NYU. Only subjects who consented to be contacted for future studies will be 
contacted about the study. Rutgers investigators will analyze de-identified data from the follow-
up study.  
 
3.1. Duration of Study 
The study period is four years.  
3.2 Study Sites 
 
Environmental and Occupational Health Institute (EOHSI), Piscataway, NJ, Mt. Sinai School of 
Medicine, New York  and NYU School of Medicine, New York. Only de-identified data will be 
shared between the study sites. 
 
3.3 Sample Size Justification  
Power analysis  
To address SA1 and SA2, we will recruit 1000 subjects from 2850 WTC cohort members without 
habitual snoring prior to 9/11. Based on our preliminary data, we expect approximately 44% will 
have developed post 9/11 OSA over 10 years and 1585 remained OSA free. The following power 
analysis is based on a total of 800 subjects with a 1:1 ratio of OSA vs. OSA-free and we expect 
the power estimates presented here to be more conservative than what the actual data will show. 
To address SA1 Hypothesis 1a, we estimated the minimal detectable difference in the risk of 
UAD between 400 OSA subjects vs.400 OSA-free subjects, using the method of Chi-square test. 
Results are summarized in Table 1. Assuming that approximately 45%OSA subjects will have 
UAD (see flowchart) and setting alpha=0.05 (two-sided),our study will have 80% power to test a 
difference of 9.7% in the risk of UAD between patients with vs. without OSA, that is, 45.0 vs 
35.3%. To compare the difference in BMI among OSA subjects with vs. without UAD 
(Hypothesis 1b), we assumed that 45% (180) out of the 400 OSA subjects will have UAD. Defined 
the effect size using Cohen’s d=(1-2)/pooled60. Based on the method of two-sample t-test, our 
study will have 80% power (and alpha=0.05, two-sided) to test a small difference, Cohen’s d of 
0.28,in BMI between OSA subjects with vs. without UAD. In our previously published study2, we 
found that BMI was 35.2±6.2 (mean±sd) in those who presumably had long standing OSA vs 
31.2±4.7 in those with increase in snoring frequency after 9/11, corresponding to Cohen’s d of 
0.73. Our study has 80% power to test a smaller difference than that found in our previous study. 
Table 1. Minimal detectable difference () in the risk of UAD between 400 subjects with OSA 
vs.400 without OSA with 80% power and alpha=0.05 (two-sided).  
 
P1*(%) 
45.0 
50.0 
55.0 
60.0 
70.0 
80.0 
85.0 
90.0 
P0 (%) 
35.3 
40.2 
45.1 
50.2 
60.6 
71.5 
77.3 
83.3 
=P1-P0 (%) 
9.7 
9.8 
9.9 
9.8 
9.4 
8.5 
7.7 
6.7 
Odd ratio† 
1.50 
1.49 
1.49 
1.49 
1.52 
1.59 
1.66 
1.80 
*P1 and P0 represent the risk of UAD in individuals with vs. without OSA, respectively. †Odds 
ratio is calculated as [P1(1-P0)]/[P0(1-P1)] 
 
To address SA2, we based our power calculations treating both nasal resistance and inflammatory 
markers as continuous measures. To assess the association of UAD with nasal resistance and 

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inflammation (Hypothesis 2a), we first conservatively estimated that approximately 180 (45%) 
OSA subjects and 142 (35.3%) OSA-free subjects will have UAD (column 2 in Table 1); this gives 
us a total of 322 subjects with UAD and 478 UAD- free subjects. Using a two-sample t-test and 
Bonferroni adjustment in the alpha level, our study will have 80% power (with alpha=0.025, two-
sided) to test a difference, in Cohen’s d, of 0.22 in nasal resistance, and 80% power (with 
alpha=0.025/8=0.003, two-sided) to test a difference d=0.28 in each of the 8 inflammatory markers 
(cell count, IL-8, IL-6, TNF-alpha, interferon gamma; IL-4 and IL-10; and ECP). Similarly, using 
a two-sample t-test with 400 OSA subjects and 400 OSA-free subjects (Hypothesis 2b), our study 
will have 80% power (with alpha=0.025, two-sided) to test a difference of d=0.22 in nasal 
resistance, and 80% power (with alpha=0.025/4=0.00625, two-sided) to test a difference of d=0.27 
in each of the 8 inflammatory markers. 
To address SA3, we will randomize 400 subjects with OSA, stratified by nasal resistance, into two 
sequences of treatment: CPAPFlex followed by CPAP alone vs. CPAP alone followed by CPAPFlex. 
To address Hypothesis 3a, we based our power analysis on the method of Fisher’s Z test61 for 
correlation coefficients. With 400 participants and setting alpha at 0.05 (two-sided), we will have 
80% power to test a small (negative) correlation of -0.14. To address Hypothesis 3b, we assume 
that 50% of our subjects (200) will have high nasal resistance, based on our pilot data in non-WTC 
subjects. In Aloia et al43, they found that CPAPFlex significantly improved adherence of CPAP 
by1.2h per night (3.5±2.8h for CPAP and 4.7±2.2h for CPAPFlex corresponding to Cohen’s d of 
0.49).  Assuming an effect size of CPAPFlex improvement between high vs. low nasal resistance at 
80% of the effect seen in Aloia et al., i.e.,Cohen’s d=0.40, for an improvement of 20 minutes per 
night assuming the SD of the improvement to be 60 min (in paired/cross-over studies SD is usually 
smaller than that in unpaired studies), setting power=80% and alpha=5% (two sided), to test an 
effect size d=0.40 we will need 100 subjects each with high  and low nasal resistance, based on 
the method of two-sample t-test with equal variance. With a total of 400 subjects, we have enough 
power to test this hypothesis.  
To address Hypothesis 3c, we expect that 200 subjects will have high nasal resistance and half 
(100) of them will receive CPAPFlex at the initiation of treatment per randomization. Using a two 
sample t-test, we will have 80% power (alpha=0.05, 2-sided) to test a difference of 19.4min 
(SD=60min) in improvement between subjects with high nasal resistance and CPAPFlex offered at 
CPAP at initiation, compared to the other subjects. After accounting for 40% CPAP rejection, we 
will be able to test a difference of 25min (SD=60min) in the CPAPFlex improvement. 
 
3.4 Subject Selection and Enrollment Considerations  
We propose to enroll 500 subjects from each center with enrollment of approximately 160 subjects 
projected each of the first 3 years. Estimating OSA in the cohort: Of the 3800 responders at the 
two sites 25% of the population (~700 subjects) are expected to developed OSA over the last 10 
years based on population OSA prevalence/incidence estimates. About 1500 subjects have been 
identified with persistent UAD (based on review of charts) of who 25% will be excluded because 
of pre 911 habitual snoring. Of the remaining 1125, we expect 50% (~565 subjects) to have 
developed OSA. Therefore, we expect that of the 2850 (3800 total minus 950 habitual snorers) 
subjects, approximately 1265 (700+565) individuals (i.e. 44%) have developed post 9/11 OSA 
over the last 10 years and 1585 remain OSA free. We plan to recruit 1000 subjects, and estimate 
that 44% (440) will have OSA and 56% (560) will be OSA free. 
 

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3.5.1 Inclusion Criteria 
Subjects identified as new onset snoring (pre-post-9/11score of ≤2 to 3-4) or non-snorer (score of 
≤2 to ≤2) 
 
3.5.2 Exclusion Criteria 
(i) Gross skeletal alterations affecting the upper airway (eg.micrognathia) (ii) Unstable chronic 
medical conditions known to affect OSA (CHF, stroke) (iii) Pregnancy or intent to become 
pregnant within the period of the protocol (v) Inability to sign informed consent form (iv) habitual 
snorer or diagnosis of OSA prior to 9/11/01 (pre-9/11 score of 3-4) (v) a perforated septum (vi) 
treatment for sleep apnea including surgery, current (within the past 2 months) use of a mandibular 
advancement device, or current (within the past 2 months) use of CPAP (vii) First WTCHP 
monitoring visit after 2/1/13 (viii) if the  V1 questionnaire regarding snoring prior to September 
11, 2001 is unavailable, the patient will be asked if he/she currently snores. Patients with no V1 
snoring questionnaire who currently snore will be excluded. 
3.5.3 Subject Recruitment 
 
Two recruitment methods for the WTCHP responders at Rutgers Robert Wood Johnson Medical 
School (RWJMS) may be used for the study. 
  
Clinic recruitment 
The primary recruitment for the WTCHP responders at Rutgers RWJMS will be in-person during 
a clinic visit. Prior to each appointment, the WTCHP staff mail appointment packets to responders. 
The packets contain a letter confirming their appointment, a copy of the WTCHP consent, and 
approved at-home questionnaires. As part of this mailing packet, a pre-visit flyer (Pre-Visit Study 
Announcement) announcing the study will be included. As WTC responders return to the clinic 
for an annual monitoring or treatment exam, the clinic staff will check the medical chart for 
eligibility. A member of the clinic staff will confirm that the patient has agreed to be contacted for 
future studies and that the subject had not reported habitual snoring (snoring several nights a week) 
prior to 9/11. A study flyer will be placed in the file. If the patient appears to be eligible, a nurse 
or physician will inform the patient about the study, give the patient a copy of the approved flyer 
and ask if they are interested. If the patient is interested in participating, they will be asked to 
provide their name, email/street address, and phone number on a postcard so that a member of the 
research team can speak with him/her about the research study. A box labeled with the study name 
will be placed in the waiting room to collect postcards from interested patients. The box is under 
observation by clinic staff and will be emptied by the research staff each day. If the patient cannot 
be reached by phone and did provide their street address, a follow up letter will be mailed to them. 
The letter will ask the patient to contact the research staff if he/she is still interested in the study. 
If the email address was provided, an approved email will be sent asking the subject to contact the 
research staff. 
 
Interested patients will also be given the option of speaking with a study investigator during the 
clinic visit. The study investigator (the research coordinator/assistant) will meet with him/her in a 
private area to inform the potential subject about the study and go through the screening script. In 
addition, flyers and postcards will be placed in the clinic waiting room. Information about the 
study will also be posted on the EOHSI website (http://eohsi.rutgers.edu/content/research-
volunteers).  

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Mail recruitment 
If the recruitment rate of WTCHP responders at Rutgers RWJMS via clinic visit is insufficient to 
meet recruitment goals, names of WTCHP responders at Rutgers RWJMS (the same study 
population) will be recruited by mail. Under WTCHP guidelines, for any mailing, names of 
responders at Rutgers RWJMS must be obtained from the Data Coordinating Center (DCC) for 
the WTCHP. Once the DCC has mailed the names to Dr. Udasin, the medical records will be 
checked to select responders who did not report habitual snoring prior to 9/11/01. The responders 
who did not snore will be sent a letter from Dr. Udasin, the principal investigator and medical 
director of the Rutgers RWJMS Clinical Center of the WTCHP. The letter will give the responders 
information about the study and let them know that they will be called by one of the study 
investigators. The letter will be followed by a phone call within a few weeks. This will give the 
responder some time to consider the study prior to being called by the study investigator.  
 
To supplement the two recruitment methods, information about the study will be posted on the 
EOHSI website (http://eohsi.rutgers.edu/content/research-volunteers). 
 
3.5.4 Consent Procedures 
 
Clinic Recruitment: If the subject has asked to be contacted about the study (placed a contact card 
in the clinic box), a study investigator (research assistant, research coordinator) will call the subject 
and read the study screening script for clinic contacts.  
Mail Recruitment: If the subject has been recruited by mailing, a member of the clinic staff will 
call the subject and read the study screening script for DCC contacts. 
 
After reading the script (either for clinic contacts or DCC contacts), if the subject is interested in 
participating, their contact information will be recorded, a copy of the consent form will be mailed, 
and an appointment will be made for the first clinic visit. The subject will be called the preceding 
workday to confirm the appointment. The subject will be asked if he/she is experiencing seasonal 
allergies or had a recent cold. If yes, the appointment will be re-scheduled so that all symptoms 
have subsided at least 2 weeks prior to the appointment. 
 
Clinic contacts only: If the subject is in the clinic and requests information about the study, the 
screening may be done in-person, in a private office. If eligible, the subject will be given a consent 
form to read. After reading it, the investigator will review the study and answer any questions. The 
consent form will be signed by the subject and the investigator. The subject will be given a copy 
of the signed document. An appointment will be made for the clinical visit. 
 
If the subject wishes to think about participating, he/she will be given a copy of the consent form 
to take home. The investigator will record contact information and contact the subject in a few 
days. If the subject wishes to participate, an appointment will be made for the clinic visit. Consent 
will be obtained on the day of the clinic visit as outlined below.  
 
Consent Signature 
Clinic and DCC contacts: Subjects may return the signed consent form by mail. Once the consent 
form is received, an investigator will call the subject, answer any questions, and confirm 
participation. These subjects may then do the home sleep monitoring prior to their first clinic visit. 

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The monitor will be mailed with a signed copy of the consent form. If the clinic visit is scheduled 
first, on the day of the clinic visit, the consent form will be reviewed with the subject by a member 
of the study team. All questions will be answered. If the subject wishes to enroll, he/she will be 
asked to sign and date the consent form. The study investigator will also sign and date the consent 
form. The subject will be given a copy of the signed document. 
 
3.5.5 Subject Costs and Compensation 
After the completion of the clinic visit and the ARES home monitoring, subjects will be provided 
payment of $100 dollars as compensation for their time. Subjects who have been diagnosed with 
sleep apnea and placed on CPAP will be allowed to keep the machine after completion of the 
study, if desired. Subjects will have an opportunity to refuse to participate at any time during the 
study.  
 
4. Study Variables 
 
 
4.1 Independent Variables or Interventions  
Both CPAP and CPAPFlex are standard treatments for sleep apnea. This study will test the efficacy 
of each treatment based on independent measures of nasal resistance.  
 
4.2 Dependent Variables or Outcome Measures 
The study seeks to exam the relationship between several independent variables including UAD 
(determined by physical exam and nasal symptom questionnaire), nasal resistance (measured by 
rhinomanometry) and nasal inflammation (measured by inflammation markers in nasal lavage 
fluid).  
Evaluation of sleep apnea will be based on sleep study performed in the home.  
 
4.3 Risk of Harm  
The physical risks to the study are minimal. All procedures are non-invasive and often performed 
in clinical settings. Nasal lavage may cause minor discomfort and could result in a minor nose 
bleed. Participants may experience slight discomfort from the pressure of the strap of the ARES 
monitor. The strap may be loosened. Additionally, in rare cases (<0.5%), participants have had a 
mild skin allergy to the synthetic fabric on the strap. The participants will be instructed to 
discontinue use of the monitor if any skin reaction is suspected. Some participants may be 
concerned about the diagnosis of sleep apnea. These subjects will discuss the diagnosis with the 
study physician and receive treatment with CPAP. Some people find CPAP uncomfortable. The 
subject may choose to continue or discontinue the use of CPAP. The other risk of the study is the 
disclosure of PHI. Every effort will be made to keep all PHI confidential.  
 
4.4 Potential for Benefit 
Patients with OSA will receive treatment. They will have an opportunity to evaluate two modes of 
treatment with CPAP (CPAP and CPAPFlex) and select the most comfortable mode. Subjects 
diagnosed with OSA will be allowed to keep their CPAP machines following the study period, 
unless they specifically indicate that they do not wish to use it, in which case the devices will be 
returned to the sleep laboratory.  
Normal subjects will not benefit directly from participation in this study.  However, the data from 
the study will provide new knowledge about conditions common to WTC exposed individuals. 

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Evaluation of standard therapies in this population will help provide guidelines to physicians 
caring for these patients.  
 
5.   Data Handling and Statistical Analysis 
Statistical analysis plan 
All data (questionnaires, results of physical exams) will be de-identified (coded by study ID) and 
entered into electronic files on password-protected computers. Only study team members will have 
access to the data. The link between PHI and the study identifier will be kept in a password 
protected file on a password protected computer in the research coordinator’s office. The link will 
be maintained for a period of 6 years after the closure of the study. Signed consent forms and 
subject contact sheets will be kept in a locked cabinet in the research coordinator’s private office. 
Research data will not be included in the subject’s medical records.  
 
Statistical analysis will be primarily performed on an intent-to-treat basis. For all analyses, the 
statistical significance will be defined by a p-value < 0.05, unless specified otherwise. Bonferroni 
corrections will be applied to multiple testing, where appropriate. 
SA1: Examine the relationships between post-9/11 OSA, upper airway disease and body 
mass index. 
We will cross-tabulate the distributions of OSA and UAD to calculate the frequencies and 
proportions. Logistic regression analysis, with OSA as the dependent variable and UAD as the 
independent variable, will be subsequently used to evaluate the association of OSA and UAD 
without and with controlling for age, gender, weight gain, smoking and alcohol use. We will use 
a two-sample t-test to compare BMI between OSA subjects with vs. without UAD, followed by 
the linear regression analysis controlling for age, gender, weight gain, smoking and alcohol use. 
In subjects with both UAD and OSA, we will calculate and test the correlation coefficient of BMI 
and AHI to check if they are not correlated.  
SA2: Determine the relationship between post-911 OSA, upper airway disease, nasal 
inflammation and nasal resistance. 
We will first explore the distribution of nasal resistance and each of the inflammatory markers(cell 
count, IL-8, IL-6, TNF-alpha, interferon gamma; IL-4 and IL-10; eosinophil cationic protein 
(ECP)by calculating the histograms, means, standard deviations and medians, etc., and compare 
these measures between subjects with vs. without UAD using the two-sample t-test. To evaluate 
the association of UAD with nasal resistance and inflammatory markers, we will use logistic 
regression analysis with UAD (yes/no) as the dependent variable, and nasal resistance and 
inflammatory markers as the independent variables. Subsequent subset analysis will be performed 
to test the individual association of UAD vs. nasal resistance and each inflammatory marker. 
Analysis will also be conducted without and with controlling for age, gender, BMI, AHI, smoking 
status, alcohol use and use of nasal steroids. Similar statistical methods will be used with OSA as 
the dependent variable. We will evaluate whether the association between UAD and OSA is 
attributed to both increased nasal resistance and inflammation. To do this, we will fit a logistic 
regression model with OSA as the independent variable, UAD, nasal resistance and inflammation 
as the dependent variable.  
SA3. Relate nasal resistance to CPAP adherence in patients with OSA and show that 
reduction of expiratory pressure using CPAPFlex will improve CPAP adherence.   
We will first explore the distributions of nasal resistance and adherence of CPAP, both in 
continuous scale and the discrete scale. We will calculate the correlation between nasal resistance 
and CPAP when both are treated continuous measures, and use chi-square test when both are 

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discrete variables. To control for age, gender, BMI, AHI, and etc, we will use the linear regression 
(in continuous case) and logistic regression (in discrete case) analyses as we evaluate these 
associations. We will use mixed model analysis for repeated measures from the cross-over design. 
Specifically, we will use the average hours of CPAP/CPAPFlex use over the last 2 weeks in each 
phase as the dependent variable. If the use of CPAPFlex improves adherence to CPAP in subjects 
with high nasal resistance, but not in those with low nasal resistance, we expect to observe a 
significant interaction of treatment assignment and nasal resistance. Variables such as age, gender, 
BMI, AHI etc, will be further controlled for in these statistical analyses. We will use linear 
regression analysis with the difference in the average use between CPAP and CPAPFlex as the 
dependent variable, treatment sequence (CPAP followed by CPAPFlex vs CPAPFlex followed by 
CPAP), nasal resistance [high vs. low] and their interaction as the independent variable.  
 
6. Data and Safety Monitoring  
All procedures in the study are minimal risk. Both CPAP and CPAPFlex have equal efficacy for 
the treatment of OSA.  The PI will monitor this study for all patient safety issues. The PIs, Dr. 
Sunderram along with Dr. Ayappa (MSSM), will review these data as soon as they are available 
on each subject. Subjects will be given an access number to call during the work day during the 
study. Aggregate data reviews will be conducted annually at a minimum, and presented for review 
by the Rutgers-RWJMS, MSSM IRB and NYU IRB. 
 
7. Reporting Results 
 
7.1 Individual Results 
All patients will be given the results of their overnight sleep monitoring. Those diagnosed with 
OSA will be asked to meet with the study physician to review the results and discuss the 
diagnosis and treatment options. At the end of the study, those subjects who participated in the 
CPAP evaluation will be given a report documenting the appropriate titration for treatment and 
recommendations for follow-up. Subjects will also be asked if they wish to share the study 
results with the WTCHP clinic. If so, the subjects will be asked to sign an authorization 
allowing the study staff to release the records to the WTCHP clinic. No release of study 
information will be made without a written authorization. 
 
7.2 Aggregate Results 
Subjects will be given the option to receive a summary of the study results. Additionally, the 
summary results will be available on Clinical Trials.gov.  
 
7.3 Professional Reporting 
Results of the study will be published in peer-reviewed journals and may be presented at 
professional meetings. A description of this clinical trial will be available on 
ClinicalTrials.gov, as required by U.S. Law.  
 
8. Bibliography 
 
1. 
Lioy PJ, Georgopoulos P. The anatomy of the exposures that occurred around the World 
Trade Center site: 9/11 and beyond. Ann N Y Acad Sci. Sep 2006;1076:54-79. 

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2. 
Sunderram J, Udasin I, Kelly-McNeil K, et al. Unique features of obstructive sleep apnea 
in World Trade Center responders with aerodigestive disorders. J Occup Environ Med. 
Sep 2011;53(9):975-980. 
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Herbert R, Moline J, Skloot G, et al. The World Trade Center disaster and the health of 
workers: five-year assessment of a unique medical screening program. Environ Health 
Perspect. Dec 2006;114(12):1853-1858. 
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Moline JM, Herbert R, Levin S, et al. WTC medical monitoring and treatment program: 
comprehensive health care response in aftermath of disaster. Mt Sinai J Med. Mar-Apr 
2008;75(2):67-75. 
5. 
Lioy PJ, Pellizzari E, Prezant D. The World Trade Center aftermath and its effects on 
health: understanding and learning through human-exposure science. Environ Sci 
Technol. Nov 15 2006;40(22):6876-6885. 
6. 
Chen LC, Thurston G. World Trade Center cough. Lancet. Dec 2002;360 Suppl:s37-38. 
7. 
McGee JK, Chen LC, Cohen MD, et al. Chemical analysis of World Trade Center fine 
particulate matter for use in toxicologic assessment. Environ Health Perspect. Jun 
2003;111(7):972-980. 
8. 
Levin S, Herbert R, Skloot G, et al. Health effects of World Trade Center site workers. 
Am J Ind Med. Dec 2002;42(6):545-547. 
9. 
Skloot G, Goldman M, Fischler D, et al. Respiratory symptoms and physiologic 
assessment of ironworkers at the World Trade Center disaster site. Chest. Apr 
2004;125(4):1248-1255. 
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Herbstman JB, Frank R, Schwab M, et al. Respiratory effects of inhalation exposure 
among workers during the clean-up effort at the World Trade Center disaster site. 
Environ Res. Sep 2005;99(1):85-92. 
11. 
de la Hoz RE, Shohet MR, Chasan R, et al. Occupational toxicant inhalation injury: the 
World Trade Center (WTC) experience. Int Arch Occup Environ Health. Feb 
2008;81(4):479-485. 
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de la Hoz RE, Shohet MR, Wisnivesky JP, Bienenfeld LA, Afilaka AA, Herbert R. Atopy 
and upper and lower airway disease among former World Trade Center workers and 
volunteers. J Occup Environ Med. Sep 2009;51(9):992-995. 
13. 
Noah TL, Zhou H, Zhang H, et al. Diesel exhaust exposure and nasal response to 
attenuated influenza in normal and allergic volunteers. Am J Respir Crit Care Med. Jan 
15 2012;185(2):179-185. 
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Romieu I, Barraza-Villarreal A, Escamilla-Nunez C, et al. Dietary intake, lung function 
and airway inflammation in Mexico City school children exposed to air pollutants. Respir 
Res. 2009;10:122. 
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Kongerud J, Madden MC, Hazucha M, Peden D. Nasal responses in asthmatic and 
nonasthmatic subjects following exposure to diesel exhaust particles. Inhal Toxicol. Aug 
2006;18(9):589-594. 
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Nikasinovic L, Just J, Sahraoui F, Seta N, Grimfeld A, Momas I. Nasal inflammation and 
personal exposure to fine particles PM2.5 in asthmatic children. J Allergy Clin Immunol. 
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